JP2001163770A - Intraorally rapid disintegration tablet and method for producing the same - Google Patents
Intraorally rapid disintegration tablet and method for producing the sameInfo
- Publication number
- JP2001163770A JP2001163770A JP34890399A JP34890399A JP2001163770A JP 2001163770 A JP2001163770 A JP 2001163770A JP 34890399 A JP34890399 A JP 34890399A JP 34890399 A JP34890399 A JP 34890399A JP 2001163770 A JP2001163770 A JP 2001163770A
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- Japan
- Prior art keywords
- tablet
- saccharide
- disintegrant
- tableting
- tablet according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は特定の物理的形態に
より特徴づけられた医薬製剤に関し、より具体的には基
体が粉砕物と未粉砕物から形成される口腔内速崩壊型錠
剤及びそれらの製造方法に関する。TECHNICAL FIELD The present invention relates to a pharmaceutical preparation characterized by a specific physical form, and more specifically to a rapidly disintegrating tablet in the oral cavity in which a substrate is formed from a pulverized substance and an unpulverized substance. It relates to a manufacturing method.
【０００２】[0002]
【従来の技術】高齢化社会が急速に進む中、従来の医薬
品経口固形製剤、例えば錠剤、カプセル剤、顆粒剤、散
剤などでは服用する際に困難をきたすことがある。高齢
者の場合、嚥下能力の低下から錠剤及びカプセル剤の服
用はそれらの大きさに左右され、顆粒剤及び散剤に関し
ては、それらが口腔内に残留すると不快感が残ることに
なる。また、上記経口固形製剤は服用時に水を必要とす
ることから、服用の困難性により多量の水を要するケー
スも多い。高齢者ほど慢性疾患の羅患率が高くなるた
め、近年、長期投与の服用に適した、飲み易くかつ取り
扱い易い実用的な製剤の開発が望まれている。例えば、
口腔内速崩壊型錠剤、ペースト状製剤、ゼリー状製剤が
挙げられており、特に、口腔内速崩壊型錠剤は服用後口
腔内で速やかに崩壊または溶解するため、水なしでも場
所や時間を問わず適宜容易に服用でき、高齢者のみなら
ず小児などにも適した製剤とされている。2. Description of the Related Art As the aging society progresses rapidly, conventional oral solid pharmaceutical preparations such as tablets, capsules, granules and powders sometimes have difficulty in taking them. In the case of elderly people, taking tablets and capsules depends on their size due to a decrease in swallowing ability, and when granules and powder are left in the oral cavity, discomfort will remain. In addition, since the oral solid preparation requires water at the time of administration, it is often the case that a large amount of water is required due to difficulty in administration. Since the morbidity of chronic diseases increases with the age of the elderly, development of practical preparations suitable for long-term administration and easy to drink and handle has been desired in recent years. For example,
Oral rapidly disintegrating tablets, paste-like preparations and jelly-like preparations are mentioned.In particular, oral disintegrating tablets disintegrate or dissolve quickly in the oral cavity after ingestion. It can be easily taken as appropriate and is suitable for not only elderly people but also children.
【０００３】一般に、錠剤の崩壊性と硬度は互いに相反
する関係にあり、崩壊性を高めるには硬度を低下しなけ
ればならない。しかしながら、錠剤硬度は、製造、包装
及び流通過程、更には服用時の包装からの取り出しなど
において重要な要素となる。硬度が不十分な錠剤は、上
記各過程においてその形状を保持できず、更に用量の正
確な投与にも困難をきたすことなる。そのため、適度な
硬度及び速やかな崩壊性を有する口腔内速崩壊型錠剤の
製造技術の開発が望まれており、以下のような種々の手
段が提案されている。[0003] In general, the disintegration and hardness of a tablet are in an opposite relationship to each other, and the hardness must be reduced in order to increase the disintegration. However, tablet hardness is an important factor in the manufacturing, packaging and distribution processes, as well as in taking out from packaging when taking. A tablet having insufficient hardness cannot maintain its shape in the above-mentioned steps, and furthermore, it is difficult to accurately administer a dose. Therefore, it is desired to develop a technique for producing a rapidly disintegrating oral tablet having appropriate hardness and rapid disintegration, and the following various means have been proposed.
【０００４】例えば、口腔内速崩壊型錠剤として、薬効
成分をキャリアーとなるマトリックス中に溶解後凍結乾
燥して製造する錠剤が知られている（マニュファクチュ
アリングケミスト、Manuf. Chemist. Feb. 36-37（199
0)）。しかし、この製造方法では、凍結乾燥の製造設備
が必要であると共に製造に長時間を要するため製造コス
トが高くなる傾向がある。また、得られる錠剤は、汎用
包装材であるＰＴＰ（Press Through Package）包装か
ら押し出せない程硬度が低いため、容器裏面のシールを
剥がして錠剤を取り出す特殊な包装材が必要となる。製
造工程や包装材からの取り出し時に錠剤の崩れや割れが
生じ易く、取り扱い性は高齢者用として満足できるもの
ではない。For example, as an orally rapidly disintegrating tablet, a tablet produced by dissolving a pharmaceutically active ingredient in a matrix serving as a carrier and freeze-drying it is known (Manufacturing Chemist, Manuf. Chemist. Feb. 36-37). (199
0)). However, this manufacturing method requires a freeze-drying manufacturing facility and requires a long time for manufacturing, so that the manufacturing cost tends to be high. Further, the obtained tablet has such a low hardness that it cannot be extruded from a PTP (Press Through Package) package, which is a general-purpose packaging material. Therefore, a special packaging material for removing the tablet by peeling off the seal on the back surface of the container is required. Tablets are easily broken or cracked during the manufacturing process or when taken out of the packaging material, and the handleability is not satisfactory for elderly people.
【０００５】一方、湿式造粒物を圧縮成形して製造する
口腔内速崩壊型錠剤として、例えば、特開平５−２７１
０５４号公報には、薬効成分、糖類及びその粒子表面が
湿る程度の水分を含む造粒物を打錠して製造された錠剤
が記載されている。また、国際公開ＷＯ９５／２０３８
０号公報には、成形性の低い糖類及び成形性の高い糖類
を含有する造粒物を圧縮成形して製造された錠剤が記載
されている。これらの錠剤の製造方法には、生理学的に
許容される有機溶媒または水を噴霧し乾燥する湿式造粒
工程が採用されている。更に、特開平８−２９１０５１
号公報には、薬効成分、水溶性結合剤及び水溶性賦形剤
を含む造粒物を圧縮成形した後、追加の工程として、特
殊な装置による加湿及び乾燥工程を必要とする製造方法
が記載されている。また、国際公開ＷＯ９７／４７２８
７号公報には、薬効成分、平均粒子径３０μｍ以下の糖
類及び崩壊剤を含有する混合物を、造粒後圧縮成形する
口腔内速崩壊型錠剤の製造方法が記載されている。この
製造方法は、造粒工程前に糖類を粉砕処理し、配合され
る糖類の粒子径が前記のように３０μｍ以下に調整され
ることに特徴がある。なお、このような湿式造粒工程は
打錠する際の各成分の圧縮性を改善し錠剤硬度を高める
のに必要であるが、加湿や乾燥を伴うため水や熱に対し
て不安定な薬効成分が適応できないなどの問題を残して
いる。On the other hand, as a rapidly disintegrating intraoral tablet produced by compression-molding a wet granulated product, for example, JP-A-5-271
No. 054 describes a tablet produced by tableting a granulated product containing a pharmaceutically active ingredient, a saccharide, and water to such an extent that the particle surface becomes wet. In addition, International Publication WO95 / 2038
No. 0 describes a tablet produced by compression-molding a granule containing a saccharide having low moldability and a saccharide having high moldability. The method for producing these tablets employs a wet granulation step of spraying and drying a physiologically acceptable organic solvent or water. Further, Japanese Patent Application Laid-Open No. 8-291051
JP-A No. 7-1980 describes a manufacturing method that requires a humidification and drying step using a special device as an additional step after compression-molding a granulated substance containing a medicinal ingredient, a water-soluble binder and a water-soluble excipient. Have been. In addition, International Publication WO97 / 4728
No. 7 discloses a method for producing a rapidly disintegrating tablet in the oral cavity, which comprises granulating a mixture containing a medicinal ingredient, a saccharide having an average particle diameter of 30 μm or less, and a disintegrant, followed by granulation. This production method is characterized in that saccharides are pulverized before the granulation step, and the particle diameter of the saccharides to be blended is adjusted to 30 μm or less as described above. In addition, such a wet granulation process is necessary to improve the compressibility of each component at the time of tableting and to increase the tablet hardness, but it involves humidification and drying, and thus has an unstable drug effect against water and heat. The problem remains that the components cannot be adapted.
【０００６】更に、上記刊行物に開示された口腔内速崩
壊型錠剤が難水溶性薬効成分を含有する場合には、その
薬効成分の生体内への吸収率の向上を図るために、薬効
成分の溶出性を改善する何等かの工程を製造過程に含め
る必要がある。このような工程として、例えば、薬効成
分と製剤添加物の複合体形成、固体分散体や混合粉砕手
法による薬効成分粒子の微細化などが挙げられる。しか
し、いずれの手法を用いるにせよ、新たな工程を追加す
るため製造工程がより煩雑になる。Further, when the orally rapidly disintegrating tablet disclosed in the above publication contains a poorly water-soluble medicinal component, the medicinal component is required to improve the absorption rate of the medicinal component into the living body. It is necessary to include some steps in the production process for improving the dissolution property of the compound. Examples of such a step include formation of a complex of a medicinal ingredient and a pharmaceutical additive, miniaturization of medicinal ingredient particles by a solid dispersion or a mixing and pulverization technique, and the like. However, whichever method is used, the manufacturing process becomes more complicated because a new process is added.
【０００７】[0007]
【発明が解決しようとする課題】したがって、本発明の
目的は、適度な硬度及び口腔内での速やかな崩壊性を持
ち、しかも煩雑な工程を経ることなく簡便に得ることが
できる口腔内速崩壊型錠剤及びその製造方法を提供する
ことにある。SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a rapid intraoral disintegration which has an appropriate hardness and a quick disintegration property in the oral cavity, and which can be easily obtained without complicated steps. An object of the present invention is to provide a shaped tablet and a method for producing the same.
【０００８】[0008]
【課題を解決するための手段】本発明者らは、上記課題
を解決すべき鋭意検討した結果、錠剤の添加剤として常
用されている糖類及び崩壊剤を混合物とし、それらを共
粉砕して得られる微細化された粒子混合物（又は共粉砕
物）を未処理の糖類と組み合わせて使用すると、従来の
錠剤化に必須であった溶解、凍結、造粒、加湿、乾燥工
程を介することなく、直接打錠法により目的とする口腔
内速崩壊型錠剤が得られることを見出した。Means for Solving the Problems The present inventors have conducted intensive studies to solve the above problems, and as a result, obtained a mixture of sugars and disintegrants commonly used as additives for tablets, and co-crushing them. When the finely divided particle mixture (or co-ground product) is used in combination with an untreated saccharide, it can be directly used without the melting, freezing, granulating, humidifying, and drying steps, which are essential for conventional tableting. It has been found that the desired oral rapidly disintegrating tablet can be obtained by the tableting method.
【０００９】こうして本発明によれば、糖類及び崩壊剤
を含有する混合物の共粉砕物、並びに糖類の未粉砕物を
含んでなる打錠用末の圧縮成形物であり、かつ、適度な
硬度と速やかな崩壊性を有する口腔内速崩壊型錠剤、が
提供される。Thus, according to the present invention, there is provided a co-ground product of a mixture containing a saccharide and a disintegrant, and a compression-molded product of a tableting powder containing an unground material of a saccharide, and having an appropriate hardness and An oral rapidly disintegrating tablet having rapid disintegration is provided.
【００１０】また、本発明によれば、前記口腔内速崩壊
型錠剤の効率のよい製造方法であって、（Ａ）糖類及び
崩壊剤を含有する混合物を磨砕型粉砕機で共粉砕する工
程、（Ｂ）こうして得られた共粉砕物を糖類の未粉砕物
又は糖類及び崩壊剤の未粉砕物と物理混合して打錠用末
を形成する工程、（Ｃ）次いで該打錠用末を直接打錠法
にて圧縮成形する工程、を含んでなる製造方法が提供さ
れる。Further, according to the present invention, there is provided an efficient method for producing the rapidly disintegrating tablet in the oral cavity, wherein (A) a step of co-grinding a mixture containing a saccharide and a disintegrant with a grinding grinder. (B) a step of physically mixing the thus-obtained co-ground material with an unground material of saccharide or an unground material of saccharide and a disintegrant to form a tableting powder; Compression molding by a direct compression method.
【００１１】以下、本発明を詳細に説明する。本発明の
口腔内速崩壊型錠剤において、「適度な硬度」とは、具
体的に後述する通例の硬度試験で３ｋｇ以上、好ましく
は５ｋｇ以上となり、通常の製造工程及び流通過程で錠
剤の摩損による重量減少、欠け割れがほとんどない硬度
を意味する。更に、本発明の錠剤硬度が３ｋｇ以上であ
ることは、ＰＴＰ包装のみならず、ガラス、プラスチッ
クなどの容器に錠剤を封入したボトル容器にも適用可
能、すなわち、流通過程で生じる錠剤間または錠剤−容
器壁間の接触に十分耐えうると考えられる。また、「速
やかに崩壊」とは、健康な成人に経口投与される際に水
を服用することなく、唾液により口腔内において１分３
０秒以内、好ましくは１分以内、更に好ましくは４０秒
以内に錠剤全量が崩壊・分散する程度の崩壊性を意味す
る。なお、口腔内の乾いた或いは唾液の少ない人におい
ては、口腔内を濡らす程度の水を用いることにより本錠
剤を適用することができる。更に、本錠剤を通常の錠剤
と同様に水と共にそのまま服用しても何ら差し支えな
い。Hereinafter, the present invention will be described in detail. In the orally rapidly disintegrating tablet of the present invention, "appropriate hardness" is 3 kg or more, preferably 5 kg or more in a usual hardness test specifically described later, and is caused by attrition of the tablet in a normal production process and a distribution process. It means hardness with little weight loss and almost no cracks. Further, the tablet hardness of 3 kg or more of the present invention can be applied not only to PTP packaging but also to a bottle container in which a tablet is sealed in a glass or plastic container. It is believed that it can withstand contact between the container walls sufficiently. The term "rapidly disintegrates" refers to the fact that, when orally administered to a healthy adult, the patient does not take water and receives one minute 3
The disintegration means that the whole tablet disintegrates and disperses within 0 seconds, preferably within 1 minute, more preferably within 40 seconds. It should be noted that the present tablet can be applied to a person who has a dry or low saliva in the oral cavity by using water enough to wet the oral cavity. Furthermore, the present tablet can be taken with water as it is, similarly to a normal tablet.
【００１２】本発明において、主賦形剤として使用する
糖類とは、医薬製剤の技術分野で使用されうる単糖及び
二糖、並びにそれらの糖アルコールを意味する。これら
の具体的なものとしては、マンニトール、エリスリトー
ル、キシリトール、乳糖及びグルコース、更に、マルト
ース、ソルビトース、トレハロース、ショ糖及び果糖な
どを挙げることができる。これらは単独でも２種以上組
み合わせても用いることができる。前者のマンニトー
ル、エリスリトール、キシリトール、乳糖などが好まし
いが特に、マンニトールは、適度な甘味と冷涼感がある
こと、吸湿性が小さいこと、適度な硬度及び速やかな崩
壊性が得やすいことから、嗜好性、安定性及び製造性の
面で有利である。上記各公報に開示された口腔内速崩壊
型錠剤において、マンニトールのような成形性の低い糖
類を使用する場合、例えば、成形性の低い糖類に成形性
の高い糖類を添加して造粒（国際公開ＷＯ９５／２０３
８０号公報参照）、或いは錠剤中に含まれる成形性の低
い糖類の全量を粉砕した後に崩壊剤を添加して造粒（国
際公開ＷＯ９７／４７２８７号公報参照）することによ
り、打錠工程での圧縮成形性を高める手法が記載されて
いる。しかし、本発明においては、成形性の低い糖類で
も未粉砕の状態で錠剤中に８０重量％程度含むことがで
きること、加湿や乾燥を伴う湿式造粒工程を必要としな
いことなどの特徴を有している。In the present invention, the saccharide used as the main excipient means monosaccharides and disaccharides which can be used in the technical field of pharmaceutical preparations, and their sugar alcohols. Specific examples thereof include mannitol, erythritol, xylitol, lactose and glucose, as well as maltose, sorbitol, trehalose, sucrose and fructose. These can be used alone or in combination of two or more. The former is preferably mannitol, erythritol, xylitol, lactose, etc., and in particular, mannitol has good sweetness and coolness, low hygroscopicity, moderate hardness and quick disintegration, and thus palatability. , Stability and manufacturability. When a saccharide having low moldability such as mannitol is used in the orally rapidly disintegrating tablets disclosed in the above publications, for example, a saccharide having low moldability is added to a saccharide having high moldability to granulate (International Published WO95 / 203
No. 80) or a tablet obtained by pulverizing the entire amount of saccharides having low moldability contained in a tablet and then adding a disintegrant to granulate (see WO 97/47287). A technique for improving the compression moldability is described. However, the present invention has such features that even a sugar having low formability can be contained in a tablet in an uncrushed state at about 80% by weight, and a wet granulation step involving humidification and drying is not required. ing.
【００１３】一般に、錠剤硬度を高めるには、水溶性結
合剤として、例えば、ポリビニルピロリドン、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、ポリ
ビニルアルコールなどが使用されているが、通常の圧縮
成形過程で得られる錠剤は速やかな崩壊性を示さない。
本発明では、このような水溶性結合剤を使用せずに、糖
類と崩壊剤の共粉砕物を適量添加するため、造粒工程を
必要としない簡便な直接打錠法により、適度な硬度を有
しかつ口腔内で速やかに崩壊する錠剤を成形することが
できる。理論により拘束されるものでないが、本発明の
錠剤にしたがえば、特定の粉砕方法により微粉細化され
た糖類及び崩壊剤の粒子又は粉末を、これらの粒子に比
しかなり大きな未粉砕糖類粒子等に添加して使用するこ
とで、各粒子間又は粉末間の接触面積が有意に増大し、
そのため、これらの粒子の混合物を圧縮成形するだけ
で、一定の硬度を有するが、他方、水溶性高分子等の結
合剤を実質的に利用しないので、速やかな崩壊性を示す
ものと考えられる。In general, in order to increase tablet hardness, for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol and the like are used as a water-soluble binder. Does not show any disintegration.
In the present invention, without using such a water-soluble binder, in order to add an appropriate amount of a co-ground product of a saccharide and a disintegrant, a suitable hardness by a simple direct compression method that does not require a granulation step. Tablets that have and rapidly disintegrate in the mouth can be formed. Without being bound by theory, according to the tablets of the present invention, the particles or powder of the saccharide and disintegrant finely divided by a particular pulverizing method may be unmilled saccharide particles considerably larger than these particles. Etc., the contact area between each particle or powder significantly increases,
For this reason, it is considered that although a mixture of these particles is merely subjected to compression molding, it has a certain hardness, but on the other hand, it does not substantially use a binder such as a water-soluble polymer, so that it exhibits rapid disintegration.
【００１４】このような作用を奏するために、前述の糖
類と組み合わせて使用できる崩壊剤としては、例えば、
クロスポビドン、クロスカルメロースナトリウム、低置
換度ヒドロキシプロピルセルロース、カルボキシメチル
澱粉ナトリウム、部分α化澱粉などが挙げられ、これら
は単独でも２種以上組み合わせても用いることができ
る。このような崩壊剤の中では、クロスポビドン及び低
置換度ヒドロキシプロピルセルロースが、所望の錠剤の
硬度及び崩壊性を達成する上で好ましい。[0014] Disintegrants which can be used in combination with the above-mentioned saccharides to exhibit such effects include, for example,
Examples include crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, partially pregelatinized starch, and the like, and these can be used alone or in combination of two or more. Among such disintegrants, crospovidone and low substituted hydroxypropylcellulose are preferred for achieving the desired tablet hardness and disintegration properties.
【００１５】本発明の主たる特徴の一つは、糖類及び崩
壊剤を含有する混合物の共粉砕物を使用することにあ
る。共粉砕物とは、糖類と崩壊剤とが混合物として一緒
に粉砕にかけられたものであることを意味する。したが
って、詳細には後述するが、糖類と崩壊剤を個別に粉砕
して得た混合物より本発明にしたがう共粉砕物では、一
方が他方の粉砕助剤として作用することが予測されるた
め微細化が一層促進されるものと考えられる。One of the main features of the present invention is to use a co-milled mixture of a saccharide and a disintegrant. Co-ground means that the saccharide and the disintegrant are ground together as a mixture. Therefore, as will be described in detail later, in a co-ground product according to the present invention from a mixture obtained by separately grinding a saccharide and a disintegrant, one is expected to act as the other grinding aid, so Is thought to be further promoted.
【００１６】このような共粉砕物を提供するための糖類
と崩壊剤の使用割合は、本発明の目的に沿う限り如何な
る割合であってもよいが、一般的に、糖類対崩壊剤は、
重量比で、３：１〜１９：１の範囲に設定するのが好ま
しい。The ratio of the saccharide and the disintegrant used to provide such a co-ground product may be any ratio as long as it is in accordance with the purpose of the present invention.
The weight ratio is preferably set in the range of 3: 1 to 19: 1.
【００１７】本発明にしたがう錠剤では、上記共粉砕物
以外の材料として、前記糖類の未粉砕物又は糖類の未粉
砕物及び崩壊剤の未粉砕物を含んでなり、これらの材料
が打錠用末を形成し圧縮成形されている。また、本発明
の錠剤は、上述の適度な硬度と速やかな崩壊性を有する
圧縮成形物であることも要件である。以上のような要件
を具備するには、共粉砕物は、錠剤総重量当たり２０〜
５０重量％を占めることが好ましい。２０重量％未満で
は、適度な硬度を達成することが困難である場合が多
く、また５０重量％を超えると速やかな崩壊性が損なわ
れる場合がある。The tablet according to the present invention comprises, as materials other than the above-mentioned co-ground material, the above-mentioned unground material of the saccharide or the unground material of the saccharide and the non-ground material of the disintegrant. The powder is formed and compression molded. Further, the tablet of the present invention is also required to be a compression-molded product having the above-described appropriate hardness and rapid disintegration. In order to satisfy the above requirements, the co-ground product should be 20 to
It preferably accounts for 50% by weight. If it is less than 20% by weight, it is often difficult to achieve an appropriate hardness, and if it exceeds 50% by weight, rapid disintegration may be impaired.
【００１８】通常、上記打錠用末２００ｍｇを、直径
（φ）８ｍｍの杵を用い、単発打錠機にて打錠圧１００
０ｋｇで打錠したとき、硬度３ｋｇ以上を有し、かつ口
腔内で1分３０秒以内に崩壊する錠剤を得ることができ
る。上記のような共粉砕の使用に加え、上記崩壊剤は、
一般的に粒子間の結合を促進する効果をある程度有して
いるため、その配合量によって錠剤の速崩壊性を維持し
つつ錠剤硬度を高めることに寄与する場合もある。しか
し、マンニトールのような成形性の低い糖類の一部を共
粉砕物の形態で使用しない場合には、圧縮成形物に適度
な硬度を保持するために上記崩壊剤を多量に含める必要
がある。しかしこうして製造される錠剤は、服用時に口
腔内における崩壊剤の残留による不快感が残る可能性が
高く、水なしで服用容易な口腔内速崩壊型錠剤を提供す
ることができない。なお、マンニトールと崩壊剤の共粉
砕物を使用する代わりに、マンニトール及び崩壊剤の各
単味粉砕物を混合し、次いでマンニトールの未粉砕物或
いはマンニトール及び崩壊剤の未粉砕物に添加しても、
適度な硬度を有する圧縮成形物を得ることは極めて困難
であった。Normally, a tableting pressure of 100 mg was applied to a tableting powder of 200 mg by a single-shot tableting machine using a punch having a diameter (φ) of 8 mm.
When the tablet is compressed at 0 kg, a tablet having a hardness of 3 kg or more and disintegrating in the oral cavity within 1 minute and 30 seconds can be obtained. In addition to using co-milling as described above, the disintegrant is
In general, the compound has an effect of promoting the bonding between particles to some extent, and depending on the compounding amount, may contribute to increasing the tablet hardness while maintaining the quick disintegration property of the tablet. However, when a part of the saccharide having low formability such as mannitol is not used in the form of a co-ground product, it is necessary to include a large amount of the above-mentioned disintegrant in order to maintain an appropriate hardness in the compression-formed product. However, the tablets produced in this manner are likely to cause discomfort due to the residual disintegrant in the oral cavity when ingested, and cannot provide a rapidly disintegrating oral tablet without water. Incidentally, instead of using the co-ground material of mannitol and disintegrant, each plain crushed material of mannitol and disintegrant may be mixed and then added to the unground material of mannitol or the unground material of mannitol and disintegrant. ,
It was extremely difficult to obtain a compression-molded product having an appropriate hardness.
【００１９】本発明において用いられる薬効成分は、経
口で摂取できるいかなる医薬成分も含むことができ、水
溶性のみならず難水溶性薬効成分も使用することができ
る。更に、苦味のないか少ないものが好ましいが、苦味
を有するものでも使用できる。このような薬効成分とし
て、睡眠鎮静薬、例えば、エスタゾラム、ニトラゼパ
ム、フェノバルビタールナトリウムなど、抗不安薬、例
えば、ジアゼパム、クロルジアゼポキシドなど、向精神
病薬、例えば、リスペリドン、ピモジド、クロルプロマ
ジンなど、抗パーキンソン薬、例えば、レボドパ、塩酸
アマンタジンなど、解熱鎮痛消炎薬、例えば、アセトア
ミノフェン、イブプロフェン、インドメタシンなど、抗
ヒスタミン薬、例えば、塩酸ジフェンヒドラミン、マレ
イン酸クロルフェニラミン、塩酸ホモクロルシクリジン
など、血圧降下薬、例えば、ニフェジピン、ベシル酸ア
ムロジピン、塩酸デラプリルなど、高脂血症用薬、例え
ば、クリノフィブラート、ニコモールなど、糖尿病用
薬、例えば、トルブタミド、グリクロピラジドなど、気
管支拡張薬、例えば、テオフィリン、塩酸ピルブテロー
ルなど、骨格筋弛緩薬、例えば、メトカルバモール、ク
ロルゾキサゾンなど、抗真菌薬、例えば、イトラコナゾ
ール、フルコナゾールなど、抗生物質、例えば、セファ
レキシン、エリスロマイシンなど、消化性潰瘍用薬、例
えば、シメチジン、ファモチジンなど、消化管運動賦活
薬、例えば、シサプリド、塩酸イトプリドなど、ビタミ
ン、例えば、アスコルビン酸、塩酸ピリドキシンなどが
挙げられる。これらの薬効成分は、１種または２種以上
を組み合わせて含むことができる。The medicinal component used in the present invention may include any medicinal component that can be taken orally, and not only water-soluble but also poorly water-soluble medicinal components can be used. Further, those having no or little bitterness are preferred, but those having bitterness can also be used. As such medicinal ingredients, sleep sedatives, for example, estazolam, nitrazepam, phenobarbital sodium and the like, anxiolytics, for example, diazepam, chlordiazepoxide and the like, psychotropic drugs, for example, risperidone, pimozide, chlorpromazine and the like, antiparkinson drugs, For example, levodopa, amantadine hydrochloride, etc., antipyretic analgesic and anti-inflammatory drugs, for example, acetaminophen, ibuprofen, indomethacin, etc., antihistamines, for example, diphenhydramine hydrochloride, chlorpheniramine maleate, homochlorcyclidine hydrochloride, blood pressure lowering drugs, For example, nifedipine, amlodipine besylate, delapril hydrochloride, etc., drugs for hyperlipidemia, for example, clinofibrate, nicomol, etc., drugs for diabetes, for example, tolbutamide, glyclopyrazide, etc. Bronchodilators, for example, theophylline, pyrbuterol hydrochloride, etc., skeletal muscle relaxants, for example, metcarbamol, chlorzoxazone, etc., antifungals, for example, itraconazole, fluconazole, etc., antibiotics, for example, cephalexin, erythromycin, etc. Ulcer drugs, for example, cimetidine, famotidine and the like, gastrointestinal motility stimulants, for example, cisapride and itopride hydrochloride, vitamins, for example, ascorbic acid, pyridoxine hydrochloride and the like. These active ingredients can be used alone or in combination of two or more.
【００２０】上記薬効成分は、糖類と崩壊剤の混合物の
共粉砕工程中、或いはその共粉砕物と糖類の未粉砕物な
どの打錠用末中に添加することができる。なお、薬効成
分が難水溶性の場合は、錠剤からの薬効成分の溶出性を
高めて投与後の生体内吸収率を改善するために、糖類と
崩壊剤の混合物中に薬効成分を含めた後、粉砕工程にか
けて薬効成分粒子を微細化することが好ましい。本発明
において、「難水溶性薬効成分」とは、水への溶解度が
約０．１ｍｇ／ｍｌ以下で、比較的安定な結晶性を有す
る薬効成分を意味する。なお、本発明の錠剤において、
最終製品である錠剤中の薬効成分の含有量は、薬効成分
の種類などによって異なるが、通常０．０５〜６０重量
％、好ましくは０．５〜３０重量％程度である。ただ
し、薬効成分が水溶性かつその配合率が錠剤中の１０重
量％以上となる場合は、共粉砕物と糖類の未粉砕物など
の物理混合物中に添加し、打錠用末とするのが好まし
い。The above-mentioned medicinal component can be added during the step of co-grinding the mixture of the saccharide and the disintegrant, or into the powder for tableting such as the unground material of the co-ground and the saccharide. When the medicinal component is poorly water-soluble, after the medicinal component is included in the mixture of the saccharide and the disintegrant in order to enhance the dissolution of the medicinal component from the tablet and improve the in vivo absorption rate after administration. It is preferable to pulverize the medicinal component particles through a pulverizing step. In the present invention, the “poorly water-soluble medicinal ingredient” means a medicinal ingredient having a relatively stable crystallinity with a solubility in water of about 0.1 mg / ml or less. In the tablet of the present invention,
The content of the medicinal component in the tablet as the final product varies depending on the kind of the medicinal component and the like, but is usually about 0.05 to 60% by weight, preferably about 0.5 to 30% by weight. However, when the medicinal component is water-soluble and its compounding ratio is 10% by weight or more in the tablet, it is necessary to add it to a physical mixture such as a co-ground material and an unground material of saccharides to obtain a tableting powder. preferable.
【００２１】打錠用末は、本発明の効果に悪影響を及ぼ
さない限り、錠剤の製造に一般に用いられる種々の添加
剤を含むことができる。ただし、本発明では先に述べた
共粉砕物の使用により錠剤硬度を高めていると考えられ
ることから、一般に知られている結合剤は必ずしも使用
する必要はない。結合剤以外の添加剤としては、酸味
料、例えば、クエン酸、酒石酸、リンゴ酸など、発泡
剤、例えば、重曹、炭酸ナトリウムなど、人工甘味料、
例えば、アスパルテーム、サッカリンナトリウム、ステ
ビアなど、香料、例えば、レモン、オレンジ、メントー
ルなど、滑沢剤、例えば、ステアリン酸マグネシウム、
ショ糖脂肪酸エステル、タルクなど、着色剤、例えば、
食用黄色５号、食用赤色２号及び食用青色２号などの食
用色素、食用レーキ色素、酸化鉄など、を挙げることが
できる。これらの添加剤は、１種または２種以上を組み
合わせて使用することができ、糖類と崩壊剤の混合の共
粉砕工程中、或いはその共粉砕物と糖類の未粉砕物など
の物理混合工程中で、適宜適量添加することができる。The tableting powder may contain various additives generally used in tablet production as long as the effects of the present invention are not adversely affected. However, in the present invention, since it is considered that the tablet hardness is increased by using the co-ground product described above, it is not always necessary to use a generally known binder. Additives other than binders include acidulants, for example, citric acid, tartaric acid, malic acid, etc., foaming agents, for example, sodium bicarbonate, sodium carbonate, etc., artificial sweeteners,
For example, aspartame, saccharin sodium, stevia and the like, fragrances such as lemon, orange, menthol and the like, lubricants such as magnesium stearate,
Coloring agents such as sucrose fatty acid esters and talc, for example,
Food dyes such as Food Yellow No. 5, Food Red No. 2 and Food Blue No. 2, edible lake dyes, iron oxide and the like can be mentioned. These additives can be used alone or in combination of two or more. During the co-milling step of mixing the saccharide and the disintegrant, or during the physical mixing step of the co-milled product and the unmilled saccharide, etc. And an appropriate amount can be appropriately added.
【００２２】次に、本発明の製造方法について詳述す
る。本発明の製造方法においては、まず、上記主賦形剤
である糖類の一部に上記崩壊剤を添加した後、粉砕する
ことで糖類と崩壊剤の混合物の共粉砕物を調製する。そ
の際、必要に応じて薬効成分及びその他の添加剤を同時
に添加して共粉砕物を調製してもよい。特に、難水溶性
薬効成分の場合は、この混合物の共粉砕工程に添加する
ことにより薬効成分粒子の微細化が可能であり、製造工
程を変更または追加することなく難水溶性薬効成分の溶
出性を容易に改善することができる。このことは、例え
ば、難水溶性薬効成分を糖類などの低分子量水溶性賦形
剤と共粉砕すると、薬効成分の物理化学的特性、例え
ば、結晶形などを変えることなく、容易に１〜数μｍ、
場合によっては１μｍ以下まで微細化できることが公知
であることからも理解できるであろう（粉体と工業、2
4、53-59（1992）参照）。また、難水溶性薬効成分を上
記崩壊剤であるクロスポビドンと共粉砕すると、薬効成
分の溶出性が改善されることも公知である（コリド
ンR、KollidonR、第２版、BASF、pp.171-173（199
3））。これらの事実から、本発明の共粉砕物中に存在
しうる糖類、崩壊剤及び薬効成分が効率よく微細化され
ていることが理解できるであろう。Next, the production method of the present invention will be described in detail. In the production method of the present invention, first, the disintegrant is added to a part of the saccharide as the main excipient, and then the mixture is pulverized to prepare a co-ground product of a mixture of the saccharide and the disintegrant. At that time, if necessary, a medicinal ingredient and other additives may be simultaneously added to prepare a co-ground product. Particularly, in the case of a poorly water-soluble medicinal ingredient, it is possible to make the medicinal ingredient particles finer by adding the mixture to the co-grinding step, and to dissolve the poorly water-soluble medicinal ingredient without changing or adding a manufacturing process. Can be easily improved. This means that, for example, when a poorly water-soluble medicinal ingredient is co-ground with a low molecular weight water-soluble excipient such as a saccharide, the physicochemical properties of the medicinal ingredient, for example, without changing the crystal form, can easily be one to several. μm,
In some cases, it can be understood from the fact that it is known that the particle size can be reduced to 1 μm or less (powder and industrial, 2
4 , 53-59 (1992)). It is also known that when a poorly water-soluble medicinal ingredient is co-ground with the above-mentioned disintegrant crospovidone, the dissolution property of the medicinal ingredient is improved (Kollidon R , Kollidon R , 2nd edition, BASF, pp. 171). -173 (199
3)). From these facts, it can be understood that the saccharides, disintegrants and medicinal components that can be present in the co-ground product of the present invention are efficiently miniaturized.
【００２３】上記混合物の粉砕工程は、従来から慣用さ
れている水を使用しない乾式粉砕法であるが、好ましく
用いることができる粉砕機は磨砕型、例えば、乳鉢、ボ
ールミル、ロッドミル、振動ボールミル、振動ロッドミ
ルなどである。具体的には、例えば、共粉砕物中に糖類
と崩壊剤が重量比で３：１〜１９：１になるように振動
ロッドミル内に仕込み、使用する機種及び仕込み量、量
比などによって異なるが、５分以上、好ましくは５〜２
０分間粉砕する。薬効成分及びその他の添加剤を必要量
添加して同時に粉砕する場合も同様である。ただし、難
水溶性薬効成分を添加する際には、錠剤からの薬効成分
の所期の溶出性が達成されるように、仕込量及び粉砕時
間を設定する必要がある。製造温度は、一般に室温（２
０〜３０℃程度）でよく、特に調整する必要はないが、
湿度に関しては、粉砕過程での種類などの吸湿を考慮し
て、相対湿度を６０％以下とすることが製造上好まし
い。また、衝突型の粉砕機、例えば、ハンマーミル、ジ
ェットミルなどでは、一般に十分に粉砕することができ
ず、適度な硬度に劣る錠剤しか得られない場合が多く、
難水溶性薬効成分の溶出性を改善する目的上、このよう
な粉砕機の使用は避ける方がよい。The above-mentioned pulverizing step of the mixture is a dry pulverization method which does not use water, which has been conventionally used, and a pulverizer which can be preferably used is a pulverizing type such as a mortar, a ball mill, a rod mill, a vibrating ball mill, and the like. Vibrating rod mill and the like. Specifically, for example, the saccharide and the disintegrant are charged into the vibrating rod mill such that the weight ratio of the saccharide and the disintegrant is 3: 1 to 19: 1 in the co-ground product, and it differs depending on the model used, the charged amount, the amount ratio, and the like. 5 minutes or more, preferably 5 to 2
Mill for 0 minutes. The same applies to the case where necessary amounts of a medicinal ingredient and other additives are added and pulverized at the same time. However, when adding a poorly water-soluble medicinal ingredient, it is necessary to set the charge amount and the pulverization time so that the desired elution of the medicinal ingredient from the tablet is achieved. The production temperature is generally room temperature (2
0-30 ° C.), and there is no particular need to adjust,
With respect to humidity, it is preferable in terms of manufacturing that the relative humidity be 60% or less in consideration of moisture absorption such as types in the pulverization process. In addition, collision-type pulverizers, for example, a hammer mill, a jet mill, etc., generally cannot be sufficiently pulverized, and often only tablets having a moderate hardness are obtained.
It is better to avoid using such a crusher for the purpose of improving the dissolution of poorly water-soluble medicinal components.
【００２４】次に、上記粉砕工程で得られた共粉砕物
を、糖類の未粉砕物又は糖類の未粉砕物及び崩壊剤の未
粉砕物と物理混合し、打錠用末とする。その際、必要に
応じて薬効成分及びその他の添加剤を同時に添加し、打
錠用末を調製することができる。この混合工程では、通
常の物理混合に用いられる、ビニール袋、Ｖ型混合機な
どが使用されるが、これらの手段に限定されない。ただ
し、混合回数または時間は、打錠用末における薬効成分
の均一性を保持し、圧縮成形時の打錠障害（例えば、ス
ティッキング）を防止するために必要に応じて配合され
た滑沢剤の効果などを勘定して設定する。なお、打錠用
末の流動性が低い場合には、打錠工程で得られる錠剤の
硬度及び崩壊性に対して悪影響を及ぼさない限り、この
混合工程に用いられる上記主賦形剤である糖類の一部を
予め適当な方法により造粒しておいてもよい。Next, the co-ground product obtained in the above-mentioned grinding step is physically mixed with an unground material of saccharide or an unground material of saccharide and a non-ground material of a disintegrant to obtain a tableting powder. At that time, if necessary, a medicinal ingredient and other additives can be added simultaneously to prepare a tableting powder. In this mixing step, a plastic bag, a V-type mixer, or the like used for ordinary physical mixing is used, but is not limited to these means. However, the number of times or the time of mixing may be determined by the amount of the lubricant compounded as necessary to maintain the uniformity of the medicinal component in the powder for tableting and prevent tableting trouble during compression molding (for example, sticking). Set the effects and so on. In addition, when the fluidity of the tableting powder is low, the saccharide as the main excipient used in the mixing step is used as long as it does not adversely affect the hardness and disintegration of the tablet obtained in the tableting step. May be previously granulated by an appropriate method.
【００２５】打錠工程では、一般に粉末の圧縮成形に常
用されている打錠機、例えば、単発打錠機或いはロータ
リー式打錠機を使用することができる。打錠圧は、例え
ば、打錠用末２００ｍｇを、直径（φ）８ｍｍの杵及び
単発打錠機を用いて打錠する場合、通常、２００〜１５
００ｋｇ、好ましくは５００〜１０００ｋｇ程度に設定
する。打錠時の温度は、通常室温（２０〜３０℃程度）
でよく、特に調整する必要はない。本発明の口腔内速崩
壊型錠剤は適度な硬度を有しているため、円形、楕円
形、カプセル形などの所望される形状に加工することが
できる。このような錠剤の直径或いは長径は、通常６〜
１５ｍｍであり、その重量は、通常、８０ｍｇから１０
００ｍｇとなるが、これに限定されるものではない。ま
た、錠剤に分割するための割線を刻んだ分割錠とするこ
とも可能であり、半錠投与が多く望まれる高齢者医療に
おいて特に有用である。更に、これらの錠剤は、その硬
度及び崩壊性に悪影響を及ぼさない程度に、一般に被覆
製剤の製造で用いられるコーティング方法にて被覆され
ていてもよい。In the tableting step, a tableting machine generally used for powder compression molding, for example, a single-shot tableting machine or a rotary tableting machine can be used. The tableting pressure is typically, for example, 200 to 15 when tableting 200 mg of tableting powder using a punch having a diameter (φ) of 8 mm and a single-shot tableting machine.
00 kg, preferably about 500 to 1000 kg. The temperature during tableting is usually room temperature (about 20 to 30 ° C)
No special adjustment is required. Since the orally rapidly disintegrating tablet of the present invention has an appropriate hardness, it can be processed into a desired shape such as a circle, an ellipse, and a capsule. The diameter or major axis of such tablets is usually 6 to
15 mm and weighs typically 80 mg to 10
00 mg, but not limited to this. In addition, it is also possible to use a divided tablet in which a score line for dividing the tablet is cut, and this is particularly useful in medical treatment for the elderly, in which half tablet administration is desired. Further, these tablets may be coated by a coating method generally used in the production of a coated preparation to the extent that the hardness and disintegration are not adversely affected.
【００２６】本発明の口腔内速崩壊型錠剤は、適度な硬
度及び口腔内での速やかな崩壊性を有しているため、飲
み易くかつ取り扱いが容易である。したがって、含有す
る薬効成分に応じて適用される患者、特に高齢者の長期
投与の服用に適しており、また、小児患者の予防や治療
にも用いることができる。The intraorally rapidly disintegrating tablet of the present invention has an appropriate hardness and a rapid disintegration property in the oral cavity, so that it is easy to drink and easy to handle. Therefore, it is suitable for long-term administration to patients, particularly the elderly, which is applied according to the contained medicinal component, and can also be used for prevention and treatment of pediatric patients.
【００２７】本発明の製造方法によれば、汎用の粉砕
機、混合機、打錠機を使用できるため従来の製造装置が
そのまま利用できる。更に、薬効成分の溶解特性により
製造工程を変更または追加する必要もない。したがっ
て、本発明の製造方法は、煩雑な工程を経ることなく製
造工程が極めて簡便であり、製造コスト、製造時間など
の面から、従来の口腔内速崩壊型錠剤の製造方法に比較
して有利である。According to the production method of the present invention, a general-purpose pulverizer, mixer and tableting machine can be used, so that a conventional production apparatus can be used as it is. Further, there is no need to change or add a manufacturing process depending on the solubility characteristics of the medicinal ingredient. Therefore, the production method of the present invention is extremely simple in the production process without complicated steps, and is advantageous in terms of production cost, production time, etc. as compared with the conventional method for producing a rapidly disintegrating tablet in the oral cavity. It is.
【００２８】[0028]
【実施例】以下、実施例、比較例及び評価試験を挙げて
本発明を詳述するが、これらは本発明を限定することを
意図するものではない。EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples, Comparative Examples, and Evaluation Tests, but these are not intended to limit the present invention.
【００２９】評価試験は以下の方法で行った。 （１）硬度測定 錠剤の直径方向の破壊強度を錠剤硬度計（ＴＢＨ２８、
エルウェカ社製）にて測定した。測定は３回行われ、結
果は３回の平均値を表す。 （２）厚み測定 錠剤の厚みをマイクロメーター（ＳＭ−５２８、テック
ロック社製）にて測定した。測定は３回行われ、結果は
３回の平均値を表す。 （３）口腔内崩壊試験 健康な成人男子の口腔内に水なしで本発明の口腔内速崩
壊型錠剤を含ませ、錠剤が口腔内の唾液のみで完全に崩
壊・分散するまでの時間を測定した。試験は３人で行わ
れ、結果は３人の平均値を表す。 （４）溶出試験 溶出試験器（ＮＴＲ−ＶＳ３、富山産業社製）にて、薬
効成分５ｍｇ或いはそれを含む錠剤を３７℃の水９００
ｍｌに投入し、パドルを５０ｒｐｍで回転させながら、
経時的に溶出液を採取した。採取した溶出液を細孔径
０．２μｍのフィルターで濾過し、その濾液を適宜希釈
した後、分光光度計（ＵＶ−２２００Ａ、島津製作所社
製）を用い、２３６ｎｍにて吸光度を測定法することに
より薬効成分の溶出率を求めた。試験は３回行われ、結
果は３回の平均値を表す。The evaluation test was performed by the following method. (1) Hardness measurement The breaking strength in the diameter direction of the tablet was measured using a tablet hardness tester (TBH28,
Elweca). The measurements were performed three times and the results represent the average of the three measurements. (2) Thickness measurement The thickness of the tablets was measured with a micrometer (SM-528, manufactured by Tech Rock Co., Ltd.). The measurements were performed three times and the results represent the average of the three measurements. (3) Oral disintegration test The oral disintegrating tablet of the present invention is contained in the mouth of a healthy adult male without water, and the time required for the tablet to completely disintegrate and disperse with only saliva in the oral cavity is measured. did. The test was performed on three people and the results represent the average of three people. (4) Dissolution test In a dissolution tester (NTR-VS3, manufactured by Toyama Sangyo Co., Ltd.), 5 mg of a pharmaceutically active ingredient or a tablet containing the same was added to water 900 at 37 ° C.
ml, and while rotating the paddle at 50 rpm,
The eluate was collected over time. The collected eluate was filtered through a filter having a pore size of 0.2 μm, and the filtrate was appropriately diluted, followed by measuring the absorbance at 236 nm using a spectrophotometer (UV-2200A, manufactured by Shimadzu Corporation). The elution rate of the medicinal component was determined. The test was performed three times and the results represent the average of the three.
【００３０】以下、錠剤の例及び比較試験結果を示す。The following are examples of tablets and comparative test results.
【００３１】実施例１〜３ マンニトール３．６ｇ（東和化成社製）及びクロスポビ
ドン０．４ｇ（ＩＳＰテクノロジー社製）を含む２成分
粉末を、振動ロッドミル（ＴＩ−１００、ＣＭＴ社製）
を用いて２０分間粉砕して共粉砕物とした。この共粉砕
物３ｇに未粉砕物のマンニトール６．９５ｇ及びステア
リン酸マグネシウム０．０５ｇ（堺化学工業社製）を添
加し、ビニール袋内で１００回よく混合して打錠用末を
調製した。その後、単発打錠機（Ｊ４、井内盛栄堂）に
て、直径（φ）８ｍｍの隅角平型の打錠用杵を用い、錠
剤重量２００ｍｇ、打錠圧１０００ｋｇで打錠して実施
例１の錠剤を得た。また、共粉砕物３ｇに未粉砕物のマ
ンニトール６．７５ｇ、クロスポビドン０．２ｇ及びス
テアリン酸マグネシウム０．０５ｇを添加した後、同様
に打錠して実施例２の錠剤を得た。更に、共粉砕物３ｇ
に未粉砕物のマンニトール６．５５ｇ、クロスポビドン
０．４ｇ及びステアリン酸マグネシウム０．０５ｇを添
加した後、同様に打錠して実施例３の錠剤を得た。Examples 1 to 3 A two-component powder containing 3.6 g of mannitol (manufactured by Towa Kasei Co., Ltd.) and 0.4 g of crospovidone (manufactured by ISP Technology Co., Ltd.) was mixed with a vibrating rod mill (TI-100, manufactured by CMT).
For 20 minutes to obtain a co-ground product. 6.95 g of unmilled mannitol and 0.05 g of magnesium stearate (manufactured by Sakai Chemical Industry Co., Ltd.) were added to 3 g of the co-milled product and mixed well in a plastic bag 100 times to prepare a tableting powder. Then, using a single-shot tableting machine (J4, Iuchi Seikeido), the tablet was pressed at a tablet weight of 200 mg and a tableting pressure of 1000 kg using a flat-tablet punch having a diameter (φ) of 8 mm and a tableting pressure of 1000 kg. Tablets were obtained. Further, 6.75 g of unmilled mannitol, 0.2 g of crospovidone and 0.05 g of magnesium stearate were added to 3 g of the co-milled product, and the mixture was compressed in the same manner to obtain a tablet of Example 2. Furthermore, 3g of co-ground product
6.55 g of unmilled mannitol, 0.4 g of crospovidone and 0.05 g of magnesium stearate were added to the mixture, and the mixture was compressed in the same manner to obtain a tablet of Example 3.
【００３２】実施例１〜３の成分組成及び錠剤の評価試
験結果を表１に示す。Table 1 shows the component compositions of Examples 1 to 3 and the evaluation test results of the tablets.
【００３３】[0033]
【表１】 表１より、圧縮成形性の低い未粉砕のマンニトールを約
７０重量％含む錠剤でも、マンニトール及びクロスポビ
ドンを含有する混合物の共粉砕物を３０重量％含有する
と、硬度５ｋｇ以上で口腔内崩壊時間１分以内の錠剤が
直接打錠法にて容易に製造できることがわかる。更に、
未粉砕のクロスポビドンを添加すると、その添加量に応
じて錠剤硬度は低下したが、４重量％添加した実施例３
によると、約５ｋｇの硬度を維持しつつ口腔内崩壊時間
が約３０秒となり、口腔内速崩壊型錠剤として優れた特
性を有していることがわかる。[Table 1] From Table 1, it can be seen that even a tablet containing about 70% by weight of unmilled mannitol having low compression moldability, containing 30% by weight of a co-ground product of a mixture containing mannitol and crospovidone, has a hardness of 5 kg or more and an oral disintegration time of 1%. It can be seen that tablets within minutes can be easily produced by the direct compression method. Furthermore,
When unground pulverized crospovidone was added, the tablet hardness was reduced in accordance with the amount of the addition.
According to the results, the oral disintegration time was about 30 seconds while maintaining the hardness of about 5 kg, indicating that the tablet has excellent properties as an oral rapid disintegrating tablet.
【００３４】比較例１〜３ 未粉砕物のマンニトール９．６５ｇ、クロスポビドン
０．３ｇ及びステアリン酸マグネシウム０．０５ｇを、
実施例１と同様の方法で混合・打錠を行い、比較例１の
錠剤を得た。また、マンニトール４ｇ及びクロスポビド
ン４ｇを、それぞれ振動ロッドミルで２０分間粉砕して
単味粉砕物とした。この単味粉砕物のマンニトール２．
７ｇ及びクロスポビドン０．３ｇに、未粉砕物のマンニ
トール６．９５ｇ及びステアリン酸マグネシウム０．０
５ｇを添加した後、実施例１と同様の方法で混合・打錠
を行い、比較例２の錠剤を得た。更に、単味粉砕物のマ
ンニトール２．７ｇ及びクロスポビドン０．３ｇに、未
粉砕物のマンニトール６．５５ｇ、クロスポビドン０．
４ｇ及びステアリン酸マグネシウム０．０５ｇを添加し
た後、実施例１と同様の方法で混合・打錠を行い、比較
例３の錠剤を得た。Comparative Examples 1 to 3 9.65 g of unmilled mannitol, 0.3 g of crospovidone and 0.05 g of magnesium stearate were added to
Mixing and tableting were performed in the same manner as in Example 1 to obtain tablets of Comparative Example 1. In addition, 4 g of mannitol and 4 g of crospovidone were each pulverized by a vibrating rod mill for 20 minutes to obtain a plain pulverized product. 1. Mannitol of this simple ground product
7 g and crospovidone 0.3 g, unmilled mannitol 6.95 g and magnesium stearate 0.0
After adding 5 g, mixing and tableting were performed in the same manner as in Example 1 to obtain a tablet of Comparative Example 2. Further, 2.7 g of mannitol and 0.3 g of crospovidone as a simple ground product, 6.55 g of mannitol as an unground product and 0.5 g of crospovidone were added.
After adding 4 g and 0.05 g of magnesium stearate, mixing and tableting were performed in the same manner as in Example 1 to obtain a tablet of Comparative Example 3.
【００３５】比較例１〜３の成分組成及び錠剤の評価試
験結果を表２に示す。Table 2 shows the component compositions of Comparative Examples 1 to 3 and the evaluation test results of the tablets.
【００３６】[0036]
【表２】 表２より、未粉砕のマンニトールに未粉砕のクロスポビ
ドンを添加しても錠剤硬度は１ｋｇ以下であることがわ
かる。更に、マンニトール及びクロスポビドンの単味粉
砕物を、実施例１及び実施例３と同様の成分組成となる
ように添加した比較例２及び比較例３の錠剤の硬度は、
３ｋｇ未満となり、製造工程及び流通過程で崩れない適
度な硬度を有する錠剤が得られないことを示す。[Table 2] Table 2 shows that the tablet hardness is 1 kg or less even when unmilled crospovidone is added to unmilled mannitol. Furthermore, the hardness of the tablets of Comparative Examples 2 and 3 in which mannitol and crospovidone plain crushed substances were added so as to have the same component composition as in Examples 1 and 3,
It is less than 3 kg, indicating that a tablet having an appropriate hardness that does not collapse during the production process and the distribution process cannot be obtained.
【００３７】実施例４〜６ 実施例３の成分組成及び製造方法で錠剤を得た。ただ
し、マンニトール３．６ｇ及びクロスポビドン０．４ｇ
を含む２成分粉末の共粉砕時間を、５、１０、３０分と
変化させて、それぞれを実施例４、実施例５及び実施例
６とした。Examples 4 to 6 Tablets were obtained by the component composition and production method of Example 3. However, 3.6 g of mannitol and 0.4 g of crospovidone
The co-milling time of the two-component powder containing was changed to 5, 10, and 30 minutes, respectively, to obtain Example 4, Example 5, and Example 6, respectively.
【００３８】実施例４〜６の錠剤の評価試験結果を表３
に示す。Table 3 shows the evaluation test results of the tablets of Examples 4 to 6.
Shown in
【００３９】[0039]
【表３】 表３より、マンニトール及びクロスポビドンの共粉砕物
を調製する粉砕工程において、粉砕時間を長くすると、
錠剤硬度が上昇して口腔内崩壊時間が増加することがわ
かる。しかし、実施例３の成分組成においては、共粉砕
時間が５〜３０分であれば、錠剤硬度３ｋｇ以上で口腔
内崩壊時間１分以内の錠剤が得られることが示されてい
る。実施例４では口腔内崩壊時間が約２０秒と短く、口
腔内速崩壊型錠剤として特に優れた特性を有していた。[Table 3] From Table 3, in the grinding step of preparing a co-ground product of mannitol and crospovidone, if the grinding time is increased,
It can be seen that the tablet hardness increases and the oral disintegration time increases. However, in the component composition of Example 3, it is shown that if the co-milling time is 5 to 30 minutes, a tablet having a tablet hardness of 3 kg or more and an oral disintegration time of 1 minute or less can be obtained. In Example 4, the oral disintegration time was as short as about 20 seconds, and had particularly excellent properties as an oral rapid disintegrating tablet.
【００４０】実施例７〜１０ 実施例３と同様の製造方法であるが、その成分組成中の
マンニトールを、エリスリトール（日研化学社製）、キ
シリトール（東和化成社製）、乳糖（ＤＭＶ社製）及び
グルコース（松谷化学工業社製）に変えて、それぞれ実
施例７、実施例８、実施例９及び実施例１０の錠剤を得
た。ただし、エリスルトールを配合した実施例７のみ、
共粉砕時間を６０分、打錠圧を１４００ｋｇとした。Examples 7 to 10 The same production method as in Example 3 was used, except that mannitol in the composition was changed to erythritol (manufactured by Niken Kagaku), xylitol (manufactured by Towa Kasei), lactose (manufactured by DMV). ) And glucose (manufactured by Matsutani Chemical Industry Co., Ltd.) to obtain tablets of Example 7, Example 8, Example 9 and Example 10, respectively. However, only Example 7 containing erythritol,
The co-milling time was 60 minutes and the tableting pressure was 1400 kg.
【００４１】実施例７〜１０の錠剤の評価試験結果を表
４に示す。Table 4 shows the evaluation test results of the tablets of Examples 7 to 10.
【００４２】[0042]
【表４】 表４より、主賦形剤としてマンニトール以外の糖類を配
合した場合でも、錠剤硬度３ｋｇ以上かつ口腔内崩壊時
間１分３０秒以内の錠剤が得ることがわかる。[Table 4] Table 4 shows that even when a saccharide other than mannitol is blended as the main excipient, a tablet having a tablet hardness of 3 kg or more and an oral disintegration time of 1 minute 30 seconds or less is obtained.
【００４３】実施例１１〜１４ 実施例３と同様の製造方法であるが、その成分組成中の
クロスポビドンを、クロスカルメロースナトリウム（旭
化成工業社製）、低置換度ヒドロキシプロピルセルロー
ス（信越化学工業社製）、カルボキシメチル澱粉ナトリ
ウム（松谷化学工業社製）及び部分α化澱粉（旭化成工
業社製）に変えて、それぞれ実施例１１、実施例１２、
実施例１３及び実施例１４の錠剤を得た。Examples 11 to 14 The production method is the same as that of Example 3, except that crospovidone in the composition of the ingredients is croscarmellose sodium (manufactured by Asahi Kasei Kogyo), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.) Examples 11 and 12, respectively, instead of sodium carboxymethyl starch (manufactured by Matsutani Chemical Industry Co., Ltd.) and partially pregelatinized starch (manufactured by Asahi Kasei Kogyo Co., Ltd.)
The tablets of Example 13 and Example 14 were obtained.
【００４４】実施例１１〜１４の錠剤の評価試験結果を
表５に示す。Table 5 shows the evaluation test results of the tablets of Examples 11 to 14.
【００４５】[0045]
【表５】 表５より、クロスポビドン以外の崩壊剤を配合した実施
例１１〜１４の錠剤でも、実施例３と同様に錠剤硬度が
３ｋｇ以上で口腔内崩壊時間が１分以内となり、口腔内
速崩壊型錠剤として優れた特性を有していた。[Table 5] From Table 5, even in the tablets of Examples 11 to 14 in which disintegrants other than crospovidone were blended, the tablet hardness was 3 kg or more and the oral disintegration time was within 1 minute as in Example 3, and the oral rapid disintegrating tablet And had excellent characteristics.
【００４６】次に、本発明において薬効成分を含有した
実施例及び比較例を示す。Next, Examples and Comparative Examples containing a medicinal ingredient in the present invention will be shown.
【００４７】実施例１５〜１６ 実施例３の共粉砕物３ｇに未粉砕物のマンニトール３．
５５ｇ、クロスポビドン０．４ｇ、水溶性薬効成分であ
るアスコルビン酸３．０ｇ（和光純薬工業社製）及びス
テアリン酸マグネシウム０．０５ｇを添加した後、実施
例３と同様に混合・打錠して実施例１５の錠剤を得た。
また、上記共粉砕物３ｇに未粉砕物のマンニトール０．
５５ｇ、クロスポビドン０．４ｇ、アスコルビン酸６．
０ｇ及びステアリン酸マグネシウム０．０５ｇを添加し
た後、同様に混合・打錠して実施例１６の錠剤を得た。Examples 15-16 Unmilled mannitol was added to 3 g of the co-milled product of Example 3.
55 g, 0.4 g of crospovidone, 3.0 g of ascorbic acid as a water-soluble medicinal ingredient (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.05 g of magnesium stearate were added, and then mixed and tableted in the same manner as in Example 3. Thus, a tablet of Example 15 was obtained.
In addition, 3 g of the above-mentioned co-pulverized product was added with unmilled mannitol 0.1%.
5. 55 g, crospovidone 0.4 g, ascorbic acid 6.
0 g and 0.05 g of magnesium stearate were added, followed by mixing and tableting in the same manner to obtain a tablet of Example 16.
【００４８】実施例１５〜１６の成分組成及び錠剤の評
価試験結果を表６に示す。Table 6 shows the component compositions of Examples 15 and 16 and the results of evaluation tests on the tablets.
【００４９】[0049]
【表６】 表６より、本発明の錠剤は、アスコルビン酸を約６０重
量％含有する場合でも口腔内速崩壊型錠剤として優れた
特性を有していることがわかる。本発明の製造方法にお
いては、未粉砕物のマンニトールと同様に圧縮成形性の
低い水溶性薬効成分を多量に含めうることも理解できる 実施例１７〜１８ マンニトール３．６ｇ、クロスポビドン０．４ｇ及び難
水溶性薬効成分であるニフェジピン０．３４ｇ（和光純
薬工業社製）を含む３成分粉末を、振動ロッドミルを用
いて２０分間共粉砕した。この共粉砕物３．２５ｇに未
粉砕物のマンニトール６．３ｇ、クロスポビドン０．４
ｇ及びステアリン酸マグネシウム０．０５ｇを添加した
後、実施例３と同様に混合・打錠して実施例１７の錠剤
を得た。一方、実施例３の共粉砕物３ｇに未粉砕物のマ
ンニトール６．３ｇ、クロスポビドン０．４ｇ、ニフェ
ジピン０．２５ｇ及びステアリン酸マグネシウム０．０
５ｇを添加した後、同様に混合・打錠して実施例１８の
錠剤を得た。ただし、実施例１７〜１８の打錠圧は共に
８００ｋｇとした。[Table 6] Table 6 shows that the tablet of the present invention has excellent properties as a rapidly disintegrating oral tablet even when it contains about 60% by weight of ascorbic acid. In the production method of the present invention, it can also be understood that a large amount of a water-soluble medicinal ingredient having low compression moldability can be contained in a large amount as in the case of unmilled mannitol. Examples 17-18 3.6 g of mannitol, 0.4 g of crospovidone and A three-component powder containing 0.34 g of nifedipine (manufactured by Wako Pure Chemical Industries, Ltd.), which is a poorly water-soluble medicinal ingredient, was co-ground using a vibrating rod mill for 20 minutes. 6.3 g of unmilled mannitol and crospovidone 0.4 were added to 3.25 g of the co-milled product.
g and 0.05 g of magnesium stearate were added, followed by mixing and tableting in the same manner as in Example 3 to obtain a tablet of Example 17. On the other hand, 6.3 g of unmilled mannitol, 0.4 g of crospovidone, 0.25 g of nifedipine and 0.03 g of magnesium stearate were added to 3 g of the co-milled product of Example 3.
After the addition of 5 g, the mixture was similarly mixed and tableted to give a tablet of Example 18. However, the tableting pressure in Examples 17 and 18 was 800 kg.
【００５０】実施例１７〜１８の成分組成及び錠剤の評
価試験結果を表７に示す。Table 7 shows the component compositions of Examples 17 to 18 and the evaluation test results of the tablets.
【００５１】[0051]
【表７】 表７より、ニフェジピンをマンニトールと崩壊剤の共粉
砕工程中に添加した実施例１７、及び共粉砕物とマンニ
トール未粉砕物の物理混合工程中に添加した実施例１８
の両錠剤は、口腔内速崩壊型錠剤として優れた特性を有
していることがわかる。[Table 7] According to Table 7, Example 17 in which nifedipine was added during the co-milling step of mannitol and a disintegrant, and Example 18 in which the co-milled substance and the unmilled mannitol were added during the physical mixing step
It can be seen that both tablets have excellent properties as intraorally fast disintegrating tablets.
【００５２】なお、上記実施例１７〜１８により製造さ
れた錠剤の溶出試験の結果を図１に示す。FIG. 1 shows the results of the dissolution test of the tablets produced in Examples 17 and 18.
【００５３】図１より、ニフェジピンは難水溶性薬効成
分であるため、物理混合工程に添加した実施例１８で
は、錠剤からの薬効成分の溶出性が遅かった。一方、ニ
フェジピンを共粉砕工程中に添加して微細化した実施例
１７では、薬効成分の溶出性を著しく改善できることが
示されている。本発明の製造方法においては、難水溶性
薬効成分を混合粉砕工程中に添加することにより、製造
工程の追加または変更することなく、速やかな薬効成分
の溶出性を有する口腔内速崩壊型錠剤を得ることが可能
であることが明らかである。As shown in FIG. 1, since nifedipine is a poorly water-soluble medicinal component, the dissolution of the medicinal component from the tablet was slow in Example 18 where it was added to the physical mixing step. On the other hand, in Example 17 in which nifedipine was added during the co-milling step to make the composition finer, it was shown that the dissolution property of the medicinal component can be significantly improved. In the production method of the present invention, by adding a poorly water-soluble medicinal ingredient during the mixing and pulverizing step, without adding or changing the manufacturing step, an orally rapidly disintegrating tablet having a rapid dissolution property of the medicinal ingredient can be obtained. It is clear that it is possible to obtain.
【図１】実施例１７〜１８に従って製造された錠剤、並
びに薬効成分のみ（対照）からの薬効成分の経時的溶出
挙動を示すグラフである。黒丸は薬効成分のみを、黒三
角は実施例１７の、そして黒四角は実施例１８の錠剤か
らの薬効成分の溶出を示す。FIG. 1 is a graph showing the time-dependent elution behavior of a medicinal ingredient from a tablet produced according to Examples 17 to 18 and a medicinal ingredient alone (control). Closed circles indicate only the active ingredient, solid triangles indicate the elution of the active ingredient from the tablet of Example 17, and solid squares indicate the elution of the active ingredient from the tablet of Example 18.
フロントページの続き (72)発明者 伊藤 邦雄 静岡県駿東郡長泉町納米里174番地13号 Ｆターム(参考） 4C076 AA37 BB01 CC01 CC04 CC11 CC15 CC16 CC22 CC32 DD25 DD38 DD41C DD67 EE16B EE32B EE38B FF06 FF70 GG03 GG14 Continuation of the front page (72) Inventor Kunio Ito 174 No. 13 Nomeri, Nagaizumi-cho, Sunto-gun, Shizuoka Pref.F-term (reference)
Claims (12)
砕物、並びに糖類の未粉砕物を含んでなる打錠用末の圧
縮成形物であり、かつ、適度な硬度と速やかな崩壊性を
有する口腔内速崩壊型錠剤。Claims: 1. A co-ground product of a mixture containing a saccharide and a disintegrant, and a compression-molded product of a tableting powder containing an unground material of a saccharide, and having an appropriate hardness and rapid disintegration. Orally disintegrating tablet in the mouth.
請求項１記載の錠剤。2. The tablet according to claim 1, wherein the tableting powder further contains an uncrushed disintegrant.
又は２記載の錠剤。3. The tableting powder according to claim 1, further comprising a medicinal ingredient.
Or the tablet according to 2.
有する混合物中に含められた請求項３記載の錠剤。4. The tablet according to claim 3, wherein the poorly water-soluble medicinal ingredient is contained in a mixture containing a saccharide and a disintegrant.
ルコールからなる群より選ばれる少なくとも１種である
請求項１〜４のいずれかに記載の錠剤。5. The tablet according to claim 1, wherein the saccharide is at least one selected from the group consisting of monosaccharides and disaccharides, and sugar alcohols thereof.
カルメロースナトリウム、低置換度ヒドロキシプロピル
セルロース、カルボキシメチル澱粉ナトリウム及び部分
α化澱粉からなる群より選ばれる少なくとも１種である
請求項１〜５記載の錠剤。6. The disintegrant is at least one selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch and partially pregelatinized starch. Tablets.
精神病薬、抗パーキンソン薬、解熱鎮痛消炎薬、抗ヒス
タミン薬、血圧降下薬、高脂血症用薬、糖尿病用薬、気
管支拡張薬、骨格筋弛緩薬、抗真菌薬、抗生物質、消化
性潰瘍用薬、消化管運動賦活薬及びビタミンからなる群
より選ばれる請求項３〜６のいずれかに記載の錠剤。7. The medicinal component is a sleep sedative, an anxiolytic, an antipsychotic, an antiparkinsonian, an antipyretic analgesic / antiinflammatory, an antihistamine, a hypotensive, a hyperlipidemic, a diabetic, a bronchial The tablet according to any one of claims 3 to 6, which is selected from the group consisting of a dilator, a skeletal muscle relaxant, an antifungal, an antibiotic, a drug for peptic ulcer, a gastrointestinal motility enhancer, and a vitamin.
３：１〜１９：１で含有する混合物の共粉砕物を、錠剤
の総重量当たり２０〜５０重量％で含む請求項１〜７の
いずれかに記載の錠剤。8. The composition according to claim 1, comprising a co-ground product of a mixture containing the saccharide and the disintegrant in a weight ratio of 3: 1 to 19: 1, respectively, in an amount of 20 to 50% by weight based on the total weight of the tablet. The tablet according to any one of the above.
沢剤及び着色剤からなる群より選ばれる少なくとも１種
を更に含有する請求項１〜８のいずれかに記載の錠剤。9. The tablet according to claim 1, further comprising at least one selected from the group consisting of an acidulant, a foaming agent, an artificial sweetener, a flavor, a lubricant, and a colorant.
砕型粉砕機で共粉砕し、こうして得られた共粉砕物を糖
類の未粉砕物又は糖類及び崩壊剤の未粉砕物と物理混合
して打錠用末を形成し、次いで該打錠用末を直接打錠法
にて圧縮成形する工程を含んでなる請求項１又は２記載
の錠剤の製造方法。10. A mixture containing a saccharide and a disintegrant is pulverized by a grinding-type pulverizer, and the thus obtained co-pulverized material is physically mixed with an unground pulverized saccharide or an unground pulverized saccharide and a disintegrant. The method for producing a tablet according to claim 1 or 2, comprising a step of forming a tableting powder by compression and then compression-molding the tableting powder by a direct tableting method.
形成する工程で含まれる請求項１０記載の製造方法。11. The method according to claim 10, wherein the medicinal component is included in a co-milling step or a step of forming a tableting powder.
せる請求項１１記載の製造方法。12. The production method according to claim 11, wherein the poorly water-soluble medicinal component is included in the co-grinding step.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34890399A JP3435664B2 (en) | 1999-12-08 | 1999-12-08 | Oral fast disintegrating tablet and method for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34890399A JP3435664B2 (en) | 1999-12-08 | 1999-12-08 | Oral fast disintegrating tablet and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2001163770A true JP2001163770A (en) | 2001-06-19 |
| JP3435664B2 JP3435664B2 (en) | 2003-08-11 |
Family
ID=18400171
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP34890399A Expired - Fee Related JP3435664B2 (en) | 1999-12-08 | 1999-12-08 | Oral fast disintegrating tablet and method for producing the same |
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| Country | Link |
|---|---|
| JP (1) | JP3435664B2 (en) |
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