JP2004067670A - Single substance spherical particle, food and medicine by using the same, and method for producing them - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide spherical particles consisting of a sugar alcohol, sodium chloride, vitamin C, etc., and useful for a granulation coating in medicine manufacturing and for a food. <P>SOLUTION: The spherical particles consist of spheres obtained by granulating particles containing ≥95 wt. % water soluble single substance and having ≤1.2 aspect ratio, ≥0.65 g/ml bulk density of aggregate and ≤35° angle of repose, and is characterized with that (1) the water soluble single substance consists of 1 kind selected from the sugar alcohol, vitamin C and sodium chloride, (2) the viscosity of a saturated aqueous solution of the water soluble single substance is ≤10 cps within 25-45°C range, and (3) the spherical particles have ≤1.0 % degree of abrasion. <P>COPYRIGHT: (C)2004,JPO

Description

【００２３】
表１の単一物質を比べると、グラニュー糖は他の単一物質より粘度が際だって高いことがわかる。
従来、グラニュー糖がバインダー（結合剤）として用いられている事例があるが、その場合のバインダーとして使用する液の粘度は、通常１００ｃｐｓ前後であり、加温した場合でも４０ｃｐｓ程度である。しかし、本発明の単一物質の水溶液に求められる粘度は低く、通常の結合剤の範疇にないことがわかる。
【００２４】
単一物質の例としては、糖アルコール、ビタミンＣ、塩化ナトリウム、乳糖などがある。とりわけ、糖アルコール、塩化ナトリウムはアルデヒド基を持たないためメイラード反応がなく、医薬の造粒コーテイング用球形粒の原料として好ましい。また、同時に食品用球形粒の原料としても好ましい。
単一物質としての糖アルコールの例としては、Ｄ−マンニトール及びエリスリトールの各単独、又はそれらの混合物などがあるが、特に好ましくはＤ−マンニトールである。また、単一物質としてのビタミンＣの例としては、Ｌ−アスコルビン酸及びＬ−アスコルビン酸ナトリウムの各単独又はその混合物などが挙げられる。
【００２５】
本発明において核として使用される単一物質造粒物あるいは単一物質結晶粒子は、少なくとも５００μｍパスの粒径であり、特にその粒径が３００μｍパス、１５０μｍオンのものが好ましく用いられる。単一物質造粒物あるいは単一物質結晶粒子の粒径が大きくなると、得られる球形粒の径も大きくなる。
本発明で球形粒の製造に使用される単一物質粉末は、７５μｍパスの単一物質の結晶の粉末であり、好ましくは核となる単一物質造粒物あるいは単一物質粒子の平均粒径に対して５分の１〜１０分の１以下のものである。単一物質粉末は、その粒径が小さい程良好であり、単一物質の結晶の微粉末を用いることができる。具体的には、糖アルコール、ビタミンＣ及び塩化ナトリウムなどの微粉末が挙げられる。また、圧縮されていたり、吸湿して固まっている場合は、公知の乾式粉砕機などで７５μｍ以下になるまで粉砕して用いられる。
【００２６】
本発明の単一物質造粒物とは、単一物質粉末を造粒して得られたものである。単一物質造粒物の製造は、水又は単一物質の水溶液を添加して造粒する方法であるため、単一物質は水溶性である必要がある。
【００２７】
本発明の方法に使用する造粒物は、たとえば押し出し造粒方法では、単一物質粉末をニーダーに仕込み、水又は単一物質の水溶液を加えて混練りし、押し出し造粒し、乾燥後、篩分けすることによって製造される。
また、湿式攪拌造粒方法では、攪拌造粒機（深江工業株式会社製、商品名、ハイスピードミキサー）に単一物質粉末を仕込み、水又は単一物質の水溶液を加え、攪拌造粒することによって製造される。
また、遠心流動造粒法では、遠心流動造粒機（フロイント産業株式会社製、商品名、スパイラフロー）に単一物質粉末を仕込み、水又は単一物質の水溶液を加え、遠心流動造粒することによって製造される。
【００２８】
また、遠心転動造粒法では、まず、ニーダーに単一物質粉末を仕込み、水又は単一物質の水溶液を加えて混練り後、パワーミルで整粒し、これを遠心転動造粒機（フロイント産業株式会社製、商品名、ＣＦグラニュレーター）に仕込み、水又は単一物質の水溶液を加え、遠心転動造粒する。
【００２９】
本発明の単一物質球形粒におけるアスペクト比とは、球形粒の長軸と短軸との比であり、真球度を示す目安となるものである。そして、長軸、短軸の比は、球形粒をスライドグラス上にランダムに置き、写真撮影し、５０個の球形粒について長軸の長さ（長径）と長軸の中点から垂直に引いた短軸の長さ（短径）を各々測定し、各々について短径に対する長径の比を求め、５０個の平均値で示したものである。
【００３０】
本発明の単一物質球形粒におけるカサ密度は、１００ｍｌのメスシリンダー（重量Ｗ）に球形粒を軽く山盛りに入れた後、摺り切り秤量した重量Ｗｂを秤量し、（Ｗｂ−Ｗ）／１００より求めた値であり、５回測定の平均値で示される。
【００３１】
本発明の単一物質球形粒における安息角の測定は、特開平６−２０５９５９号公報に記載されている野上・杉原法によって行い、５回の測定の平均値で示したものである。測定器は図２に示されているように、４枚のガラス板を貼り合わせて作成されている図２に示される装置であり、該装置による安息角の測定は、Ａ壁に沿って試料約２００ｍｌをガラス床となっているＢ面上にロートを使って静かに流し込み、Ｂ面の前方開口端から試料の流れ出しが始まるまで流し込みを続け、試料の流れ出しが起った時点におけるＢ面上の試料層の傾斜上面がＢ面（水平面）となす角度を分度器Ｃで読み取ることによって行われる。
【００３２】
本発明の単一物質球形粒の集合体における摩損度とは、粒子同士、あるいは粒子と器壁とが触れ合うときの衝撃によって、粒子は破壊されないが、粒子表面が摩耗する度合を数値化したものである。その測定は、容器に一定量の球形粒子を入れ、回転ないしは振動を与え、一定時間後に取り出して、摩耗によって球形粒子から剥離した粉末を、ふるいで取り除き元の重量との比を求め、パーセンテージで表すことによって行われる。
【００３３】
具体的な摩損度の測定の一例を示すと、球形粒重量Ｗｔ（約１０ｇ）を精密に量りとり、内径３２ｍｍ×深さ６５ｍｍのステンレス製円筒容器に入れ、ＳＰＥＸ社製ミキサーミルを用い、１１００ｒｐｍで正確に１０分間振とうした後、５０号（３００μｍ）ふるいに移して、篩分け操作を行い、その残留量Ｗｓ（ｇ）を精密に量りとって次式により摩損度を求める。
【００３４】
【数１】

この摩損度は、通常１．０％以下であることが好ましく、より好ましくは０．５％以下である。
【００３５】
本発明の単一物質球形粒の製造工程で採用されている固定化処理とは、球形粒の表面を平滑にするための処理及び摩損度の改善のための処理の双方を意味している。
本発明の単一物質からなる球形粒の製造に使用できる水溶性高分子としては、ゼラチン、カゼインなどの動物系、アルギン酸、カラギーナン、ヘミセルロース、ゼインなどの植物系、カルボキシメチルセルロース、メチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースなどのセルロース系、ポリビニルピロリドン、ポリアクリル酸塩、ポリビニルアルコールなどの合成系、やプルランなどが例示されるが、これらに限定されるものではない。
【００３６】
水溶性高分子は希薄水溶液として使用される。水溶性高分子の希薄水溶液の濃度は各種の水溶性高分子のバインダーとしての結合力が弱くなるように、水溶性高分子ごとに実験的に定められる。
【００３７】
本発明では、５％未満の範囲で水溶性ビタミン類、解熱鎮痛剤等の種々の薬剤（薬効を有する種々の物質）から適宜選ばれた薬剤が本発明の単一物質球形粒に含まれることができる。むろん実質的に１００％単一物質球形粒としてもよい。また、本発明では、５％未満の範囲で水溶性ビタミン類、香料などから適宜選ばれた食品や食品添加物を単一物質球形粒に含ませることができる。むろん実質的に１００％単一物質からなる球形粒としてもよい。
【００３８】
本発明の単一物質球形粒の製造に使用される遠心転動装置は、処理容器底部にほぼ水平に回転する平滑な回転円板と、前記回転円板を回転させる回転軸と、処理容器の内壁部と前記回転円板の円周部に位置する縁部との間に形成される環状の空隙であるスリットと、前記スリットより処理容器内にスリットエアを供給するためのスリットエア供給装置と処理容器内の被処理物（単一物質結晶又は単一物質造粒物）へ水、単一物質水溶液、水溶性高分子の希薄水溶液から選ばれた少なくとも１種を噴霧するためのスプレーノズルと被処理物へ粉末を散布する粉末散布装置とを有するものである。この装置の例としては図１に示されるフロイント産業株式会社製のＣＦグラニュレータ（以下ＣＦ装置と略す）がある。（但し、スリットエア供給装置は図示せず）。
【００３９】
上記のＣＦ装置は造粒コーティング装置と呼ばれる範ちゅうに入るものであるが、本発明の方法で使用できる造粒コーティング装置は上記特定のＣＦ装置に限定されず、前記基本的な構成を有する装置であれば各種の造粒コーティング装置が使用できる。ＣＦ装置を種々変形可能にする例としては、回転円板の上に立設される回転軸や、回転円板の縁部が上方に反っているタイプだけでなく水平なタイプでもよく、また、回転円板の上面は少なくとも粉体に接している部分が平滑である必要があるが、円板の中心部には突起物があってもよく、種々変形が可能なのはいうまでもない。
【００４０】
本発明の流動層装置は、遠心転動装置で製造された湿潤球形粒を入れるための収納容器と、前記球形粒を流動させる流動エアを供給する流動エア供給装置と、前記球形粒に単一物質水溶液及び／又は水溶性高分子溶液の希薄水溶液を噴霧するためのスプレーノズルとを有するものであり、例えば、フロイント産業株式会社製、商品名、「フローコーター」（以下「ＦＬ装置」と略す）が使用可能である。この装置は流動層造粒コーティング装置の範ちゅうに入り、本発明では前記の基本的な構成を有する装置であれば前記の特定のＦＬ装置に限定されず、通気部を有する回転円板を備えた流動層装置（例えばフロイント産業株式会社製のローターコンテナを備えたＦＬ装置や遠心流動造粒コーティング装置、商品名「スパイラフロー」）など種々のものを用いることができる。
【００４１】
本発明の単一物質球形粒の製造に使用される遠心転動装置において噴霧する液は、水単独でもよいが、所望により少量の水溶性高分子を溶解させてもよいし、単一物質水溶液、又はこれらに着色剤等を少量添加したものであってもよい。しかし、通常は水単独の使用が好ましい。
【００４２】
次に本発明の単一物質球形粒製造方法を図１に示したＣＦ装置を参照しながら説明する。
図中、符号１は造粒容器、２は回転円板、２ａは円板縁部、３は回転軸、４はスリット、４ａはスリットエア、５はエアチャンバー、６は除湿装置、７は熱交換器、８は単一物質粉末、９は散布装置、１０は噴霧用液、１１はタンク、１２は定流量ポンプ、１３はスプレーノズル、１４は噴霧用エアー、１５は製品排出装置、１６はステーターカバー、１７はスリットエア用空気を表す。
【００４３】
図１のＣＦ装置では、図示しないモーター等の駆動機構によって回転軸３を回転し、回転円板２を回転させながら、スリットエア用空気１７が除湿装置６、熱交換器７、エアチャンバー５を通ってスリットエア４ａとしてスリット４から造粒容器１内に供給され、単一物質造粒物（あるいは単一物質粒子）が回転円板上に仕込まれる。
【００４４】
同時に単一物質粉末８が散布装置９よりスリットエア４ａの吹き出し縁部２ａ付近に散布されて、これが単一物質造粒物（あるいは単一物質）と混合され、同時に噴霧用液１０がタンク１１よりスプレーノズル１３を経てスリット４近傍の単一物質造粒物（あるいは単一物質）に噴霧され、造粒が行われて湿潤単一物質球形粒が製造される。
【００４５】
このようにして製造された湿潤単一物質球形粒は、ついで図示していないＦＬ装置に送られ、そこで流動用エアーによって流動化された状態で単一物質水溶液等の液体の噴霧条件下にコーティングと乾燥が行われる固定化処理が施されて最終製品である前記物性を備えた単一物質球形粒が製造される。
【００４６】
本発明の医薬の形態としては、その内部に上記球形粒を含有する限りにおいて、製剤化可能なすべての剤形があり得るが、好ましくは、顆粒剤又は該顆粒剤を内包するカプセル剤である。
球形粒の含有割合は、それを用いる製剤の種類によって異なるが、例えば、顆粒剤の場合には、通常、製剤全体に対して、約５〜９０重量％、好ましくは約２０〜７０重量％である。
用いる球形粒としては、薬物との安定性等の点から、球形粒を構成する単一物質がＤ−マンニトールを主原料として他の成分、例えばキシリトール、エリスリトール等の糖アルコールを含有するものであってもよい。
【００４７】
医薬活性成分は、球形粒の内部又は外部のいずれに存在してもよいが、好ましくは外部に存在する。
医薬活性成分としては、例えば、解熱鎮痛剤、鼻炎薬、循環器系薬、消化器系薬、抗生物質、化学療法剤、ビタミン剤、麻薬性鎮痛薬、ホルモン剤、抗うつ薬、抗炎症薬、抗精神薬等が例示され、具体的には塩酸フェニルプロパノールアミン、アスピリン、イブプロフェン、インドメタシン、フェニトイン、アセトアミノフェノン、エテンザミド、モルヒネ、ニフェジピン、フェノバルビタール、セファレキシン等が例示される。
【００４８】
次に本発明医薬品の代表的な製法を説明する。まず球形粒の表面に、所望により結合剤の存在下、医薬活性成分を含有する粉末又は液状物質をコーティングして主薬相を形成させ、素顆粒を調製する。その際コーティング方法としては、攪拌造粒、遠心転動造粒、流動層造粒、通常型又は通気型コーティングパン等が例示される。
次に、該素顆粒を適宜、表面処理することにより顆粒剤が得られる。この際、徐放性タイプのものを得たい場合には、表面処理の方法として、例えば、所望により撥水性物質を含有する物質を粉末コーティングしたりした後、徐放性ポリマーによりフィルムコーティングを施す等の操作を行えばよい。
【００４９】
該撥水性物質としては、例えば、硬化ヒマシ油などの硬化グリセリン脂肪酸エステル類、ステアリン酸類等の高級脂肪酸類、ステアリン酸マグネシウム等の高級脂肪酸金属塩類、ステアリルアルコール等の高級アルコール、カルナバロウ等のワックス類等が例示される。
【００５０】
徐放性ポリマーとしては、エチルセルロース、メタアクリル酸エチル・メタアクリル酸塩化トリメチルアンモニウムエチルコポリマー（オイドラギッドＲＳ）、セラック、高重合度ポリビニルアルコール、ポリビニルピロリドン、ポリ塩化ビニル、セルロースアセテート、ポリウレタン、テトラフルオロエタン、ポリスチレン、ポリプロピレン、乳酸重合体、ヒドロキシエチルメタアクリレート、ポリエチレンテレフタレート、ポリエチレン、ポリアミド、ポリアクリロニトリル、ポリカルボン酸、シアノアクリレート重合体などが例示される。
【００５１】
【実施例】
以下、実施例によって本発明を詳細に説明するが、本発明はこれらの実施例に限定されるものではない。
実施例１
攪拌造粒機（深江工業株式会社製、商品名、ハイスピードミキサーＦＳ−２５）の造粒容器にＤ−マンニトール粉末を３ｋｇ仕込み、Ｄ−マンニトールの２０重量％水溶液を加えつつ、アジテーターとチョッパーを回転しながら攪拌造粒を行い、終了後、造粒物を取り出した。この造粒物を乾燥後、３５５μｍから５００μｍに篩別して、球形造粒用の核として使用するＤ−マンニトール造粒物を得た。
【００５２】
次に、遠心転動造粒装置（フロイント産業株式会社製、商品名、ＣＦグラニュレーターＣＦ−３６０、以下ＣＦ装置と略す）の造粒容器に、核として前記のように得られたＤ−マンニトール造粒物を１ｋｇ仕込み、スリットエアーを供給しながら、回転円板を１８０ｒｐｍで回転させた。続いて、平均粒径７．４μｍのＤ−マンニトール粉末１ｋｇを２５ｇ／ｍｉｎの供給速度でＤ−マンニトール造粒物に散布しつつ、Ｄ−マンニトール２０重量％水溶液４００ｍｌを０．８ｋｇ／ｃｍ^２　の圧力を加えながら、噴霧造粒し、湿潤状態のＤ−マンニトール球形粒を得た。
【００５３】
次に、得られた湿潤球形粒を流動層造粒装置（フロイント産業株式会社製、商品名、フローコーターＦＬ−５、以下ＦＬ装置と略す）の造粒容器に入れ、６０℃で乾燥しながら、Ｄ−マンニトールの２０重量％水溶液１ｋｇを４０ｍｌ／ｍｉｎの速度で噴霧コーテイングした。こうして５００μｍから７１０μｍのＤ−マンニトール球形粒が８４．５％の収率で得られた。
この球形粒のアスペクト比は１．０９であり、集合体としてのカサ密度は０．７０ｇ／ｍｌ、安息角は３１度であった。また、この球形粒の表面は図５で示すとおり、平滑であり、摩損度は０．２７％であった。
【００５４】
実施例２
Ｄ−マンニトール粉末２ｋｇをニーダーに仕込み、水２００ｇを加えて１５分間練り合わせた後、４ｍｍスクリーンを付したパワーミルを用いてほぐし、湿潤造粒物を得た。この湿潤造粒物を核としてＣＦ装置に仕込み、２００ｒｐｍで回転し、水７０ｍｌを５ｍｌ／ｍｉｎの速度で噴霧造粒した。これを乾燥し、篩過して球形造粒用の核としてＤ−マンニトール造粒物を得た。この造粒物の粒径範囲は２１２μｍから３５５μｍであった。
【００５５】
核としてＤ−マンニトール造粒物（３５５μｍ〜５００μｍ）の代わりに前記Ｄ−マンニトール造粒物（２１２μｍ〜３５５μｍ）を用いた他は実施例１と同様に操作したところ、３００μｍから５００μｍのＤ−マンニトール球形粒が８０．２％の収率で得られた。
この球形粒のアスペクト比は１．１０であり、カサ密度は０．７２ｇ／ｍｌ、安息角は３２度であった。得られた球形粒の表面は図５と同様に平滑であり、摩損度は０．３４％であった。
【００５６】
実施例３
実施例２で得られた核であるＤ−マンニトール造粒物（２１２μｍ〜３５５μｍ）１ｋｇをＣＦ装置に仕込み、スリットエアーを供給しながら、１８０ｒｐｍで回転円板を回転させた。続いて、平均粒径７．４μｍの粉末Ｄ−マンニトール１ｋｇを２５ｇ／ｍｉｎの供給速度で核に散布しつつ、ヒドロキシプロピルセルロース（日本曹達株式会社製、商品名、ＨＰＣ−Ｌ）１重量％水溶液２４０ｍｌを０．８ｋｇ／ｃｍ^２　の圧力を加え、４０分間、核に噴霧造粒した。これを乾燥し、篩別してＤ−マンニトール湿潤球形粒を得た。
【００５７】
次に、得られた湿潤球形粒をＦＬ装置の造粒容器に入れ、６０℃で乾燥しながら、Ｄ−マンニトールの２０重量％水溶液１ｋｇを４０ｍｌ／ｍｉｎの速度で噴霧コーテイングした。こうして３００μｍから５００μｍのＤ−マンニトール球形粒が７８．５％の収率で得られた。
この球形粒のアスペクト比は１．１５であり、カサ密度は０．７１ｇ／ｍｌ、安息角は３３度であった。得られた球形粒の表面は図５と同様に平滑であり、摩損度は０．３５％であった。
【００５８】
実施例４
予めＣＦ装置の造粒容器内にスリットエアーを供給しながら、１８０μｍから３５５μｍに篩過した結晶ビタミンＣ（Ｌ−アスコルビン酸）５００ｇを核としてＣＦ装置の回転円板上に仕込み、２００ｒｐｍで回転円板を回転させた。続いて、平均粒径２１．４μｍの粉末ビタミンＣ（Ｌ−アスコルビン酸）１５５０ｇを６０ｇ／ｍｉｎの供給速度で核に散布しつつ、水を０．８ｋｇ／ｃｍ^２　の圧力で１０ｍｌ／ｍｉｎの速度で核に噴霧造粒し湿潤球形粒を得た。
【００５９】
この湿潤球形粒をＦＬ装置に仕込み、６０℃で流動乾燥した。乾燥終了後、同一の流動条件下にビタミンＣ（Ｌ−アスコルビン酸）２０重量％水溶液８００ｇを４０ｍｌ／ｍｉｎの速度で噴霧、乾燥してコーテイングした。こうして３５５μｍから６００μｍの実質的に１００％ビタミンＣ（Ｌ−アスコルビン酸）のみからなる球形粒が７５％の収率で得られた。この球形粒のアスペクト比は１．１０であり、集合体としてのカサ密度０．８６ｇ／ｍｌ、安息角は３１度であった。得られた球形粒の表面は図７に示すように平滑であり、摩損度は０．４６％であった。
【００６０】
実施例５
７５μｍの篩いを通過した粉末ビタミンＣ（Ｌ−アスコルビン酸ナトリウム結晶）１ｋｇに１０重量％ＨＰＣ−Ｌ水溶液１００ｍｌを加え、ニーダーで練り合わせてた後、０．５ｍｍのスクリーンで押し出し造粒し、乾燥し、整粒し、篩いを用いて粒径５００μｍから７１０μｍのビタミンＣ（Ｌ−アスコルビン酸ナトリウム）造粒物を得た。
【００６１】
予めＣＦ装置の造粒容器内にスリットエアーを供給しながら、前記ビタミンＣ造粒物（Ｌ−アスコルビン酸ナトリウム）５００ｇを核としてＣＦ装置の回転円板上に仕込み、２００ｒｐｍで回転円板を回転させた。続いて、平均粒径２１．４μｍの粉末ビタミンＣ（Ｌ−アスコルビン酸ナトリウム結晶）１０００ｇを６０ｇ／ｍｉｎの供給速度で核に散布しつつ、水を０．８ｋｇ／ｃｍ^２　の圧力で１０ｍｌ／ｍｉｎの速度で核に噴霧造粒し湿潤球形粒を得た。
この湿潤球形粒をＦＬ装置に仕込み、６０℃で流動乾燥した。乾燥終了後、同一の流動条件下にビタミンＣ（Ｌ−アスコルビン酸ナトリウム）２０重量％水溶液８００ｇを４０ｍｌ／ｍｉｎの速度で噴霧、乾燥してコーテイングした。
【００６２】
こうして７１０μｍから１０００μｍの実質的に１００％ビタミンＣ（Ｌ−アスコルビン酸ナトリウム）のみからなる球形粒が８２％の収率で得られた。この球形粒のアスペクト比は１．０９であり、カサ密度０．８０ｇ／ｍｌ、安息角は３１度であった。得られた球形粒の表面は図７と同様に平滑であり、摩損度は０．３９％であった。
【００６３】
実施例６
予めＣＦ装置の造粒容器内にスリットエアーを供給しながら、３００μｍから５００μｍに篩過した塩化ナトリウム結晶１０００ｇを核としてＣＦ装置の回転円板上に仕込み、２００ｒｐｍで回転円板を回転させた。続いて、平均粒径２５．７μｍの予め粉砕された塩化ナトリウム粉末１２００ｇを６０ｇ／ｍｉｎの供給速度で核に散布しつつ、水を０．８ｋｇ／ｃｍ^２　の圧力で１０ｍｌ／ｍｉｎの速度で核に噴霧造粒し湿潤球形粒を得た。
【００６４】
この湿潤球形粒をＦＬ装置に仕込み、６０℃で流動乾燥した。こうして３５５μｍから６００μｍの実質的に１００％塩化ナトリウム結晶のみからなる球形粒が７５％の収率で得られた。この球形粒のアスペクト比は１．１０であり、カサ密度１．０９ｇ／ｍｌ、安息角は３１度であった。得られた球形粒の表面は図８に示すように平滑であり、摩損度は０．４６％であった。
【００６５】
実施例７
遠心転動造粒装置（ＣＦ−３６０）を使用し、スリットエアを供給しながら、３５５〜５００μｍのＤ−キシリトール結晶３００ｇを仕込み、１６０〜２００ｒｐｍで回転円板を回転させた。次いで、平均粒径２５．７μｍの粉砕Ｄ−キシリトール２４００ｇを３０ｇ／ｍｉｎの速度で散布しつつ、１．０ｋｇ／ｃｍ^２　の圧力でＤ−キシリトール５０％水溶液を５ｍｌ／ｍｉｎの速度で噴霧し、造粒した。
得られた湿潤球形粒を流動層造粒装置（ＦＬＯ−５）に入れ、６０℃で乾燥した。次いで、この球形粒２００ｇを流動層造粒装置（ＦＬＯ−ＭＩＮＩ）に入れ、５重量％シェラックエタノール／水溶液８０ｇを４ｍｌ／ｍｉｎの速度で噴霧コーティングした。７１０〜１０００μｍの球形粒が８２．０％の収率で得られた。この球形粒の長径／短径比は１．０９であり、かさ密度は０．７１０、安息角は３１°である、走査型電子顕微鏡で表面を観察したところ、結晶は見えず、平滑であった。
【００６６】
比較例１
実施例７で使用したＤ−キシリトール水溶液の代わりに５重量％のＨＰＣ−Ｌ水溶液を使用した以外は実施例７と同様の方法で造粒した。得られた造粒物は、長径／短径比が１．２以上であり、目的とする球形粒は形成されなかった。
【００６７】
比較例２
実施例７で得られた湿潤球形粒を流動層造粒装置ＦＬＯ−５に入れ、６０℃で乾燥した。この方法により７１０〜１０００μｍの球形粒が８３．２％収率で得られた。この球形粒の長径／短径比が１．０９であり、かさ密度は０．７０６ｇ／ｍｌ、安息角は３１°であった。得られた球形粒の表面は平滑とは言いがたく、数十μｍオーダーの粉末が付着した状態であった。また、室内で数時間放置しておくと、Ｄ−キシリトールの吸湿性が高いことから凝集が起こっていた。
【００６８】
実施例８
比較例２で得られた球形粒２００ｇを流動層造粒装置（ＦＬＯ−ＭＩＮＩ）に入れ、６重量％ツェインエタノール／水溶液６６．７ｇを５ｍｌ／ｍｉｎの速度で噴霧コーティングした。７１０〜１０００μｍの球形粒が８２．２％収率で得られた。この球形粒の長径／短径比が１．０９であり、かさ密度は０．７１５ｇ／ｍｌ、安息角は３１°であり、走査型電子顕微鏡で表面を観察したところ、結晶は見えず平滑であった。また、室内で放置しても凝集は起こらなかった。
【００６９】
実施例９
比較例２で得られた球形粒２００ｇを流動層造粒装置（ＦＬＯ−ＭＩＮＩ）に入れ、５重量％ポリ酢酸ビニル酢酸エチル溶液８０ｇを４ｍｌ／ｍｉｎの速度で噴霧コーティングした。７１０〜１０００μｍの球形粒が８１．４％収率で得られた。この球形粒の長径／短径比が１．０９であり、かさ密度は０．７１４ｇ／ｍｌ、安息角は３１°であり、走査型電子顕微鏡で表面を観察したところ、結晶は見えず平滑であった。また、室内で放置しても凝集は起こらなかった。
【００７０】
比較例３
比較例２で得られた球形粒２００ｇを流動層造粒装置（ＦＬＯ−ＭＩＮＩ）に入れ、５重量％ＨＰＭＣ水溶液８０ｇを４ｍｌ／ｍｉｎの速度で噴霧コーティングした。７１０〜１０００μｍの球形粒が８０．３％収率で得られた。この球形粒の長径／短径比が１．０９であり、かさ密度は０．７１６ｇ／ｍｌ、安息角は３１°であり、走査型電子顕微鏡で表面を観察したところ、結晶は見えず平滑であった。しかし、室内で放置すると凝集が起こっていた。
【００７１】
実施例１０
実施例１で得られたＤ−マンニトール球形粒３ｋｇを遠心流動造粒装置（ＣＦ３６０型、フロイント産業（株））に仕込み、スリットエアーを供給しながら回転円盤を２００ｒｐｍで回転させた。続いて塩酸フェニルプロパノールアミンの粉末２．７ｋｇを徐々に散布しながら、エチルセルロースの２％エタノール溶液を４〜６ｇ／ｍｉｎの速度でスプレーして被覆造粒し、素顆粒を得た。次に該素顆粒５ｋｇを流動層造粒装置（ＷＳＧ５型、（株）大川原製作所）に仕込み、５０℃の乾燥空気を送って流動させた。そこに、エチルセルロース水分散液（アクアコート、旭化成）に可塑剤としてクエン酸トリエチル、滑沢剤としてタルクを配合して調製した１５％濃度のコーティング液を、１５ｇ／ｍｉｎの速度でスプレーした後、６０℃で５時間キュアリングを行うことにより徐放性顆粒剤を得た。
【００７２】
比較例４
実施例１で得られた湿潤球形粒をＦＬ装置に仕込み、６０℃で乾燥して、５００μｍから７１０μｍのＤ−マンニトール球形粒を８１．８％の収率で得た。この球形粒のアスペクト比は１．０９であり、カサ密度は０．６９ｇ／ｍｌ、安息角は３１度であった。図４に示すように、得られた球形粒の表面には、数十μｍオーダーの粉末が付着していた。また、表面平滑性が乏しいことに由来して摩損度が大きく１１．３％であった。
【００７３】
比較例５
実施例２で得られた核であるＤ−マンニトール造粒物（２１２μｍ〜３５５μｍ）１ｋｇをＣＦ−３６０に仕込み、スリットエアーを供給しながら、１８０ｒｐｍで回転円板を回転させた。続いて、平均粒径７．４μｍの粉末Ｄ−マンニトール１ｋｇを２５ｇ／ｍｉｎの供給速度で散布しつつ、ヒドロキシプロピルセルロース（日本曹達株式会社製、商品名、ＨＰＣ−Ｌ）５重量％水溶液２４０ｍｌを０．８ｋｇ／ｃｍ^２　の圧力を加え、４０分間、噴霧造粒した。
できあがった湿潤粒子は核に付着しなかった粉末が多く、粗大粒が多くあった。この粒子のアスペクト比は１．２以上であり、目的とする球形粒は得られなかった。
【００７４】
比較例６
実施例４で得られた湿潤球形粒をＦＬ装置に仕込み、６０℃で乾燥した結果、３５５μｍから６００μｍの球形粒が７３％の収率で得られた。この球形粒のアスペクト比は１．１０であり、集合体としてのカサ密度は０．８１ｇ／ｍｌ、安息角は３１度であった。
図６に示すように、球形粒の表面状態は数μｍの粉末ビタミンＣ（Ｌ−アスコルビン酸）が付着した状態であり、表面平滑性に乏しく、摩損度は１０．４０％と大きなものであった。
【００７５】
比較例７
実施例６の水の代わりにＨＰＣ−Ｌの５重量％水溶液を使用した以外は実施例６と同様な方法で造粒したところ、できあがった造粒物のアスペクト比が１．２を越えており、目的とする球形粒はできなかった。
【００７６】
実施例６と比較例７とを比べると、ＨＰＣ−Ｌなどの水溶性高分子をバインダー（結合剤）として用いると、水溶性高分子の結合力の強さが障害になって、球形粒が形成されない結果になった。
また、実施例６と比較例７の比較から、水の代わりにＨＰＣ−Ｌなどの水溶性高分子を用いる場合は、水溶性高分子のバインダー（結合剤）としての結合力が弱くなるように、水溶性高分子は希薄水溶液として用いる必要があることが分かる。このような水溶性高分子の希薄水溶液の濃度は、各水溶性高分子ごとに実験的に求めることができる。
【００７７】
試験例１
各種添加剤について、球形粒用原料としての適合性をさらに検討するために、塩酸フェニルプロパノールアミンとの配合性を熱分析法により求めた。結果を表２に示す。
【００７８】
【表２】

【００７９】
測定条件：
（１）薬物及び添加剤を５ｍｇずつ混合（混練処理）
（２）測定温度：２５℃→２５０℃
（３）昇温速度：５℃／分
（４）Ｔ：急激な熱分解開始温度
【００８０】
塩酸フェニルプロパノールアミンとの相互作用が小さい球形粒の原料としては、従来タイプ（参考例）よりも本発明用（実施例）の添加剤の方がよく、中でもＤ−マンニトールを併用した場合には、薬物単独の場合と比べて、ほとんど熱分解開始温度の低下が認められないことが判明した。
【００８１】
試験例２
医薬活性成分として塩酸フェニルプロパノールアミンを含有する本発明顆粒について、保存安定性を調べた。本発明顆粒としては、実施例７で得られたマンニトール球形粒含有のものを、また対照としては結晶セルロース球形粒含有のものをそれぞれ使用した。結果を表３に示す。
【００８２】
【表３】

顆粒の保存安定性は、球形粒成分として結晶セルロースよりもＤ−マンニトールを主成分として用いた場合の方が著しく高いことが判明した。
【００８３】
【発明の効果】
以上に説明した本発明の単一物質球形粒は、糖アルコール、ビタミンＣ、塩化ナトリウムなどの結晶を主成分としているので、従来の蔗糖（又は蔗糖と澱粉との混合物）を用いた球形粒に比べて低カロリーあるいはノンカロリーであるという利点がある。また、水に溶け難い結晶セルロースを主成分とする球形粒のように崩壊が全く起こらないという難点もなく、適度の崩壊性を有することから、溶出制御医薬の核として理想的な特性を具備する球形粒である。
【００８４】
また、固定化処理による表面平滑化により、球形粒の上にコーティングする薬剤や溶出制御層のコーティング厚さの均一化がはかられ、従って厚さによって溶出速度が変化する溶出制御層の厚さのコントロールや有効血中濃度を担保する薬剤量のコントロールが可能となり、徐放性製剤として最適な設計ができるようになった。
【００８５】
本発明の単一物質球形粒は、その表面を固定化処理していることにより、表面平滑度にすぐれ、摩損しにくい球形粒となったため、徐放性製剤等を製造する際、造粒効率あるいはコーティング効率が上がり、生産性の向上と原価低減が見込まれるという利点をもっている。
また、球形粒中に薬剤を入れられるようになったため、球形粒の上にコーティングする薬剤層及び溶出制御層をそれぞれ２層にすれば、合わせて３層の徐放性薬剤となり、溶解性のｐＨ依存性を何段階かに変えた制御層を設けることにより、今までにない徐放性製剤ができるようになった。
【００８６】
本発明の糖アルコール球形粒や塩化ナトリウム球形粒は、単一物質のみであるかあるいは単一物質の比率がきわめて高いため、薬物との反応が少なく、球形粒中に薬物を入れられる長所をもっている。特に単一物質単独の構成で表面が平滑な球形粒は従来製造できず、本発明により初めて医薬業界へ提供できるものである。
【００８７】
本発明の糖アルコール球形粒や塩化ナトリウム球形粒からなる単一物質単独あるいは単一物質の比率がきわめて高い球形粒は、メイラード反応がないか、あるいは少なく、球形粒中に食品や食品添加物を入れられる長所をもっている。特に単一物質単独の構成で表面が平滑な球形粒は従来製造できなかったものであり、本発明により初めて食品業界へ提供できるものである。
【００８８】
本発明のビタミンＣ球形粒はビタミンＣ単独あるいはビタミンＣの比率がきわめて高く、その表面が平滑な球形粒は従来製造できず、本発明により初めて医薬業界や食品業界へ提供できるものである。
【００８９】
本発明により提供される球形粒含有医薬は保存安定性にすぐれている。特にＤ−マンニトールを主成分とする球形粒を含有する顆粒剤やそのカプセル剤は、例えば塩酸フェニルプロパノールアミン等のアミン類との反応性が小さいので、とりわけ好ましい。
【図面の簡単な説明】
【図１】本発明で使用できる造粒コーティング装置の一例を示す図である。
【図２】単一物質球形粒の安息角の測定法を説明する図である。
【図３】電子顕微鏡で観察した本発明で用いられる粉末単一物質（粉末Ｄ−マンニトール）の表面状態を示す写真である。
【図４】電子顕微鏡で観察した固定化処理を行わない単一物質（Ｄ−マンニトール）球形粒の表面状態を示す写真である。
【図５】電子顕微鏡で観察した本発明の単一物質（Ｄ−マンニトール）球形粒の表面状態を示す写真である。
【図６】電子顕微鏡で観察した固定化処理を行わない単一物質（Ｌ−アスコルビン酸）球形粒の表面状態を示す写真である。
【図７】電子顕微鏡で観察した本発明の単一物質（Ｌ−アスコルビン酸）球形粒の表面状態を示す写真である。
【図８】電子顕微鏡で観察した本発明の単一物質（塩化ナトリウム）球形粒の表面状態を示す写真である。
【符号の説明】
１：造粒容器、２：回転円板、３：回転軸、４：スリット、５：エアチャンバー、６：除湿装置、７：熱交換器、８：単一物質粉末、９：散布装置、１０：噴霧用液、１１：タンク、１２：定流量ポンプ、１３：スプレーノズル、１４：噴霧用エアー、１５：製品排出装置、１６：ステーターカバー、１７：スリットエア用空気[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to spherical particles of a single type of substance having high surface smoothness and low friability. In particular, the present invention relates to a spherical particle comprising a sugar alcohol, sodium chloride, and vitamin C, which is useful for granule coating in pharmaceutical production and for food.
[0002]
[Prior art]
Spherical particles used as raw materials for pharmaceuticals are mainly used as seeds for sustained-release preparations and enteric preparations. As this kind of spherical particles for pharmaceutical preparations, for example, “NF” (National Formulary) includes “Suger spheres” containing sucrose / corn starch as a main raw material, and “Natural Pharmaceutical Excipient Standards” Supplementary Regulations 1993) include purified sucrose (trade name, Nonparel-103, manufactured by Freund Corporation), purified sucrose / corn starch mixture (trade name, nonparel-101, manufactured by Freund Corporation), crystalline cellulose granules (Asahi Chemical Industry) (Trade name, selfie), etc. are listed as spherical particles.
[0003]
All of the materials used as raw materials for these spherical particles have physicochemical properties suitable for spheroidization. For example, the core of a group of spherical particles of the above-mentioned trade name "non-parel" is granulated sugar. Although it is a monoclinic 8-12 dodecahedron, its aqueous solution is also effective as a binder (binder) and is therefore suitable for spheroidization. The trade name “Selfia” has a nucleus. Although it is not a spherical particle, it is a substance that can be easily spheroidized because crystalline cellulose as a raw material component is a short fiber.
[0004]
Conventionally, for example, in the case of the product name "Nonparel-103", granulated sugar is charged into a centrifugal rolling device (manufactured by Freund Corporation, CF granulator, hereinafter abbreviated as "CF device"), and an aqueous solution of sucrose is used as a binder. It is known that sucrose can be produced by spraying fine particles or fine powder of sucrose while spraying, coating the sucrose on granulated sugar as a core, and granulating the sucrose into a sphere. In the case of the nonpareil-103, it can be said that granulated sugar and sucrose are 100% sucrose because they have the same chemical composition.
Similarly, in the case of the above-mentioned product name “Nonparel-101”, a mixture of sucrose and starch (starch) is charged while granulated sugar is charged in a CF device and a mixed aqueous solution of sucrose and starch (starch) is sprayed as a binder. It is known that the particles can be produced by spraying fine particles or fine powders of the above, coating on granulated sugar as a core, and granulating into spherical forms. In the case of this non-pareil-101, the ratio of sucrose to starch (starch) is 65-85%: 35-15%.
[0005]
Similarly, as for granulation from the nucleus, Japanese Unexamined Patent Publication (Kokai) No. 5-299661 discloses spherical particles having a diameter of 0.1 to 1 mm comprising a mixture of a water-soluble substance such as lactose and a water-insoluble substance such as cellulose. A manufacturing method is disclosed.
[0006]
Any of these spherical particles can be used as spherical particles for pharmaceutical preparations.However, among drugs, there are not a few agents that cause a browning reaction such as a Maillard reaction with a raw material of such spherical particles. When using such a drug, it is necessary to perform a complicated test to confirm the possibility of use.
[0007]
For example, lactose is attracting attention as a raw material for the production of spherical particles for pharmaceutical preparations since it is a substance having low reactivity that is less likely to cause a Maillard reaction with various drugs. Japanese Patent Application Laid-Open No. 6-205959 discloses lactose. Which has a ratio of major axis to minor axis of 1.2 or less, and has a bulk density of 0.7 g / ml or more and an angle of repose of 35 degrees or less as an aggregate and a method for producing the same. Have been.
[0008]
[Problems to be solved by the invention]
However, in the case of lactose spherical particles with low reactivity with drugs, lactose itself has no function as a binder. Has not been successful in building.
For example, regarding the production method disclosed in the above-mentioned JP-A-5-229961, when lactose is contained at a mixing ratio of lactose and crystalline cellulose of 95% or more, the particles are macroscopically spherical, but microscopic. When using a scanning electron microscope to look at the surface, the lactose powder is in the form of irregularities attached to the surface, and due to these irregularities, the spherical particles are further coated with the drug and sustained release. In the case of producing an aqueous preparation, the preparation was liable to be worn away, and thus a reduction in yield (coating efficiency, granulation efficiency) was inevitable.
[0009]
Similarly, in the case of the production method disclosed in JP-A-6-205959, when the lactose content is set to 95% or more, a phenomenon in which the surface of spherical particles becomes coarse microscopically occurs. It has been found by the inventors.
In addition, as can be seen from the attached drawings, such a phenomenon applies to other than lactose. In the case of sugar alcohol, sodium chloride, vitamin C, etc., it has been possible to produce spherical particles having a smooth surface and consisting of substantially 100% single substance. Did not.
[0010]
SUMMARY OF THE INVENTION An object of the present invention is to provide a substantially single substance which has solved the problems of conventional spherical granules made from sucrose (or a mixture of sucrose and starch), crystalline cellulose, a mixture of lactose and crystalline cellulose, and the like. It is another object of the present invention to provide a novel spherical granule composed of only the same and a production method thereof. It is still another object of the present invention to provide foods and medicines containing these spherical particles.
[0011]
[Means for Solving the Problems]
The present inventors have further studied to increase the surface smoothness of spherical particles substantially consisting of a single substance and to reduce the abrasion resistance. Thus, a production method in which a single substance aqueous solution was sprayed in a fluidized bed, dried, and immobilized on the surface of the spherical particles was established, thereby completing the present invention.
[0012]
The present invention includes the following inventions.
(1) A spherical particle having an aspect ratio of 1.2 or less, formed by granulating particles containing 95% by weight or more of a water-soluble single substance, having a bulk density of 0.65 g / ml or more, and a repose angle Spherical particles of 35 degrees or less,
(A) the water-soluble single substance is composed of one selected from the group consisting of sugar alcohol, vitamin C and sodium chloride;
(B) the viscosity of a saturated aqueous solution of the water-soluble single substance is 10 cps or less in a range of 25 ° C to 45 ° C;
(C) The friability of the spherical particles is 1.0% or less.
Spherical grains characterized by the following.
[0013]
(2) The spherical particles according to (1), wherein the sugar alcohol is D-mannitol and / or erythritol.
(3) The spherical particles according to (1), wherein the vitamin C is L-ascorbic acid and / or sodium-ascorbate.
(4) The spherical particles according to (1), wherein the single substance is composed of a substance containing 95% by weight or more of xylitol.
[0014]
(5) A spherical particle for food, comprising the spherical particle according to any one of (1) to (4).
(6) Spherical granules for granulation coating in food production, comprising the spherical granules according to any one of (1) to (4).
[0015]
(7) Spherical granules for granulation coating in the manufacture of pharmaceuticals, comprising the spherical granules according to any one of (1) to (4).
(8) The spherical particles for granulation coating in the production of a medicament according to (7), wherein the spherical particles comprise sugar alcohol-containing spherical particles.
[0016]
(9) A medicine comprising the spherical particles according to (7) or (8).
(10) The medicament according to (9), which contains phenylpropanolamine hydrochloride as a medicinal component.
[0017]
(11) The medicament according to (9) or (10), wherein the medicament is a granule or a capsule.
[0018]
(12) A method for producing a medicine, comprising using the spherical particles for granulation coating according to (7) or (8) as a carrier.
[0019]
BEST MODE FOR CARRYING OUT THE INVENTION
The single substance used in the present invention is preferably, for example, a substance conforming to the single substance standard of the Japanese Pharmacopoeia (hereinafter abbreviated as the Pharmacopoeia) (for example, the thirteenth revised Pharmacopoeia) when used in medicine. It is not limited to.
[0020]
In the present invention, the term “single substance” means not only a pure single chemical substance but also, for example, L-ascorbic acid and sodium L-ascorbate which are chemically and physiologically the same as vitamin C. Further, it also means a mixture of substances known to be the same kind of each other, such as D-mannitol and erythritol, which are chemically and physiologically similar substances as sugar alcohols.
"Single substance" also means that a single substance as defined above contains another kind of substance in an amount of up to 5% by weight.
[0021]
The properties to be possessed by the single substance used in the present invention must be a substance that can be ground into a powder, and since it is used as an aqueous solution, it must be water-soluble. When the single substance is a crystal, the single substance crystal adheres to the outer surface of the nucleus and grows into a sphere, so that most of the substances constituting the spherical grains have a crystal structure.
Further, the single substance is required to have a saturated aqueous solution having a viscosity of 10 cps or less. Particularly, the viscosity of the saturated aqueous solution of the single substance to be used is 10 cps or less at 25 ° C. to 45 ° C. using a B-type viscometer. Is essential.
Table 1 below shows the values of the viscosity of saturated aqueous solutions of various single substances measured with a B-type viscometer.
[0022]
[Table 1]

[0023]
A comparison of the single substances in Table 1 shows that the granulated sugar has a significantly higher viscosity than the other single substances.
Conventionally, there is a case where granulated sugar is used as a binder (binder). In that case, the viscosity of the liquid used as the binder is usually about 100 cps, and even when heated, it is about 40 cps. However, it is understood that the viscosity required for the aqueous solution of the single substance of the present invention is low, and is not in the category of a usual binder.
[0024]
Examples of single substances include sugar alcohols, vitamin C, sodium chloride, lactose and the like. In particular, sugar alcohols and sodium chloride do not have a Maillard reaction because they do not have an aldehyde group, and are preferred as raw materials for spherical particles for pharmaceutical granulation coating. It is also preferable as a raw material for spherical particles for food.
Examples of the sugar alcohol as a single substance include D-mannitol and erythritol alone or a mixture thereof, with D-mannitol being particularly preferred. Examples of vitamin C as a single substance include L-ascorbic acid and sodium L-ascorbate alone or in a mixture thereof.
[0025]
The single-substance granules or single-substance crystal particles used as nuclei in the present invention have a particle diameter of at least 500 μm pass, and particularly those having a particle diameter of 300 μm pass and 150 μm on are preferably used. As the particle size of the single substance granulated product or single substance crystal particles increases, the diameter of the spherical particles obtained also increases.
The single-substance powder used in the production of the spherical particles in the present invention is a single-substance crystal powder of a 75 μm pass, preferably a single-substance granulated substance serving as a core or an average particle diameter of a single-substance particle. Is 1/5 to 1/10 or less. The single substance powder is better as the particle size is smaller, and a fine powder of a single substance crystal can be used. Specifically, fine powders such as sugar alcohol, vitamin C and sodium chloride can be mentioned. When the powder is compressed or hardened by absorbing moisture, it is pulverized by a known dry pulverizer or the like until it becomes 75 μm or less.
[0026]
The single substance granulated product of the present invention is obtained by granulating a single substance powder. Since the production of a single substance granulated substance is a method of granulating by adding water or an aqueous solution of a single substance, the single substance needs to be water-soluble.
[0027]
The granulated material used in the method of the present invention is, for example, in an extrusion granulation method, a single substance powder is charged into a kneader, water or an aqueous solution of a single substance is added and kneaded, extruded, granulated, and dried. Manufactured by sieving.
In the wet stirring granulation method, a single substance powder is charged into a stirring granulator (trade name, high speed mixer manufactured by Fukae Kogyo Co., Ltd.), and water or an aqueous solution of a single substance is added, followed by stirring and granulating. Manufactured by
In the centrifugal flow granulation method, a single substance powder is charged into a centrifugal flow granulator (trade name, Spiral Flow, manufactured by Freund Corporation), and water or an aqueous solution of a single substance is added to perform centrifugal flow granulation. Manufactured by
[0028]
In the centrifugal tumbling granulation method, first, a single substance powder is charged into a kneader, and water or an aqueous solution of a single substance is added and kneaded. Then, water or an aqueous solution of a single substance is added, and the mixture is centrifugally tumbled and granulated.
[0029]
The aspect ratio of the single-substance spherical particles of the present invention is the ratio between the major axis and the minor axis of the spherical particles, and is a measure of sphericity. The ratio of the long axis to the short axis is determined by randomly placing spherical particles on a slide glass, photographing, and vertically drawing the length of the long axis (long axis) and the midpoint of the long axis for 50 spherical particles. The length (minor axis) of each of the minor axes was measured, and the ratio of the major axis to the minor axis was determined for each of the minor axes.
[0030]
The bulk density of the single-substance spherical particles of the present invention is obtained by weighing the weight Wb obtained by placing the spherical particles lightly on a 100-ml measuring cylinder (weight W), and then weighing the weight, and calculating (Wb-W) / 100. It is a value obtained and is shown as an average value of five measurements.
[0031]
The measurement of the angle of repose in the single substance spherical particles of the present invention is performed by the Nogami-Sugihara method described in JP-A-6-205959, and is shown as an average value of five measurements. As shown in FIG. 2, the measuring device is an apparatus shown in FIG. 2 which is made by bonding four glass plates together. About 200 ml is gently poured into the glass floor using a funnel on the surface B, and the flow is continued from the front open end of the surface B until the sample starts to flow. The angle between the inclined upper surface of the sample layer and the surface B (horizontal plane) is read by a protractor C.
[0032]
The friability in the aggregate of the single substance spherical particles of the present invention is a numerical value of the degree of wear of the particle surface, although the particles are not destroyed by an impact when the particles come into contact with each other or the particles and the vessel wall. It is. The measurement is performed by putting a certain amount of spherical particles in a container, applying rotation or vibration, taking out after a certain period of time, removing the powder separated from the spherical particles by abrasion, sifting the powder, obtaining the ratio with the original weight, and calculating the ratio by percentage. It is done by representing.
[0033]
As an example of a specific measurement of the friability, the spherical particle weight Wt (about 10 g) is precisely weighed, placed in a stainless steel cylindrical container having an inner diameter of 32 mm and a depth of 65 mm, and using a SPEX mixer mill at 1100 rpm. After being shaken accurately for 10 minutes, the mixture is transferred to a No. 50 (300 μm) sieve, sieving operation is performed, and the residual amount Ws (g) is accurately measured, and the friability is determined by the following equation.
[0034]
(Equation 1)

The friability is usually preferably 1.0% or less, more preferably 0.5% or less.
[0035]
The immobilization treatment employed in the production process of the single substance spherical particles of the present invention means both a treatment for smoothing the surface of the spherical particles and a treatment for improving the friability.
Examples of the water-soluble polymer that can be used for the production of spherical particles composed of a single substance of the present invention include gelatin, animal systems such as casein, alginic acid, carrageenan, hemicellulose, plant systems such as zein, carboxymethylcellulose, methylcellulose, and hydroxyethylcellulose. Examples include, but are not limited to, cellulosics such as hydroxypropylcellulose and hydroxypropylmethylcellulose, synthetic systems such as polyvinylpyrrolidone, polyacrylates, and polyvinyl alcohol, and pullulan.
[0036]
The water-soluble polymer is used as a dilute aqueous solution. The concentration of the dilute aqueous solution of the water-soluble polymer is experimentally determined for each water-soluble polymer so that the binding force of various water-soluble polymers as a binder is weakened.
[0037]
In the present invention, the single substance spherical particles of the present invention contain a drug appropriately selected from various drugs (various substances having a medicinal effect) such as water-soluble vitamins and antipyretic analgesics in a range of less than 5%. Can be. Of course, substantially 100% single substance spherical particles may be used. In the present invention, foods and food additives appropriately selected from water-soluble vitamins and flavors in a range of less than 5% can be contained in the single substance spherical particles. Needless to say, spherical particles substantially consisting of 100% single substance may be used.
[0038]
The centrifugal rolling device used for producing the single substance spherical particles of the present invention includes a smooth rotating disk that rotates substantially horizontally at the bottom of the processing container, a rotating shaft that rotates the rotating disk, and a processing container. A slit which is an annular gap formed between an inner wall portion and an edge portion located at a circumferential portion of the rotating disk, and a slit air supply device for supplying slit air from the slit into the processing chamber. A spray nozzle for spraying at least one selected from water, an aqueous solution of a single substance, and a dilute aqueous solution of a water-soluble polymer onto an object to be processed (a single substance crystal or a single substance granulated substance) in a processing vessel; And a powder spraying device for spraying the powder to the object to be processed. As an example of this apparatus, there is a CF granulator (hereinafter abbreviated as CF apparatus) manufactured by Freund Corporation shown in FIG. (However, the slit air supply device is not shown).
[0039]
The above-mentioned CF device falls into the category called a granulation coating device, but the granulation coating device that can be used in the method of the present invention is not limited to the above-mentioned specific CF device, and the device having the above-mentioned basic configuration is used. If so, various granulation coating apparatuses can be used. Examples of the CF device that can be variously deformed include a rotating shaft erected on a rotating disk and a type in which the edge of the rotating disk is warped upward as well as a horizontal type. At least the portion of the upper surface of the rotating disk that is in contact with the powder needs to be smooth, but there may be a protrusion at the center of the disk, and it goes without saying that various deformations are possible.
[0040]
The fluidized bed apparatus of the present invention includes a storage container for storing wet spherical particles produced by a centrifugal rolling device, a fluidizing air supply device for supplying fluidizing air for flowing the spherical particles, and a single unit for the spherical particles. A spray nozzle for spraying a dilute aqueous solution of a substance aqueous solution and / or a water-soluble polymer solution. For example, a product name, “Flow Coater” (hereinafter abbreviated as “FL device”, manufactured by Freund Corporation) ) Can be used. This apparatus falls into the category of a fluidized bed granulation coating apparatus, and the present invention is not limited to the above-mentioned specific FL apparatus as long as the apparatus has the above-mentioned basic configuration, and includes a rotating disk having a ventilation section. And various types of fluidized bed apparatuses (for example, FL apparatus equipped with a rotor container manufactured by Freund Corporation), centrifugal fluidized-granulation coating apparatus, trade name “Spiral Flow”.
[0041]
The liquid to be sprayed in the centrifugal rolling device used for producing the single-substance spherical particles of the present invention may be water alone, or may optionally dissolve a small amount of a water-soluble polymer, or may be a single-substance aqueous solution. Alternatively, a small amount of a coloring agent or the like may be added thereto. However, it is usually preferred to use water alone.
[0042]
Next, the method for producing a single substance spherical particle of the present invention will be described with reference to the CF apparatus shown in FIG.
In the figure, reference numeral 1 denotes a granulating container, 2 denotes a rotating disk, 2a denotes a disk edge, 3 denotes a rotating shaft, 4 denotes a slit, 4a denotes a slit air, 5 denotes an air chamber, 6 denotes a dehumidifier, and 7 denotes heat. Exchanger, 8 single substance powder, 9 spraying device, 10 spraying liquid, 11 tank, 12 constant flow pump, 13 spray nozzle, 14 spray air, 15 product discharge device, 16 The stator cover 17 represents air for slit air.
[0043]
In the CF device shown in FIG. 1, while the rotating shaft 3 is rotated by a driving mechanism such as a motor (not shown) and the rotating disk 2 is rotated, the air 17 for the slit air passes through the dehumidifier 6, the heat exchanger 7, and the air chamber 5. Through the slit 4 as a slit air 4a, it is supplied from the slit 4 into the granulation container 1, and the single substance granulated substance (or single substance particles) is charged on the rotating disk.
[0044]
At the same time, the single substance powder 8 is sprayed from the spraying device 9 to the vicinity of the blowing edge 2a of the slit air 4a, and this is mixed with the single substance granulated material (or single substance). The single substance granulated material (or single substance) in the vicinity of the slit 4 is sprayed through the spray nozzle 13 and granulated to produce wet single substance spherical particles.
[0045]
The wet single substance spherical particles thus produced are then sent to an FL apparatus (not shown), where they are coated with a liquid such as a single substance aqueous solution while being fluidized by flowing air. Then, a single substance spherical particle having the above-mentioned physical properties, which is a final product, is produced.
[0046]
As the form of the medicament of the present invention, there can be any dosage form that can be formulated as long as it contains the above-mentioned spherical particles therein, but it is preferably a granule or a capsule containing the granule. .
The content of the spherical particles varies depending on the type of the preparation using the same. For example, in the case of granules, the content is usually about 5 to 90% by weight, preferably about 20 to 70% by weight, based on the whole preparation. is there.
As the spherical particles to be used, a single substance constituting the spherical particles contains D-mannitol as a main raw material and other components, for example, sugar alcohols such as xylitol and erythritol, from the viewpoint of stability with the drug. You may.
[0047]
The pharmaceutically active ingredient may be present either inside or outside the spherical granules, but is preferably outside.
Pharmaceutical active ingredients include, for example, antipyretic analgesics, rhinitis drugs, cardiovascular drugs, digestive drugs, antibiotics, chemotherapeutics, vitamins, narcotic analgesics, hormones, antidepressants, anti-inflammatory drugs , Phenylpropanolamine hydrochloride, aspirin, ibuprofen, indomethacin, phenytoin, acetaminophenone, etenzazamide, morphine, nifedipine, phenobarbital, cephalexin, and the like.
[0048]
Next, a typical production method of the drug of the present invention will be described. First, the surface of the spherical particles is coated with a powder or liquid substance containing a pharmaceutically active ingredient in the presence of a binder, if desired, to form a main drug phase, thereby preparing elementary granules. In this case, examples of the coating method include agitation granulation, centrifugal tumbling granulation, fluidized bed granulation, a normal type or aeration type coating pan and the like.
Next, a granule is obtained by appropriately subjecting the elementary granules to a surface treatment. At this time, if it is desired to obtain a sustained-release type, as a surface treatment method, for example, powder-coating a substance containing a water-repellent substance if desired, and then performing film coating with a sustained-release polymer And the like.
[0049]
Examples of the water-repellent substance include hardened glycerin fatty acid esters such as hardened castor oil, higher fatty acids such as stearic acid, higher fatty acid metal salts such as magnesium stearate, higher alcohols such as stearyl alcohol, and waxes such as carnauba wax. Etc. are exemplified.
[0050]
Examples of the sustained-release polymer include ethyl cellulose, ethyl methacrylate / methacrylated trimethylammonium ethyl copolymer (Eudragid RS), shellac, high polymerization degree polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl chloride, cellulose acetate, polyurethane, tetrafluoroethane , Polystyrene, polypropylene, lactic acid polymer, hydroxyethyl methacrylate, polyethylene terephthalate, polyethylene, polyamide, polyacrylonitrile, polycarboxylic acid, cyanoacrylate polymer and the like.
[0051]
【Example】
Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
Example 1
3 kg of D-mannitol powder was charged into a granulation container of a stirring granulator (Fukae Kogyo Co., Ltd., trade name, High Speed Mixer FS-25), and an agitator and a chopper were added while a 20% by weight aqueous solution of D-mannitol was added. Agitation granulation was performed while rotating, and after completion, the granulated product was taken out. After drying the granules, the granules were sieved from 355 μm to 500 μm to obtain D-mannitol granules to be used as cores for spherical granulation.
[0052]
Next, D-mannitol obtained as a nucleus as described above as a core was placed in a granulation container of a centrifugal tumbling granulator (manufactured by Freund Corporation, trade name, CF granulator CF-360, hereinafter abbreviated as CF device). The rotating disk was rotated at 180 rpm while 1 kg of the granulated material was charged and the slit air was supplied. Subsequently, 400 kg of a 20% by weight aqueous solution of D-mannitol was sprayed onto 0.8 kg / cm 2 while 1 kg of D-mannitol powder having an average particle size of 7.4 μm was sprayed on the D-mannitol granules at a feed rate of 25 g / min. ² While applying the pressure, spray granulation was performed to obtain wet D-mannitol spherical particles.
[0053]
Next, the obtained wet spherical particles are placed in a granulation vessel of a fluidized bed granulator (trade name, flow coater FL-5, manufactured by Freund Corporation) and dried at 60 ° C. And 1 kg of a 20% by weight aqueous solution of D-mannitol was spray-coated at a rate of 40 ml / min. In this way, 500-710 μm spherical D-mannitol particles were obtained with a yield of 84.5%.
The aspect ratio of the spherical particles was 1.09, the bulk density as an aggregate was 0.70 g / ml, and the angle of repose was 31 degrees. The surface of the spherical particles was smooth as shown in FIG. 5, and the friability was 0.27%.
[0054]
Example 2
2 kg of D-mannitol powder was charged into a kneader, 200 g of water was added and kneaded for 15 minutes, and then loosened using a power mill equipped with a 4 mm screen to obtain a wet granulated product. The wet granulated product was charged into a CF device as a core, rotated at 200 rpm, and spray granulated with 70 ml of water at a speed of 5 ml / min. This was dried and sieved to obtain D-mannitol granules as cores for spherical granulation. The particle size range of the granulated product was 212 μm to 355 μm.
[0055]
The same operation as in Example 1 was carried out except that the D-mannitol granulated product (212 μm to 355 μm) was used instead of the D-mannitol granulated product (355 μm to 500 μm) as a nucleus, the D-mannitol of 300 μm to 500 μm was used. Spherical grains were obtained with a yield of 80.2%.
The aspect ratio of the spherical particles was 1.10, the bulk density was 0.72 g / ml, and the angle of repose was 32 degrees. The surface of the obtained spherical particles was smooth as in FIG. 5, and the friability was 0.34%.
[0056]
Example 3
1 kg of the core D-mannitol granules (212 μm to 355 μm) obtained in Example 2 was charged into a CF device, and the rotating disk was rotated at 180 rpm while supplying slit air. Subsequently, 1 kg of a 1% by weight aqueous solution of hydroxypropylcellulose (trade name, HPC-L, manufactured by Nippon Soda Co., Ltd.) was sprinkled with 1 kg of powder D-mannitol having an average particle size of 7.4 μm on the core at a supply rate of 25 g / min. 240 ml to 0.8 kg / cm ² And spray granulation was performed on the core for 40 minutes. This was dried and sieved to obtain D-mannitol wet spherical particles.
[0057]
Next, the obtained wet spherical particles were placed in a granulation container of an FL apparatus, and 1 kg of a 20% by weight aqueous solution of D-mannitol was spray-coated at a rate of 40 ml / min while drying at 60 ° C. Thus, D-mannitol spherical particles of 300 μm to 500 μm were obtained with a yield of 78.5%.
The aspect ratio of the spherical particles was 1.15, the bulk density was 0.71 g / ml, and the angle of repose was 33 degrees. The surface of the obtained spherical particles was smooth as in FIG. 5, and the friability was 0.35%.
[0058]
Example 4
While supplying slit air to the granulation container of the CF device in advance, 500 g of crystalline vitamin C (L-ascorbic acid) sieved from 180 μm to 355 μm is charged on a rotating disk of the CF device using 500 g of the core as a core, and the rotating circle is rotated at 200 rpm. The plate was rotated. Subsequently, while spraying 1550 g of powdered vitamin C (L-ascorbic acid) having an average particle diameter of 21.4 μm onto the core at a supply rate of 60 g / min, water was added at 0.8 kg / cm. ² The core was spray-granulated at a pressure of 10 ml / min to obtain wet spherical particles.
[0059]
The wet spherical particles were charged into a FL device and fluidized and dried at 60 ° C. After the drying was completed, 800 g of a 20% by weight aqueous solution of vitamin C (L-ascorbic acid) was sprayed and dried at a rate of 40 ml / min under the same flow conditions and coated. Thus, spherical particles of 355 μm to 600 μm consisting essentially of only 100% vitamin C (L-ascorbic acid) were obtained in a yield of 75%. The aspect ratio of the spherical particles was 1.10, the bulk density as an aggregate was 0.86 g / ml, and the angle of repose was 31 degrees. The surface of the obtained spherical particles was smooth as shown in FIG. 7, and the friability was 0.46%.
[0060]
Example 5
100 ml of a 10% by weight HPC-L aqueous solution was added to 1 kg of powdered vitamin C (sodium L-ascorbate crystal) passed through a 75 μm sieve, kneaded with a kneader, extruded through a 0.5 mm screen, granulated, and dried. The mixture was sized, and a granulated product of vitamin C (sodium L-ascorbate) having a particle size of 500 μm to 710 μm was obtained using a sieve.
[0061]
While supplying slit air to the granulation container of the CF device in advance, 500 g of the above-mentioned vitamin C granulated product (sodium L-ascorbate) is charged on a rotating disk of the CF device using the core as a nucleus, and the rotating disk is rotated at 200 rpm. I let it. Subsequently, while spraying 1000 g of powdered vitamin C (crystals of sodium L-ascorbate) having an average particle diameter of 21.4 μm onto the core at a supply rate of 60 g / min, water was added at 0.8 kg / cm. ² The core was spray-granulated at a pressure of 10 ml / min to obtain wet spherical particles.
The wet spherical particles were charged into a FL device and fluidized and dried at 60 ° C. After the drying was completed, 800 g of a 20% by weight aqueous solution of vitamin C (sodium L-ascorbate) was sprayed at a rate of 40 ml / min, dried and coated under the same flow conditions.
[0062]
Thus, spherical granules consisting essentially of only 100% vitamin C (sodium L-ascorbate) of 710 μm to 1000 μm were obtained in a yield of 82%. The spherical particles had an aspect ratio of 1.09, a bulk density of 0.80 g / ml, and a repose angle of 31 degrees. The surface of the obtained spherical particles was smooth as in FIG. 7, and the friability was 0.39%.
[0063]
Example 6
While supplying slit air to the granulation container of the CF device in advance, 1000 g of sodium chloride crystals sieved from 300 μm to 500 μm were charged on a rotating disk of the CF device with the nucleus as a nucleus, and the rotating disk was rotated at 200 rpm. Subsequently, while spraying 1200 g of pre-ground sodium chloride powder having an average particle size of 25.7 μm on the core at a supply speed of 60 g / min, water was added at 0.8 kg / cm. ² The core was spray-granulated at a pressure of 10 ml / min to obtain wet spherical particles.
[0064]
The wet spherical particles were charged into a FL device and fluidized and dried at 60 ° C. Thus, spherical particles of 355 μm to 600 μm consisting essentially of only 100% sodium chloride crystals were obtained in a yield of 75%. The spherical particles had an aspect ratio of 1.10, a bulk density of 1.09 g / ml, and an angle of repose of 31 degrees. The surface of the obtained spherical particles was smooth as shown in FIG. 8, and the friability was 0.46%.
[0065]
Example 7
Using a centrifugal tumbling granulator (CF-360), 300 g of D-xylitol crystals of 355 to 500 μm were charged while supplying slit air, and the rotating disk was rotated at 160 to 200 rpm. Next, while spraying 2400 g of pulverized D-xylitol having an average particle size of 25.7 μm at a speed of 30 g / min, the dispersion was 1.0 kg / cm. ² A 50% aqueous solution of D-xylitol was sprayed at a pressure of 5 ml / min to granulate.
The obtained wet spherical particles were placed in a fluidized bed granulator (FLO-5) and dried at 60 ° C. Next, 200 g of the spherical particles were placed in a fluidized bed granulator (FLO-MINI) and spray-coated with 80 g of a 5% by weight shellac ethanol / water solution at a rate of 4 ml / min. 710-1000 μm spherical particles were obtained with a yield of 82.0%. The ratio of the major axis to the minor axis of the spherical grains was 1.09, the bulk density was 0.710, and the angle of repose was 31 °. When the surface was observed with a scanning electron microscope, no crystals were seen and the grains were smooth. Was.
[0066]
Comparative Example 1
Granulation was carried out in the same manner as in Example 7 except that a 5% by weight aqueous solution of HPC-L was used instead of the aqueous solution of D-xylitol used in Example 7. The obtained granulated product had a ratio of major axis / minor axis of 1.2 or more, and the intended spherical particles were not formed.
[0067]
Comparative Example 2
The wet spherical granules obtained in Example 7 were placed in a fluidized bed granulator FLO-5 and dried at 60 ° C. By this method, spherical particles of 710 to 1000 μm were obtained in a yield of 83.2%. The long diameter / short diameter ratio of the spherical particles was 1.09, the bulk density was 0.706 g / ml, and the angle of repose was 31 °. The surface of the obtained spherical particles is hard to say smooth, Ten It was in a state where powder of the order of μm was attached. In addition, when left in a room for several hours, D-xylitol had high hygroscopicity, so that aggregation occurred.
[0068]
Example 8
200 g of the spherical granules obtained in Comparative Example 2 was placed in a fluidized bed granulator (FLO-MINI), and spray-coated with 66.7 g of a 6% by weight zein ethanol / water solution at a rate of 5 ml / min. 710-1000 μm spherical particles were obtained in 82.2% yield. The ratio of the major axis / minor axis of the spherical particles was 1.09, the bulk density was 0.715 g / ml, the angle of repose was 31 °, and the surface was observed with a scanning electron microscope. there were. Aggregation did not occur even when left indoors.
[0069]
Example 9
200 g of the spherical particles obtained in Comparative Example 2 were placed in a fluidized bed granulator (FLO-MINI), and spray-coated with 80 g of a 5% by weight polyvinyl acetate ethyl acetate solution at a rate of 4 ml / min. 710-1000 μm spherical particles were obtained in 81.4% yield. The ratio of the major axis to the minor axis of the spherical particles was 1.09, the bulk density was 0.714 g / ml, the angle of repose was 31 °, and the surface was observed with a scanning electron microscope. there were. Aggregation did not occur even when left indoors.
[0070]
Comparative Example 3
200 g of the spherical particles obtained in Comparative Example 2 was placed in a fluidized bed granulator (FLO-MINI), and spray-coated with 80 g of a 5% by weight aqueous HPMC solution at a rate of 4 ml / min. Spherical grains of 710-1000 μm were obtained in 80.3% yield. The ratio of the major axis to the minor axis of the spherical grains was 1.09, the bulk density was 0.716 g / ml, the angle of repose was 31 °, and the surface was observed with a scanning electron microscope. there were. However, when left indoors, aggregation occurred.
[0071]
Example 10
3 kg of the D-mannitol spherical particles obtained in Example 1 were charged into a centrifugal fluidized-bed granulator (Model CF360, Freund Corporation), and the rotating disk was rotated at 200 rpm while supplying slit air. Subsequently, while slowly spraying 2.7 kg of phenylpropanolamine hydrochloride powder, a 2% ethanol solution of ethyl cellulose was sprayed at a rate of 4 to 6 g / min to perform coating granulation to obtain elementary granules. Next, 5 kg of the elementary granules were charged into a fluidized bed granulator (type WSG5, Okawara Seisakusho Co., Ltd.) and fluidized by sending dry air at 50 ° C. After spraying a 15% concentration coating solution prepared by mixing triethyl citrate as a plasticizer and talc as a lubricant with an aqueous dispersion of ethyl cellulose (Aquacoat, Asahi Kasei) at a rate of 15 g / min, Curing was performed at 60 ° C. for 5 hours to obtain sustained release granules.
[0072]
Comparative Example 4
The wet spherical particles obtained in Example 1 were charged into an FL apparatus and dried at 60 ° C. to obtain 500-710 μm D-mannitol spherical particles at a yield of 81.8%. The aspect ratio of the spherical particles was 1.09, the bulk density was 0.69 g / ml, and the angle of repose was 31 degrees. As shown in FIG. 4, a powder of the order of several tens of μm was adhered to the surface of the obtained spherical particles. In addition, the friability was large and 11.3% due to poor surface smoothness.
[0073]
Comparative Example 5
1 kg of D-mannitol granules (212 μm to 355 μm) as the core obtained in Example 2 were charged into CF-360, and the rotating disk was rotated at 180 rpm while supplying slit air. Subsequently, while spraying 1 kg of powder D-mannitol having an average particle diameter of 7.4 μm at a supply rate of 25 g / min, 240 ml of a 5% by weight aqueous solution of hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd., HPC-L) was added. 0.8kg / cm ² And spray granulation was performed for 40 minutes.
The finished wet particles had many powders that did not adhere to the nuclei, and had many coarse particles. The aspect ratio of the particles was 1.2 or more, and the desired spherical particles could not be obtained.
[0074]
Comparative Example 6
The wet spherical particles obtained in Example 4 were charged into an FL device and dried at 60 ° C. As a result, spherical particles of 355 μm to 600 μm were obtained with a yield of 73%. The aspect ratio of the spherical particles was 1.10, the bulk density as an aggregate was 0.81 g / ml, and the angle of repose was 31 degrees.
As shown in FIG. 6, the surface state of the spherical particles was a state in which powdered vitamin C (L-ascorbic acid) of several μm was adhered, the surface was poor in smoothness, and the friability was as large as 10.40%. Was.
[0075]
Comparative Example 7
Granulation was performed in the same manner as in Example 6 except that a 5% by weight aqueous solution of HPC-L was used instead of water in Example 6, and the resulting granulated product had an aspect ratio exceeding 1.2. The desired spherical particles could not be obtained.
[0076]
Comparing Example 6 with Comparative Example 7, when a water-soluble polymer such as HPC-L is used as a binder, the strength of the binding force of the water-soluble polymer becomes an obstacle and spherical particles are formed. The result was not formed.
Also, from a comparison between Example 6 and Comparative Example 7, when a water-soluble polymer such as HPC-L is used instead of water, the binding strength of the water-soluble polymer as a binder (binder) is reduced. It can be seen that the water-soluble polymer must be used as a dilute aqueous solution. The concentration of such a dilute aqueous solution of a water-soluble polymer can be determined experimentally for each water-soluble polymer.
[0077]
Test example 1
In order to further examine the suitability of various additives as raw materials for spherical particles, the compatibility with phenylpropanolamine hydrochloride was determined by a thermal analysis method. Table 2 shows the results.
[0078]
[Table 2]

[0079]
Measurement condition:
(1) 5 mg each of drug and additive are mixed (kneading treatment)
(2) Measurement temperature: 25 ° C → 250 ° C
(3) Heating rate: 5 ° C / min
(4) T: rapid thermal decomposition onset temperature
[0080]
As a raw material for spherical particles having a small interaction with phenylpropanolamine hydrochloride, the additive for the present invention (Example) is better than the conventional type (Reference Example), especially when D-mannitol is used in combination. It was found that the thermal decomposition onset temperature was hardly reduced as compared with the case of using the drug alone.
[0081]
Test example 2
The storage stability of the granules of the present invention containing phenylpropanolamine hydrochloride as a pharmaceutically active ingredient was examined. As the granules of the present invention, those containing the mannitol spherical particles obtained in Example 7 and those containing the crystalline cellulose spherical particles as the control were used. Table 3 shows the results.
[0082]
[Table 3]

The storage stability of the granules was found to be significantly higher when D-mannitol was used as the main component than crystalline cellulose as the spherical granule component.
[0083]
【The invention's effect】
Since the single substance spherical particles of the present invention described above contain crystals of sugar alcohol, vitamin C, sodium chloride and the like as main components, they can be converted into spherical particles using conventional sucrose (or a mixture of sucrose and starch). It has the advantage of being low in calories or non-calories. In addition, there is no difficulty that disintegration does not occur at all like spherical particles mainly composed of crystalline cellulose that is hardly soluble in water, and since it has a moderate disintegration property, it has ideal properties as a core of an elution control drug. It is a spherical grain.
[0084]
In addition, by smoothing the surface by the immobilization treatment, the coating thickness of the drug coated on the spherical particles and the elution control layer can be made uniform, and thus the elution speed varies depending on the thickness. And the amount of the drug that ensures effective blood concentration can be controlled, and the optimal design as a sustained-release preparation can be achieved.
[0085]
The single substance spherical particles of the present invention have excellent surface smoothness due to the surface immobilization treatment, and become spherical particles that are hard to be abraded. Alternatively, there is an advantage that coating efficiency is improved, and productivity is improved and cost is reduced.
In addition, since the drug can be put into the spherical particles, if the drug layer and the elution control layer to be coated on the spherical particles are each two layers, a total of three layers of the sustained-release drug will be obtained, By providing a control layer in which the pH dependency is changed in several steps, an unprecedented sustained-release preparation can be obtained.
[0086]
Since the sugar alcohol spherical particles and the sodium chloride spherical particles of the present invention are composed of only a single substance or have a very high ratio of the single substance, they have little reaction with a drug and have an advantage that a drug can be put in the spherical particle. . In particular, spherical particles having a smooth surface with a single substance alone cannot be produced conventionally, and can be provided to the pharmaceutical industry for the first time by the present invention.
[0087]
The spherical particles having a single substance alone or the extremely high ratio of the single substance consisting of the sugar alcohol spherical particles and the sodium chloride spherical particles of the present invention have no or little Maillard reaction, and the food or food additive is contained in the spherical particles. Has the advantage of being able to enter. In particular, spherical particles having a smooth surface with a single substance alone cannot be produced conventionally, and can be provided to the food industry for the first time by the present invention.
[0088]
The vitamin C spherical particles of the present invention have a very high ratio of vitamin C alone or vitamin C, and spherical particles having a smooth surface cannot be conventionally produced.
[0089]
The medicament containing spherical particles provided by the present invention has excellent storage stability. In particular, granules containing spherical particles containing D-mannitol as a main component and capsules thereof are particularly preferable because of their low reactivity with amines such as phenylpropanolamine hydrochloride.
[Brief description of the drawings]
FIG. 1 is a diagram showing an example of a granulation coating device that can be used in the present invention.
FIG. 2 is a diagram illustrating a method of measuring the angle of repose of a single substance spherical particle.
FIG. 3 is a photograph showing the surface state of a single substance powder (powder D-mannitol) used in the present invention, observed by an electron microscope.
FIG. 4 is a photograph showing a surface state of a single substance (D-mannitol) spherical particle not subjected to an immobilization treatment, observed by an electron microscope.
FIG. 5 is a photograph showing the surface state of the single substance (D-mannitol) spherical particles of the present invention observed by an electron microscope.
FIG. 6 is a photograph showing a surface state of a single substance (L-ascorbic acid) spherical particles not subjected to an immobilization treatment, observed by an electron microscope.
FIG. 7 is a photograph showing the surface state of the single substance (L-ascorbic acid) spherical particles of the present invention observed by an electron microscope.
FIG. 8 is a photograph showing the surface state of the single substance (sodium chloride) spherical particles of the present invention observed by an electron microscope.
[Explanation of symbols]
1: Granulation container, 2: Rotating disk, 3: Rotation axis, 4: Slit, 5: Air chamber, 6: Dehumidifier, 7: Heat exchanger, 8: Single substance powder, 9: Sprayer, 10 : Spray liquid, 11: tank, 12: constant flow pump, 13: spray nozzle, 14: spray air, 15: product discharger, 16: stator cover, 17: slit air

Claims (12)

A spherical particle having an aspect ratio of 1.2 or less, formed by granulating particles containing 95% by weight or more of a water-soluble single substance, having a bulk density of 0.65 g / ml or more and an angle of repose of 35 degrees or less Spherical particles,
(A) the water-soluble single substance is composed of one selected from the group consisting of sugar alcohol, vitamin C and sodium chloride;
(B) the viscosity of a saturated aqueous solution of the water-soluble single substance is 10 cps or less in a range of 25 ° C to 45 ° C;
(C) The spherical particles are characterized by a friability of 1.0% or less. The spherical particles according to claim 1, wherein the sugar alcohol is D-mannitol and / or erythritol. The spherical particles according to claim 1, wherein the vitamin C is L-ascorbic acid and / or sodium L-ascorbate. The spherical particles according to claim 1, wherein the single substance comprises a substance containing 95% by weight or more of xylitol. A spherical particle for food, comprising the spherical particle according to any one of claims 1 to 4. A spherical particle for granulation coating in food production, comprising the spherical particle according to any one of claims 1 to 4. A spherical particle for granulation coating in the manufacture of a medicament, comprising the spherical particle according to any one of claims 1 to 4. The spherical particles for granulation coating in the manufacture of a medicine according to claim 7, comprising spherical particles containing a sugar alcohol. A medicine comprising the spherical particles according to claim 7. The medicament according to claim 9, comprising phenylpropanolamine hydrochloride as a medicinal component. The medicament according to claim 9, wherein the medicament is a granule or a capsule. A method for producing a medicine, comprising using the spherical particles for granulation coating according to claim 7 or 8 as a carrier.

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