JP5466880B2 - Orally disintegrating tablets - Google Patents
Orally disintegrating tablets Download PDFInfo
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- JP5466880B2 JP5466880B2 JP2009121941A JP2009121941A JP5466880B2 JP 5466880 B2 JP5466880 B2 JP 5466880B2 JP 2009121941 A JP2009121941 A JP 2009121941A JP 2009121941 A JP2009121941 A JP 2009121941A JP 5466880 B2 JP5466880 B2 JP 5466880B2
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Description
本発明は、高い錠剤硬度と少量の水分で急速に崩壊可能な崩壊性とを備えた口腔内崩壊錠とそのための組成物並びに口腔内崩壊錠の製造方法に関する。 The present invention relates to an orally disintegrating tablet having a high tablet hardness and a disintegrating property capable of rapidly disintegrating with a small amount of water, a composition therefor, and a method for producing an orally disintegrating tablet.
近年、急速に高齢者の人口に占める割合が増加し、それに伴って高齢者用薬剤の開発が進められている。種々の生理機能などが低下した高齢者による薬剤摂取を容易にするため、口腔内速崩壊錠が注目されている。このような速崩壊錠としては、薬物を分散、溶解した液やペーストを、予め錠剤の形状に成形されたブリスターシートのポケットに充填し凍結乾燥して製した商品名「Zydis」（旧R.P.Schere社，現CardinalHeaith社（英国））が知られている。この凍結乾燥法で製造された製剤は、急速な崩壊性を示す反面、強度が弱く、極度に脆い。 In recent years, the proportion of the elderly in the population has increased rapidly, and accordingly, development of drugs for the elderly has been promoted. In order to facilitate the ingestion of drugs by elderly people with various physiological functions and the like, intraoral quick disintegrating tablets have attracted attention. As such a rapidly disintegrating tablet, a product name “Zydis” (formerly RP Schere), which is prepared by filling a liquid or paste in which a drug is dispersed and dissolved in a pocket of a blister sheet previously formed into a tablet shape and freeze-drying. Is now known as CardinalHeaith (UK). The preparation produced by this freeze-drying method exhibits rapid disintegration, but is weak in strength and extremely brittle.
一方、湿潤した練合物を鋳型に充填し、圧縮し成形後、乾燥させて錠剤に製する湿製錠を利用した成形方法も知られている。この湿式錠剤法による製法では低い圧力で成形されるため、乾燥により適度な空隙を有する多孔性の錠剤となり、崩壊性に優れている。しかし、流動性の低い湿潤粉体を充填、圧縮するため、製造工程において、充填バラツキが大きくなりやすいとともに、製造装置への貼り付きが生じやすい。また、特殊な成形機が必要であるとともに、形状を保ったまま軟らかい成形物を乾燥するための特殊乾燥機が必要なこともあり、工業的に生産性が十分でない。 On the other hand, there is also known a molding method using a wet tablet in which a wet kneaded product is filled in a mold, compressed and molded, and then dried into a tablet. Since this wet tablet manufacturing method is molded at a low pressure, it becomes a porous tablet having appropriate voids by drying, and is excellent in disintegration. However, since the wet powder having low fluidity is filled and compressed, in the manufacturing process, the filling variation tends to be large and sticking to the manufacturing apparatus tends to occur. In addition, a special molding machine is required, and a special drying machine for drying a soft molded product while maintaining its shape may be necessary, and industrial productivity is not sufficient.
湿潤粉体ではなく通常の粉体を用い、通常の製造設備で生産が可能な乾式錠剤法を利用して、口腔内崩壊錠を製造することも知られている。この方法では、口腔内で３０秒以内程度で速やかに崩壊し、製造過程や流通過程で錠剤のワレやカケを抑制できる十分な硬度を有する製剤を得ることができる。例えば、ＷＯ２００６／０８５４９７（特許文献１）には、ａ）活性成分、ｂ）糖または糖アルコール（乳糖、Ｄ−マンニトールなど）、ｃ）冷水可溶分が１０〜２０重量％である部分アルファー化デンプン、およびｄ）崩壊剤（クロスポビドン、トウモロコシデンプンなど）を含有する口腔内崩壊錠が開示されている。しかし、この製剤は口腔内での崩壊性が未だ十分でない。また、この製剤は硬度が小さいだけでなく、時間の経過に伴って吸湿して硬度がさらに低下する場合がある。 It is also known to produce an orally disintegrating tablet using a dry tablet method that can be produced by ordinary production equipment using ordinary powder instead of wet powder. In this method, it is possible to obtain a preparation having a sufficient hardness capable of rapidly disintegrating within about 30 seconds in the oral cavity and suppressing tablet cracking and chipping during the production process and distribution process. For example, WO 2006/085497 (Patent Document 1) includes a) an active ingredient, b) a sugar or sugar alcohol (lactose, D-mannitol, etc.), and c) a partial alpha-formation having a cold water soluble content of 10 to 20% by weight. Disintegrating orally disintegrating tablets containing starch and d) disintegrants (crospovidone, corn starch, etc.) are disclosed. However, this preparation is not yet sufficiently disintegratable in the oral cavity. Moreover, this formulation may not only have a low hardness, but may also absorb moisture over time and further reduce the hardness.
ＷＯ００／０７８２９２（特許文献２）には、ａ）活性成分、ｂ）平均粒子径が３０μｍ〜３００μｍの糖または糖アルコール、ｃ）崩壊剤（カルメロースカルシウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、クロスポビドンなど）およびｄ）セルロース類（結晶セルロース、粉末セルロース、低置換度ヒドロキシプロピルセルロース、カルメロースなど）を含有してなる速崩壊性固形製剤が開示され、固形製剤１００重量部に対して、糖または糖アルコールを４０〜９５重量部含有し、崩壊剤を０．５〜１５重量部含有し、セルロース類を０．５〜４０重量部含有することも開示されている。特開２００５−１１２８６１号公報（特許文献３）には、水への溶解度が０．５ｍｇ／ｍｌ以上の薬理活性成分、一次粒子の平均粒子径が３０μｍ以上でかつ比表面積が０．４ｍ２／ｇ以下であるＤ−マンニトールの結晶または微粒子およびクロスポビドンを含有する口腔内速崩壊性錠剤が開示され、滑沢剤が錠剤の表面にのみ含有されていることも開示されている。しかし、これらの製剤は時間の経過に伴って吸湿して硬度が低下し、破損しやすくなる。また、これらの製剤は口腔内での崩壊性が未だ十分でない。 WO 00/078292 (Patent Document 2) includes a) an active ingredient, b) a sugar or sugar alcohol having an average particle size of 30 μm to 300 μm, c) a disintegrant (carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, A rapidly disintegrating solid preparation containing crospovidone and the like) and d) celluloses (crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, carmellose and the like) is disclosed. Alternatively, it is disclosed that 40 to 95 parts by weight of sugar alcohol, 0.5 to 15 parts by weight of disintegrant, and 0.5 to 40 parts by weight of cellulose are contained. JP-A-2005-112861 (Patent Document 3) discloses a pharmacologically active ingredient having a solubility in water of 0.5 mg / ml or more, an average primary particle diameter of 30 μm or more, and a specific surface area of 0.4 m 2 / Intraorally rapidly disintegrating tablets containing crystals or fine particles of D-mannitol and crospovidone that are not more than g are disclosed, and it is also disclosed that a lubricant is contained only on the surface of the tablets. However, these preparations absorb moisture with the passage of time, the hardness decreases, and breakage easily occurs. Moreover, these preparations are not yet sufficiently disintegratable in the oral cavity.
ＷＯ２００３／１０３７１３（特許文献４）には、平均粒子径３１μｍ〜８０μｍのＤ−マンニトール、活性成分、崩壊剤（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、カルメロースカルシウム及びクロスカルメロースナトリウム）及び０．０１〜０．５重量％のステアリン酸もしくはステアリン酸金属塩を含有する口腔内速崩壊錠が開示され、活性成分の含有量が０．１〜５０重量％、低置換度ヒドロキシプロピルセルロースの含有量が１〜１０重量％である口腔内速崩壊錠も開示されている。この文献には、ステアリン酸又はステアリン酸金属塩が錠剤のほぼ表面に局在していることも記載されている。この製剤は崩壊性に優れているものの、硬度が小さいだけでなく、時間の経過に伴って吸湿して硬度がさらに低下し易く、破損しやすくなる。 In WO2003 / 103713 (Patent Document 4), D-mannitol having an average particle size of 31 μm to 80 μm, an active ingredient, a disintegrant (low-substituted hydroxypropylcellulose, crystalline cellulose, carmellose calcium and croscarmellose sodium) and 0. Disclosed is an orally rapidly disintegrating tablet containing 01 to 0.5% by weight of stearic acid or a stearic acid metal salt, the content of active ingredient is 0.1 to 50% by weight, and the content of low-substituted hydroxypropylcellulose Also disclosed is an orally rapidly disintegrating tablet in which 1 to 10% by weight. This document also describes that stearic acid or metal stearate is localized almost on the surface of the tablet. Although this preparation is excellent in disintegration, it not only has a low hardness, but also absorbs moisture with the passage of time, and the hardness tends to further decrease and easily break.
特開２００８−１２７３２０号公報（特許文献５）には、ａ）医薬有効成分、ｂ）Ｄ−マンニトール、ｃ）デンプン、低置換度ヒドロキシプロピルセルロース、繊維素グリコール酸およびヒドロキシプロピルスターチから選ばれる１種または２種以上の崩壊剤を混合し、２％水溶液の粘度（以下表示粘度と呼称する）が２５ｍＰａ・ｓ以下の結合剤を固形剤組成物全量の２重量％以下の量で用いて、湿式造粒・乾燥したものを圧縮成型してなる口腔内速崩壊性固形製剤が開示され、Ｄ−マンニトールと崩壊剤との混合比が１０：１〜１：１であること、結合剤がポリビニルピロリドン、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、メチルセルロース又はポリビニルアルコールであることも記載されている。しかし、この固形製剤も口腔内での崩壊性が十分でない。 JP 2008-127320 A (Patent Document 5) includes 1) selected from a) active pharmaceutical ingredient, b) D-mannitol, c) starch, low-substituted hydroxypropylcellulose, fibrin glycolic acid and hydroxypropyl starch. Mixing seeds or two or more disintegrants, using a binder having a viscosity of 2% aqueous solution (hereinafter referred to as indicated viscosity) of 25 mPa · s or less in an amount of 2% by weight or less of the total amount of the solid composition, An oral rapid disintegrating solid preparation formed by compression molding a wet granulated and dried product is disclosed, the mixing ratio of D-mannitol and disintegrant is 10: 1 to 1: 1, and the binder is polyvinyl. It is also described that it is pyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose or polyvinyl alcohol. However, this solid preparation is not sufficiently disintegratable in the oral cavity.
このように、速崩壊性錠剤は、機能的に少量の水や口中の唾液で迅速に崩壊するように設計されているため、吸湿性が大きい。そのため、高湿度（又は加湿）条件下で保存すると、吸湿した水分により錠剤が膨張して錠剤硬度が大きく低下し、自動錠剤分包機に適さない。さらに、前記製剤の口腔内崩壊性は、前記瞬時崩壊製剤「Zydis」に比べ大きく劣り、服用時の患者負担を軽減するには更なる口腔内崩壊時間の短縮が必要である。 Thus, since a rapidly disintegrating tablet is functionally designed to disintegrate rapidly with a small amount of water or saliva in the mouth, it has high hygroscopicity. Therefore, when it is stored under high humidity (or humidification) conditions, the tablet expands due to moisture absorbed, and the tablet hardness is greatly reduced, which is not suitable for an automatic tablet packaging machine. Furthermore, the orally disintegrating property of the preparation is greatly inferior to the instant disintegrating preparation “Zydis”, and it is necessary to further reduce the disintegration time in the oral cavity in order to reduce the burden on the patient when taking the medicine.
なお、前記特許文献３及び５に記載の滑沢剤が表面に偏在した製剤の調製に関し、特開平６−２１８０２８号公報（特許文献６）には、湿潤した練合物を鋳型に充填し、１錠当たり５〜１００Ｋｇで圧縮して成型する湿製錠の成型方法が開示され、湿製錠の圧縮面もしくは、圧縮パンチ表面に粉末を塗布して圧縮することも開示されている。また、特開２００１−２０５４９３号公報（特許文献７）には、杵先を臼孔内に挿入した状態で上杵及び下杵を互いに相寄る向きに移動、押圧することにより、臼孔内に充填した粉末を上杵下端面及び下杵上端面間で圧縮成形する回転式粉末圧縮成形機において、上杵と下杵とのそれぞれの端面及び臼孔に粉末の充填に先立って粉末滑沢剤を噴射する粉末滑沢剤噴射手段を具備した回転式粉末圧縮成形機が開示されている。 In addition, regarding preparation of a preparation in which the lubricant described in Patent Documents 3 and 5 is unevenly distributed on the surface, JP-A-6-218028 (Patent Document 6) is filled with a wet kneaded material in a mold, A method for molding a wet tablet that is compressed and molded at 5 to 100 kg per tablet is disclosed, and it is also disclosed that a powder is applied to a compression surface of a wet tablet or a compression punch surface and compressed. Japanese Patent Laid-Open No. 2001-205493 (Patent Document 7) discloses that the upper heel and the lower heel are moved and pressed toward each other in a state where the heel is inserted into the mortar, so that In a rotary powder compression molding machine that compresses the filled powder between the upper and lower lower end surfaces and the lower upper end surface, a powder lubricant prior to filling the powder into the end surfaces and mortars of the upper and lower irons. There is disclosed a rotary powder compression molding machine equipped with a powder lubricant spraying means for spraying powder.
従って、本発明の目的は、口腔内の少量の唾液により速やかに崩壊する口腔内崩壊錠（又は口腔内速崩錠）、そのための組成物及び前記崩壊錠の製造方法を提供することにある。 Accordingly, an object of the present invention is to provide an orally disintegrating tablet (or an orally rapidly disintegrating tablet) that rapidly disintegrates with a small amount of saliva in the oral cavity, a composition therefor, and a method for producing the disintegrating tablet.
本発明の他の目的は、硬度が高く、高湿度（加湿）条件下で長期間に亘り保存しても硬度の低下を抑制できるとともに、少量の水分又は口腔内の少量の唾液で極めて短時間に崩壊可能な口腔内崩壊錠、そのための組成物及び前記崩壊錠の製造方法を提供することにある。 Another object of the present invention is that the hardness is high, and even when stored for a long period of time under high humidity (humidification) conditions, the decrease in hardness can be suppressed, and a small amount of water or a small amount of saliva in the oral cavity can be used for a very short time. It is to provide an orally disintegrating tablet which can be disintegrated, a composition therefor and a method for producing the disintegrating tablet.
本発明のさらに他の目的は、製造過程及び流通過程でワレやカケが発生しない十分な硬度を有しているにも拘わらず、圧倒的に急速な口腔内崩壊性を保持し、加湿条件下で保存しても吸湿による錠剤硬度の低下の小さな口腔内崩壊錠、そのための組成物及び前記崩壊錠の製造方法を提供することにある。 Yet another object of the present invention is to maintain an overwhelmingly rapid disintegration in the oral cavity despite the fact that it has sufficient hardness so that cracks and chips do not occur in the production process and distribution process. It is an object to provide an orally disintegrating tablet having a small decrease in tablet hardness due to moisture absorption, a composition therefor, and a method for producing the disintegrating tablet.
本発明者らは、前記課題を達成するため鋭意検討した結果、糖類をベース成分とする薬物含有固形製剤において、固形製剤で汎用される崩壊剤（スーパー崩壊剤と称される崩壊剤など）ではなく水膨潤性の小さな崩壊剤と、少量の水溶性結合剤と、表面に偏在する少量の滑沢剤とを用いると、高い硬度を長期間に亘り維持しつつ、口腔内での崩壊性を著しく向上できることを見いだし、本発明を完成した。 As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that in drug-containing solid preparations containing saccharide as a base component, disintegrants (such as disintegrants called super disintegrants) widely used in solid preparations. When using a disintegrant with small water swellability, a small amount of water-soluble binder, and a small amount of lubricant unevenly distributed on the surface, the disintegration property in the oral cavity is maintained while maintaining high hardness for a long period of time. The present invention has been completed by finding that it can be remarkably improved.
すなわち、本発明の口腔内崩壊錠は、（Ａ）薬物、（Ｂ）平均粒子径１０〜５００μｍを有し、かつ糖、糖アルコール及びアミノ酸から選択された少なくとも一種の粒状ベース成分、（Ｃ）吸水時の膨潤率が１．３以下の崩壊剤、（Ｄ）水溶性結合剤、及び（Ｅ）滑沢剤を含有し、（Ｄ）水溶性結合剤の含有量が錠剤１００重量部に対して１重量部以下であり、（Ｅ）滑沢剤の含有量が錠剤１００重量部に対して０．５重量部以下である。 That is, the orally disintegrating tablet of the present invention has (A) a drug, (B) an average particle size of 10 to 500 μm, and at least one granular base component selected from sugar, sugar alcohol and amino acid, (C) It contains a disintegrant having a swelling ratio of 1.3 or less upon water absorption, (D) a water-soluble binder, and (E) a lubricant, and (D) the content of the water-soluble binder is 100 parts by weight of the tablet. 1 part by weight or less, and (E) the lubricant content is 0.5 parts by weight or less with respect to 100 parts by weight of the tablet.
このような錠剤において、（Ｂ）粒状ベース成分の平均粒子径は、８０〜２５０μｍ程度であってもよい。また、（Ｃ）崩壊剤は、結晶セルロース及びデンプン類から選択された少なくとも一種であってもよい。より具体的には、（Ｃ）崩壊剤が結晶セルロースであり、崩壊剤の含有量が錠剤１００重量部に対して１〜３０重量部であってもよい。さらに、（Ｄ）水溶性結合剤の２重量％水溶液の粘度は３．０ｍＰａ・ｓ（２０℃）以下であってもよく、（Ｄ）水溶性結合剤はポリビニルアルコールであってもよい。また、（Ｄ）水溶性結合剤は２．５Ｎ／ｍｍ２以上の結合剤の錠剤強度を与える。この結合剤の錠剤強度は、Ｄ−マンニトール９９重量部と結合剤１重量部との混合物（又はＤ−マンニトール９９重量部を結合剤１重量部の水溶液で造粒した造粒物）を、打錠圧５．０ｋＮで製した錠剤（直径φ８ｍｍ、重量２００ｍｇ）の硬度を錠剤の破断面積で除した値として規定できる。（Ｅ）滑沢剤は、錠剤の表面又は表層部に偏在していてもよい。すなわち、（Ｅ）滑沢剤は、錠剤の内部に含有されておらず、錠剤の表面又は表層部に含有されていてもよい。 In such a tablet, the average particle size of the (B) granular base component may be about 80 to 250 μm. Further, (C) the disintegrant may be at least one selected from crystalline cellulose and starches. More specifically, (C) the disintegrant may be crystalline cellulose, and the content of the disintegrant may be 1 to 30 parts by weight with respect to 100 parts by weight of the tablet. Further, (D) the viscosity of a 2% by weight aqueous solution of a water-soluble binder may be 3.0 mPa · s (20 ° C.) or less, and (D) the water-soluble binder may be polyvinyl alcohol. Further, (D) the water-soluble binder gives the tablet strength of the binder of 2.5 N / mm 2 or more. The tablet strength of this binder was determined by punching a mixture of 99 parts by weight of D-mannitol and 1 part by weight of binder (or a granulated product obtained by granulating 99 parts by weight of D-mannitol with an aqueous solution of 1 part by weight of binder). It can be defined as a value obtained by dividing the hardness of a tablet (diameter: 8 mm, weight: 200 mg) manufactured at a tablet pressure of 5.0 kN by the breaking area of the tablet. (E) The lubricant may be unevenly distributed on the surface or the surface layer of the tablet. That is, (E) lubricant is not contained in the tablet, and may be contained on the surface or surface layer of the tablet.
このような口腔内崩壊錠は、（Ａ）薬物、（Ｂ）平均粒子径１００〜２００μｍを有し、かつ糖、糖アルコール及びアミノ酸から選択された少なくとも一種の粒状ベース成分、（Ｃ）結晶セルロース及びデンプン類から選択された少なくとも一種の崩壊剤、（Ｄ）２重量％水溶液の粘度が３．０ｍＰａ・ｓ（２０℃）以下のポリビニルアルコール、及び（Ｅ）錠剤の表面又は表層部に偏在した滑沢剤を含有し、（Ｄ）水溶性結合剤の含有量が錠剤１００重量部に対して０．５重量部以下であり、（Ｅ）滑沢剤の含有量が錠剤１００重量部に対して０．０１〜０．３重量部である口腔内崩壊錠を包含する。前記崩壊剤は、汎用の崩壊剤、例えば、アルファー化デンプン、カルボキシメチルスターチ類（カルボキシメチルスターチナトリウムなど）、カルボキシメチルセルロース類（カルメロースカルシウム、クロスカルメロースナトリウムなどのカルボキシメチルセルロース、その架橋物若しくはそれらのアルカリ金属又はアルカリ土類金属塩）、低置換度ヒドロキシプロピルセルロース及びクロスポビドンを含まない。 Such an orally disintegrating tablet comprises (A) a drug, (B) an average particle size of 100 to 200 μm, and at least one granular base component selected from sugar, sugar alcohol and amino acid, (C) crystalline cellulose And (D) polyvinyl alcohol having a viscosity of 2% by weight aqueous solution of 3.0 mPa · s (20 ° C.) or less, and (E) uneven distribution on the surface or surface layer of the tablet. Containing a lubricant, (D) the content of the water-soluble binder is 0.5 parts by weight or less based on 100 parts by weight of the tablet, and (E) the content of the lubricant is based on 100 parts by weight of the tablet Orally disintegrating tablets in an amount of 0.01 to 0.3 parts by weight. The disintegrant is a general-purpose disintegrant such as pregelatinized starch, carboxymethyl starches (such as sodium carboxymethyl starch), carboxymethylcelluloses (carboxymethylcellulose such as carmellose calcium and croscarmellose sodium, cross-linked products thereof, or the like Alkali metal or alkaline earth metal salt), low-substituted hydroxypropylcellulose and crospovidone.
本発明は、錠剤１００重量部に対して０．５重量部以下の割合で（Ｅ）滑沢剤を用いて打錠し、口腔内崩壊錠を製造するための組成物であって、（Ａ）薬物、（Ｂ）平均粒子径１０〜５００μｍを有し、かつ糖、糖アルコール及びアミノ酸から選択された少なくとも一種の粒状ベース成分、（Ｃ）吸水時の膨潤率が１．３以下の崩壊剤、及び（Ｄ）水溶性結合剤を含有し、（Ｄ）水溶性結合剤の含有量が錠剤１００重量部に対して１重量部以下である製剤組成物（打錠組成物）も包含する。さらに、本発明は、（Ａ）薬物、（Ｂ）平均粒子径１０〜５００μｍを有し、かつ糖、糖アルコール及びアミノ酸から選択された少なくとも一種の粒状ベース成分、（Ｃ）吸水時の膨潤率が１．３以下の崩壊剤、及び（Ｄ）水溶性結合剤を含有し、（Ｄ）水溶性結合剤の含有量が錠剤１００重量部に対して１重量部以下である組成物を、錠剤１００重量部に対して０．５重量部以下の（Ｅ）滑沢剤を用いて（又は前記所定量の（Ｅ）滑沢剤とともに）打錠する口腔内崩壊錠の製造方法も包含する。この方法において、滑沢剤を杵及び／又は臼に付着させて打錠してもよい。すなわち、外部滑沢法を採用して打錠組成物を打錠してもよい。さらに、本発明の方法では、少なくとも（Ａ）薬物及び（Ｂ）粒状ベース成分を含む混合物を（Ｄ）水溶性結合剤の水溶液を用いて造粒（例えば、流動層造粒）し、生成した造粒物と（Ｃ）崩壊剤との混合物を、（Ｅ）滑沢剤を杵及び／又は臼に付着させて打錠し、口腔内崩壊錠を製造してもよい。 The present invention is a composition for producing an orally disintegrating tablet by tableting with (E) a lubricant at a ratio of 0.5 parts by weight or less with respect to 100 parts by weight of a tablet. ) A drug, (B) an average particle size of 10 to 500 μm, and at least one granular base component selected from sugar, sugar alcohol and amino acid, (C) a disintegrant having a swelling ratio of 1.3 or less upon water absorption And (D) a water-soluble binder, and (D) a pharmaceutical composition (tablet composition) in which the content of the water-soluble binder is 1 part by weight or less with respect to 100 parts by weight of the tablet. Further, the present invention provides (A) a drug, (B) at least one granular base component having an average particle diameter of 10 to 500 μm and selected from sugar, sugar alcohol and amino acid, and (C) swelling rate upon water absorption. A disintegrant containing 1.3 or less, and (D) a water-soluble binder, and (D) a composition having a water-soluble binder content of 1 part by weight or less based on 100 parts by weight of the tablet. Also included is a method for producing an orally disintegrating tablet that is tableted with 0.5 parts by weight or less (E) lubricant (or with the predetermined amount of (E) lubricant) per 100 parts by weight. In this method, the lubricant may be attached to the punch and / or mortar for tableting. That is, the tableting composition may be tableted using an external lubrication method. Furthermore, in the method of the present invention, a mixture containing at least (A) a drug and (B) a granular base component is granulated (for example, fluidized bed granulation) using an aqueous solution of (D) a water-soluble binder. Orally disintegrating tablets may be produced by tableting a mixture of the granulated product and (C) a disintegrating agent with (E) a lubricant attached to a punch and / or a mortar.
本発明では、特定の崩壊剤と少量の水溶性結合剤と少量の滑沢剤とを含むため、口腔内の少量の唾液により錠剤を速やかに崩壊できる。特に、錠剤の硬度が高く、長期間に亘り保存しても硬度の低下を抑制できるとともに、口腔内又は少量の水分で極めて短時間に崩壊できる。 In the present invention, since a specific disintegrant, a small amount of a water-soluble binder, and a small amount of a lubricant are included, the tablet can be rapidly disintegrated with a small amount of saliva in the oral cavity. In particular, the hardness of the tablet is high, and even when stored for a long period of time, a decrease in hardness can be suppressed, and it can be disintegrated in the oral cavity or in a very short time with a small amount of moisture.
［口腔内崩壊錠及びそのための組成物］
本発明の口腔内崩壊錠（錠剤）及びそのための組成物（固形製剤組成物）は、（Ａ）薬物と、（Ｂ）平均粒子径１０〜５００μｍを有し、かつ糖、糖アルコール及びアミノ酸から選択された少なくとも一種の粒状ベース成分と、（Ｃ）吸水膨潤率の小さな崩壊剤と、（Ｄ）少量の水溶性結合剤と、（Ｅ）少量の滑沢剤（又は錠剤の表面に局在化した滑沢剤）とを含有している。
[Oral disintegrating tablet and composition therefor]
The orally disintegrating tablet (tablet) of the present invention and the composition (solid preparation composition) therefor have (A) a drug, (B) an average particle size of 10 to 500 μm, and sugar, sugar alcohol and amino acid. At least one selected granular base component, (C) a disintegrant with a low water absorption swell, (D) a small amount of a water-soluble binder, and (E) a small amount of a lubricant (or localized on the surface of the tablet). ).
（Ａ）薬物
薬物の種類は特に制限されず、薬理活性成分、例えば、消化性潰瘍用剤（胃粘膜修復剤など）、精神神経用剤（抗精神病剤など）、アルツハイマー型認知症治療剤、消化器官用剤（抗高脂血症剤、抗糖尿病薬、食後過血糖改善剤など）、睡眠導入剤又は催眠鎮静剤、低血圧治療剤、降圧剤、偏頭痛治療剤、抗ヒスタミン薬、アレルギー用剤、気管支喘息治療剤、Ｈ２受容体拮抗薬、不整脈用剤などが例示できる。また、薬物は生理活性成分も含む。これらの薬物は単独で又は二種以上組み合わせて合剤とすることができる。
(A) Drug The type of drug is not particularly limited, and pharmacologically active ingredients such as peptic ulcer agent (such as gastric mucosal repair agent), neuropsychiatric agent (such as antipsychotic agent), Alzheimer type dementia therapeutic agent, Gastrointestinal (antihyperlipidemic, antidiabetic, postprandial hyperglycemic, etc.), sleep inducer or hypnotic sedative, hypotension, antihypertensive, migraine, antihistamine, allergy Agents, bronchial asthma treatment agents, H2 receptor antagonists, arrhythmia agents and the like. The drug also includes a physiologically active ingredient. These drugs can be used alone or in combination of two or more.
薬物の含有量は薬物の種類に応じて広い範囲（例えば、錠剤１００重量部に対して０．００１〜５０重量部）から選択でき、通常、錠剤１００重量部に対して、０．０１〜３０重量部（例えば、０．１〜２５重量部）、好ましくは０．０１〜２０重量部（例えば、０．１〜１５重量部）程度であり、０．０１〜１２重量部（例えば、０．０１〜１０重量部）程度であってもよい。 The content of the drug can be selected from a wide range (for example, 0.001 to 50 parts by weight with respect to 100 parts by weight of the tablet) depending on the type of the drug, and usually 0.01 to 30 with respect to 100 parts by weight of the tablet. Parts by weight (for example, 0.1 to 25 parts by weight), preferably about 0.01 to 20 parts by weight (for example, 0.1 to 15 parts by weight), and 0.01 to 12 parts by weight (for example, 0. It may be about 01 to 10 parts by weight).
（Ｂ）粒状ベース成分
製剤のベース成分は薬理的に不活性な水溶性粒状物で構成されており、糖、糖アルコール及びアミノ酸から選択された少なくとも一種が使用される。これらの粒状ベース成分は賦形剤として分類される場合がある。糖としては、例えば、乳糖、ショ糖、ブドウ糖、果糖、麦芽糖、トレハロース、ショ糖に酵素を作用させたパラチノース（三井製糖（株）、商標名）、パラチノースを水素添加したパラチニット（三井製糖（株）、商標名）などの単糖類及び二糖類などが挙げられる。糖アルコールとしては、例えば、マンニトール（Ｄ−マンニトール）、キシリトール、ソルビトール、エリスリトール、マルチトールなどが例示できる。これらの糖及び糖アルコールは単独で又は二種以上組み合わせて使用できる。これらの糖及び糖アルコールのうち、乳糖や糖アルコール類（マンニトールなど）を用いる場合が多い。
(B) Granular base component The base component of the preparation is composed of a pharmacologically inert water-soluble granular material, and at least one selected from sugars, sugar alcohols and amino acids is used. These particulate base components may be classified as excipients. Examples of the sugar include lactose, sucrose, glucose, fructose, maltose, trehalose, palatinose obtained by reacting an enzyme with sucrose (Mitsui Sugar Co., Ltd., trade name), and palatinose hydrogenated with palatinose (Mitsui Sugar Co., Ltd.) ) And trade names) and the like. Examples of the sugar alcohol include mannitol (D-mannitol), xylitol, sorbitol, erythritol, maltitol and the like. These sugars and sugar alcohols can be used alone or in combination of two or more. Of these sugars and sugar alcohols, lactose and sugar alcohols (such as mannitol) are often used.
アミノ酸としては、グリシン、アラニン、アルギニンなどが例示できる。これらのアミノ酸も単独で又は二種以上組み合わせて使用でき、前記糖及び／又は糖アルコールと組み合わせて使用してもよい。これらのアミノ酸のうち、服用感の面からグリシン、アラニンが好ましい。 Examples of amino acids include glycine, alanine, arginine and the like. These amino acids can also be used alone or in combination of two or more, and may be used in combination with the sugar and / or sugar alcohol. Among these amino acids, glycine and alanine are preferable from the viewpoint of taking feeling.
粒状ベース成分の平均粒子径は、１０〜５００μｍ（例えば、３０〜５００μｍ）程度の範囲から選択でき、通常、１５〜３００μｍ（例えば、２０〜３００μｍ）、好ましくは３０〜２５０μｍ（例えば、５０〜２５０μｍ）、さらに好ましくは１００〜２００μｍ程度であり、粒状ベース成分の平均粒子径は１５〜２５０μｍ（例えば、３０〜２００μｍ）、好ましくは５０〜２５０μｍ（例えば、８０〜２５０μｍ）程度であってもよい。なお、粒状ベース成分の粒子径が大きいほど、錠剤内での水の浸透性が向上し口腔内崩壊時間が短縮されるが、大きすぎると口腔内のザラツキを感じ、服用感又は食感を損なう。粒状ベース成分の平均粒子径は、例えば、シンパテック（SYMPATEC）社製のレーザー解析式粒度測定器[ヘロスアンドロドス(HELOS＆RODOS)]で測定できる。 The average particle size of the granular base component can be selected from a range of about 10 to 500 μm (for example, 30 to 500 μm), and is usually 15 to 300 μm (for example, 20 to 300 μm), preferably 30 to 250 μm (for example, 50 to 250 μm). ), More preferably about 100 to 200 μm, and the average particle size of the granular base component may be about 15 to 250 μm (for example, 30 to 200 μm), preferably about 50 to 250 μm (for example, 80 to 250 μm). In addition, the larger the particle size of the granular base component, the better the water permeability in the tablet and the shorter the disintegration time in the mouth, but if it is too large, the mouth feels rough and the feeling of taking or eating is impaired. . The average particle size of the granular base component can be measured by, for example, a laser analysis type particle size measuring instrument [HELOS & RODOS] manufactured by SYMPATEC.
なお、粒度の大きな粒状ベース成分を用いると、崩壊性は向上するものの、成形性が若干低下しやすくなる。本発明では、粒度の大きな粒状ベース成分を用いても、所定の崩壊剤（結晶セルロースなど）と外部滑沢剤とを用いることにより、高い崩壊性を維持しつつ成形性を向上できる。 When a granular base component having a large particle size is used, although the disintegration property is improved, the moldability tends to be slightly lowered. In the present invention, even if a granular base component having a large particle size is used, moldability can be improved while maintaining high disintegration by using a predetermined disintegrant (such as crystalline cellulose) and an external lubricant.
粒状ベース成分の割合は、崩壊剤などの製剤成分の種類及び使用割合などに応じて選択でき、通常、錠剤１００重量部に対して、５０〜９８重量部（例えば、５５〜９７重量部）、好ましくは６０〜９５重量部（例えば、６５〜９０重量部）、さらに好ましくは７０〜８５重量部程度であり、５５〜８０重量部（例えば、６０〜７５重量部）程度である場合が多い。 The proportion of the granular base component can be selected according to the type and use ratio of the formulation component such as a disintegrant, and is usually 50 to 98 parts by weight (for example, 55 to 97 parts by weight) with respect to 100 parts by weight of the tablet. Preferably it is 60-95 weight part (for example, 65-90 weight part), More preferably, it is about 70-85 weight part, and it is about 55-80 weight part (for example, 60-75 weight part) in many cases.
（Ｃ）崩壊剤
本発明では、スーパー崩壊剤などの汎用の崩壊剤ではなく、吸水時の膨潤率（吸水膨潤率）が１．３以下の崩壊剤を用いる。崩壊剤の吸水膨潤率は、例えば、０．５〜１．３（例えば、０．５５〜１．２５）、好ましくは０．６〜１．２（例えば、０．６〜１．１５）、さらに好ましくは０．６〜１．１（例えば、０．６〜１）程度である。吸水時の膨潤率（吸水膨潤率）が１．３を越える崩壊剤を含有させると、湿度（又は加湿）条件下での錠剤の硬度が著しく低下するか、錠剤中心部への水の浸透が低下して口腔内崩壊時間が遅延し、所望の口腔内崩壊錠を得られなくなる。なお、吸水時の膨潤率は、次のようにして測定できる。室温（１５〜２５℃、特に２０℃）で、試料１０ｇをメスシリンダーに入れて試料の体積を測定して膨潤前の体積とし、さらに水を加えて１００ｍｌとし、１時間後の崩壊剤の体積を膨潤後の体積とする。この膨潤後の体積を膨潤前の体積で除した値を吸水時の膨潤率とすることができる。このような低膨潤率の崩壊剤としては、結晶セルロース、デンプン類が該当する。種々の崩壊剤について吸水時の膨潤率を調べた結果を以下の表１に示す。
(C) Disintegrant In the present invention, a disintegrant having a swelling ratio (water absorption swelling ratio) of 1.3 or less at the time of water absorption is used instead of a general-purpose disintegrant such as a super disintegrant. The water absorption swelling rate of the disintegrant is, for example, 0.5 to 1.3 (for example, 0.55 to 1.25), preferably 0.6 to 1.2 (for example, 0.6 to 1.15), More preferably, it is about 0.6 to 1.1 (for example, 0.6 to 1). When a disintegrating agent having a swelling rate (water absorption swelling rate) exceeding 1.3 is incorporated, the hardness of the tablet under humidity (or humidification) condition is remarkably lowered, or the penetration of water into the center of the tablet is caused. The oral disintegration time is delayed and the desired orally disintegrating tablet cannot be obtained. In addition, the swelling rate at the time of water absorption can be measured as follows. At room temperature (15 to 25 ° C., particularly 20 ° C.), put 10 g of the sample into a graduated cylinder, measure the volume of the sample to obtain the volume before swelling, and further add water to make 100 ml. Volume of disintegrant after 1 hour Is the volume after swelling. A value obtained by dividing the volume after swelling by the volume before swelling can be defined as the swelling ratio upon water absorption. Examples of such a disintegrant having a low swelling rate include crystalline cellulose and starches. Table 1 below shows the results of examining the swelling rate at the time of water absorption of various disintegrants.
上記表から、吸水膨潤率が１．３以下の崩壊剤には、結晶セルロース及びデンプン類（ヒドロキシプロピルスターチを含む）が含まれ、これらの崩壊剤から選択された少なくとも一種が使用される。結晶セルロースは、粉粒体が使用され、目開き３８μｍの篩を大部分が通過する微粒子であってもよく造粒した粒状物であってもよい。結晶セルロースは、「セオラス」、「アビセル」、「セルフィア」、「ファーマセル」などの商品名で市販されている。デンプン類は、バレイョデンプン、トウモロコシデンプン、コメデンプン、コムギデンプンなどの未処理又は未加工デンプンの他、ヒドロキシプロピルスターチなどのヒドロキシアルキルスターチも含む。これらの崩壊剤は単独で又は二種以上組み合わせて使用できる。 From the above table, disintegrants having a water absorption swelling ratio of 1.3 or less include crystalline cellulose and starches (including hydroxypropyl starch), and at least one selected from these disintegrants is used. The crystalline cellulose is used in the form of fine particles, and may be fine particles that pass through most of a sieve having an opening of 38 μm or may be a granulated granular material. Crystalline cellulose is commercially available under trade names such as “Theoras”, “Avicel”, “Selfia”, “Pharmacel”. Starches include untreated or unprocessed starch such as potato starch, corn starch, rice starch and wheat starch, as well as hydroxyalkyl starch such as hydroxypropyl starch. These disintegrants can be used alone or in combination of two or more.
好ましい崩壊剤は、結晶セルロース、未処理又は未加工デンプン（バレイョデンプン、トウモロコシデンプン、特にトウモロコシデンプン）である。なお、結晶セルロースは崩壊剤として機能するとともに賦形剤としても機能する。そのため、成形性の劣る組成物であっても、崩壊剤として結晶セルロースを用いることにより、成形性（又は打錠性）を向上できる。 Preferred disintegrants are crystalline cellulose, raw or raw starch (potato starch, corn starch, especially corn starch). Note that crystalline cellulose functions as a disintegrant and also as an excipient. Therefore, even if it is a composition with inferior moldability, moldability (or tabletability) can be improved by using crystalline cellulose as a disintegrant.
なお、上記表からも明らかなように、本発明で用いる崩壊剤は、一般的な崩壊剤（スーパー崩壊剤と称される崩壊剤を含む）を含まない。すなわち、アルファー化デンプン（完全又は部分アルファー化デンプン）、カルボキシメチルスターチ類（カルボキシメチルスターチナトリウムなど）、カルボキシメチルセルロース類（カルメロース、カルメロースカルシウム、クロスカルメロースナトリウムなどのカルボキシメチルセルロース、その架橋物若しくはそれらのアルカリ金属又はアルカリ土類金属塩）、低置換度ヒドロキシプロピルセルロース及びクロスポビドンを含まない。 As is clear from the above table, the disintegrant used in the present invention does not contain a general disintegrant (including a disintegrant called a super disintegrant). That is, pregelatinized starch (fully or partially pregelatinized starch), carboxymethyl starches (such as sodium carboxymethyl starch), carboxymethylcelluloses (carboxymethylcellulose such as carmellose, carmellose calcium, croscarmellose sodium, cross-linked products thereof, or the like Alkali metal or alkaline earth metal salt), low-substituted hydroxypropylcellulose and crospovidone.
（Ｃ）崩壊剤の嵩密度（結晶セルロースなどの集合体の嵩密度）も崩壊性に影響を及ぼす。崩壊剤（結晶セルロースなど）の嵩密度は、例えば、０．２３ｇ／ｃｍ３以下（例えば、０．０５〜０．２ｇ／ｃｍ３）、好ましくは０．１８ｇ／ｃｍ３以下（例えば、０．０７〜０．１７ｇ／ｃｍ３）、さらに好ましくは０．１５ｇ／ｃｍ３以下（例えば、０．１０〜０．１５ｇ／ｃｍ３）であり、通常、０．０８〜０．１７ｇ／ｃｍ３程度である場合が多い。 (C) The bulk density of the disintegrant (the bulk density of aggregates such as crystalline cellulose) also affects the disintegration property. The bulk density of the disintegrant (such as cellulose), for example, 0.23 g / cm 3 or less (e.g., 0.05 to 0.2 g / cm 3), preferably 0.18 g / cm 3 or less (e.g., 0. 07~0.17g / cm 3), more preferably from 0.15 g / cm 3 or less (e.g., 0.10~0.15g / cm 3), usually, 0.08~0.17g / cm 3 approximately In many cases.
崩壊剤の含有量は、崩壊剤の種類に応じて選択でき、錠剤１００重量部に対して１〜４０重量部（例えば、５〜３５重量部）、好ましくは３〜３０重量部（例えば、５〜２５重量部）程度であってもよく、通常、１０〜３５重量部（例えば、１２〜３３重量部、特に１５〜３０重量部）程度である。より具体的には、結晶セルロースの割合は、錠剤１００重量部に対して１〜３０重量部（例えば、２〜２５重量部）、好ましくは３〜２０重量部（例えば、３〜１５重量部）、さらに好ましくは５〜１０重量部程度である。デンプン類の割合は、錠剤１００重量部に対して１〜４０重量部、好ましくは５〜３０重量部（例えば、５〜２５重量部）、さらに好ましくは７〜２５重量部（例えば、１０〜２５重量部）程度であり、１０〜２０重量部程度であってもよい。なお、崩壊剤の総量が多すぎると口腔内での服用感が損なわれ、少なすぎると所望の口腔内崩壊性及び錠剤硬度が得られない。 Content of a disintegrating agent can be selected according to the kind of disintegrating agent, and is 1-40 weight part (for example, 5-35 weight part) with respect to 100 weight part of tablets, Preferably it is 3-30 weight part (for example, 5). ˜25 parts by weight), and usually about 10 to 35 parts by weight (for example, 12 to 33 parts by weight, particularly 15 to 30 parts by weight). More specifically, the ratio of the crystalline cellulose is 1 to 30 parts by weight (for example, 2 to 25 parts by weight), preferably 3 to 20 parts by weight (for example, 3 to 15 parts by weight) with respect to 100 parts by weight of the tablet. More preferably, it is about 5 to 10 parts by weight. The ratio of starch is 1 to 40 parts by weight, preferably 5 to 30 parts by weight (for example, 5 to 25 parts by weight), more preferably 7 to 25 parts by weight (for example, 10 to 25 parts by weight) with respect to 100 parts by weight of the tablet. Part by weight), or about 10 to 20 parts by weight. In addition, when there is too much total amount of a disintegrating agent, the ingestion feeling in an intraoral area will be impaired, and when too small, desired oral disintegration property and tablet hardness will not be obtained.
結晶セルロースとデンプン類とはそれぞれ単独で用いてもよいが、二種類併用するのが好ましい。結晶セルロースとデンプン類との重量割合は、前者／後者＝５／９５〜９５／５程度の広い範囲から選択でき、通常、５／９５〜８０／２０、好ましくは１０／９０〜７５／２５（例えば、１２／８８〜７０／３０）、さらに好ましくは１５／８５〜６５／３５程度であってもよい。 Crystalline cellulose and starches may be used alone, but two types are preferably used in combination. The weight ratio between crystalline cellulose and starch can be selected from a wide range of the former / the latter = 5/95 to 95/5, and is usually 5/95 to 80/20, preferably 10/90 to 75/25 ( For example, it may be 12/88 to 70/30), more preferably about 15/85 to 65/35.
（Ｄ）水溶性結合剤
水溶性結合剤としては、ポリビニルアルコール類、ポリビニルピロリドン（ＰＶＰ）、ポリエチレングリコール（ＰＥＧ）、セルロースエーテル類［メチルセルロース（ＭＣ）、ヒドロキシエチルセルロース（ＨＥＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）など］などが例示できる。これらの水溶性結合剤は単独で又は二種以上組み合わせて使用できる。好ましい水溶性結合剤はポリビニルアルコール類及び／又はポリビニルピロリドン（ＰＶＰ）、特にポリビニルアルコール類である。ポリビニルアルコール類としては、例えば、ポリビニルアルコール（完全ケン化ポリビニルアルコール、部分ケン化ポリビニルアルコール）、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリエチレン・ポリビニルアルコール共重合体などが挙げられる。ポリビニルアルコール類としては、完全ケン化ポリビニルアルコールを用いる場合が多い。ポリビニルアルコール類も単独で又は二種以上組み合わせて使用できる。ポリビニルアルコール類は、市販されている単品を使用してもよく、プレミックス品（OPA DRY AMB（日本カラコン社製、ポリビニルアルコールを含むプレミックス品）など）を使用してもよい。
(D) Water-soluble binder Examples of water-soluble binders include polyvinyl alcohols, polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), cellulose ethers [methyl cellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC). ), Hydroxypropylmethylcellulose (HPMC) and the like]. These water-soluble binders can be used alone or in combination of two or more. Preferred water-soluble binders are polyvinyl alcohols and / or polyvinyl pyrrolidone (PVP), especially polyvinyl alcohols. Examples of the polyvinyl alcohols include polyvinyl alcohol (fully saponified polyvinyl alcohol, partially saponified polyvinyl alcohol), polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene / polyvinyl alcohol copolymer, and the like. As polyvinyl alcohols, fully saponified polyvinyl alcohol is often used. Polyvinyl alcohols can also be used alone or in combination of two or more. As the polyvinyl alcohol, a commercially available single product may be used, or a premix product (OPA DRY AMB (manufactured by Nippon Colorcon, premix product containing polyvinyl alcohol) or the like) may be used.
水溶性結合剤は、高い錠剤硬度を付与する結合剤が好ましく、このような水溶性結合剤は、Ｄ−マンニトール９９重量部と結合剤１重量部との混合物（又はＤ−マンニトール９９重量部を結合剤１重量部の水溶液で、流動層造粒法で造粒した造粒物）を、打錠圧５．０ｋＮで製した錠剤（直径φ８ｍｍ、重量２００ｍｇ）の硬度を錠剤の破断面積で除した値（結合剤の錠剤強度）で評価できる。この結合剤の錠剤強度が大きいほど、結合剤の結合力が大きいといえる。水溶性結合剤は、結合剤の錠剤強度が２Ｎ／ｍｍ２以上（例えば、２〜５Ｎ／ｍｍ２）、好ましくは２．３Ｎ／ｍｍ２以上（例えば、２．３〜４Ｎ／ｍｍ２）、さらに好ましくは２．５Ｎ／ｍｍ２以上（例えば、２．５〜３．５Ｎ／ｍｍ２）であるのが好ましい。なお、流動層造粒法の条件は後述する実施例の条件を参照でき、例えば、４２メッシュ篩で篩過したＤ−マンニトール４９５ｇを流動層造粒乾燥機に投入し、給気温度７０℃で、水溶性結合剤５ｇの水溶液（例えば、濃度０．４重量％水溶液）を噴霧して造粒し、乾燥し、生成した顆粒を２２メッシュ篩で整粒することにより、前記造粒物を得ることができる。 The water-soluble binder is preferably a binder that imparts high tablet hardness, and such a water-soluble binder comprises a mixture of 99 parts by weight of D-mannitol and 1 part by weight of a binder (or 99 parts by weight of D-mannitol). The hardness of a tablet (diameter: 8 mm, weight: 200 mg) made from a 1 part by weight aqueous solution of a binder and granulated by fluidized bed granulation at a tableting pressure of 5.0 kN is divided by the breaking area of the tablet. Value (tablet strength of the binder). It can be said that as the tablet strength of the binder increases, the binding strength of the binder increases. The water-soluble binder has a tablet strength of 2 N / mm 2 or more (for example, 2 to 5 N / mm 2 ), preferably 2.3 N / mm 2 or more (for example, 2.3 to 4 N / mm 2 ), More preferably, it is 2.5 N / mm 2 or more (for example, 2.5 to 3.5 N / mm 2 ). The conditions of the fluidized bed granulation method can refer to the conditions of the examples described later. For example, 495 g of D-mannitol sieved with a 42 mesh sieve is put into a fluidized bed granulation dryer, and the supply temperature is 70 ° C. Then, an aqueous solution of 5 g of a water-soluble binder (for example, an aqueous solution having a concentration of 0.4% by weight) is sprayed and granulated, dried, and the resulting granule is sized with a 22 mesh sieve to obtain the granulated product. be able to.
さらに、崩壊性を向上させるため、水溶性結合剤は低粘度タイプの結合剤であるのが好ましく、水溶性結合剤の２重量％水溶液の粘度は、温度２０℃において、６Ｐａ・ｓ以下（例えば、１〜５．５Ｐａ・ｓ程度）、好ましくは５Ｐａ・ｓ以下（例えば、１．５〜４．５Ｐａ・ｓ程度）、さらに好ましくは４ｍＰａ・ｓ以下（例えば、１．５〜４Ｐａ・ｓ程度）、特に３ｍＰａ・ｓ以下（例えば、１．５〜３Ｐａ・ｓ程度）であってもよい。なお、結合剤の水溶液粘度は回転粘度計(B型粘度計、東京計器)を用いて測定できる。 Furthermore, in order to improve disintegration, the water-soluble binder is preferably a low-viscosity type binder, and the viscosity of a 2% by weight aqueous solution of the water-soluble binder is 6 Pa · s or less (for example, at a temperature of 20 ° C.) 1 to 5.5 Pa · s), preferably 5 Pa · s or less (eg, about 1.5 to 4.5 Pa · s), more preferably 4 mPa · s or less (eg, about 1.5 to 4 Pa · s). ), Particularly 3 mPa · s or less (for example, about 1.5 to 3 Pa · s). The aqueous solution viscosity of the binder can be measured using a rotational viscometer (B-type viscometer, Tokyo Keiki).
口腔内での崩壊性を高めるため、本発明の錠剤は水溶性結合剤の含有量が少ないという特色がある。水溶性結合剤の含有量は、錠剤１００重量部に対して、１重量部以下（例えば、０．０１〜１．０重量部）、好ましくは０．０５〜０．７重量部（例えば、０．０５〜０．６重量部）、さらに好ましくは０．０７〜０．５重量部（例えば、０．１〜０．５重量部）、特に０．１〜０．４重量部（例えば、０．１〜０．３重量部）程度であり、０．０７〜０．２５重量部（例えば、０．１〜０．２重量部）程度であってもよい。結合剤の割合が多すぎると、錠剤の硬度は大きくなるものの、速崩壊性が失われ、少なすぎると、錠剤の硬度が低下したり、打錠時に打錠障害が発生したりする。 In order to enhance the disintegration property in the oral cavity, the tablet of the present invention has a feature that the content of the water-soluble binder is small. The content of the water-soluble binder is 1 part by weight or less (eg, 0.01 to 1.0 part by weight), preferably 0.05 to 0.7 part by weight (eg, 0 to 100 parts by weight of the tablet). 0.05 to 0.6 parts by weight), more preferably 0.07 to 0.5 parts by weight (for example, 0.1 to 0.5 parts by weight), particularly 0.1 to 0.4 parts by weight (for example, 0 0.1 to 0.3 parts by weight), or about 0.07 to 0.25 parts by weight (for example, 0.1 to 0.2 parts by weight). If the proportion of the binder is too large, the tablet hardness increases, but the rapid disintegration property is lost. If the amount is too small, the tablet hardness decreases or a tableting failure occurs during tableting.
なお、水溶性結合剤の使用量を少なくすると、錠剤の崩壊性を向上できるものの、錠剤の強度及び硬度が低下する。そのため、少量であっても錠剤の強度及び硬度を向上できる水溶性結合剤を用いるのが好ましい。このような水溶性結合剤は、前記錠剤強度で評価でき、ＨＰＣ、ＨＰＭＣなどのセルロースエーテル類に比べて、ポリビニルピロリドン（ＰＶＰ）、特にポリビニルアルコール類は、少量であっても錠剤強度を向上できる。特に、低粘度の水溶性結合剤を用いると、少量であっても、高い崩壊性を維持しつつ、錠剤の強度及び硬度を向上できる。 In addition, when the usage-amount of a water-soluble binder is decreased, although the disintegration property of a tablet can be improved, the intensity | strength and hardness of a tablet will fall. Therefore, it is preferable to use a water-soluble binder that can improve the strength and hardness of the tablet even in a small amount. Such a water-soluble binder can be evaluated by the tablet strength, and compared with cellulose ethers such as HPC and HPMC, polyvinyl pyrrolidone (PVP), particularly polyvinyl alcohols, can improve tablet strength even in a small amount. . In particular, when a low-viscosity water-soluble binder is used, the strength and hardness of the tablet can be improved while maintaining high disintegration even in a small amount.
（Ｅ）滑沢剤
滑沢剤としては、例えば、飽和高級脂肪酸又はその金属塩若しくは多価アルコールとのエステル（又は飽和高級アルコールと多価カルボン酸とのエステル又はその塩）、タルクなどが例示できる。より具体的には、ステアリン酸、ステアリン酸金属塩（カルシウム塩、マグネシウム塩、アルミニウム塩など）、ショ糖脂肪酸エステル、フマル酸ステアリルナトリウムなどが例示できる。これらの滑沢剤も単独で又は二種以上組み合わせて使用できる。好ましい滑沢剤は、ステアリン酸マグネシウムである。
(E) Lubricant Examples of the lubricant include, for example, saturated higher fatty acids, their metal salts or esters with polyhydric alcohols (or esters of saturated higher alcohols and polyvalent carboxylic acids or their salts), talc and the like. it can. More specifically, stearic acid, stearic acid metal salts (calcium salt, magnesium salt, aluminum salt, etc.), sucrose fatty acid ester, sodium stearyl fumarate and the like can be exemplified. These lubricants can also be used alone or in combination of two or more. A preferred lubricant is magnesium stearate.
本発明の錠剤は、崩壊性を向上させるため、滑沢剤の含有量が少ないという特色がある。滑沢剤の含有量は、錠剤１００重量部に対して０．５重量部以下（例えば、０．０１〜０．５重量部）、好ましくは０．０１〜０．３重量部（例えば、０．０５〜０．２５重量部）、さらに好ましくは０．０１〜０．２重量部（例えば、０．０５〜０．１５重量部）程度である。 The tablet of the present invention has a feature that the content of the lubricant is small in order to improve disintegration. The content of the lubricant is 0.5 parts by weight or less (for example, 0.01 to 0.5 parts by weight), preferably 0.01 to 0.3 parts by weight (for example, 0 parts by weight) with respect to 100 parts by weight of the tablet. 0.05 to 0.25 parts by weight), more preferably about 0.01 to 0.2 parts by weight (for example, 0.05 to 0.15 parts by weight).
さらに、滑沢剤は、錠剤の表面（又は表層部）に偏在又は付着しているのが好ましい。すなわち、滑沢剤は、錠剤の内部に含有されておらず錠剤の表面又は表層部に偏在又は付着して含有されている。錠剤の表面に滑沢剤を偏在させることにより、滑沢剤の使用量を低減しつつ、錠剤の硬度を高め、しかも錠剤の崩壊性を向上できる。 Furthermore, the lubricant is preferably unevenly distributed or adhered to the surface (or surface layer portion) of the tablet. That is, the lubricant is not contained inside the tablet but is unevenly distributed or adhered to the surface or surface layer of the tablet. By unevenly distributing the lubricant on the surface of the tablet, it is possible to increase the hardness of the tablet and improve the disintegration property of the tablet while reducing the amount of the lubricant used.
本発明の錠剤及びそのための組成物（固形製剤組成物）は、少なくとも前記成分（Ａ）〜（Ｅ）で構成してもよく、製剤組成物（打錠組成物）は前記成分（Ａ）〜（Ｄ）で構成し、錠剤１００重量部に対して０．５重量部以下の割合で（Ｅ）滑沢剤を用いて打錠し、錠剤（口腔内崩壊錠）を形成してもよい。前記錠剤及び組成物は、固形製剤で一般的に使用される添加剤、例えば、賦形剤（軽質無水ケイ酸など）、前記以外の崩壊剤、前記以外の滑沢剤、界面活性剤、甘味剤、酸味剤、発泡剤、香料、着色剤などを含有していてもよい。これらの添加剤の使用量は崩壊性及び錠剤硬度に悪影響を及ぼさない範囲で選択でき、添加剤の使用量は、例えば、錠剤１００重量部に対して０．０１〜５重量部、好ましくは０．０２〜１重量部、さらに好ましくは０．０５〜０．２５重量部程度であってもよい。 The tablet of the present invention and the composition (solid preparation composition) therefor may be composed of at least the above components (A) to (E), and the preparation composition (tablet composition) is composed of the above components (A) to (E). It may comprise (D) and may be tableted with (E) lubricant at a ratio of 0.5 parts by weight or less to 100 parts by weight of the tablet to form a tablet (orally disintegrating tablet). The tablets and compositions are additives commonly used in solid preparations, for example, excipients (such as light anhydrous silicic acid), disintegrants other than the above, lubricants other than the above, surfactants, sweetness An agent, a sour agent, a foaming agent, a fragrance, a colorant and the like may be contained. The amount of these additives used can be selected within a range that does not adversely affect the disintegration property and tablet hardness. The amount of the additive used is, for example, 0.01 to 5 parts by weight, preferably 0 with respect to 100 parts by weight of the tablet. It may be about 0.02 to 1 part by weight, more preferably about 0.05 to 0.25 part by weight.
本発明の錠剤は、少量の水又は口腔内の少量の唾液により速やかに崩壊する。例えば、錠剤を噛まずに、錠剤が口腔内で完全に崩壊するまでの時間を測定したとき、本発明の口腔内速崩壊錠の崩壊時間は、通常、２０〜３０秒、好ましくは１０〜２０秒、さらに好ましくは５〜１０秒である。さらに、本発明の錠剤は、錠剤硬度が高いだけでなく高湿度（加湿）条件下で保存しても硬度の低下を抑制できる。本発明の錠剤の初期硬度は、例えば、５０Ｎ以上（例えば、５０〜６５Ｎ）、好ましくは５２〜６３Ｎ（例えば、５４〜６２Ｎ）程度であってもよく、吸湿硬度は、２５℃、相対湿度７５％で１週間に亘り保存したとき、３０Ｎ以上（例えば、３０〜５０Ｎ）、好ましくは３２〜４７Ｎ（例えば、３３〜４５Ｎ）、さらに好ましくは３５〜４２Ｎ程度であってもよい。 The tablet of the present invention rapidly disintegrates with a small amount of water or a small amount of saliva in the oral cavity. For example, when the time until the tablet is completely disintegrated in the oral cavity is measured without chewing the tablet, the disintegration time of the rapidly disintegrating tablet in the oral cavity of the present invention is usually 20-30 seconds, preferably 10-20. Second, more preferably 5 to 10 seconds. Furthermore, the tablet of the present invention not only has high tablet hardness, but also can suppress a decrease in hardness even when stored under high humidity (humidification) conditions. The initial hardness of the tablet of the present invention may be, for example, about 50 N or more (for example, 50 to 65 N), preferably about 52 to 63 N (for example, 54 to 62 N), and the moisture absorption hardness is 25 ° C. and the relative humidity is 75. %, When it is stored for 1 week, it may be 30 N or more (for example, 30 to 50 N), preferably 32 to 47 N (for example, 33 to 45 N), more preferably about 35 to 42 N.
［口腔内崩壊錠の製造方法］
本発明の口腔内崩壊錠は、前記成分（Ａ）〜（Ｅ）を含む製剤組成物（混合物、又は打錠組成物）を打錠することにより調製できる。打錠に供される打錠組成物は、前記成分（Ａ）〜（Ｅ）の混合物であってもよいが、好ましい方法では、外部滑沢法を利用して、（Ｅ）滑沢剤を杵及び／又は臼に付着させて前記成分（Ａ）〜（Ｄ）を含む打錠組成物を打錠する。この方法では、予め少なくとも（Ａ）薬物、（Ｂ）粒状ベース成分及び（Ｃ）崩壊剤を含む混合物（粉粒状混合物）を（Ｄ）水溶性結合剤の水溶液を用いて造粒し、生成した造粒物（打錠組成物）を、（Ｅ）滑沢剤を杵及び／又は臼に付着させて打錠してもよい。外部滑沢法では、通常、少なくとも（Ａ）薬物及び（Ｂ）粒状ベース成分を含む混合物（粉粒状混合物）を（Ｄ）水溶性結合剤の水溶液を用いて予め造粒し、生成した造粒物と（Ｃ）崩壊剤との混合物（打錠組成物）を、（Ｅ）滑沢剤を杵及び／又は臼に付着させて打錠する場合が多い。なお、外部滑沢法では杵及び／又は臼に付着した滑沢剤が打錠に伴って錠剤に含有される。また、造粒過程では、必要により（Ｃ）崩壊剤などを併用して造粒してもよい。また、造粒には、転動造粒法、押出造粒法、流動層造粒法などの慣用の造粒法が利用でき、好ましくは流動層造粒法が利用できる。
[Method for producing orally disintegrating tablets]
The orally disintegrating tablet of the present invention can be prepared by tableting a pharmaceutical composition (mixture or tableting composition) containing the components (A) to (E). The tableting composition to be used for tableting may be a mixture of the above components (A) to (E). However, in a preferred method, an external lubricant method is used, and (E) a lubricant is added. The tableting composition containing the components (A) to (D) is tableted by adhering to a pestle and / or mortar. In this method, a mixture (a granular mixture) containing at least (A) a drug, (B) a granular base component, and (C) a disintegrant is granulated with an aqueous solution of (D) a water-soluble binder, and generated. The granulated product (tablet composition) may be tableted by attaching (E) a lubricant to the punch and / or mortar. In the external lubrication method, usually, a mixture (powder mixture) containing at least (A) a drug and (B) a particulate base component is granulated in advance using an aqueous solution of (D) a water-soluble binder, and the resulting granulation is produced. In many cases, the mixture (tablet composition) of the product and (C) the disintegrant is tableted by attaching the lubricant (E) to the pestle and / or the mortar. In the external lubrication method, the lubricant attached to the punch and / or mortar is contained in the tablet along with tableting. Moreover, in the granulation process, you may granulate using (C) disintegrating agent together as needed. For granulation, a conventional granulation method such as a rolling granulation method, an extrusion granulation method, or a fluidized bed granulation method can be used, and preferably a fluidized bed granulation method can be used.
外部滑沢法では、予め滑沢剤を噴霧（連続的又は間欠的に噴霧）して杵及び／又は臼に付着させるための外部滑沢剤供給装置と、噴霧されて錠剤成形に利用されなかった余剰の滑沢剤を連続的に回収するための外部滑沢剤回収装置とを備えた打錠機を用い、前記組成物を打錠（外部滑沢打錠）、特に連続的に打錠し、連続的に錠剤に成形することができる。この方法において、滑沢剤は定常的な風量の気流中に分散させて杵及び／又は臼に吹き付けるのが好ましい。また、薬物を含む粉体（打錠用組成物）を、回転式粉末圧縮成形機を用いて打錠することにより、本発明の口腔内速崩壊錠を製造することができる。外部滑沢剤供給装置及び回収装置を備えた回転式粉末圧縮成形機については、例えば、「外部滑沢噴霧システム」（楠尚著、製剤機械技術研究会誌、製剤機械技術研究会、２００１年、第１０巻、第２号、ｐ．６０〜６６）、前記特許文献７、特開２００１−２９３５９９号公報などを参照できる。 In the external lubricant method, an external lubricant supply device for spraying the lubricant in advance (spraying continuously or intermittently) to adhere to the pestle and / or mortar, and sprayed and not used for tableting Using a tableting machine equipped with an external lubricant recovery device for continuously recovering surplus lubricant, and tableting the composition (external lubricant tableting), especially tableting continuously And can be continuously formed into tablets. In this method, the lubricant is preferably dispersed in a steady air flow and sprayed onto the pestle and / or die. Moreover, the intraoral rapidly disintegrating tablet of this invention can be manufactured by tableting the powder (composition for tableting) containing a drug using a rotary powder compression molding machine. Regarding the rotary powder compression molding machine equipped with an external lubricant supply device and a recovery device, for example, “External Lubrication Spray System” (Mao Naotsu, Journal of Formulation Machine Technology Study Group, Formulation Machine Technology Study Group, 2001, Vol. 10, No. 2, p. 60-66), Patent Document 7, JP-A 2001-293599, and the like.
本発明の製造方法では、打錠という簡単な操作で、口腔内での崩壊性に極めて優れ、硬度の高い口腔内崩壊錠を工業的に有利に製造できる。また、湿潤した粉末を用いる必要がないため、錠剤の生産性を高めることができる。さらに、外部滑沢法を利用して打錠すると、錠剤中の空隙率が低く、そのため小型の錠剤を製造でき、製剤設計の自由度が大きいという利点を有する。また、外部滑沢法（又は外部滑沢打錠法）を利用すると、滑沢剤が錠剤のほぼ表面に局在しているので、必然的に錠剤の内部に滑沢剤が存在して崩壊の遅延が生じる従来の方法と異なり、口腔内での速やかな崩壊性及び適度な引っ張り強度を示す。 In the production method of the present invention, an orally disintegrating tablet that is extremely excellent in disintegration property in the oral cavity and has high hardness can be industrially advantageously produced by a simple operation of tableting. In addition, since it is not necessary to use a wet powder, the productivity of tablets can be increased. Furthermore, when tableting is performed using an external lubrication method, there is an advantage that the void ratio in the tablet is low, so that a small tablet can be produced, and the degree of freedom in formulation design is great. Also, when using the external lubrication method (or external lubrication tableting method), the lubricant is localized almost on the surface of the tablet. Unlike the conventional method in which the delay occurs, rapid disintegration in the oral cavity and moderate tensile strength are exhibited.
以下に、実施例に基づいて本発明をより詳細に説明するが、本発明はこれらの実施例によって限定されるものではない。以下の実施例において、外部滑沢剤供給装置及び回収装置を備えた外部滑沢噴霧システム（以下、「外部滑沢噴霧システム」と称する）（ＥＬＳ−Ｐ１、（株）菊水製作所製）を用い回転式打錠機（ＶＩＲＧＯ、（株）菊水製作所製）で錠剤を製造する方法において、噴霧されたものの製剤成分として利用されなかった余剰の滑沢剤（ステアリン酸マグネシウム）は、吸塵機などで構成される回収装置により連続的に回収した。また、外部滑沢噴霧システムを用いて得られた錠剤１錠中のステアリン酸マグネシウム量は、原子発光分析法でマグネシウム量を測定することにより求めた。口腔内崩壊時間の測定は、成人男子４名で行ない、平均値を崩壊時間とした。口腔内で錠剤を噛まずに、錠剤が完全に崩壊するまでの時間を測定した。 Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. In the following examples, an external lubricant spray system (hereinafter referred to as “external lubricant spray system”) (ELS-P1, manufactured by Kikusui Seisakusho Co., Ltd.) provided with an external lubricant supply device and a recovery device is used. In the method for producing tablets with a rotary tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), excess lubricant (magnesium stearate) that was sprayed but not used as a formulation component was collected with a dust absorber or the like. It was continuously recovered by the configured recovery device. Further, the amount of magnesium stearate in one tablet obtained using an external lubrication spray system was determined by measuring the amount of magnesium by atomic emission spectrometry. The oral disintegration time was measured by four adult males, and the average value was taken as the disintegration time. The time until the tablet completely disintegrated was measured without chewing the tablet in the oral cavity.
口腔内速崩壊錠の硬度は、デジタル硬度計（PTB311E、Pharm Test GmbH Germany）で測定した。吸湿後の錠剤の硬度（吸湿硬度）は２５℃、相対湿度７５％で１週間保存品した錠剤について測定した。 The hardness of the intraoral quick disintegrating tablet was measured with a digital hardness meter (PTB311E, Pharm Test GmbH Germany). The hardness of the tablets after moisture absorption (moisture absorption hardness) was measured for tablets stored for 1 week at 25 ° C. and 75% relative humidity.
各実施例および比較例に用いた結合剤の２重量％水溶液の粘度（２０℃）および結合剤の錠剤強度を表２に示す。結合剤の粘度は回転粘度計（Ｂ型粘度計、東京計器（株）製）を用いて測定した。結合剤の錠剤強度測定用の検体は、β型Ｄ−マンニトール結晶（ロケット社：Pearlitol 160C）９９重量部を結合剤１重量部の４重量％水溶液で流動層造粒した顆粒を単発式打錠機（Tabflex、岡田精工（株）製）で打錠して調製した。 Table 2 shows the viscosity (20 ° C.) of the 2 wt% aqueous solution of the binder used in each Example and Comparative Example and the tablet strength of the binder. The viscosity of the binder was measured using a rotational viscometer (B-type viscometer, manufactured by Tokyo Keiki Co., Ltd.). The specimen for measuring the tablet strength of the binder is a single-punch tableted granulation granulated by fluidized bed granulation of 99 parts by weight of β-type D-mannitol crystals (Rocket: Pearlitol 160C) with 4 parts by weight of 1 part by weight of binder. It was prepared by tableting with a machine (Tabflex, manufactured by Okada Seiko Co., Ltd.).
実施例１
表３に口腔内速崩壊錠の処方を示す。内添加原料（造粒末原料）を４２メッシュ篩で篩過し、流動層造粒乾燥機（ＭＰ−０１、パウレック（株）製）に投入し、ポリビニルアルコールの０．４重量％水溶液を噴霧して造粒を行った。給気温度は７０℃とし、乾燥の終点の排気温度を４０℃とした。得られた顆粒を２２メッシュ篩で整粒を行った後、整粒物と、ステアリン酸マグネシウムを除く外添加原料（結晶セルロース、トウモロコシデンプン及び軽質無水ケイ酸）とをＶ型混合機（ＶＩ−１０、（株）徳寿工作所製）で３分間混合し、打錠末を得た。打錠機（ＶＩＲＧＯ、（株）菊水製作所製）を用いて、打錠末を外部滑沢法にて打錠し錠剤（直径φ８ｍｍ及び重量２００ｍｇ）を得た。なお、表３中、「部」は「重量部」を示す（以下同じ）。
Example 1
Table 3 shows the formulation of the intraoral quick disintegrating tablet. The internally added raw material (granulated powder raw material) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (MP-01, manufactured by Paulek Co., Ltd.), and sprayed with a 0.4 wt% aqueous solution of polyvinyl alcohol. And granulated. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized using a 22 mesh sieve, and then the sized product and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid) excluding magnesium stearate were mixed into a V-type mixer (VI- 10 and manufactured by Tokuju Kogakusho Co., Ltd. for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tableting powder was tableted by the external lubrication method to obtain tablets (diameter φ8 mm and weight 200 mg). In Table 3, “parts” indicates “parts by weight” (the same applies hereinafter).
得られた口腔内速崩壊錠の錠剤硬度（初期硬度）は６０Ｎ、吸湿後の硬度（吸湿硬度）は３６Ｎであり、口腔内崩壊時間は１１秒であった。 The tablet hardness (initial hardness) of the obtained orally rapidly disintegrating tablet was 60 N, the hardness after moisture absorption (moisture absorption hardness) was 36 N, and the oral disintegration time was 11 seconds.
実施例２
表４に口腔内速崩壊錠の処方を示す。内添加原料（造粒末原料）を４２メッシュ篩で篩過し、流動層造粒乾燥機（ＭＰ−０１、パウレック（株）製）に投入し、ポリビニルアルコールの０．４重量％水溶液を噴霧して造粒を行った。給気温度は７０℃とし、乾燥の終点の排気温度を４０℃とした。得られた顆粒を２２メッシュ篩で整粒を行った後、整粒物と、ステアリン酸マグネシウムを除く外添加原料（結晶セルロース、トウモロコシデンプン及び軽質無水ケイ酸）とをＶ型混合機（ＶＩ−１０、（株）徳寿工作所製）で３分間混合し、打錠末を得た。打錠機（ＶＩＲＧＯ、（株）菊水製作所製）を用いて、打錠末を実施例１と同様にして外部滑沢法にて打錠し、口腔内崩壊錠（直径φ８ｍｍ及び重量２００ｍｇ）を得た。
Example 2
Table 4 shows the formulation of the intraoral rapidly disintegrating tablet. The internally added raw material (granulated powder raw material) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (MP-01, manufactured by Paulek Co., Ltd.), and sprayed with a 0.4 wt% aqueous solution of polyvinyl alcohol. And granulated. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized using a 22 mesh sieve, and then the sized product and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid) excluding magnesium stearate were mixed into a V-type mixer (VI- 10 and manufactured by Tokuju Kogakusho Co., Ltd. for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tableting powder was tableted by the external lubrication method in the same manner as in Example 1, and an orally disintegrating tablet (diameter φ8 mm and weight 200 mg) was obtained. Obtained.
得られた口腔内速崩壊錠の錠剤硬度（初期硬度）は５５Ｎ、吸湿後の硬度（吸湿硬度）は３７Ｎであり、口腔内崩壊時間は７秒であった。 The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 55 N, the hardness after moisture absorption (moisture absorption hardness) was 37 N, and the oral disintegration time was 7 seconds.
実施例３
表５に口腔内速崩壊錠の処方を示す。内添加原料（造粒末原料）を４２メッシュ篩で篩過し、流動層造粒乾燥機（ＭＰ−０１、パウレック（株）製）に投入し、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体の０．４重量％水溶液を噴霧して造粒を行った。給気温度は７０℃とし、乾燥の終点の排気温度を４０℃とした。得られた顆粒を２２メッシュ篩で整粒を行った後、整粒物と、ステアリン酸マグネシウムを除く外添加原料（結晶セルロース、トウモロコシデンプン及び軽質無水ケイ酸）とをＶ型混合機（ＶＩ−１０、（株）徳寿工作所製）で３分間混合し、打錠末を得た。打錠機（ＶＩＲＧＯ、（株）菊水製作所製）を用いて、打錠末を実施例１と同様にして外部滑沢法にて打錠し、口腔内崩壊錠（直径φ８ｍｍ及び重量２００ｍｇ）を得た。
Example 3
Table 5 shows the formulation of the intraoral quick disintegrating tablet. The internally added raw material (granulated powder raw material) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (MP-01, manufactured by Paulek Co., Ltd.), and polyvinyl alcohol / acrylic acid / methyl methacrylate co-polymerized. Granulation was performed by spraying a 0.4 wt% aqueous solution of the coalescence. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized using a 22 mesh sieve, and then the sized product and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid) excluding magnesium stearate were mixed into a V-type mixer (VI- 10 and manufactured by Tokuju Kogakusho Co., Ltd. for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tableting powder was tableted by the external lubrication method in the same manner as in Example 1, and an orally disintegrating tablet (diameter φ8 mm and weight 200 mg) was obtained. Obtained.
得られた口腔内速崩壊錠の錠剤硬度（初期硬度）は６１Ｎ、吸湿後の硬度（吸湿硬度）は４０Ｎであり、口腔内崩壊時間は８秒であった。 The obtained tablet rapidly disintegrating in the oral cavity had an tablet hardness (initial hardness) of 61 N, moisture absorption after moisture absorption (moisture absorption hardness) of 40 N, and oral disintegration time of 8 seconds.
実施例４
表６に口腔内速崩壊錠の処方を示す。内添加原料（造粒末原料）を４２メッシュ篩で篩過し、流動層造粒乾燥機（ＭＰ−０１、パウレック（株）製）に投入し、ポリビニルアルコールの０．４重量％水溶液を噴霧して造粒を行った。給気温度は７０℃とし、乾燥の終点の排気温度を４０℃とした。得られた顆粒を２２メッシュ篩で整粒を行った後、整粒物と、ステアリン酸マグネシウムを除く外添加原料（結晶セルロース、トウモロコシデンプン及び軽質無水ケイ酸）とをＶ型混合機（ＶＩ−１０、（株）徳寿工作所製）で３分間混合し、打錠末を得た。打錠機（ＶＩＲＧＯ、（株）菊水製作所製）を用いて、打錠末を実施例１と同様にして外部滑沢法にて打錠し、口腔内崩壊錠（直径φ８ｍｍ及び重量２００ｍｇ）を得た。
Example 4
Table 6 shows the formulation of the intraoral quick disintegrating tablet. The internally added raw material (granulated powder raw material) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (MP-01, manufactured by Paulek Co., Ltd.), and sprayed with a 0.4 wt% aqueous solution of polyvinyl alcohol. And granulated. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized using a 22 mesh sieve, and then the sized product and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid) excluding magnesium stearate were mixed into a V-type mixer (VI- 10 and manufactured by Tokuju Kogakusho Co., Ltd. for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tableting powder was tableted by the external lubrication method in the same manner as in Example 1, and an orally disintegrating tablet (diameter φ8 mm and weight 200 mg) was obtained. Obtained.
得られた口腔内速崩壊錠の錠剤硬度（初期硬度）は５６Ｎ、吸湿後の硬度（吸湿硬度）は３８Ｎであり、口腔内崩壊時間は７秒であった。 The tablet hardness (initial hardness) of the obtained orally rapidly disintegrating tablet was 56 N, the hardness after moisture absorption (moisture absorption hardness) was 38 N, and the oral disintegration time was 7 seconds.
実施例５
表７に口腔内速崩壊錠の処方を示す。内添加原料（造粒末原料）を４２メッシュ篩で篩過し、流動層造粒乾燥機（ＭＰ−０１、パウレック（株）製）に投入し、ポリビニルアルコールの０．４重量％水溶液を噴霧して造粒を行った。給気温度は７０℃とし、乾燥の終点の排気温度を４０℃とした。得られた顆粒を２２メッシュ篩で整粒を行った後、整粒物と、ステアリン酸マグネシウムを除く外添加原料（結晶セルロース、トウモロコシデンプン及び軽質無水ケイ酸）とをＶ型混合機（ＶＩ−１０、（株）徳寿工作所製）で３分間混合し、打錠末を得た。打錠機（ＶＩＲＧＯ、（株）菊水製作所製）を用いて、打錠末を実施例１と同様にして外部滑沢法にて打錠し、口腔内崩壊錠（直径φ８ｍｍ及び重量２００ｍｇ）を得た。
Example 5
Table 7 shows the formulation of the intraoral quick disintegrating tablet. The internally added raw material (granulated powder raw material) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (MP-01, manufactured by Paulek Co., Ltd.), and sprayed with a 0.4 wt% aqueous solution of polyvinyl alcohol. And granulated. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized using a 22 mesh sieve, and then the sized product and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid) excluding magnesium stearate were mixed into a V-type mixer (VI- 10 and manufactured by Tokuju Kogakusho Co., Ltd. for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tableting powder was tableted by the external lubrication method in the same manner as in Example 1, and an orally disintegrating tablet (diameter φ8 mm and weight 200 mg) was obtained. Obtained.
得られた口腔内速崩壊錠の錠剤硬度（初期硬度）は５４．４Ｎ、吸湿後の硬度（吸湿硬度）は３８．６Ｎであり、口腔内崩壊時間は７秒であった。 The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 54.4 N, the hardness after moisture absorption (moisture absorption hardness) was 38.6 N, and the oral disintegration time was 7 seconds.
実施例６
表８に口腔内速崩壊錠の処方を示す。内添加原料（造粒末原料）を４２メッシュ篩で篩過し、流動層造粒乾燥機（ＭＰ−０１、パウレック（株）製）に投入し、ポリビニルアルコールの０．４重量％水溶液を噴霧して造粒を行った。給気温度は７０℃とし、乾燥の終点の排気温度を４０℃とした。得られた顆粒を２２メッシュ篩で整粒を行った後、整粒物と、ステアリン酸マグネシウムを除く外添加原料（結晶セルロース、トウモロコシデンプン及び軽質無水ケイ酸）とをＶ型混合機（ＶＩ−１０、（株）徳寿工作所製）で３分間混合し、打錠末を得た。打錠機（ＶＩＲＧＯ、（株）菊水製作所製）を用いて、打錠末を実施例１と同様にして外部滑沢法にて打錠し、口腔内崩壊錠（直径φ８ｍｍ及び重量２００ｍｇ）を得た。
Example 6
Table 8 shows the formulation of the intraoral rapidly disintegrating tablet. The internally added raw material (granulated powder raw material) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (MP-01, manufactured by Paulek Co., Ltd.), and sprayed with a 0.4 wt% aqueous solution of polyvinyl alcohol. And granulated. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized using a 22 mesh sieve, and then the sized product and externally added raw materials (crystalline cellulose, corn starch and light anhydrous silicic acid) excluding magnesium stearate were mixed into a V-type mixer (VI- 10 and manufactured by Tokuju Kogakusho Co., Ltd. for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tableting powder was tableted by the external lubrication method in the same manner as in Example 1, and an orally disintegrating tablet (diameter φ8 mm and weight 200 mg) was obtained. Obtained.
得られた口腔内速崩壊錠の錠剤硬度（初期硬度）は５５Ｎ、吸湿後の硬度（吸湿硬度）は３９Ｎであり、口腔内崩壊時間は１０秒であった。 The tablet speed (initial hardness) of the obtained rapidly disintegrating tablet in the oral cavity was 55 N, the hardness after moisture absorption (moisture absorption hardness) was 39 N, and the oral disintegration time was 10 seconds.
比較例1
表９に口腔内速崩壊錠の処方を示す。内添加原料（造粒末原料）を４２メッシュ篩で篩過し、流動層造粒乾燥機（ＭＰ−０１、パウレック（株）製）に投入し、ヒドロキシプロピルセルロースの４％重量水溶液を噴霧して造粒を行った。給気温度は７０℃とし、乾燥の終点の排気温度を４０℃とした。得られた顆粒を２２メッシュ篩で整粒を行った後、整粒物と、ステアリン酸マグネシウムを除く外添加原料（トウモロコシデンプン及び軽質無水ケイ酸）とをV型混合機（ＶＩ−１０、（株）徳寿工作所製）で３分間混合し、打錠末を得た。打錠機（ＶＩＲＧＯ、（株）菊水製作所製）を用いて、打錠末を実施例１と同様にして外部滑沢法にて打錠し、口腔内崩壊錠（直径φ８ｍｍ及び重量２００ｍｇ）を得た。
Comparative Example 1
Table 9 shows the formulation of the intraoral quick disintegrating tablet. The internally added raw material (granulated powder raw material) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (MP-01, manufactured by Paulek Co., Ltd.), and sprayed with a 4% by weight aqueous solution of hydroxypropylcellulose. And granulated. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. After the obtained granules were sized using a 22 mesh sieve, the sized product and externally added raw materials (corn starch and light anhydrous silicic acid) excluding magnesium stearate were mixed with a V-type mixer (VI-10, ( (Made by Tokuju Kosakusho Co., Ltd.) for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tableting powder was tableted by the external lubrication method in the same manner as in Example 1, and an orally disintegrating tablet (diameter φ8 mm and weight 200 mg) was obtained. Obtained.
得られた口腔内速崩壊錠の錠剤硬度（初期硬度）は５４Ｎ、吸湿後の硬度（吸湿硬度）は１９Ｎであり、口腔内崩壊時間は２５秒であった。 The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 54 N, the hardness after moisture absorption (moisture absorption hardness) was 19 N, and the oral disintegration time was 25 seconds.
比較例２
表１０に口腔内速崩壊錠の処方を示す。内添加原料（造粒末原料）を４２メッシュ篩で篩過し、流動層造粒乾燥機（ＭＰ−０１、パウレック（株）製）に投入し、精製水を噴霧して造粒を行った。給気温度は７０℃とし、乾燥の終点の排気温度を４０℃とした。得られた顆粒を２２メッシュ篩で整粒を行った後、整粒物と、ステアリン酸マグネシウムを除く外添加原料（軽質無水ケイ酸）とをＶ型混合機（ＶＩ−１０、（株）徳寿工作所製）で３分間混合し、打錠末を得た。打錠機（ＶＩＲＧＯ、（株）菊水製作所製）を用いて、打錠末を実施例１と同様にして外部滑沢法にて打錠し、口腔内崩壊錠（直径φ８ｍｍ及び重量２００ｍｇ）を得た。
Comparative Example 2
Table 10 shows the formulation of the intraoral rapidly disintegrating tablet. The internally added raw material (granulated powder raw material) was sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (MP-01, manufactured by Paulek Co., Ltd.), and granulated by spraying purified water. . The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. The obtained granules were sized using a 22 mesh sieve, and then the sized product and an externally added raw material (lightly anhydrous silicic acid) excluding magnesium stearate were mixed into a V-type mixer (VI-10, Tokuju Co., Ltd.). (Made by Kosakusho) for 3 minutes to obtain a tableting powder. Using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.), the tableting powder was tableted by the external lubrication method in the same manner as in Example 1, and an orally disintegrating tablet (diameter φ8 mm and weight 200 mg) was obtained. Obtained.
得られた口腔内速崩壊錠の錠剤硬度（初期硬度）は５１Ｎ、吸湿後の硬度（吸湿硬度）は３９Ｎであり、口腔内崩壊時間は５０秒であった。 The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 51 N, the hardness after moisture absorption (moisture absorption hardness) was 39 N, and the oral disintegration time was 50 seconds.
比較例３
表１１に口腔内速崩壊錠の処方を示す。内添加原料（造粒末原料）を４２メッシュ篩で篩過し、流動層造粒乾燥機（ＭＰ−０１、パウレック（株）製）に投入し、ＨＰＣ−Ｌ ４重量％水溶液を噴霧して造粒を行った。給気温度は７０℃とし、乾燥の終点の排気温度を４０℃とした。得られた顆粒を２２メッシュ篩で整粒を行った後、整粒物と外添加原料（軽質無水ケイ酸）とをＶ型混合機（ＶＩ−１０、（株）徳寿工作所製）で３分間混合し、打錠末を得た。打錠機（ＶＩＲＧＯ、（株）菊水製作所製）を用いて打錠し、口腔内崩壊錠（直径φ８ｍｍ及び重量２００ｍｇ）を得た。
Comparative Example 3
Table 11 shows the formulation of the intraoral quick disintegrating tablet. The internally added raw material (granulated powder raw material) is sieved with a 42 mesh sieve, put into a fluidized bed granulator / dryer (MP-01, manufactured by Pauleck Co., Ltd.), and sprayed with a 4% by weight aqueous solution of HPC-L. Granulation was performed. The supply air temperature was 70 ° C., and the exhaust temperature at the end of drying was 40 ° C. After the obtained granules are sized with a 22 mesh sieve, the sized product and the externally added raw material (light anhydrous silicic acid) are mixed with a V-type mixer (VI-10, manufactured by Tokuju Kogakusho Co., Ltd.). The mixture was mixed for a minute to obtain a tableting powder. Tableting was performed using a tableting machine (VIRGO, manufactured by Kikusui Seisakusho) to obtain an orally disintegrating tablet (diameter φ8 mm and weight 200 mg).
得られた口腔内速崩壊錠の錠剤硬度（初期硬度）は４２Ｎ、吸湿後の硬度（吸湿硬度）は２３．１Ｎであり、口腔内崩壊時間は２５秒であった。 The tablet speed (initial hardness) of the obtained orally rapidly disintegrating tablet was 42 N, the hardness after moisture absorption (moisture absorption hardness) was 23.1 N, and the oral disintegration time was 25 seconds.
実施例及び比較例の結果を表１２に示す。 Table 12 shows the results of Examples and Comparative Examples.
表１２から明らかなように、比較例に比べて実施例では錠剤の初期硬度及び吸湿硬度のいずれもが高く、実用的に何ら問題のない硬度を有している。しかも、口腔内での崩壊時間が約１０秒以下と極めて高い崩壊性を備えている。 As is clear from Table 12, in the Examples, both the initial hardness and moisture absorption hardness of the tablet are higher than those in the Comparative Examples, and the hardness has no practical problem. Moreover, the disintegration time in the oral cavity is about 10 seconds or less and has a very high disintegration property.
本発明の錠剤は、口腔内で圧倒的に速い崩壊性を有するとともに、錠剤硬度を向上できる。そのため、高齢者などであっても水なしで又は少量の水で容易に服用できるとともに、製造工程及び輸送工程並びに分包工程で錠剤のカケなどが生じることがなく、錠剤の品質を向上できる。 The tablet of the present invention has an overwhelmingly fast disintegration property in the oral cavity and can improve tablet hardness. Therefore, even an elderly person can easily take it without water or with a small amount of water, and the quality of the tablet can be improved without the occurrence of chipping of the tablet in the production process, transport process and packaging process.
Claims (11)
少なくとも（Ａ）薬物、（Ｂ）粒状ベース成分及びデンプン類を含む混合物を（Ｄ）水溶性結合剤を用いて造粒し、生成した造粒物と結晶セルロース及びデンプン類との混合物を、（Ｅ）滑沢剤を杵及び／又は臼に付着させて打錠して得られた口腔内崩壊錠。 (A) a drug, (B) an average particle size of 10 to 500 μm, and at least one granular base component selected from sugar, sugar alcohol and amino acid; (C) a swelling ratio upon absorption of water of 1.3 or less A disintegrant, (D) a water-soluble binder, and (E) a lubricant, (C) the disintegrant contains crystalline cellulose and starches, and (D) the content of the water-soluble binder is 100 weights of tablets. 1 part by weight or less with respect to part, and (E) an orally disintegrating tablet with a lubricant content of 0.5 part by weight or less with respect to 100 parts by weight of the tablet,
A mixture comprising at least (A) a drug, (B) a granular base component and starches is granulated using (D) a water-soluble binder, and a mixture of the resulting granulated product with crystalline cellulose and starches is ( E) Orally disintegrating tablets obtained by tableting with a lubricant attached to the punch and / or mortar .
（Ａ）薬物、（Ｂ）平均粒子径１０〜５００μｍを有し、かつ糖、糖アルコール及びアミノ酸から選択された少なくとも一種の粒状ベース成分、（Ｃ）吸水時の膨潤率が１．３以下の崩壊剤、及び（Ｄ）水溶性結合剤を含有し、
（Ｃ）崩壊剤が結晶セルロース及びデンプン類を含み、
（Ｄ）水溶性結合剤の含有量が錠剤１００重量部に対して１重量部以下であり、かつ
少なくとも（Ａ）薬物、（Ｂ）粒状ベース成分及びデンプン類を含む混合物を（Ｄ）水溶性結合剤を用いて造粒し、生成した造粒物と結晶セルロース及びデンプン類との混合物である製剤組成物。 A composition for producing an orally disintegrating tablet by tableting by attaching (E) a lubricant to a punch and / or mortar at a ratio of 0.5 parts by weight or less with respect to 100 parts by weight of a tablet. ,
(A) a drug, (B) an average particle size of 10 to 500 μm, and at least one granular base component selected from sugar, sugar alcohol and amino acid; (C) a swelling ratio upon absorption of water of 1.3 or less Containing a disintegrant, and (D) a water-soluble binder,
(C) the disintegrant comprises crystalline cellulose and starches;
(D) der than 1 part by weight per 100 parts by weight of the tablet content of the water-soluble binder is, and
At least (A) a drug, Ru mixture der of granules and crystalline cellulose and starch and granulated, the resulting with a mixture (D) a water-soluble binder comprising a (B) particulate base component and starches Formulation composition.
少なくとも（Ａ）薬物及び（Ｂ）粒状ベース成分を含む混合物を（Ｄ）水溶性結合剤の水溶液を用いて造粒し、生成した造粒物と（Ｃ）崩壊剤との混合物を、（Ｅ）滑沢剤を杵及び／又は臼に付着させて打錠する製造方法。 (A) a drug, (B) an average particle size of 10 to 500 μm, and containing at least one granular base component selected from sugar, sugar alcohol and amino acid, (C) crystalline cellulose and starch, A disintegrant having a swelling rate of 1.3 or less, and (D) a water-soluble binder, and (D) a composition having a water-soluble binder content of 1 part by weight or less based on 100 parts by weight of the tablet. , A method for producing an orally disintegrating tablet, wherein 0.5 parts by weight or less of (E) lubricant is attached to a punch and / or mortar for tableting with respect to 100 parts by weight of the tablet ,
A mixture containing at least (A) a drug and (B) a particulate base component is granulated using (D) an aqueous solution of a water-soluble binder, and a mixture of the resulting granulated product and (C) a disintegrant is (E ) A manufacturing method in which a lubricant is attached to a punch and / or mortar for tableting .
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| EP3744314A1 (en) * | 2019-05-31 | 2020-12-02 | Shin-Etsu Chemical Co., Ltd. | Method for producing tablet |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5733930B2 (en) * | 2009-09-09 | 2015-06-10 | 武田薬品工業株式会社 | Solid preparation |
| JP6037687B2 (en) * | 2011-07-08 | 2016-12-07 | サノフィ株式会社 | Orally disintegrating tablets containing glimepiride |
| JP6320107B2 (en) * | 2014-03-26 | 2018-05-09 | 杏林製薬株式会社 | Orally disintegrating tablets |
| JP7322475B2 (en) * | 2019-04-04 | 2023-08-08 | ニプロ株式会社 | Tablets containing azilsartan |
| WO2021095092A1 (en) * | 2019-11-11 | 2021-05-20 | 大塚製薬株式会社 | Orally disintegrating tablet |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11199517A (en) * | 1997-10-31 | 1999-07-27 | Meiji Seika Kaisha Ltd | Intraoral fast disintegrable tablet |
| EP1203580A4 (en) * | 1999-06-18 | 2004-06-30 | Takeda Chemical Industries Ltd | Quickly disintegrating solid preparations |
| JP2003034655A (en) * | 2001-05-15 | 2003-02-07 | Takeda Chem Ind Ltd | Fast degradable solid tablet |
| EP1552851A1 (en) * | 2002-06-10 | 2005-07-13 | Dainippon Pharmaceutical Co., Ltd. | Rapidly disintegrating tablet and process for producing the same |
| JP2006232680A (en) * | 2005-02-22 | 2006-09-07 | Kyoto Pharmaceutical Industries Ltd | Disintegrator for tablet and tablet using the same |
| JP5123517B2 (en) * | 2005-11-14 | 2013-01-23 | 帝人ファーマ株式会社 | Ambroxol oral disintegrating tablet |
| JP4963846B2 (en) * | 2006-03-03 | 2012-06-27 | エルメッド エーザイ株式会社 | Orally disintegrating tablet and method for producing the same |
| JP2008127320A (en) * | 2006-11-20 | 2008-06-05 | Zensei Yakuhin Kogyo Kk | Solid preparation quickly disintegrating in oral cavity |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3744314A1 (en) * | 2019-05-31 | 2020-12-02 | Shin-Etsu Chemical Co., Ltd. | Method for producing tablet |
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