JP3568567B2 - High moldability excipient and method for producing the same - Google Patents

Description

（但し、ａ＝０．８５〜０．９０，ｂ＝０．０５〜０．１０であり、そしてＰは結晶セルロースに対する圧縮圧力［ｋｇｆ／ｃｍ^２ ］、Ｖ_０ は結晶セルロースの見掛け比容積［ｃｍ^３ ／ｇ］、Ｖは圧縮圧力Ｐにおける結晶セルロースの比容積［ｃｍ^３ ／ｇ］を表す）
【００１１】
▲２▼ 白色粉末結晶セルロースの平均重合度が１８０〜２２０である点にも特徴を有する。また、
▲３▼ ５００ｍｇの白色粉末状結晶セルロースを１００ｋｇｆ／ｃｍ^２ で１０秒間圧縮することにより得られる底面の面積が１ｃｍ^２ である円柱状成形体の直径方向の破壊強度が１０ｋｇｆ以上であり、かつ、崩壊時間が１００秒以内である点にも特徴を有する。また、
▲４▼ 円柱状成形体の直径方向の破壊強度が１１ｋｇｆ以上である点にも特徴を有する。また、
▲５▼ 吸着水分が５〜６％である時の吸着水横緩和時間が０．０００２４秒以下である点にも特徴を有する。また、
▲６▼ セルロース質物質を酸加水分解あるいはアルカリ酸化分解し、精製して得られたセルロース粒子を、固形分濃度が５〜４０重量％、ｐＨが５〜８．５、電気伝導度が３００μＳ／ｃｍ以下の湿潤状態あるいは水分散状態で１００℃以上に加熱処理し、乾燥する▲１▼〜▲５▼のいずれかに記載の高成形性賦形剤の製造方法を提供する。また、
▲７▼ 固形分濃度が５〜２３重量％のセルロース粒子を加熱処理する点にも特徴を有する。また、
▲８▼ ドラム乾燥機あるいはベルト乾燥機を用いて加熱処理および乾燥を行う点にも特徴を有する。また、
【００１２】
▲９▼ セルロース質物質を酸加水分解あるいはアルカリ酸化分解し、精製して得られたセルロース粒子を、固形分濃度が２３重量％以下、ｐＨが５〜８．５、電気伝導度が３００μＳ／ｃｍ以下の水分散状態とし、ついで薄膜状態で乾燥する▲１▼〜▲５▼のいずれかに記載の高成形性賦形剤の製造方法を提供する。また、
（１０） ドラム乾燥機あるいはベルト式乾燥機を用いて乾燥を行う点にも特徴を有する。
【００１３】
以下、本発明について詳細に説明する。
（Ａ） 高成形性賦形剤
本発明の高成形性賦形剤は実質的にセルロースからなる。「実質的」とはセルロース本来の機能を失わない程度にヘミセルロース、リグニン、油脂などの成分を含んでいても良いことを意味する。その含有量は水分を除いた本発明物質のおおよそ１０％以下である。
【００１４】
本発明でいう結晶セルロースとは、精製木材パルプ、竹パルプ、コットンリンター、ラミーなどのセルロース質物質を酸加水分解、あるいはアルカリ酸化分解して得られるものであって、平均重合度は１８０〜３７５の白色粉末状の物質である。
この物質は特定の重合度を有するために、セルロース粉末の中でも特に高い成形性を有するものであるが、その平均重合度は１８０〜３７５の範囲である必要がある。
平均重合度が１８０未満だと成形性が不足するので好ましくなく、また、３７５を超えると繊維性が現れるため、粉体としての流動性が低下するので好ましくない。平均重合度が１８０〜２２０の場合に成形性と崩壊性のバランスが良好なので好ましい。
【００１５】
本発明の高成形性賦形剤は、その酢酸保持率が２８０％以上、好ましくは２９０％以上であり、その上限は特に制限されないが、通常３５３％（実施例４）程度である。そして、上記 （１） 式（川北の式）（ａ＝０．８５〜０．９０、ｂ＝０．０５〜０．１０）で表される圧縮特性を有するものである。
本発明における酢酸保持率とは、試料粉末を約１０倍重量の酢酸に室温で３０分間浸漬し、次いで２０００Ｇで遠心分離を行い、上澄みを除いた場合に試料が保持できる酢酸の量を示す値であり、絶乾試料重量に対する酢酸の重量百分率で表される。
酢酸はセルロース粉末に吸収されるが非晶領域に存在する遊離水酸基の水素結合（これは一般に、角質化組織と呼ばれる）を解離するほど強い膨潤力を持たず〔Ｒ．ＨＡＳＥＢＥ，Ｋ．ＭＡＴＳＵＭＯＴＯ，Ｈ．ＭＡＥＤＡ，Ｓｅｎ’ｉＧａｋｋａｉｓｈｉ，Ｖｏｌ．１２，ｐ２０３〜２０７（１９５５）〕、また、遠心力をかけて試料を圧密し粒子間隙の酢酸の保持量を制限していることから、結局、酢酸保持率とは粒子自身の多孔性とその強度を示すものである。本発明ではこの酢酸保持率が２８０％以上でなければならない。
【００１６】
また、川北の式〔Ｋ．ＫＡＷＡＫＩＴＡ，Ｙ．ＴＳＵＴＳＵＭＩ，Ｂｕｌｌ．Ｃｈｅｍ．Ｓｏｃ．Ｊａｐａｎ，Ｖｏｌ．３９，Ｎｏ．７，ｐ１３６４〜１３６８（１９６６）〕とは粉体の加圧による体積の変化を表した実験式であり、加圧初期において体積の変化が大きい粉体に、特によく一致すると言われている。結晶セルロースも川北の式によく一致する粉体の一つである。
川北の式は下記（１） 式で表され、ａとｂは定数であり、Ｐは結晶セルロースに対する圧縮圧力［ｋｇｆ／ｃｍ^２ ］、Ｖ_０ は結晶セルロースの見掛け比容積［ｃｍ^３ ／ｇ］、Ｖは圧縮圧力Ｐにおける結晶セルロース〔粉体あるいは錠剤〕の比容積［ｃｍ^３ ／ｇ］を表すものである。
【数３】

結晶セルロースの場合、定数ａおよびｂは大きいほど成形性が高い傾向があるが、本発明においては定数ａは０．８５〜０．９０、好ましくは０．８６〜０．８９、定数ｂは０．０５〜０．１０、好ましくは０．０６〜０．０９の範囲内にあることが必要である。
ａおよび／あるいはｂがこの値より低いと成形性が不充分である。また、ａおよびｂが範囲内であっても前述の酢酸保持力が２８０％未満であるか、あるいはａおよび／あるいはｂがこの値より高いと加圧圧縮により錠剤の圧密が著しく進行するために、錠剤の崩壊性が悪化する。
【００１７】
（Ｂ） 高成形性賦形剤の製造方法
基本的には、本発明の高成形性賦形剤は、酸やアルカリあるいは分解生成物がほとんど存在しない湿潤状態もしくは水分散状態のセルロース粒子を加熱処理し、乾燥させることによって製造することができるが、もし加熱処理を施さない場合は水分散状態のセルロース粒子を薄膜状態で乾燥することによって製造することができる。
【００１８】
（ｉ） まず、加熱処理を施す場合の製造方法について説明する。
即ち、セルロース質物質を酸加水分解もしくはアルカリ酸化分解し、必要があればその前あるいは後に機械的処理（摩砕等）を施すことによりセルロース粒子を得る。このセルロース粒子は水の他に、酸やアルカリなどの不必要な成分を含んでいるので、ろ過や遠心分離、膜分離技術などを用いてこれらを除去し、精製する。
こうして得られたセルロース粒子は、必要に応じて水を加え、固形分濃度が５〜４０重量％、好ましくは１０〜２３重量％、２５℃におけるｐＨが５〜８．５、好ましくは５．５〜８．０、電気伝導度が３００μＳ／ｃｍ以下、好ましくは１５０μＳ／ｃｍ以下の特定の湿潤状態、あるいは水分散状態で加熱処理に供する必要がある。
この時、純水のみならず、有機溶媒を少量含む水を用いても良い。
固形分濃度が５〜２３重量％の場合は特に加熱処理効果および製造効率が高いので好ましく採用できる。
既存の結晶セルロースの製造方法では、例えば、酸加水分解の終了時点でセルロース粒子の水分散体が１００℃以上の加熱を受けている状態をとっていたが、酸や分解生成物が多量に存在していたので、後述するような構造変化を取り得ず、本発明のような効果は発揮されていなかった。
【００１９】
上記加熱処理は、通常使用されるオートクレーブや高粘性流体用熱交換機（例えば神鋼パンテック（株）製フリサーム）などを用いて約１００℃以上、好ましくは約１２０℃に加熱すればよく、その温度を保つ時間は短時間でよい。但し、湿潤状態、あるいは水分散状態のセルロース粒子は非常に伝熱が悪いので昇温し難く、通常のオートクレーブを用いるような場合には、処理時間を充分長くするか、充分撹拌する必要がある。
このような加熱処理によってセルロース粒子同士、あるいは水素イオン、水酸化物イオン、水分子などは相互作用を起こす。例えば、水分散体の場合は粘度の増加（ゲル化）とｐＨの低下をもたらす。
どのような構造をとっているかは明らかでないが、セルロース粒子同士、あるいは水素イオン、水酸化物イオン、水分子などが会合してゲル化していることは想像に難くない。この構造は室温まで冷却しても壊れないが、ガラス棒などで軽く撹拌すると直ちに粘度が低下し、そして同時に、ｐＨが上昇し、加熱処理前の状態に戻る。
但し、加熱処理の本質はこのような巨視的なゲル構造ではなく、もっと微視的な構造変化であろう。それは、系全体の構造は壊れても、セルロース粒子の軟凝集が観察されることから、微視的には依然として粒子の会合は維持しているものと考えられるからである。
微視的に粒子が会合しているであろうもう一つの傍証は水の乾燥速度にある。一度加熱処理したセルロース粒子水分散体は、加熱処理しないものに比べ１０％以上乾燥速度が速く、この理由は粒子が会合しているので乾燥物が疎な構造を取るために水分の拡散が良好となるためと考えられる。
【００２０】
このようにして加熱処理を施した後、種々の方法で水分を蒸発し乾燥させる。
乾燥方法は、ディスクタイプあるいは空気使用の二流体ノズルタイプのアトマイザーを用いる噴霧乾燥や棚段熱風乾燥など、通常の方法を用いることができる。
この乾燥処理は一度冷却処理を施した後に行っても良いし、また、冷却することなく連続的に行っても良い。ここでいう「連続的」とは、水分の蒸発とセルロース粒子水分散体の昇温を同時に行う際に、水分の存在する状態で１００℃以上に昇温した後に乾燥が終了することを含む。但し、このときの水分は気体状態であっても良い。
【００２１】
加熱処理と乾燥処理を同時に行う好適な例としてはドラム乾燥機やベルト乾燥機を用いる方法をあげることができる。また、１００℃以上の水蒸気を用い、二流体ノズルで噴霧乾燥する方法なども有効である。ドラム乾燥機を用いて乾燥する場合のセルロース粒子水分散体は、固形分（セルロース粒子）濃度が１０〜２３重量％、２５℃におけるｐＨが５〜８．５、２５℃における電気伝導度が３００μＳ／ｃｍ以下であることが好ましい。
また、乾燥条件はドラム表面温度が１０５〜１５０℃程度とし、そして乾燥終了時点での乾燥品の水分が３〜５％程度になるように、ドラムクリアランス、ドラム回転速度、セルロース粒子分散液の供給量などを適宜選択する。
【００２２】
（ｉｉ）次に、加熱処理を施さなくてもよい場合の製造方法について説明する。
即ち、本発明の高成形性賦形剤は、加熱処理を施さない場合は、水分散状態のセルロース粒子をガラス板やアルミ板などの支持体に薄く伸展した状態で乾燥することにより製造することができる。
その場合は固形分濃度が２３重量％以下、ｐＨが５〜８．５、電気伝導度が３００μＳ／ｃｍ以下の水分散状態であることが必要である。
具体的な例としては、ガラス板やアルミ板にセルロース粒子の水分散体を薄く伸展し、室温乾燥あるいは通風乾燥するか、あるいはドラム乾燥機やベルト乾燥機を用いて乾燥する方法などが挙げられる。
加熱処理を施した後に、薄膜状態で乾燥することが必要である。
薄膜状態で乾燥することにより成形性が高く、かつ、崩壊性に優れた結晶セルロースが得られる理由は明らかではないが、ガラス板のような支持体に接することで棒状のセルロース粒子が２次元的に配列し、かつ、乾燥収縮が制限される、つまり、角質化が抑えられるためと考えられる。
【００２３】
結晶セルロース等の製造にドラム乾燥機の使用が可能なことは、例えば特公昭４０−２６２７４号公報に記載があるが、圧縮成形性が高く、かつ、崩壊性が良好な結晶セルロースを製造するために上記のような条件を選択しなければならないことについては何等記載がなく、従来知られていない技術であった。
また、従来常用されていた噴霧乾燥法や熱風乾燥法などは、たとえ送風温度が１００℃以上であっても、水の蒸発潜熱のために品温は１００℃まで上がらぬうちに乾燥してしまうので「加熱処理」が施されておらず、また、薄膜状態も取り得ないので本発明の技術とは異なるものである。
こうして得られた粉体は、必要に応じて粉砕、篩分などを行い、粒度分布を調整して使用に供する。
【００２４】
（Ｃ） 高成形性賦形剤の粒径等
（ｉ） 本発明の高成形性賦形剤は、篩分法によって粒度分布を測定する場合、実質的に３５５μｍの目開きの篩にとどまる留分は無く、累積５０重量％の粒度で表される平均粒径は３０〜１２０μｍであることが、特に４０〜１００μｍであることが好ましい。
「実質的」とは粉体の流動性などの機能を損なわない程度に比較的大きな粒子を含んでいても良いことを意味し、その値はおおよそ５重量％以下である。
平均粒径が３０μｍ未満では微小な粒子が多すぎるために、粉体としての流れが悪化し、そして錠剤の崩壊性が悪化するので好ましくない。また、平均粒径が１２０μｍを越えると粉体が粗大化してしまい、成形性の低下、および、他の粉体原料との混合性の悪化が生じるので好ましくない。
【００２５】
（ｉｉ）さらに、本発明の高成形性賦形剤は見掛け比容積が４．０〜６．０ｃｍ^３ ／ｇ、好ましくは４．５〜５．０ｃｍ^３ ／ｇ、見掛けタッピング比容積が２．４ｃｍ^３ ／ｇ以上、好ましくは１．５ｃｍ^３ ／ｇ以上の結晶セルロースであることが好ましい。
見掛け比容積が４．０ｃｍ^３ ／ｇ未満であると成形性が低下し、６．０ｃｍ^３ ／ｇを超えると粉体の流動性が低下するので好ましくない。
見掛けタッピング比容積が２．４ｃｍ^３ ／ｇ未満であると、錠剤が圧密化されて崩壊性が悪化するので好ましくない。見掛けタッピング比容積の上限は見掛け比容積の値より自動的に６．０ｃｍ^３ ／ｇと決められるが、この値以下であれば特に支障ない。
従って、見掛けタッピング比容積は、２．４〜６．０ｃｍ ^３ ／ｇである必要がある。
【００２６】
（ｉｉｉ） また、本発明の高成形性賦形剤はＢＥＴ法（吸着物質として窒素を使用）で測定される比表面積が２０ｍ^２ ／ｇ未満であり、特に１０ｍ^２ ／ｇ未満であることが好ましい。
比表面積が２０ｍ^２ ／ｇ以上になると、結晶セルロース粒子が自身の内部に径の大きな（約０．０１μｍ以上）細孔を持たざるを得ず、粒子の強度が弱くなるために、錠剤が圧密されてしまい、結局、崩壊が悪化するので好ましくない。
【００２７】
（ｉｖ）まとめ
前述の通り、従来は結晶セルロース等の成形性を向上するために見掛け比容積を増加させるよう腐心されてきたが、見掛けタッピング比容積や比表面積について何等考慮がなかったため、崩壊性が悪化するという事態を引き起こしていた。
ところが、本発明者らは上記（Ｂ） 項で説明する独自の乾燥方法（要するに、特定の固形分濃度、特定のｐＨ、特定の電気伝導度と言う、特定の湿潤状態または水分散状態で１００℃以上で加熱・乾燥するか、或いは特定の水分散状態で薄膜状に乾燥する方法）を開発することにより、酢酸保持率、見掛け比容積、見掛けタッピング比容積、比表面積を特定の範囲にコントロールすることが可能となり、従来には存在しなかった、成形性と崩壊性のバランスのとれた結晶セルロースを発明するに至ったのである。
【００２８】
（Ｄ） 標準錠剤の調製法
（ｉ） 標準錠剤の調製法について説明する。
即ち、標準錠剤を調製するには赤外吸収分析において臭化カリウム錠剤を作るときに使用されるような金型を使用する。
但し、圧縮成形時には減圧しないので特にそのような構造は必要なく、単に金属性の臼と杵がある構造のものでよい。また片側圧縮タイプでも両側圧縮タイプでもよい。杵の圧縮面は円柱状の成形体を得るために、平面で、かつ、面積が１ｃｍ^２ の円形である必要がある。
このような金型に本発明物質（白色粉末状結晶セルロース）５００ｍｇ（吸着水分を含む）を仕込み、圧力ゲージのついた加圧装置（ハンドプレス）にて１００ｋｇｆ／ｃｍ^２ まで圧縮し、この圧力を１０秒間保持し、ついで金型より取り出すことにより標準錠剤を調製する事ができる。圧縮および圧力の保持、抜圧は万能引張圧縮試験機〔例えば、（株）島津製作所製オートグラフ〕などで行うこともできる。
【００２９】
（ｉｉ）次に、標準錠剤の破壊強度および崩壊時間の測定方法について説明する。
すなわち、▲１▼ 破壊強度は、標準錠剤（円柱形）の側面を二つの平行な面で挟み、応力を加え、標準錠剤が破壊したときの応力をもって破壊強度とする。標準錠剤を圧縮する面は一方が固定であり、一方が一定速度で移動する。その移動速度は４〜１３ｃｍ／分程度である。この測定には市販の錠剤硬度計や前述の万能引張圧縮試験機を利用する事ができる。
▲２▼ 崩壊時間の測定は第十二改正日本薬局方、一般試験法、錠剤の崩壊試験法を用いて行う。
【００３０】
（ｉｉｉ） 高成形性賦形剤の破壊強度と崩壊時間
本発明の高成形性賦形剤は、前述の方法で標準錠剤（５００ｍｇの白色粉末状結晶セルロースを１００ｋｇｆ／ｃｍ ^２ で１０秒間圧縮することにより得られる底面の面積が１ｃｍ ^２ である円柱状成形体）を製した場合、その直径方向の破壊強度は１０ｋｇｆ以上、好ましくは１１ｋｇｆ以上であり、その崩壊時間は１００秒以内、好ましくは９０秒以内である。
前述したように既存の賦形剤は成形性が高いと崩壊時間が長くなるため、本発明のように高成形性でありながら崩壊性も優れる賦形剤は知られていなかった。
一般に錠剤の破壊強度は約４ｋｇｆ以上が実用的に必要であると言われており〔「医薬品の投与剤形（医歯薬出版発行）」１９８３年、ｐ１５７〕、また、速溶性錠剤（服用後の速やかな薬効発現を目的とした、２０分以内に薬物の７５％以上が溶解するような錠剤）の崩壊時間は１５分以内であることが求められている〔「医薬品の開発１１巻・製剤の単位操作と機械（廣川書店発行）」１９８９年、ｐ６５〕。
【００３１】
しかしながら、例えば成形性の乏しい薬物を多量に配合する必要があり、かつ、速溶性錠剤であることが必要なかぜ薬を製する場合において、既存の賦形剤は標準錠剤の破壊強度が１０ｋｇｆを越えないか、その崩壊時間が１００秒を越えるか、あるいはその両方であったので、前述の速溶性錠剤の２つの性能を満たすことが困難であった。
本発明の高成形性賦形剤はこのような問題を解決するものである。
つまり本発明の高成形性賦形剤を錠剤処方に配合すると、従来の賦形剤よりも錠剤破壊強度が高く、そして優れた崩壊性の錠剤を製することができるのである。標準錠剤の強度が１１ｋｇｆ以上の場合は高成形性賦形剤を配合した錠剤の強度も高くなるので、特に好ましい。
【００３２】
（ｉｉｉ） 高成形性賦形剤の吸着水横緩和時間
本発明の高成形性賦形剤は、本発明品が水分を５〜６％含有するときにプロトンＮＭＲスペクトル法にて測定される吸着水横緩和時間が０．０００２４秒以下であることが好ましい。
一般に、吸着水を有する固体試料のＮＭＲスペクトルを１Ｈ溶液ＮＭＲプルーブを用いて測定すると吸着水に由来する一本のブロードなピークが得られるので、このピークの半値幅より吸着水横緩和時間を計算する事ができる。この値が０．０００２４秒を超えると成形性が低下するので好ましくない。
この原因は明らかではないが、以下のように推測する。
つまり、吸着水横緩和時間が短いということは水分子の運動性がより束縛されているということだから、吸着水と水素結合しやすようなセルロース分子の水酸基がより多く存在するのであろう。
【００３３】
（ｉｖ）結晶セルロースの圧縮成形性が高い理由の一つは、結晶セルロース粒子が応力を受けて互いに、あるいは他の粉体粒子に押しつけられたときに表面の水酸基が吸着水を介して水素結合を形成するためといわれている。よって、吸着水横緩和時間が短いほど圧縮成形に寄与できる水酸基の量が多く、そのために成形性が高くなるものと考えられる。
従来、粉体の圧縮成形性の向上は圧縮時の高圧密化が主目的に考えられていたが、結晶セルロースの成形性向上のために接触点の接触強度の向上を図ったという点で本発明は新規である。
【００３４】
（ｖ） 高成形性賦形剤の用途
本発明の高成形性賦形剤は医薬品分野において既存の賦形剤と同様に使用される。
例えば錠剤を製する場合には、直接粉末圧縮法や乾式顆粒圧縮法、湿打後末法の結合剤として使用することができるが、既存の結合剤、例えば結晶セルロースなどよりも成形性が高いので少ない配合量か、あるいは低い圧縮力で成形することが可能となる。また崩壊性が良いので崩壊剤の配合が必要ないか、あるいは少量でよい。特に賦形剤の配合量が制限される処方、例えば医薬品成分の配合量の多いかぜ薬や小型錠や、低い圧縮力での成形が必要な顆粒含有錠においては有効である。また、ブロッキング防止や流動性改善の目的で散剤に配合したり、充填性の改善を目的としてカプセル剤に配合することもできる。さらに、押し出し造粒における押し出し性改善剤や流動層造粒、高速撹拌造粒における造粒助剤など湿式造粒においても使用することができる。
その他には、高い圧縮成形性を必要とするもの、例えば食品分野における錠剤タイプの菓子や健康食品など、化粧品分野における固形ファンデーションなど、セラミクス分野における触媒など使用することができる。さらには食物繊維や食感改良剤として食品に使用することも可能である。
【００３５】
【実施例】
以下、実施例により本発明を詳細に説明するが、これらは本発明の範囲を制限しない。
なお、実施例、比較例、使用例、比較使用例におけるセルロース粒子水分散体、粉体試料および錠剤の物性の測定法は下記の通りである。
・ｐＨ［−］
セルロース粒子水分散体を２５℃に調整し、ガラス電極式水素イオン濃度計（東亜電波工業（株）製、ｐＨメーター ＨＭ−２０Ｅ型）にて測定する。
【００３６】
・電気伝導度［μＳ／ｃｍ］
セルロース粒子水分散体を２５℃に調整し、電気伝導度測定装置（横河電機（株）製、ＳＣ５１ＰＯＣＫＥＴ型）にて測定する。
・酢酸保持率［％］
粉体試料約３ｇを精秤し、試料の約１０倍重量の酢酸（純度９５％以上）に室温で３０分間浸漬する。次いで２０００Ｇで１０分間遠心分離を行い、上澄みを除く。こうして得られた酢酸湿潤物の重量（Ｗ）を測定し、次いで真空加熱乾燥し、乾燥物の重量（Ｗ_０ ）を測定し、次式にて酢酸保持率を計算する。但し、測定は２回行い、その平均値をとった。酢酸保持率＝１００・（Ｗ−Ｗ_０ ）／Ｗ_０
【００３７】
・圧縮特性（川北の式の定数ａおよびｂ）
粉体試料０．５０ｇを精秤し、底面積が１ｃｍ^２ の円柱状成形体を調製することができる片側圧縮タイプの金型に仕込み、ハンドプレスにて２００、４００、８００、１２００、１６００ｋｇｆ／ｃｍ^２ まで圧縮し、この圧力で１０秒間保持し、次いで錠剤を取り出す。各圧力で１０個、計５０個の錠剤を製し、それぞれの重量と厚みを測定し、粉体の体積減少率（Ｃ）を次式より計算する。
Ｃ＝（Ｖ_０ −Ｖ）／Ｖ_０
（ここでＶ_０ は後述する粉体の見掛け比容積［ｃｍ^３ ／ｇ］であり、Ｖは錠剤の比容積［ｃｍ^３ ／ｇ］を表す。）
圧縮圧力ＰとＰ／Ｃの関係を最小自乗法で直線回帰し（Ｐ／Ｃ＝Ｓ＋Ｐ・Ｔ）、その傾きＴと切片Ｓより、川北の式の定数ａおよびｂを計算する。
（ａ＝１／Ｔ、ｂ＝Ｔ／Ｓ）
【００３８】
・粒度分布および平均粒径
粉体試料の粒度分布はロータップ式篩振盪機（平工製作所製シーブシェーカーＡ型）によりＪＩＳ標準篩（Ｚ８８０１−１９８７）を用いて試料３０ｇを１０分間篩分することにより粒度分布を測定し、その累積５０重量％の粒度を平均粒径として表す。
４５μｍ以下の留分が多い場合はエアジェットシーブ粒度分布測定機（ＡＬＰＩＮＥ製エアジェットシーブＡ２００ＬＳ型）を用いて粒度分布を測定し、累積５０重量％の粒度を求めて平均粒径とする。
【００３９】
・見掛け比容積［ｃｍ^３ ／ｇ］
１００ｃｍ^３ のガラス製メスシリンダーに粉体試料を定量フィーダーなどを用い、２〜３分間かけて疎充填し、粉体層上面を筆のような柔らかいハケで水平にならし、その容積を読みとる。これを粉体試料の重量で除する。粉体試料の重量は容積が７０〜１００ｃｍ^３ 程度になるように適宜決定する。
・見掛けタッピング比容積［ｃｍ^３ ／ｇ］
見掛け比容積を測定後、ゴム板を敷いた机の様な衝撃の低い台の上で、手でタッピングを行う。タッピングは数ｃｍの高さから台に垂直に落とすようにして行い、粉体層の圧密が止まるまで行う。タッピング終了後、粉体層の容積を読みとり、粉体試料重量で除する。
【００４０】
・平均重合度［−］
ＩＮＤＵＳＴＲＩＡＬ ＡＮＤ ＥＮＧＩＮＥＥＲＩＮＧ ＣＨＥＭＩＳＴＲＹ Ｖｏｌ．４２，Ｎｏ．３ ｐ５０２〜５０７（１９５０）に記載された銅安溶液粘度法により測定する。
・比表面積［ｍ^２ ／ｇ］
島津製作所（株）製フローソーブＩＩ２３００を用い、吸着ガスとして窒素ガスを使用し、ＢＥＴ法により測定する。
【００４１】
・吸着水横緩和時間［ｓ］
吸着水分を５〜６％（＝１００×水分重量／（水分重量＋絶乾試料重量））に調整した粉体試料を溶液用試料管に導入し、ブルーカー社ＦＴ−ＮＭＲ（ＡＣ２００Ｐ型）、１Ｈ溶液ＮＭＲプローブを用いて測定する。吸着水横緩和時間は次式より求める。吸着水横緩和時間＝１／（得られたピークの半値幅×π）
・錠剤の重量［ｍｇ］および重量ＣＶ［％］
錠剤１０個を精秤し、その数平均値を錠剤重量、その変動係数を重量ＣＶとする。
【００４２】
・錠剤の破壊強度［ｋｇｆ］
シュロインゲル錠剤硬度計（フロイント産業（株）製、６Ｄ型）で錠剤の直径方向に荷重を加え、破壊した時の荷重で表す。繰り返し数は１０でその数平均値をとる。
・錠剤の崩壊時間［ｓ］
第十二改正日本薬局方、一般試験法、錠剤の崩壊試験法に準じて崩壊試験を行う。崩壊試験機は富山産業（株）製ＮＴ−２ＨＳ型を用い、試料６個の数平均値をとる。
【００４３】
（実施例１）
市販ＤＰパルプを細断し、１０％塩酸水溶液中で１０５℃で３０分間加水分解して得られた酸不溶解残渣を濾過、洗浄、ｐＨ調整、濃度調整を行い、固形分濃度１７％、ｐＨ６．４、電気伝導度１２０μＳ／ｃｍのセルロース粒子水分散体を得た。これをドラム乾燥機（楠木機械製作所（株）製、ＫＤＤ−１型、スチーム圧力３．５ｋｇｆ／ｃｍ^２ 、ドラム表面温度１３６℃、ドラム回転速度２ｒｐｍ、溜め部水分散体温度１００℃）で乾燥後、ハンマーミルで粉砕し、目開き４２５μｍの篩で粗大粒子を除き、試料Ａを得た。
試料Ａの基礎物性を表１に示す。
【００４４】
（実施例２）
市販ＫＰパルプを細断し、後は実施例１と同様に処理して得られた酸不溶解残渣を濾過、洗浄、ｐＨ調整、濃度調整を行い、固形分濃度２１％、ｐＨ８．４、電気伝導度２７５μＳ／ｃｍのセルロース粒子水分散体を得た。これをドラム乾燥機（スチーム圧力１．２ｋｇｆ／ｃｍ^２ 、ドラム表面温度１１０℃、ドラム回転速度０．５ｒｐｍ、溜め部水分散体温度９９〜１００℃）で乾燥後、ハンマーミルで粉砕し、目開き４２５μｍの篩で粗大粒子を除き、試料Ｂを得た。
試料Ｂの基礎物性を表１に示す。
【００４５】
（実施例３）
実施例１と同様にして得られた酸不溶解残渣を濾過、洗浄、ｐＨ調整、濃度調整を行い、固形分濃度１８％、ｐＨ７．２、電気伝導度８４μＳ／ｃｍのセルロース粒子水分散体を得た。これを噴霧乾燥機（二流体ノズル使用、水分散体を噴霧化する流体にはスチームを使用、噴霧圧力４ｋｇｆ／ｃｍ^２ 、約１５０℃）にて乾燥したのち、目開き４２５μｍの篩で粗大粒子を除き、試料Ｃを得た。
試料Ｃの基礎物性を表１に示す。
【００４６】
（比較例１）
市販ＤＰパルプを細断し、１０％塩酸水溶液中で１０５℃で３０分間加水分解して得られた酸不溶解残渣を濾過洗浄し、棚段熱風乾燥機にて８０℃で乾燥し、ハンマーミルで粉砕し、目開き４２５μｍの篩で粗大粒子を除き、試料Ｄを得た。
試料Ｄの基礎物性を表１に示す。
（比較例２）
比較例１で得た試料を、気流式粉砕機（（株）セイシン企業製、シングルトラックジェットミルＳＴＪ−２００型）で試料供給量を変えて粉砕し、特開昭６３−２６７７３１号公報記載の発明品に相当する試料Ｅ、Ｆを得た。試料Ｅ、Ｆのの基礎物性を表１に示す。
（比較例３）
市販ＳＰパルプを細断し、１％硫酸水溶液中で９９℃、３０分間加水分解して得られた酸不溶解残渣を濾過、洗浄し、棚段熱風乾燥機にて８０℃で乾燥した。乾燥物の平均重合度は４５２であった。続いてこれをハンマーミルで粉砕し、さらに磁製ボールミルで１２時間粉砕し、目開き４２５μｍの篩で粗大粒子を除き、特公昭５１−１７１７２号公報記載の発明品に相当する試料Ｇを得た。試料Ｇの基礎物性を表１に示す。
【００４７】
【表１】

【００４８】
（使用例１〜３）
試料Ａ、Ｂ、Ｃ、１５０ｇと乳糖（ＤＭＶ社製、Ｐｈａｒｍａｔｏｓｅ１００Ｍ）６００ｇをポリ袋中で３分間混合し、ついでステアリン酸マグネシウム（太平科学産業（株）製）３．７５ｇを加え更に３０秒間混合したものを、ロータリー打錠機（（株）菊水製作所製、ＣＬＥＡＮＰＲＥＳＳ ＣＯＲＲＥＣＴ １２ＨＵＫ）で８ｍｍφ、１２Ｒの杵を用いてターンテーブル回転速度２５ｒｐｍで打錠し、重量２００ｍｇの錠剤を得た。その錠剤の物性を表２に示す。
【００４９】
（比較使用例１〜３）
試料Ａ、Ｂ、Ｃの代わりに試料Ｄ、Ｅ、Ｇを用いて使用例１と同様に打錠を行った。得られた錠剤の物性を表２に示す。
【００５０】
【表２】

【００５１】
表２の結果より、試料Ｅを用いた場合（比較使用例２）では圧縮力の増加と共に破壊強度も増加するものの、崩壊時間も非常に長くなっていることがわかる。また、試料Ｄ、Ｇの場合（比較使用例１、３）は圧縮力が増加しても崩壊時間はそれほど長くはならないが、破壊強度もあまり増加しないことがわかる。
これに対し、本発明品を用いた場合（使用例１〜３）では圧縮力が増加すると共に錠剤の破壊強度も著しく増加するが崩壊時間は短いままである。特に標準錠剤の破壊強度が１１ｋｇｆ以上である試料Ａ、Ｃ（使用例１、２）では、破壊強度が高い。これらのことから本発明を使用すれば、高い破壊強度を有し、かつ、速崩壊性の錠剤を容易に作成することが可能であることがわかる。
【００５２】
（実施例４）
市販ＤＰパルプを細断し、４％硫酸水溶液中で１０５℃で３時間加水分解して得られた酸不溶解残渣を濾過、洗浄、ｐＨ調整、濃度調整を行い、固形分濃度１７％の水分散体を得た。この水分散体を実施例１と同様にして乾燥後、ハンマーミルで粉砕し、目開き４２５μｍの篩で粗大粒子を除き、試料Ｈを得た。試料Ｈの基礎物性を表３に示す。
（実施例５）
実施例１と同様にして得られた酸不溶解残渣を濾過、洗浄、ｐＨ調整、濃度調整し、固形分濃度１８％の水分散体を得た。この水分散体を高圧滅菌器（オートクレーブ）に入れ、系の温度を１２１℃で２時間保ち、水分散体の温度を１２１℃に上げた後、放冷し、取り出した。取り出したときの水分散体の温度は９５℃であった。この水分散体をガラス板上に厚さ１ｍｍ程度に薄くのばし、棚段熱風乾燥機にて８０℃で乾燥した後、剥離してハンマーミルで粉砕し、目開き４２５μｍの篩で粗大粒子を除き、試料Ｉを得た。試料Ｉの基礎物性を表３に示す。
【００５３】
（比較例４）
加水分解時間を５分間とした以外は実施例１と同様に操作を行い、得られた乾燥未粉砕物を、不二パウダル（株）製フラッシュミルＦＬ−２００型にて粉砕し、目開き４２５μｍの篩で粗大粒子を除き、試料Ｊを得た。試料Ｊの基礎物性を表３に示す。
（比較例５）
レーヨン糸くずを細断し、０．３％塩酸水溶液中で１００℃で４０分間加水分解して得られた酸不溶解残渣をデカンテーション法で洗浄し、濾過、ｐＨ調整、濃度調整し、固形分濃度１０％の水分散体を得た。この水分散体を実施例１と同様にして乾燥後、気流式粉砕機で粉砕し、目開き４２５μｍの篩で粗大粒子を除き、試料Ｋを得た。試料Ｋの基礎物性を表３に示す。
【００５４】
（比較例６）
比較例１と同様にして得た酸不溶解残渣を濾過、洗浄、脱水し、水分５０％のウェットケークを得た。これをイソプロピルアルコールに分散し、濾過、脱液、再分散を２回行い、さらに日本精機製作所（株）製ゴーリンホモジナイザー１５Ｍ型にて、４００ｋｇｆ／ｃｍ^２ の処理圧で３回分散処理を行った。このスラリーにイソプロピルアルコールを加えて固形分濃度が１０重量％になるように調整した後、窒素循環型のスプレードライヤーにて噴霧乾燥（送風温度１５０℃、排風温度８３℃）を行い、目開き４２５μｍの篩で粗大粒子を除き、特開平２−８４４０１号公報記載の発明品に相当する試料Ｌを得た。試料Ｌの直径０．０１μｍ以上の細孔の全容積（水銀ポロシメーターにて測定）は０．７ｃｍ^３ ／ｇであった。試料Ｌのその他の基礎物性を表３に示す。
（比較例７）
市販ＤＰパルプを細断し、０．５％塩酸水溶液中で１２１℃で１時間加水分解して得られた酸不溶解残渣を濾過、洗浄、脱水し、真空乾燥機にて７０℃で乾燥し、水分４．２％の乾燥物を得た。これをハンマーミルで粉砕し、目開き４２５μｍの篩で粗大粒子を除き、特公昭４０−２６２７４号公報記載の発明品に相当する試料Ｍを得た。試料Ｍの基礎物性を表３に示す。
【００５５】
【表３】

【００５６】
（使用例４、５）
試料Ｈ、Ｉ、７０ｇと乳糖（ＤＭＶ社製、Ｐｈａｒｍａｔｏｓｅ１００Ｍ）６３０ｇとステアリン酸マグネシウム（太平科学産業（株）製）３．５ｇを用い、あとは使用例１と同様に打錠した。得られた錠剤の物性を表４に示す。
（比較使用例４〜７）
試料Ｈ、Ｉの代わりに試料Ｊ、Ｋ、Ｌ、Ｍを用いて使用例４と同様に打錠を行った。得られた錠剤の物性を表４に示す。
【００５７】
【表４】

【００５８】
表４の結果より、試料Ｌを用いた場合（比較使用例６）では圧縮力の増加と共に破壊強度も増加するものの、崩壊時間も非常に長くなっていることがわかる。試料Ｊを用いた場合（比較使用例４）では圧縮力が増加してもあまり破壊強度は増加しないが、崩壊は長くなっており、また、平均粒径が１２０μｍより大きいので打錠用粉体の流動性が低く、それを反映して錠剤の重量ＣＶが高くなっている。試料Ｋ、Ｍを用いた場合（比較使用例５、７）では圧縮力が増加しても崩壊時間は非常に短いが、破壊強度があまり高くならない。
これに対し、本発明品である試料Ｈ、Ｉを用いた場合（使用例４、５）では、その配合量が約１０重量％であるにも関わらず、圧縮力が増加すると共に錠剤の破壊強度も著しく増加するが崩壊時間は比較的短く、また、重量ＣＶが低いことから、低添加量で高破壊強度、速崩壊性、重量均一性の高い錠剤の作成が可能であることがわかる。
【００５９】
（実施例６）
実施例１と同様にして得られた酸不溶解残渣を濾過、洗浄、ｐＨ調整、濃度調整し、固形分濃度１９％の水分散体を得た。この水分散体をドラム乾燥機（スチーム圧力５ｋｇｆ／ｃｍ^２ 、ドラム表面温度１４３℃、ドラム回転速度５ｒｐｍ、溜め部水分散体温度１００℃）で乾燥後、不二パウダル（株）製フラッシュミルＦＬ−２００型にて粉砕し、目開き４２５μｍの篩で粗大粒子を除き、試料Ｎを得た。試料Ｎの基礎物性を表５に示す。
（実施例７）
精製リンターを充分ほぐし、後は実施例１と同様に処理して得られた酸加水分解残渣を濾過、洗浄、ｐＨ調整、濃度調整し、固形分濃度２０％の水分散体を得た。この水分散体をドラム乾燥機（スチーム圧力３ｋｇｆ／ｃｍ^２ 、ドラム表面温度１３１℃、ドラム回転速度１ｒｐｍ、溜め部水分散体温度９９〜１００℃）で乾燥後、ハンマーミルで粉砕し、目開き４２５μｍの篩で粗大粒子を除き、試料Ｏを得た。試料Ｏの基礎物性を表５に示す。
【００６０】
（比較例８）
加水分解時間を５分間とした以外は実施例１と同様に操作を行い、試料Ｐを得た。試料Ｐの基礎物性を表５に示す。
（比較例９）
市販の結晶セルロース（アビセル＜登録商標＞ＰＨ−１０１、旭化成工業（株）製）を試料Ｑとした。試料Ｑの基礎物性を表５に示す。
（比較例１０）
市販の結晶セルロース（アビセル＜登録商標＞ＰＨ−３０１、旭化成工業（株）製）を試料Ｒとした。試料Ｒの安息角は４１度であり、特公昭５６−３８１２８号公報記載の発明品に相当する。試料Ｓの基礎物性を表５に示す。
（比較例１１）
市販の結晶セルロース（ＧＲＡＤＥ Ｍ−１０１、ＭＩＮＧ ＴＡＩ ＣＨＥＭＩＣＡＬ ＣＯ．，ＬＴＤ．製）を試料Ｓとした。試料Ｓの基礎物性を表５に示す。
【００６１】
【表５】

【００６２】
（使用例６、７）
試料Ｎ、Ｏ、１５０ｇとフェナセチン（山本化学工業製）１５０ｇと乳糖（ＤＭＶ社製、Ｐｈａｒｍａｔｏｓｅ１００Ｍ）４５０ｇをポリ袋中で３分間混合し、ついでステアリン酸マグネシウム（太平科学産業（株）製）３．７５ｇを加え更に３０秒間混合したものを、ロータリー打錠機（（株）菊水製作所製、ＣＬＥＡＮＰＲＥＳＳ ＣＯＲＲＥＣＴ １２ＨＵＫ）で８ｍｍφ、１２Ｒの杵を用いてターンテーブル回転速度２５ｒｐｍで打錠し、重量２００ｍｇの錠剤を得た。その錠剤の物性を表６に示す。
【００６３】
（比較使用例８〜１２）
試料Ｎ、Ｏの代わりに試料Ｆ、Ｐ、Ｑ、Ｒ、Ｓを用いて使用例６と同様に打錠を行った。得られた錠剤の物性を表６に示す。
【００６４】
【表６】

【００６５】
表６の結果より、試料Ｆを用いた場合（比較使用例８）では圧縮力の増加と共に破壊強度も増加するものの、崩壊時間も極端に長くなっていることが分かる。
また、試料Ｆは平均粒径が小さく、嵩高い（見掛け比容積が大きい）ことから、打錠用粉体の流動性が低く、それを反映して錠剤の重量ＣＶが高い。試料Ｐを用いた場合（比較使用例９）では圧縮力が増加しても崩壊時間は非常に短いが、破壊強度があまり高くならない。市販の結晶セルロースである試料Ｑ、Ｒ、Ｓを用いた場合（比較使用例１０、１１、１２）でも同様の結果であった。
これに対し、本発明品である試料Ｎ、Ｏ（使用例６、７）では圧縮力が増加すると共に錠剤の破壊強度も著しく増加するが崩壊時間は短いままで、さらに錠剤の重量ＣＶが低いことから、高い破壊強度を有し、速崩壊性で、かつ、錠剤の重量均一性の高い錠剤を容易に作成することが可能であることがわかる。
【００６６】
【発明の効果】
本発明の高成形性賦形剤によると、該賦形剤は圧縮成形性に優れるので、錠剤の成形に適用した場合に少量の配合で成形が可能なので、小型錠やかぜ薬のような賦形剤の配合に制限があるような場合に有用である。
また、該賦形剤は低い圧縮力で成形が可能であるから、顆粒含有錠のような高い圧縮力を避けなければならない場合にも有用である。
さらに、該賦形剤は同時に崩壊性に優れるので、特に崩壊剤を配合することなく錠剤を製すること可能である。
また、独自の乾燥方法の開発により、賦形剤を構成する結晶セルロースの粉体特性（即ち酢酸保持率、見掛け比容積、見掛けタッピング比容積、比表面積）を特定の範囲にコントロールすることが可能となり、従来には存在しなかった、成形性と崩壊性のバランスのとれた高成形性賦形剤を提供できる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to excipients for compression molding. Tablet excipients, especially in the pharmaceutical fieldAnd its manufacturing methodAbout.
More specifically, the present invention controls the powder physical properties of crystalline cellulose, and has a good balance between moldability and disintegration for compression molding excipients.And its manufacturing methodAbout.
[0002]
[Prior art]
Many powder raw materials are compression-molded for the purpose of improving handleability and imparting functions. The most important property of a compression molded product (tablet) is that it has a strength that does not cause abrasion or breakage during transportation and use. Tablets in the pharmaceutical field, in addition to this property, must have a short disintegration time for rapid pharmacological effects after taking.
The reason is that common tablets disintegrate in the gastrointestinal tract after ingestion, and then the medicinal components dissolve in the gastrointestinal fluid, are absorbed from the gastrointestinal tract wall, dissolve in the blood, circulate in the body, and have a pharmacological effect. Because it exerts its effect, the fact that the tablet disintegrates in the digestive tract immediately after taking it means that the pharmacological effect is expressed more quickly.
[0003]
By the way, since many powder raw materials are not molded even when compressed, it is necessary to mix excipients having compression moldability. In order to impart the desired strength to the tablet, it is necessary to appropriately determine (1) the amount of the excipient and (2) the compression molding force. Generally, the tablet strength increases as the amount of the excipient compounded and the compression molding force are increased.
[0004]
However, when it is desired to increase the amount of the main ingredient (powder raw material) in the tablet, for example, in the case of manufacturing a small tablet in the pharmaceutical field, the amount of the excipient is significantly restricted, and A high compression molding force puts a burden on the compression molding machine (tableting machine), and it is not preferable because it accelerates the consumption of parts. Further, the granules coated with the film and the excipient are mixed and compressed. When obtaining tablets (such tablets are called granule-containing tablets) or when tableting enzymes or antibiotics, molding with lower compression molding force is required to prevent film damage and deterioration of enzymes and antibiotics. Need to be done. For that purpose, excipients are required to be used in smaller amounts and to exhibit higher compression moldability.
[0005]
Conventionally, crystalline cellulose is known as an excipient used for such a purpose. Microcrystalline cellulose is one of the excipients widely used in the pharmaceutical field because of its high safety, high compression moldability, and good disintegration.
For crystalline cellulose, the average degree of polymerization is 15 to 375, and the bulk is 7 to 34 lb / ft.³(1.84 to 8.92 cm³/ G), the use of crystalline cellulose having a particle size of 300 μm or less for pharmaceutical tablets increases tablet strength and improves disintegration (Japanese Patent Publication No. 40-26274): average degree of polymerization is 60 to 375, apparent specific volume. Is 1.6-3.1cm³/ G, apparent tapping specific volume is 1.40cm³/ G or more, 200 mesh or more is 2-80%, and the angle of repose is 35-42 degrees. When mixed with the main drug and additives, the mixed powder has high fluidity, and when tableted, It is known that the disintegration property is faster (JP-B-56-2047, JP-B-56-38128).
[0006]
The cellulose powder having moldability has an average degree of polymerization of about 450 to 650 and a compact apparent density of 0.40 to 0.60 g / cm.³(1.67-2.50cm³/ G), and a cellulose powder having a mesh size of 200% or less and 50% or more is an excipient suitable for tablet molding (Japanese Patent Publication No. 51-17172), and a specific average particle size (30 μm or less) , Specific surface area (1.3 m²/ G) is high in moldability (Japanese Patent Application Laid-Open No. 63-267731): it has a specific crystal form (cellulose I type), and the porosity of pores having a diameter of 0.1 µm or more is high. Cellulose powder of 20% or more and 350% or more of 90% or more has high fluidity and moldability (Japanese Patent Application Laid-Open No. 1-272643): In addition, the crystalline form is I-type and the specific surface area is Is 20m²/ G or more, the total volume of pores with a diameter of 0.01 μm or more is 0.3 cm³It is known that cellulose powder having a ratio of 50% / g or more and 100 μm or less has a high fluidity and high moldability (Japanese Patent Laid-Open No. 2-84401).
[0007]
However, among them, those having higher moldability have a drawback that disintegration is poor. In order to improve the moldability of crystalline cellulose, it is effective to increase the apparent specific volume. For this purpose, conventionally, crystalline cellulose is finely pulverized (JP-A-63-267731). A device has been devised to reduce the density of the particles themselves by making them porous (Japanese Patent Application Laid-Open No. 2-84401).
The invention described in JP-A-63-267731 has a high apparent specific volume because it is a fine powder, but has a low apparent tapping specific volume, so that it can be easily compacted by compression and exhibits high compression moldability. Since the gap (water pipe) is also reduced, the disintegration is extremely poor.
[0008]
Similarly, the invention described in JP-A-2-84401 has a very high specific surface area and a large apparent specific volume because it is porous. However, since the strength of the particles themselves is low, only the compression between the particles is performed by compression. However, deformation and consolidation of the particles are caused, and eventually the gap between the tablets (water guide tube) is reduced, so that the disintegration is extremely poor.
[0009]
[Problems to be solved by the invention]
As described above, conventional crystalline cellulose or cellulose powder has a disadvantage that the disintegration is poor if the moldability is high, and the moldability is low if the disintegration is good. No excipients were known.
As described above, excipients used in the pharmaceutical field need to have high moldability and good disintegration.
[0010]
[Means for Solving the Problems]
In view of the above situation, the present inventors have intensively studied the control of the powder physical properties of crystalline cellulose and the balance between moldability and disintegration, and as a result, have reached the present invention.
That is, the present invention provides:
{Circle around (1)} White powdered crystalline cellulose having an average degree of polymerization of 180 to 375 obtained by acid hydrolysis or alkali oxidative decomposition of a cellulosic substance, and having an acetic acid retention of 280.~ 353%And has a compression characteristic of the following equation (1).And the apparent specific volume is 4.0 to 6.0 cm ³ / G, apparent tapping specific volume is 2.4 to 6.0 cm ³ / G, specific surface area is 20m ² / G, less than 355 μm or more, and the average particle size is 30 to 120 μm.Provide highly moldable excipients. Also,
(Equation 2)

(Where a = 0.85-0.90, b = 0.05-0.10, and P is the compression pressure [kgf / cm²], V₀Is the apparent specific volume of crystalline cellulose [cm³/ G] and V is the specific volume of the crystalline cellulose at the compression pressure P [cm]³/ G])
[0011]
(2) It is also characterized in that the average degree of polymerization of white powdered crystalline cellulose is 180 to 220. Also,
▲ 3 ▼  500 mg of white powdered crystalline cellulose in 100 kgf / cm²The area of the bottom surface obtained by compressing with²It is also characterized in that the columnar molded body has a breaking strength in the diameter direction of 10 kgf or more and a collapse time of 100 seconds or less. Also,
▲ 4 ▼  It is also characterized in that the crush strength in the diameter direction of the columnar molded body is 11 kgf or more. MaWas,
▲ 5 ▼  Another characteristic is that the lateral relaxation time of the adsorbed water when the adsorbed water is 5 to 6% is 0.00024 seconds or less. Also,
▲ 6 ▼  The cellulosic substance is acid-hydrolyzed or alkali-oxidized and decomposed, and the cellulose particles obtained by purification are subjected to solid concentration.5-40Heat treatment at a temperature of 100 ° C. or more in a wet state or an aqueous dispersion state having a weight%, a pH of 5 to 8.5, and an electric conductivity of 300 μS / cm or less, and drying.Any of (1) to (5)Provided is a method for producing a highly moldable excipient. Also,
▲ 7 ▼  It is also characterized in that cellulose particles having a solid content of 5 to 23% by weight are heat-treated. Also,
▲ 8 ▼  Another feature is that heat treatment and drying are performed using a drum dryer or a belt dryer. Also,
[0012]
▲ 9 ▼  Cellulose material is acid-hydrolyzed or alkali-oxidized and decomposed to obtain cellulose particles obtained by purifying water having a solid content of 23% by weight or less, a pH of 5 to 8.5, and an electric conductivity of 300 μS / cm or less. Disperse, then dry in thin filmAny of (1) to (5)Provided is a method for producing a highly moldable excipient. Also,
(10)  It is also characterized in that drying is performed using a drum dryer or a belt dryer.
[0013]
Hereinafter, the present invention will be described in detail.
(A)High formability excipient
The highly moldable excipient of the present invention consists essentially of cellulose. “Substantially” means that components such as hemicellulose, lignin, oils and fats may be contained to the extent that the original function of cellulose is not lost. Its content is about 10% or less of the substance of the present invention excluding water.
[0014]
The crystalline cellulose referred to in the present invention is obtained by acid hydrolysis or alkali oxidative decomposition of a cellulosic substance such as purified wood pulp, bamboo pulp, cotton linter, and ramie, and has an average degree of polymerization of 180 to 375. Is a white powdery substance.
Since this substance has a specific degree of polymerization, it has particularly high moldability among cellulose powders, but its average degree of polymerization must be in the range of 180 to 375.
If the average degree of polymerization is less than 180, the moldability becomes insufficient, which is not preferable. On the other hand, if it exceeds 375, fibrousness appears, which is not preferable because the fluidity as a powder decreases. When the average degree of polymerization is 180 to 220ToThis is preferable because the balance between moldability and disintegration is good.
[0015]
The highly moldable excipient of the present invention,Its acetic acid retention is 280% or more, preferably 290% or more;The upper limit is not particularly limited, but is usually about 353% (Example 4). And,the above (1) formula(Kawakita's formula) (a = 0.85 to 0.90, b = 0.05 to 0.10.)
What is acetic acid retention in the present invention?,The sample powder is immersed in about 10 times the weight of acetic acid at room temperature for 30 minutes, and then centrifuged at 2000 G. The value indicates the amount of acetic acid that can be retained by the sample when the supernatant is removed. Expressed as a percentage by weight.
Acetic acid is absorbed by cellulose powder, but does not have such a strong swelling power as to dissociate hydrogen bonds of free hydroxyl groups present in the amorphous region (generally called keratinized tissue) [R. HASEBE, K .; MATSUMOTO, H .; MAEDA, Sen'i Gakkaishi, Vol. 12, p. 203-207 (1955)], and since the sample is condensed by applying centrifugal force to limit the amount of acetic acid retained in the interparticle space, the acetic acid retention rate is eventually determined by the porosity of the particle itself and its porosity. It shows the strength. In the present invention, the acetic acid retention must be 280% or more.
[0016]
In addition, Kawakita's formula [K. KAWAKITA, Y. TSUTSUMI, Bull. Chem. Soc. Japan, Vol. 39, no. 7, pp1364-1368 (1966)] is an empirical formula representing the change in volume due to the pressurization of powder, and is said to be particularly well matched to a powder whose volume change is large in the initial stage of pressurization. Microcrystalline cellulose is also one of the powders that conforms well to Kawakita's formula.
Kawakita's equation is represented by the following equation (1), where a and b are constants, and P is the compression pressure [kgf / cm²], V₀Is the apparent specific volume of crystalline cellulose [cm³/ G], and V is the specific volume of the crystalline cellulose [powder or tablet] at the compression pressure P [cm]³/ G].
(Equation 3)

In the case of crystalline cellulose, the larger the constants a and b, the higher the moldability tends to be. In the present invention, the constant a is 0.85 to 0.90, preferably 0.86 to 0.89, and the constant b is 0. It is necessary to be in the range of 0.05 to 0.10, preferably 0.06 to 0.09.
If a and / or b are lower than this value, the moldability is insufficient. Further, even if a and b are within the range, if the above-mentioned acetic acid holding power is less than 280%, or if a and / or b is higher than this value, the compression of the tablet remarkably proceeds by pressurization and compression. In addition, the disintegration properties of the tablet deteriorate.
[0017]
(B)Method for producing highly moldable excipients
BasicallyThe highly moldable excipient of the present invention can be produced by heat-treating and drying cellulose particles in a wet state or in a water-dispersed state in which almost no acid, alkali or decomposition product is present. When the treatment is not performed, it can be produced by drying the water-dispersed cellulose particles in a thin film state.
[0018]
(I) First, a manufacturing method in the case of performing a heat treatment will be described.
That is, the cellulose substance is obtained by subjecting the cellulosic substance to acid hydrolysis or alkali oxidative decomposition and, if necessary, to a mechanical treatment (eg, grinding) before or after that. Since the cellulose particles contain unnecessary components such as acids and alkalis in addition to water, they are removed and purified by filtration, centrifugation, membrane separation technology and the like.
The cellulose particles thus obtained are added with water as needed, and the solid content concentration is increased.5-40% by weight, Preferably 10 to 23% by weight, pH at 25 ° C of 5 to 8.5, preferably 5.5 to 8.0, and electric conductivity of 300 µS / cm or less, preferably 150 µS / cm or less.specificProvide heat treatment in wet state or water dispersion stateThere is a need.
At this time, not only pure water but also water containing a small amount of an organic solvent may be used.
When the solid concentration is 5 to 23% by weight, the heat treatment effect and the production efficiency are particularly high, so that it is preferable.Can be adopted.
In the existing production method of crystalline cellulose, for example, an aqueous dispersion of cellulose particles is heated at 100 ° C. or more at the end of acid hydrolysis, but a large amount of acid and decomposition products are present. Therefore, the structural change as described below could not be obtained, and the effect as in the present invention was not exhibited.
[0019]
The heat treatment may be carried out using a commonly used autoclave or a heat exchanger for high-viscosity fluids (for example, Frisham manufactured by Shinko Pantech Co., Ltd.), etc., to about 100 ° C. or more, preferably about 120 ° C. The time to keep is short. However, the cellulose particles in a wet state or in a water-dispersed state have a very low heat transfer and are therefore difficult to raise the temperature. In a case where a normal autoclave is used, the treatment time must be sufficiently long or sufficiently stirred. .
By such a heat treatment, cellulose particles, hydrogen ions, hydroxide ions, water molecules and the like interact. For example, an aqueous dispersion results in an increase in viscosity (gelation) and a decrease in pH.
It is not clear what structure it has, but it is not hard to imagine that cellulose particles or hydrogen ions, hydroxide ions, water molecules, etc. are associated and gelled. Although this structure does not break even when cooled to room temperature, the viscosity immediately decreases when lightly stirred with a glass rod or the like, and at the same time, the pH increases and returns to the state before the heat treatment.
However, the essence of the heat treatment is not such a macroscopic gel structure but a more microscopic structural change. This is because even though the structure of the entire system is broken, soft aggregation of the cellulose particles is observed, and it is considered that the association of the particles is still maintained microscopically.
Another evidence that the particles may be microscopically associated is the rate of water drying. The aqueous dispersion of cellulose particles once heat-treated has a drying rate of 10% or more faster than that of the non-heat-treated cellulose particles. This is because the particles are associated with each other and the dried matter has a sparse structure, so that the diffusion of moisture is good. It is considered to be.
[0020]
After the heat treatment as described above, moisture is evaporated and dried by various methods.
As a drying method, an ordinary method such as spray drying using a disk type or an air-based two-fluid nozzle type atomizer or tray hot air drying can be used.
This drying treatment may be performed after the cooling treatment is once performed, or may be performed continuously without cooling. The term “continuous” as used herein means that when the evaporation of water and the temperature rise of the aqueous dispersion of cellulose particles are simultaneously performed, the drying is completed after the temperature is raised to 100 ° C. or more in the presence of water. However, the water at this time may be in a gaseous state.
[0021]
Preferable examples of simultaneously performing the heating treatment and the drying treatment include a method using a drum dryer or a belt dryer. Further, a method of spray-drying with a two-fluid nozzle using steam at 100 ° C. or higher is also effective. The aqueous dispersion of cellulose particles when dried using a drum dryer has a solid content (cellulose particle) concentration of 10 to 23% by weight, a pH at 25 ° C of 5 to 8.5, and an electrical conductivity of 300 μS at 25 ° C. / Cm or less.
The drying conditions include a drum surface temperature of about 105 to 150 ° C., and a drum clearance, a drum rotation speed, and a supply of a cellulose particle dispersion so that the moisture content of the dried product at the end of the drying is about 3 to 5%. The amount and the like are appropriately selected.
[0022]
(Ii) Next, a description will be given of a manufacturing method in which the heat treatment does not need to be performed.
That is, the high formability excipient of the present invention, when not subjected to heat treatment, can be produced by drying the cellulose particles in a water-dispersed state while being thinly spread on a support such as a glass plate or an aluminum plate. Can be.
In that case, it is necessary to be in a water-dispersed state having a solid concentration of 23% by weight or less, a pH of 5 to 8.5 and an electric conductivity of 300 μS / cm or less.
Specific examples include a method in which an aqueous dispersion of cellulose particles is thinly spread on a glass plate or an aluminum plate and dried at room temperature or with air, or dried using a drum dryer or a belt dryer. .
After heat treatment, dry in a thin film stateis necessary.
The reason why crystalline cellulose having high moldability and excellent disintegration properties can be obtained by drying in a thin film state is not clear, but rod-like cellulose particles are two-dimensionally contacted with a support such as a glass plate. It is considered that drying shrinkage is restricted, that is, keratinization is suppressed.
[0023]
The use of a drum dryer for the production of crystalline cellulose and the like is described in, for example, Japanese Patent Publication No. 40-26274. However, in order to produce crystalline cellulose having high compression moldability and good disintegration properties. There is no description that the above conditions must be selected, and this is a technique that has not been known in the past.
In addition, the conventional spray drying method or hot air drying method, even when the air blowing temperature is 100 ° C. or higher, causes the product temperature to dry before the temperature rises to 100 ° C. due to latent heat of evaporation of water. Therefore, the "heat treatment" has not been performed, and a thin film state cannot be obtained, which is different from the technique of the present invention.
The powder thus obtained is,If necessary, pulverization and sieving are performed to adjust the particle size distribution before use.
[0024]
(C) Particle size of highly moldable excipient
(I) When the particle size distribution is measured by a sieving method, the highly moldable excipient of the present invention has substantially no fraction remaining on a 355 μm mesh sieve, and is represented by a cumulative particle size of 50% by weight. The average particle size is preferably from 30 to 120 μm, particularly preferably from 40 to 100 μm.
“Substantially” means that particles that are relatively large enough to not impair the function of the powder, such as fluidity, may be contained, and the value is about 5% by weight or less.
When the average particle size is less than 30 μm, the flow as a powder is deteriorated due to too many fine particles, and the disintegration of the tablet is deteriorated. On the other hand, if the average particle size exceeds 120 μm, the powder is coarsened, and the moldability is deteriorated and the mixing property with other powder raw materials is deteriorated.
[0025]
(Ii) Furthermore, the highly moldable excipient of the present invention has an apparent specific volume of 4.0 to 6.0 cm.³/ G, preferably 4.5-5.0 cm³/ G, apparent tapping specific volume is 2.4cm³/ G or more, preferably 1.5 cm³/ G or more of crystalline cellulose.
The apparent specific volume is 4.0cm³/ G is less than 6.0 cm.³/ G is not preferred because the fluidity of the powder decreases.
Apparent tapping specific volume is 2.4cm³If it is less than / g, the tablet is densified and disintegration deteriorates, which is not preferable. The upper limit of the apparent tapping specific volume is automatically 6.0 cm from the value of the apparent specific volume.³/ G, but there is no particular problem if it is less than this value.
Therefore, the apparent tapping specific volume is 2.4 to 6.0 cm. ³ / G.
[0026]
(Iii) The high-formability excipient of the present invention has a specific surface area of 20 m as measured by the BET method (using nitrogen as an adsorbent).²/ G, especially 10 m²/ G is preferred.
Specific surface area is 20m²/ G or more, the crystalline cellulose particles have to have pores having a large diameter (about 0.01 μm or more) inside themselves, and the strength of the particles becomes weak, so that the tablet is compacted, and eventually the tablet is compacted. However, it is not preferable because the disintegration worsens.
[0027]
(Iv) Summary
As described above, in the past, efforts were made to increase the apparent specific volume in order to improve the moldability of crystalline cellulose and the like, but since no consideration was given to the apparent tapping specific volume or the specific surface area, the disintegration property deteriorated. Was causing the situation.
However, the present inventors havethe aboveItem (B)Explained inOriginal drying method (In short, a specific solid content, a specific pH, and a specific electrical conductivity are referred to as heating and drying at 100 ° C or higher in a specific wet state or water dispersion state, or drying in a specific water dispersion state as a thin film. how to) By developingAcetic acid retention,The apparent specific volume, apparent tapping specific volume, and specific surface area can be controlled to specific ranges, and the present invention led to the invention of crystalline cellulose with a balance between moldability and disintegration, which did not exist before. is there.
[0028]
(D) Standard tablet preparation method
(I) A method for preparing a standard tablet will be described.
That is, to prepare a standard tablet, a mold as used when making a potassium bromide tablet in infrared absorption analysis is used.
However, such a structure is not particularly required since the pressure is not reduced during the compression molding, and a structure having only a metal die and a punch may be used. In addition, a one-side compression type or a two-side compression type may be used. The compression surface of the punch is flat and has an area of 1 cm to obtain a cylindrical molded body.²Must be circular.
The substance of the present invention (White powdered crystalline cellulose) 500 mg (including adsorbed water) was charged, and 100 kgf / cm was applied with a pressure device (hand press) equipped with a pressure gauge.², The pressure is maintained for 10 seconds, and then the sample is removed from the mold to prepare a standard tablet. Compression, pressure holding, and depressurization can also be performed by a universal tensile / compression tester (for example, Autograph manufactured by Shimadzu Corporation).
[0029]
(Ii) Next, a method for measuring the breaking strength and disintegration time of a standard tablet will be described.
That is, (1) the breaking strength is defined as the breaking strength, in which the side face of the standard tablet (cylindrical) is sandwiched between two parallel faces, stress is applied, and the stress when the standard tablet breaks. One surface for compressing the standard tablet is fixed, and one surface moves at a constant speed. The moving speed is about 4 to 13 cm / min. For this measurement, a commercially available tablet hardness tester or the above-mentioned universal tensile compression tester can be used.
{Circle around (2)} The disintegration time is measured using the Japanese Pharmacopoeia, Twelfth Edition, the general test method, and the disintegration test method for tablets.
[0030]
(Iii)Breaking strength and disintegration time of highly moldable excipients
The highly moldable excipient of the present invention can be used as a standard tablet (500 mg of white powdered crystalline cellulose in 100 kgf / cm ² The area of the bottom surface obtained by compressing with ² Cylindrical molded body)DiametricThe breaking strength is 10 kgf or more, preferably 11 kgf or more, and the disintegration time is 100 seconds or less, preferably 90 seconds or less.
As described above, existing excipients have a long disintegration time when the moldability is high. Therefore, an excipient having high moldability and excellent disintegration as in the present invention has not been known.
In general, it is said that a breaking strength of a tablet of about 4 kgf or more is practically necessary ["Pharmaceutical administration dosage form (published by Medical and Dental Medicine)", p. 157, 1983]. The disintegration time of a tablet in which 75% or more of the drug dissolves in 20 minutes or less for the purpose of rapid onset of drug efficacy is required to be 15 minutes or less. Unit Operations and Machines (Published by Hirokawa Shoten), 1989, p65].
[0031]
However, for example, in the case of manufacturing a cold medicine that requires a large amount of a poorly moldable drug and a fast-dissolving tablet, the existing excipient has a breaking strength of a standard tablet of 10 kgf. It was difficult to meet the two performances of the fast dissolving tablets described above because they did not exceed, or the disintegration time exceeded 100 seconds, or both.
The highly moldable excipient of the present invention solves such a problem.
That is, when the highly moldable excipient of the present invention is blended into a tablet formulation, tablet disintegration strength is higher than conventional excipients, and excellent disintegrable tablets can be produced. It is particularly preferable that the strength of the standard tablet is 11 kgf or more, because the strength of the tablet containing the highly moldable excipient is also increased.
[0032]
(Iii)Adsorption water lateral relaxation time of highly moldable excipient
The highly moldable excipient of the present invention preferably has an adsorbed water transverse relaxation time of 0.00024 seconds or less as measured by proton NMR spectroscopy when the product of the present invention contains 5 to 6% of water. .
In general, when the NMR spectrum of a solid sample having adsorbed water is measured using a 1H solution NMR probe, one broad peak derived from the adsorbed water is obtained. Therefore, the transverse relaxation time of the adsorbed water is calculated from the half width of this peak. You can do it. If this value exceeds 0.00024 seconds, the moldability is undesirably reduced.
Although the cause is not clear, it is supposed as follows.
In other words, the shorter absorption water transverse relaxation time means that the mobility of the water molecules is more restricted, so that there may be more hydroxyl groups in the cellulose molecules that are liable to form hydrogen bonds with the absorbed water.
[0033]
(Iv) One of the reasons for the high compressibility of crystalline cellulose is that the hydroxyl groups on the surface form hydrogen bonds via adsorbed water when the crystalline cellulose particles are pressed against each other or against other powder particles under stress. It is said to form. Therefore, it is considered that the shorter the absorption water lateral relaxation time is, the larger the amount of hydroxyl group that can contribute to compression molding is, and the higher the moldability is.
Conventionally, the main purpose of improving the compactibility of powder was to increase the pressure at the time of compression.However, in order to improve the compactability of crystalline cellulose, the contact strength at the contact point was improved. The invention is new.
[0034]
(V)Applications of highly moldable excipients
The highly moldable excipient of the present invention is used similarly to the existing excipients in the pharmaceutical field.
For example, when manufacturing tablets, it can be used as a binder in the direct powder compression method, dry granule compression method, post-wet compression method, but it has higher moldability than existing binders, such as crystalline cellulose. It is possible to mold with a small blending amount or with a low compression force. Further, since the disintegrating property is good, it is not necessary to add a disintegrating agent, or a small amount may be used. Particularly, it is effective for a formulation in which the amount of the excipient is limited, for example, a cold medicine or a small tablet having a large amount of the pharmaceutical ingredient, or a granule-containing tablet which requires molding with a low compression force. Also, it can be blended with a powder for the purpose of preventing blocking and improving fluidity, and can be blended with a capsule for the purpose of improving fillability. Further, it can be used in wet granulation such as an extrudability improver in extrusion granulation, a fluidized bed granulation, and a granulation aid in high speed stirring granulation.
In addition, those requiring high compression moldability, such as tablet type confectionery and health foods in the food field, solid foundations in the cosmetic field, and catalysts in the ceramics field can be used. Further, it can be used in foods as a dietary fiber or a texture improving agent.
[0035]
【Example】
Hereinafter, the present invention will be described in detail with reference to examples, but these do not limit the scope of the present invention.
The methods for measuring the physical properties of the aqueous dispersion of cellulose particles, the powder sample, and the tablet in Examples, Comparative Examples, Usage Examples, and Comparative Usage Examples are as follows.
・ PH [-]
The aqueous dispersion of cellulose particles is adjusted to 25 ° C. and measured with a glass electrode type hydrogen ion concentration meter (manufactured by Toa Denpa Kogyo KK, pH meter HM-20E).
[0036]
・ Electric conductivity [μS / cm]
The aqueous dispersion of cellulose particles is adjusted to 25 ° C. and measured with an electric conductivity measuring device (SC51POCKET type, manufactured by Yokogawa Electric Corporation).
・ Acetic acid retention [%]
About 3 g of the powder sample is precisely weighed and immersed in acetic acid (purity: 95% or more) about 10 times the weight of the sample at room temperature for 30 minutes. Subsequently, centrifugation is performed at 2000 G for 10 minutes, and the supernatant is removed. The weight (W) of the acetic acid wet product thus obtained was measured and then dried by heating under vacuum to obtain a dry product (W).₀) Is measured, and the acetic acid retention is calculated by the following equation. However, the measurement was performed twice, and the average was taken. Acetic acid retention = 100 · (W−W₀) / W₀
[0037]
・ Compression characteristics (constants a and b in Kawakita's equation)
0.50 g of the powder sample is precisely weighed, and the bottom area is 1 cm.²Is prepared in a one-sided compression-type mold capable of preparing a columnar molded body of 200, 400, 800, 1200, 1600 kgf / cm by a hand press.²And hold at this pressure for 10 seconds, then remove the tablet. A total of 50 tablets are produced at each pressure, and the weight and thickness of each tablet are measured, and the volume reduction rate (C) of the powder is calculated by the following equation.
C = (V₀−V) / V₀
(Where V₀Is the apparent specific volume of the powder described below [cm³/ G] and V is the specific volume of the tablet [cm³/ G]. )
The relationship between the compression pressure P and P / C is linearly regressed by the least square method (P / C = S + PT), and the constants a and b of Kawakita's equation are calculated from the slope T and the intercept S.
(A = 1 / T, b = T / S)
[0038]
・ Particle size distribution and average particle size
The particle size distribution of the powder sample was measured by sieving 30 g of the sample for 10 minutes using a JIS standard sieve (Z8801-1987) using a low tap sieve shaker (Sieve Shaker A type, manufactured by Heiko Seisakusho), and the particle size distribution was measured. The particle size of the cumulative 50% by weight is expressed as an average particle size.
When the fraction having a particle size of 45 μm or less is large, the particle size distribution is measured using an air jet sieve particle size distribution analyzer (ALPINE type air jet sieve A200LS), and the particle size of 50% by weight is determined to be the average particle size.
[0039]
・ Apparent specific volume [cm³/ G]
100cm³The powder sample is loosely filled in a glass measuring cylinder using a quantitative feeder or the like over a period of 2 to 3 minutes, the upper surface of the powder layer is leveled with a soft brush-like brush, and the volume is read. This is divided by the weight of the powder sample. The weight of the powder sample is 70-100 cm in volume³It is determined as appropriate so that
-Apparent tapping specific volume [cm³/ G]
After measuring the apparent specific volume, tapping is performed by hand on a low impact table such as a desk covered with a rubber plate. Tapping is performed by dropping the powder vertically from a height of several centimeters onto the table until the compaction of the powder layer stops. After the tapping is completed, the volume of the powder layer is read and divided by the weight of the powder sample.
[0040]
・ Average degree of polymerization [-]
INDUSTRIAL AND ENGINEERING CHEMISTRY Vol. 42, no. 3 Measured by a copper solution viscosity method described in pages 502 to 507 (1950).
・ Specific surface area [m²/ G]
The measurement is performed by BET method using Flowsorb II2300 manufactured by Shimadzu Corporation using nitrogen gas as an adsorption gas.
[0041]
・ Horizontal relaxation time of adsorbed water [s]
A powder sample whose absorbed moisture was adjusted to 5 to 6% (= 100 × water weight / (water weight + absolute dry sample weight)) was introduced into a sample tube for solution, and FT-NMR (AC200P type) from Bruker was used. It is measured using a 1H solution NMR probe. The horizontal relaxation time of the adsorbed water is determined by the following equation. Adsorption water horizontal relaxation time = 1 / (half width of obtained peak x π)
-Tablet weight [mg] and weight CV [%]
Ten tablets are precisely weighed, the number average value is defined as the tablet weight, and the coefficient of variation is defined as the weight CV.
[0042]
・ Table breaking strength [kgf]
A load is applied in the diameter direction of the tablet with a Schroingel tablet hardness tester (manufactured by Freund Corporation, 6D type), and is expressed as the load at the time of breaking. The number of repetitions is 10, and the number average is taken.
・ Tablet disintegration time [s]
Perform disintegration tests according to the 12th Revised Japanese Pharmacopoeia, General Test Methods and Tablet Disintegration Test Methods. The disintegration tester uses Toyama Sangyo Co., Ltd. NT-2HS type, and takes the number average value of six samples.
[0043]
(Example 1)
The commercially available DP pulp is shredded, and the acid-insoluble residue obtained by hydrolysis in a 10% aqueous hydrochloric acid solution at 105 ° C. for 30 minutes is filtered, washed, pH-adjusted and concentration-adjusted to obtain a solid content of 17% and a pH of 6 .4, an aqueous dispersion of cellulose particles having an electric conductivity of 120 µS / cm was obtained. This was dried with a drum dryer (Kusuki Kikai Seisakusho Co., Ltd., KDD-1 type, steam pressure 3.5 kgf / cm).²After drying at a drum surface temperature of 136 ° C., a drum rotation speed of 2 rpm, and a water dispersion temperature of a reservoir of 100 ° C.), the mixture was pulverized with a hammer mill, and coarse particles were removed with a sieve having openings of 425 μm to obtain a sample A.
Table 1 shows the basic physical properties of Sample A.
[0044]
(Example 2)
The commercially available KP pulp is shredded, and thereafter the acid-insoluble residue obtained by treating in the same manner as in Example 1 is filtered, washed, pH-adjusted, and concentration-adjusted. The solid content concentration is 21%, pH 8.4, electricity An aqueous dispersion of cellulose particles having a conductivity of 275 μS / cm was obtained. This is dried with a drum dryer (steam pressure 1.2 kgf / cm²After drying at a drum surface temperature of 110 ° C., a drum rotation speed of 0.5 rpm, and a reservoir water dispersion temperature of 99 to 100 ° C.), the mixture was pulverized with a hammer mill, and coarse particles were removed with a sieve having openings of 425 μm to obtain a sample B. Was.
Table 1 shows the basic physical properties of Sample B.
[0045]
(Example 3)
The acid-insoluble residue obtained in the same manner as in Example 1 was subjected to filtration, washing, pH adjustment, and concentration adjustment to obtain an aqueous dispersion of cellulose particles having a solid content of 18%, a pH of 7.2, and an electric conductivity of 84 μS / cm. Obtained. This is spray-dried (using a two-fluid nozzle, using steam as the fluid for atomizing the water dispersion, spray pressure of 4 kgf / cm²After drying at about 150 ° C.), sample C was obtained by removing coarse particles with a sieve having openings of 425 μm.
Table 1 shows the basic physical properties of Sample C.
[0046]
(Comparative Example 1)
A commercially available DP pulp is shredded, and an acid-insoluble residue obtained by hydrolyzing in a 10% hydrochloric acid aqueous solution at 105 ° C. for 30 minutes is filtered and washed, and dried at 80 ° C. in a tray hot air drier to obtain a hammer mill. Then, coarse particles were removed with a sieve having an opening of 425 μm to obtain a sample D.
Table 1 shows the basic physical properties of Sample D.
(Comparative Example 2)
The sample obtained in Comparative Example 1 was pulverized with an air-flow type pulverizer (single track jet mill STJ-200, manufactured by Seishin Enterprise Co., Ltd.) while changing the sample supply amount, and described in JP-A-63-267773. Samples E and F corresponding to the invention were obtained. Table 1 shows the basic physical properties of Samples E and F.
(Comparative Example 3)
The commercially available SP pulp was chopped, and the acid-insoluble residue obtained by hydrolyzing in a 1% aqueous sulfuric acid solution at 99 ° C. for 30 minutes was filtered, washed, and dried at 80 ° C. using a tray hot air dryer. The average degree of polymerization of the dried product was 452. Subsequently, this was pulverized by a hammer mill, further pulverized by a porcelain ball mill for 12 hours, and coarse particles were removed with a sieve having an opening of 425 μm to obtain a sample G corresponding to the invention described in JP-B-51-17172. . Table 1 shows the basic physical properties of Sample G.
[0047]
[Table 1]

[0048]
(Use examples 1 to 3)
150 g of Samples A, B and C and 600 g of lactose (Pharmatose 100M, manufactured by DMV) were mixed in a plastic bag for 3 minutes, then 3.75 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) was added and mixed for another 30 seconds. The obtained product was tableted with a rotary tableting machine (CLEANPRESS CORRECT 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.) using a 8 mmφ, 12R punch at a turntable rotation speed of 25 rpm to obtain a tablet weighing 200 mg. Table 2 shows the physical properties of the tablet.
[0049]
(Comparative Use Examples 1-3)
Tableting was performed in the same manner as in Use Example 1 except that Samples D, E, and G were used instead of Samples A, B, and C. Table 2 shows the physical properties of the obtained tablet.
[0050]
[Table 2]

[0051]
From the results in Table 2, it can be seen that when the sample E was used (Comparative Use Example 2), the breaking strength was increased with an increase in the compressive force, but the disintegration time was very long. In addition, in the case of Samples D and G (Comparative Use Examples 1 and 3), it can be seen that the disintegration time is not so long even if the compressive force increases, but the breaking strength does not increase so much.
On the other hand, when the product of the present invention is used (use examples 1 to 3), the compressive force increases and the breaking strength of the tablet also increases significantly, but the disintegration time remains short. In particular, in samples A and C (use examples 1 and 2) in which the breaking strength of the standard tablet is 11 kgf or more, the breaking strength is high. From these facts, it is understood that the use of the present invention makes it possible to easily produce a tablet having high breaking strength and fast disintegration.
[0052]
(Example 4)
The commercially available DP pulp is shredded, and the acid-insoluble residue obtained by hydrolyzing in a 4% aqueous sulfuric acid solution at 105 ° C. for 3 hours is filtered, washed, pH-adjusted and concentration-adjusted. A dispersion was obtained. This aqueous dispersion was dried in the same manner as in Example 1 and then pulverized with a hammer mill, and coarse particles were removed with a sieve having openings of 425 μm to obtain Sample H. Table 3 shows the basic physical properties of Sample H.
(Example 5)
The acid-insoluble residue obtained in the same manner as in Example 1 was filtered, washed, adjusted for pH, and adjusted for concentration to obtain an aqueous dispersion having a solid content of 18%. This aqueous dispersion was put into a high-pressure sterilizer (autoclave), the temperature of the system was kept at 121 ° C. for 2 hours, and the temperature of the aqueous dispersion was raised to 121 ° C., then allowed to cool and taken out. The temperature of the aqueous dispersion at the time of removal was 95 ° C. This aqueous dispersion was spread thinly on a glass plate to a thickness of about 1 mm, dried at 80 ° C. in a hot-air dryer, then peeled and ground with a hammer mill, and coarse particles were removed with a sieve having openings of 425 μm. A sample I was obtained. Table 3 shows the basic physical properties of Sample I.
[0053]
(Comparative Example 4)
The same operation as in Example 1 was carried out except that the hydrolysis time was set to 5 minutes, and the obtained dried and unground product was pulverized with a flash mill FL-200 manufactured by Fuji Paudal Co., Ltd., and the opening was 425 μm. Sample J was obtained by removing coarse particles with a sieve. Table 3 shows the basic physical properties of Sample J.
(Comparative Example 5)
Rayon lint is cut into pieces, and the acid-insoluble residue obtained by hydrolyzing in a 0.3% hydrochloric acid aqueous solution at 100 ° C. for 40 minutes is washed by a decantation method, followed by filtration, pH adjustment, concentration adjustment, and solidification. An aqueous dispersion having a concentration of 10% was obtained. This aqueous dispersion was dried in the same manner as in Example 1 and then pulverized with an air-flow type pulverizer. Sample K was obtained by removing coarse particles with a sieve having openings of 425 μm. Table 3 shows the basic physical properties of Sample K.
[0054]
(Comparative Example 6)
The acid-insoluble residue obtained in the same manner as in Comparative Example 1 was filtered, washed and dehydrated to obtain a wet cake having a water content of 50%. This was dispersed in isopropyl alcohol, filtered, drained, and re-dispersed twice, and further subjected to 400 kgf / cm with a Gaulin homogenizer 15M manufactured by Nippon Seiki Seisaku-sho, Ltd.²The dispersion processing was performed three times at a processing pressure of. After adding isopropyl alcohol to the slurry to adjust the solid content concentration to 10% by weight, spray drying is performed with a nitrogen circulation type spray drier (blast temperature: 150 ° C., exhaust temperature: 83 ° C.), and the openings are opened. Samples L corresponding to the invention described in JP-A-2-84401 were obtained by removing coarse particles with a 425 μm sieve. The total volume of pores having a diameter of 0.01 μm or more (measured by a mercury porosimeter) of the sample L is 0.7 cm.³/ G. Table 3 shows other basic physical properties of Sample L.
(Comparative Example 7)
Commercially available DP pulp is cut into pieces, and the acid-insoluble residue obtained by hydrolyzing in a 0.5% hydrochloric acid aqueous solution at 121 ° C. for 1 hour is filtered, washed, dehydrated, and dried at 70 ° C. in a vacuum dryer. And a dried product having a water content of 4.2%. This was pulverized with a hammer mill, and coarse particles were removed with a sieve having an opening of 425 μm to obtain a sample M corresponding to the invention described in Japanese Patent Publication No. 40-26274. Table 3 shows the basic physical properties of Sample M.
[0055]
[Table 3]

[0056]
(Usage examples 4 and 5)
70 g of Samples H and I, 630 g of lactose (manufactured by DMV, Pharmatose 100M) and 3.5 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) were used. Table 4 shows the physical properties of the obtained tablet.
(Comparative Use Examples 4 to 7)
Tableting was performed in the same manner as in Use Example 4 except that Samples J, K, L, and M were used instead of Samples H and I. Table 4 shows the physical properties of the obtained tablet.
[0057]
[Table 4]

[0058]
From the results in Table 4, it can be seen that when the sample L was used (Comparative Use Example 6), the breaking strength was increased with an increase in the compressive force, but the disintegration time was very long. In the case of using sample J (Comparative Use Example 4), the breaking strength was not so much increased even if the compressive force was increased, but the disintegration was long, and the average particle size was larger than 120 μm, so that powder for tableting was used. Is low in fluidity, and the weight CV of the tablet is accordingly high. When the samples K and M were used (Comparative Use Examples 5 and 7), the disintegration time was very short even if the compressive force was increased, but the breaking strength was not so high.
On the other hand, when the samples H and I of the present invention were used (Usage Examples 4 and 5), the compression force was increased and the tablet was broken even though the blending amount was about 10% by weight. Although the strength is also remarkably increased, the disintegration time is relatively short, and the weight CV is low, which indicates that a tablet with high breaking strength, rapid disintegration, and high weight uniformity can be prepared with a small amount of addition.
[0059]
(Example 6)
The acid-insoluble residue obtained in the same manner as in Example 1 was filtered, washed, adjusted for pH, and adjusted for concentration to obtain an aqueous dispersion having a solid content of 19%. This aqueous dispersion is applied to a drum dryer (steam pressure 5 kgf / cm).²After drying at a drum surface temperature of 143 ° C., a drum rotation speed of 5 rpm, and a reservoir water dispersion temperature of 100 ° C.), the mixture was pulverized with a flash mill FL-200 manufactured by Fuji Paudal Co., Ltd., and coarsened with a sieve having openings of 425 μm. Sample N was obtained by removing the particles. Table 5 shows the basic physical properties of Sample N.
(Example 7)
The purified linter was sufficiently loosened, and the acid hydrolysis residue obtained by treating in the same manner as in Example 1 was filtered, washed, adjusted for pH, and adjusted in concentration to obtain an aqueous dispersion having a solid content of 20%. This aqueous dispersion is applied to a drum dryer (steam pressure 3 kgf / cm²After drying at a drum surface temperature of 131 ° C., a drum rotation speed of 1 rpm, and a reservoir water dispersion temperature of 99 to 100 ° C.), the mixture was pulverized with a hammer mill, and coarse particles were removed with a sieve having openings of 425 μm to obtain a sample O. Table 5 shows the basic physical properties of Sample O.
[0060]
(Comparative Example 8)
A sample P was obtained in the same manner as in Example 1, except that the hydrolysis time was changed to 5 minutes. Table 5 shows the basic physical properties of Sample P.
(Comparative Example 9)
Sample Q was commercially available crystalline cellulose (Avicel® PH-101, manufactured by Asahi Kasei Corporation). Table 5 shows the basic physical properties of Sample Q.
(Comparative Example 10)
A commercially available crystalline cellulose (Avicel (registered trademark) PH-301, manufactured by Asahi Kasei Corporation) was used as Sample R. The angle of repose of sample R is 41 degrees, which corresponds to the invention described in Japanese Patent Publication No. 56-38128. Table 5 shows the basic physical properties of Sample S.
(Comparative Example 11)
Sample S was commercially available crystalline cellulose (GRADE M-101, manufactured by MING TAI CHEMICAL CO., LTD.). Table 5 shows the basic physical properties of Sample S.
[0061]
[Table 5]

[0062]
(Usage examples 6 and 7)
2. 150 g of samples N and O, 150 g of phenacetin (manufactured by Yamamoto Kagaku Kogyo) and 450 g of lactose (manufactured by DMV, Pharmatose 100M) were mixed for 3 minutes in a plastic bag, and then magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.). 75 g was added, and the mixture was further mixed for 30 seconds. The mixture was tableted with a rotary tableting machine (CLEANPRESS CORRECT 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.) at a turntable rotation speed of 25 rpm using a 8 mmφ, 12R punch, and a tablet weighing 200 mg. Got. Table 6 shows the physical properties of the tablet.
[0063]
(Comparative Use Examples 8 to 12)
Tableting was performed in the same manner as in Use Example 6, except that Samples F, P, Q, R, and S were used instead of Samples N and O. Table 6 shows the physical properties of the obtained tablet.
[0064]
[Table 6]

[0065]
From the results in Table 6, it can be seen that when the sample F was used (Comparative Use Example 8), the breaking strength increased with an increase in the compressive force, but the disintegration time was extremely long.
In addition, since the sample F has a small average particle size and is bulky (has a large apparent specific volume), the fluidity of the tableting powder is low, and accordingly, the tablet weight CV is high. In the case of using the sample P (Comparative Use Example 9), the disintegration time is very short even if the compressive force is increased, but the breaking strength is not so high. Similar results were obtained when using commercially available crystalline cellulose samples Q, R, and S (Comparative Use Examples 10, 11, and 12).
On the other hand, in the samples N and O (use examples 6 and 7) of the present invention, the compressive force is increased and the breaking strength of the tablet is significantly increased, but the disintegration time remains short and the tablet weight CV is low. This indicates that a tablet having high breaking strength, quick disintegration, and high tablet weight uniformity can be easily prepared.
[0066]
【The invention's effect】
According to the highly moldable excipient of the present invention, the excipient is excellent in compression moldability, and when applied to tablet molding, can be molded with a small amount of compounding, so that excipients such as small tablets and cold medicine can be obtained. This is useful when there is a limitation on the formulation of the excipient.
In addition, since the excipient can be molded with a low compression force, it is also useful when a high compression force such as a tablet containing granules must be avoided.
Further, since the excipient has excellent disintegration properties at the same time, it is possible to produce tablets without adding a disintegrant.
In addition, by developing a unique drying method, it is possible to control the powder properties (ie, acetic acid retention, apparent specific volume, apparent tapping specific volume, and specific surface area) of the crystalline cellulose constituting the excipient to a specific range. It is possible to provide a highly moldable excipient that has not been conventionally existed and that has a balance between moldability and disintegrability..

Claims (10)

It is a white powdered crystalline cellulose having an average degree of polymerization of 180 to 375 obtained by acid hydrolysis or alkali oxidative decomposition of a cellulosic substance, and has an acetic acid retention of 280 to 353% , and has a compression characteristic of the following formula (1). Having an apparent specific volume of 4.0 to 6.0 cm ³ / g, an apparent tapping specific volume of 2.4 to 6.0 cm ³ / g or more, and a specific surface area of less than 20 m ² / g, A high-formability excipient characterized by having no particles having a size of 355 μm or more and having an average particle size of 30 to 120 μm .

(However, a = 0.85 to 0.90, b = 0.05 to 0.10, and P is a compressive pressure against crystalline cellulose [kgf / cm ² ], and V ₀ is an apparent specific volume of crystalline cellulose [ cm ³ / g], and V represents the specific volume [cm ³ / g] of the crystalline cellulose at the compression pressure P) The highly moldable excipient according to claim 1, wherein the average degree of polymerization of the white powdered crystalline cellulose is 180 to 220. A columnar molded body having a bottom surface area of 1 cm ² obtained by compressing 500 mg of white powdered crystalline cellulose at 100 kgf / cm ² for 10 seconds has a breaking strength in the diameter direction of 10 kgf or more, and a disintegration time high moldability excipient according to claim 1, characterized in that within 100 seconds. 3. The highly moldable excipient according to claim 2, wherein the cylindrical molded body has a breaking strength in the diameter direction of 11 kgf or more. 4. The highly moldable excipient according to any one of claims 1 to 3 , wherein the lateral relaxation time of the adsorbed water when the adsorbed moisture is 5 to 6% is 0.00024 seconds or less. The cellulose particles obtained by subjecting the cellulosic substance to acid hydrolysis or alkali oxidative decomposition and purifying the resulting cellulose particles have a solid content of 5 to 40% by weight , a pH of 5 to 8.5, and an electric conductivity of 300 μS / cm or less. The method for producing a highly moldable excipient according to claim 1, wherein the excipient is heat-treated at 100 ° C. or higher in a wet state or a water-dispersed state and dried. The high-formability excipient according to claim 6 , wherein cellulose particles having a solid content of 5 to 23% by weight are heat-treated. The method for producing a highly moldable excipient according to claim 6, wherein the heat treatment and the drying are performed using a drum dryer or a belt dryer. The cellulose particles obtained by purifying the cellulosic substance by acid hydrolysis or alkali oxidative decomposition and purifying the cellulose particles are mixed with water having a solid content of 23% by weight or less, a pH of 5 to 8.5 and an electric conductivity of 300 μS / cm or less. The method for producing a highly moldable excipient according to any one of claims 1 to 5, wherein the excipient is dispersed and then dried in a thin film state. The method for producing a highly moldable excipient according to claim 9, wherein the drying is performed using a drum dryer or a belt dryer.