JP4110235B2 - Petal-like porous substrate for sustained release body and sustained release body composition - Google Patents
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Description
【０００１】
【発明の属する技術分野】
本発明は、炭酸カルシウムを原料粒子とする花弁状多孔質構造を有するリン酸カルシウム系化合物である徐放体用花弁状多孔質基材及び、これに各種薬剤を担持してなる徐放体組成物に関し、詳しくは、農薬、抗菌剤、脱臭剤、香料、紫外線吸収剤等の各種薬剤に応じて徐放性のコントロールが可能で、プラスチック成型品、合成樹脂フィルム、合成樹脂繊維、塗料等の各種用途に優れた徐放効果を発揮する徐放体用花弁状多孔質基材及び、これに薬剤を担持してなる徐放体組成物に関する。
【０００２】
【従来の技術】
従来より、薬剤を各種基材に担持させて基材表面より薬剤を放散させる方法は種々検討されている。基材を用いる利点としては、薬剤の放散を調節できること、液体の薬剤を固体状にできるのでハンドリング性が向上する等である。基材として広く用いられているものは、活性炭、フエルト、オガクズ、ゼオライト、合成シリカ、アルミナ、珪酸カルシウム、ヒドロキシアパタイト、でんぷん、酢酸セルロース等であり、これらに担持される薬剤としては、殺虫剤、防虫剤、除草剤等の農薬類や、抗菌剤、脱臭剤、香料、紫外線吸収剤等が一般的である。
【０００３】
【発明が解決しようとする課題】
しかし乍ら、上記した如き従来の基材では、担持させた有効成分の溶出を十分にコントロールすることが困難であった。短時間で溶出してしまうと持続性が低下するのはもとより、一時的に多量の薬剤が作用するために薬害の問題が発生してしまい、また逆に有効成分の溶出が良好に行われないと殆ど効果が認められない。有効成分の溶出をコントロールする方法としては薬剤の担持量を増減するこにより行っているが、使用する薬剤の性質等によっては増減させるだけでは十分なコントロールは不可能である。従って、速効性、遅効性のコントロールを使用する用途や薬剤の種類によって自在に設定できる徐放体が望まれていた。
【０００４】
【課題を解決するための手段】
本発明者らは、上記問題を解決するべく鋭意研究の結果、特定の粒子形状、特定の比表面積と細孔径、特定の粒子径と分散度を有する粒子及び該粒子に薬剤を担持してなる徐放体組成物が所期の目的の機能を有していることを見いだし、本発明を完成した。
以下、本発明を詳記する。
【０００５】
本発明の第一は、炭酸カルシウムを原料粒子とする花弁状多孔質構造を有するリン酸カルシウム系化合物からなり、Ｃａ／Ｐの原子比が５．５６以下であり、且つ下記の式（ａ）〜（ｇ）を満足することを特徴とする徐放体用花弁状多孔質基材である。
（ａ）０．２≦ｄｘ１≦２０（μｍ）
（ｂ）０．０１≦ｄｘ２≦０．２０（μｍ）
（ｃ）５０≦Ｓｗ１≦１６５（m2／ｇ）
（ｄ）９５≦ω１≦９９
（ｅ）７０≦ω２≦９５
（ｆ）１≦α≦２ 但し、α＝ｄ５０／ｄｘ１
（ｇ）０≦β≦１．１ 但し、β＝（ｄ９０−ｄ１０）／ｄ５０
但し、
ｄｘ１：電子顕微鏡写真により測定した粒子の平均粒子径（μｍ）。
ｄｘ２：水銀圧入法により測定した細孔分布により求めた粒子の平均細孔径（μｍ）。
Ｓｗ１：窒素吸着法によるＢＥＴ比表面積（m2／ｇ）
ω１ ：ＪＩＳＫ５１０１−９１ ２０．１ 顔料試験方法の静置法による見掛け比容（ ml／ｇ）を測定し、下記の式（ｈ）により計算した静置空隙率（％）
１
（ｈ）ω１＝｛１−─────────────｝×１００（％）
２．９×［見掛け比容］
ω２：試料０．５ｇを断面積２cm2 の円筒に充填、３０kg／cm2 の圧力で３０秒間加圧、 その厚みをノギスで測定し、下記の式（ｉ）より計算した３０kg／cm2 の加圧空隙 率（％）
０．５
（ｉ）ω２＝｛１−────────────｝×１００（％）
２．９×２×［厚さ］
α ：分散係数
ｄ５０：マイクロトラックＦＲＡレーザー式粒度分布計により測定した粒子の５０％平 均粒子径（μｍ）。
β ：シャープネス。
ｄ９０：マイクロトラックＦＲＡレーザー式粒度分布計により測定した粒子のふるい通 過側累計９０％粒子径（μｍ）。
ｄ１０：マイクロトラックＦＲＡレーザー式粒度分布計により測定した粒子のふるい通 過側累計１０％粒子径（μｍ）。
【０００６】
【発明の実施の態様】
本発明の徐放体用花弁状多孔質基材の重要な特徴は粒子形状にあり、単なるリン酸カルシウム系化合物ではなく、花弁状構造を有する多孔質リン酸カルシウム系化合物で構成されていることにある。本発明の徐放体用花弁状多孔質基材は、花弁状構造であることから高比表面積であり、優れた担持性能があるのはもちろん、速効性、遅効性のコントロールを、使用する用途や薬剤の種類によって自在に設定することが可能である。
本発明の第２は、該徐放体用花弁状多孔質基材に各種薬剤を担持してなる徐放体組成物であり、該徐放体用花弁状多孔質基材を使用することにより、各種用途に適した薬剤の放出が可能である。また、本発明の徐放体組成物は、分散性と粒子の均一性に優れているため、あらゆる用途に配合可能である。例えば、分散性と粒子の均一性を要求される用途として、合成樹脂フィルムや合成樹脂繊維が挙げられるが、本発明の徐放体組成物は、これらの用途にも十分に使用可能な粉体物性を有している。
【０００７】
徐放性をコントロールする要因としては、徐放体粒子の粒子形状と粒度内容にあり、その中でも特に多孔質形状における平均細孔径と比表面積のバランスで左右される。従来の徐放体も殆どのものが多孔質形状を有し、高比表面積であるが、平均細孔径や比表面積を自在に調整することは難しく、徐放性能をコントロールすることは困難である。本発明の徐放体用花弁状多孔質基材は、単に多孔質で、高比表面積であるのではなく、使用する有効成分や用途に合わせて調整された細孔と比表面積を持つものであり、従来にはない優れた徐放性能を有する。
以下に本発明を詳述する。
【０００８】
本発明の徐放体用花弁状多孔質基材を構成する花弁状多孔質リン酸カルシウム系化合物としては特に制限はないが、非晶質リン酸カルシウム〔略号ＡＣＰ、化学式Ｃａ3 （ＰＯ4 ）2 ・ｎＨ2 Ｏ〕、フッ素アパタイト〔略号ＦＡＰ、化学式Ｃａ10（ＰＯ4 ）6 Ｆ2 〕、塩素アパタイト〔略号ＣＡＰ、化学式Ｃａ10（ＰＯ4 ）6 Ｃｌ2 〕、ヒドロキシアパタイト〔略号ＨＡＰ、化学式Ｃａ10（ＰＯ4 ）6 （ＯＨ）2 〕、リン酸八カルシウム〔略号ＯＣＰ、化学式Ｃａ8 Ｈ2 （ＰＯ4 ）6 ・５Ｈ2 Ｏ〕、リン酸三カルシウム〔略号ＴＣＰ、化学式Ｃａ3 （ＰＯ4 ）2 〕、リン酸水素カルシウム（略号ＤＣＰ、化学式ＣａＨＰＯ4 ）、リン酸水素カルシウム二水和物（略号ＤＣＰＤ、化学式ＣａＨＰＯ4 ・２Ｈ2 Ｏ）等が例示でき、一種又は二種以上でもよく、中でも組成の安定性が高いという観点からヒドロキシアパタイト、リン酸八カルシウム、リン酸三カルシウム、リン酸水素カルシウムが好ましく、ヒドロキシアパタイトが特に好ましい。また、安定性が最も高いヒドロキシアパタイトの含有率に関して言えば、全リン酸カルシウム系化合物に対して１０重量％以上が好ましく、５０重量％がより好ましく、９０重量％が最も好ましい。
【０００９】
本発明の徐放体用花弁状多孔質基材の粒子に占めるＣa/Ｐの原子比は、５．５６以下であり、効率よく薬剤を担持、及び放出を行うという観点から、３．３３以下が好ましく、１．８５以下がさらに好ましい。Ｃａ／Ｐの原子比が５．５６を越えると十分に薬剤が担持されない。また該原子比の下限は、粒子の安定性を維持するという観点から１．６０程度が好ましい。また、原料粒子として用いた炭酸カルシウムがすべてリン酸カルシウム系化合物に変化して原料粒子としての炭酸カルシウムが粒子中に存在せず、粒子重量の１００％（Ｃａ／Ｐの原子比は１〜１．６７）が花弁状多孔質リン酸カルシウム系化合物に変化しても何ら問題はない。
【００１０】
本発明における徐放体花弁状多孔質基材の平均粒子径ｄｘ１は、０．２≦ｄｘ１≦２０（μｍ）であり、好ましくは０．２≦ｄｘ１≦１０（μｍ）、さらに好ましくは０．５≦ｄｘ１≦５（μｍ）である。。平均粒子径が０．２μｍ未満の場合、粒子の凝集が著しく徐放性能が低下する。また２０μｍを越えた場合、例えば、農薬を担持して田畑等に広範囲に散布する際に飛散性が低下し、また、粒子の空隙部分が薬剤で全て満たされた場合、平均粒子径を直径とする球体の面積となり、有効面積（薬剤が放散される面積）が小さくなり、徐放性能が低下する。
【００１１】
本発明の徐放体用花弁状多孔質基材の平均細孔径ｄｘ２は、０．０１≦ｄｘ２≦０．２０（μｍ）である。平均細孔径が０．０１μｍ未満の場合、細孔径が小さいため担持された薬剤の放散が良好に行われず、徐放効果が発揮されなくなる。また１μｍを越えた場合、細孔径が大きいため担持された薬剤が短時間に放散され、徐放効果の持続性が低下する。
【００１２】
本発明の徐放体用花弁状多孔質基材の比表面積Ｓｗ１は、５０≦Ｓｗ１≦１６５（m2／ｇ）であり、好ましくは１００≦Ｓｗ１≦１６５（m2／ｇ）である。Ｓｗ１が５０m2／ｇ未満の場合、良好な薬剤の担持、徐放性能が得られず、また１６５m2／ｇを越えた場合、担持性能は高いものの、担持物の良好な発散が行われず、良好な徐放性能が得られなくなる。
【００１３】
本発明の徐放体用花弁状多孔質基材の静置空隙率ω１及び加圧空隙率ω２は、それぞれ９５≦ω１≦９９、７０≦ω２≦９５である。ω１が９５未満、ω２が７０未満の場合、空隙率が小さいため、担持量が不十分になる。またω１が９９、ω２が９５を越えた場合、担持量は十分あるものの、徐放性を有する粒子の有効面積が小さくなる。
【００１４】
本発明の徐放体用花弁状多孔質基材の粒子の分散性α及び粒子の均一性βは、それぞれ１≦α≦２、０≦β≦１．１であり、好ましくは１≦α≦１．６、０≦β≦１である。αが２を越えた場合、粗大な凝集体の割合が多くなり、徐放性能を有する粒子の有効面積が小さくなる。αが１未満の場合、微細粒子の割合が大きくなり、粒子の凝集性が強まり、徐放性能を有する粒子の有効面積が小さくなる。また、βが１．１を越えた場合、粒子径が不均一であると同時に、徐放効果にもばらつきを生じる。
【００１５】
本発明の徐放体組成物は本発明の徐放体用花弁状多孔質基材に薬剤を担持してなり、担持させる薬剤には特に限定はないが、高い徐放性能を必要とする農薬、抗菌剤、脱臭剤、香料、紫外線吸収剤等を使用すると優れた徐放性能を発揮するので好ましい。これらは単独で又は２種以上組み合わせて担持される。例えば、農薬、抗菌剤、脱臭剤、香料、紫外線吸収剤について次のものが例示される。
（農薬）
イソキサチオン、ダイアジノン、ピラクロホス、ジスルホトン、プロチオホス等の有機リン系殺虫剤、カルボスルファン、フラチオカルブ、カルボフラン等のカルボフラン系殺虫剤、アレスリン、フルシトリネート、テフルトリン、アルドリン等のピレスロイド系殺虫剤、ＤＣＩＰ、ヘプタクロール等の塩素系殺虫剤、プレチラクロール、メトラクロール、ベンチオカーブ等の除草剤成分
（抗菌剤）
塩化ベンザルコニウム、塩化セチルピリジニウム等の第４アンモニウム系、エタノール、イソプロパノール等のアルコール系、ホルマリン、グリオキザール等のアルデヒド系、クレゾール、キシレノール等のフェノール系、ソルビン酸、安息香酸等のカルボン酸系、クロルヘキシジン、ｎ−ドデシルグアニジンアセテート等のグアニジン系、２−メルカプトベンゾチアゾール、２−メチル−４−イソチアゾリン−３−オン等のチアゾール系、（１、４）−２−アミノ−２−デオキシ−β−Ｄ−グルカン、Ｎ−カルボキシメチルキトサン、グリコールキトサン、リン酸化キトサン、キトサン−２、５−アンヒドロマンノース等のキトサン系
（脱臭剤）
タンニン酸、テレピン油、ショウ脳油、天然フルボ酸
（香料）
じゃ香、アビエス油、ベルガモット油、ボロアーズ油、ローズウッド油、ローズマリー油等の天然香料、アセト酢酸エチル、アネトール、アミルシナミックアルデヒド、イソ吉草酸エチル、イソアミルアセテート等の合成香料、ローズ油、ジャスミン系、リラ系等の調合香料
（紫外線吸収剤）
２−エチルヘキシル−２−シアノ−３,３−ジフェニルアクリレート、２，４−ジヒドロキシベンゾフェノン、フェニルサリシレート、２−（２’−ヒドロキシ−５’−メチル−フェニル）−ベンゾトリアゾール
【００１６】
本発明の徐放体用花弁状多孔質基材の調製方法については、特に制限はないが、例えば、炭酸カルシウムを分散した水系中で、水可溶性リン酸又は水可溶性リン酸塩とを徐々に反応させて、原料粒子表面で花弁状多孔質リン酸カルシウム系化合物を生成させることにより調製される。具体的には、特定の原料粒子となる炭酸カルシウムの水懸濁液分散体と燐酸の希釈水溶液及び／又は特定の燐酸２水素カルシウムの水懸濁液分散体及び／又は特定の燐酸水素カルシウム２水塩の水懸濁液分散体を特定の割合で特定の混合条件において混合、特定の熟成条件で熟成後、乾燥する方法が例示される。
【００１７】
以下に、本発明の徐放体用花弁状多孔質構造を有するリン酸カルシウム系化合物の内、特に好ましく用いることのできる花弁状多孔質ヒドロキシアパタイトを主成分とした場合の調製方法について、より具体的に例示する。
【００１８】
粒度分布測定器（株式会社島津製作所製ＳＡ−ＣＰ３）により測定した平均粒子径が０．１〜５μｍである炭酸カルシウムの水懸濁液分散体と燐酸の希釈水溶液及び／又は粒度分布測定器（株式会社島津製作所製ＳＡ−ＣＰ３）により測定した平均粒子径が２〜１０μｍであるリン酸二水素カルシウムの水懸濁液分散体及び／又は粒度分布測定器（株式会社島津製作所製ＳＡ−ＣＰ３）により測定した平均粒子径が２〜１０μｍであるリン酸水素カルシウム二水塩の水懸濁液分散体をＣａ／Ｐの原子比が１．６０〜５．５６なる割合で水中で下記の混合条件で混合後、更に下記の熟成条件で熟成を行い、脱水、水洗を行い、３００度以下の乾燥雰囲気下で乾燥し、解砕仕上げを行う。
【００１９】
混合条件
本発明の徐放体用花弁状多孔質基材は、粒子の分散性，安定性等をさらに高めるために、シランカップリング剤やチタネートカップリング剤等のカップリング剤、有機酸、例えば脂肪酸，樹脂酸，アクリル酸等のα、βモノエチレン性不飽和カルボン酸及びそのエステル類，シュウ酸，クエン酸等の有機酸，酒石酸、フッ酸等の無機酸、それらの重合物及び共重合物，それらの塩，又はそれらのエステル類等の表面処理剤、界面活性剤やヘキサメタリン酸ソーダ、ピロリン酸、ピロリン酸ソーダ、トリポリリン酸、トリポリリン酸ソーダ、トリメタリン酸、ハイポリリン酸等の縮合リン酸及びその塩等を、常法に従い添加又は表面処理してもさしつかえない。
【００２１】
各種薬剤を本発明の徐放体用花弁状多孔質基材に担持させる方法としては特に制限はなく、従来の方法でよい。例えば下記の方法が挙げられる。（ａ）生成した徐放体用花弁状多孔質基材の水懸濁液に薬剤を添加して粉末化する。（ｂ）徐放体用花弁状多孔質基材の粉末に、薬剤を溶媒に溶解したものを噴霧添加する。（ｃ）薬剤を溶媒に溶解したものに徐放体用花弁状多孔質基材を浸漬する。
【００２２】
本発明の徐放体組成物に配合される他の成分としては、特に制限はないが、必要に応じて炭酸カルシウム、合成シリカ、珪酸カルシウム等の無機粒子を目的に応じて一種又は二種以上配合してもさしつかえなく、また、花弁状構造を有しない非晶質リン酸カルシウム〔略号ＡＣＰ、化学式Ｃａ3 （ＰＯ4 ）2 ・ｎＨ2 Ｏ〕、フッ素アパタイト〔略号ＦＡＰ、化学式Ｃａ10（ＰＯ4 ）6 Ｆ2 〕、塩素アパタイト〔略号ＣＡＰ、化学式Ｃａ10（ＰＯ4 ）6 Ｃｌ2 〕、ヒドロキシアパタイト〔略号ＨＡＰ、化学式Ｃａ10（ＰＯ4 ）6 （ＯＨ）2 〕、リン酸八カルシウム〔略号ＯＣＰ、化学式Ｃａ8 Ｈ2 （ＰＯ4 ）6 ・５Ｈ2 Ｏ〕、リン酸三カルシウム〔略号ＴＣＰ、化学式Ｃａ3 （ＰＯ4 ）2 〕、リン酸水素カルシウム（略号ＤＣＰ、化学式ＣａＨＰＯ4 ）、リン酸水素カルシウム二水和物（略号ＤＣＰＤ、化学式ＣａＨＰＯ4 ・２Ｈ2 Ｏ）等の本発明の徐放体用花弁状多孔質基材と異なる、花弁状構造を有しないリン酸カルシウム系化合物を目的に応じて一種又は二種以上配合してもさしつかえない。
【００２３】
【実施例】
以下に本発明を実施例を挙げてさらに詳しく説明するが、本発明はこれら実施例のみに制限されるものではない。
【００２４】
使用する炭酸カルシウムの水懸濁液分散体ａ、及びｂの調製方法。
炭酸カルシウムの水懸濁液分散体ａの調製：
比重１．０５５で温度が８℃の石灰乳（水酸化カルシウムの水懸濁液）７０００リッターに、炭酸ガス濃度２７重量％の炉ガスを２４m3の流速で導通しｐＨ９まで炭酸化反応を行い、その後４０〜５０℃で５時間撹拌熟成を行う事により粒子間のアルカリを溶出させｐＨ１０．８として分散させ、電子顕微鏡写真より測定した平均粒子径０．０５μｍで粒度分布測定器（株式会社島津製作所製ＳＡ−ＣＰ３）により測定した平均粒子径が０．４８μｍである炭酸カルシウムの水懸濁液分散体を調製した。
炭酸カルシウムの水懸濁液分散体ｂの調製：
丸尾カルシウム株式会社製重質炭酸カルシウム「スーパーＳＳＳ」（１．２m2／ｇ）に水を添加混合後、ＴＫホモミキサー（５０００ｒｐｍ，１５分間）にて撹拌分散させて固形分濃度２５％の電子顕微鏡写真より測定した平均粒子径３μｍで粒度分布測定器（株式会社島津製作所製ＳＡ−ＣＰ３）により測定した平均粒子径が３．４μｍである炭酸カルシウムの水懸濁液分散体ｂを調製した。
【００２５】
実施例１〜６、比較例１〜３
表１、２に記載した原料及び混合条件に従い、邪魔板付きステンレスタンクに直径０．６ｍのタービン羽根１枚の撹拌機付きの０．４m3ステンレスタンクに希釈濃度調製及び温調した炭酸カルシウムの水懸濁液分散体を投入し、撹拌下において燐酸の希釈水溶液を滴下混合し、記載した熟成条件に従い撹拌を行いながら熟成した。熟成終了後、固形分濃度８％に調整し、スプレ−乾燥を行うことにより炭酸カルシウムを原料粒子とする花弁状多孔質構造を有するリン酸カルシウム系化合物である徐放体用花弁状多孔質基材Ｄ１〜Ｄ６及びＥ１〜Ｅ３を調製した。なお、原料及び水の合計重量は４００kgとした。
スプレ−乾燥条件は噴霧時の粒径約０．１mm、入り口における熱風温度２５０℃、乾燥時間約１０秒、乾燥直後の乾燥品の２００℃，２時間での加熱減量が５〜８％であった。実施例１〜６で調製した徐放体用花弁状多孔質基材Ｄ１〜Ｄ６、及び比較例１〜３で調製したＥ１〜Ｅ３の粉体物性を表３、４に示す。
表３より、本発明の徐放体用花弁状多孔質基材は比表面積、細孔径、粒子径が自由に調整でき、優れた分散性と粒子径の均一性を有することが確認できる。
Ｄ１の粒子構造を示す電子顕微鏡写真を図１（１０００倍）、図２（１００００倍）に示す。図１、図２より、本発明の徐放体用花弁状多孔質基材は花弁状構造を有することが確認できる。また、Ｄ１、Ｄ３、Ｄ５について粉末Ｘ線回折図を図５、６、７に示す。図５、６の粉末Ｘ線回折の結果よりＤ１、Ｄ３についてはリン酸カルシウム系化合物と炭酸カルシウム（カルサイト）以外は認めなかった。リン酸カルシウム系化合物の主成分はヒドロキシアパタイト（ＨＡＰ）であり、微量のリン酸八カルシウム（ＯＣＰ）を含んでいることが確認できる。Ｄ５については、図７より炭酸カルシウムは認められず、リン酸カルシウム系化合物以外は認められなかった。リン酸カルシウム系化合物の主成分はヒドロキシアパタイト（ＨＡＰ）であり、微量のリン酸八カルシウム（ＯＣＰ）を含んでいることが確認できる。
尚、本発明の徐放体用花弁状多孔質基材と比較のために、後記する市販のヒドロキシアパタイトの粒子構造を示す電子顕微鏡写真を図３（１０００倍）、図４（１００００倍）に、粉末Ｘ線回折図を図８に示す。
図３、図４より、市販のヒドロキシアパタイトは微細な粒子と該粒子の凝集物であり、花弁状多孔質構造を有するものではないことが確認できる。また図８より、市販のヒドロキシアパタイトは、主成分であるヒドロキシアパタイト（ＨＡＰ）以外に微量のリン酸水素カルシウム二水和物（ＤＣＰＤ）を含んでいることが確認できる。
【００２６】
【表１】
【表２】
【表３】
【表４】
【００３０】
実施例７〜１２ 比較例４〜９
実施例１〜６で作成した本発明の徐放体用花弁状多孔質基材Ｄ１〜Ｄ６、比較例１〜３で作成したＥ１〜Ｅ３及び市販のヒドロキシアパタイト（商品名：リン酸三カルシウム、米山化学工業株式会社製）、合成シリカ（商品名：アエロジル＃１３０、日本アエロジル株式会社製）及び、珪酸カルシウム（商品名：フローライトＲ、徳山曹達株式会社製）のそれぞれ５ｇを、ナフタリンの１０％四塩化炭素溶液に浸漬した後、四塩化炭素を揮発させ、ナフタリン２ｇを担持させた徐放体組成物を得た。これらの徐放体組成物の徐放性を確認するために、温度３０℃の恒温槽に入れ、一定期間経過後の重量変化より、ナフタリンの残存率を測定した。市販のヒドロキシアパタイト、合成シリカ及び、珪酸カルシウムの粉体物性を表５に示す。また、ナフタリン残存率の測定結果を表６に示す。
表６より、本発明の徐放体組成物は、本発明の徐放体用花弁状多孔質基材を用いることにより、徐放性のコントロールが可能であり、優れた持続性を有することが確認できる。
【００３１】
【表５】
【表６】
本発明の徐放体組成物について、各種薬剤として農薬、抗菌剤、脱臭剤、香料、紫外線吸収剤を用いた場合を以下に例示する。
【００３４】
実施例１３〜１８ 比較例１０〜１５
実施例１〜６で作成した本発明の徐放体用花弁状多孔質基材Ｄ１〜Ｄ６、比較例１〜３で作成したＥ１〜Ｅ３、及び市販のヒドロキシアパタイト、合成シリカ及び、珪酸カルシウムのそれぞれを担体として、土壌殺虫成分であるピラクロホスをミキサー混合し、各担体に対してピラクロホスが５重量％の徐放体組成物を得た。以下の試験方法でこれら徐放体の効果を確認した。結果を表７に示す。
表７より、本発明の徐放対組成物は持続性の高い殺虫効果を有することが確認できる。（試験方法）
対象植物：トマト
対象害虫：サツマイモネコブセンチュウ
試験スケール：４００cm2
添加量：３mg／cm2
測定方法：試料添加後３０日後の根りゅう状態を確認
【００３５】
【表７】
Ａ：根りゅうが多数確認できる
Ｂ：根りゅうが数カ所確認できる
Ｃ：根りゅうが殆ど確認出来ない
【００３６】
実施例１９〜３０ 比較例１６〜２７
実施例１〜６で作成した本発明の徐放体用花弁状多孔質基材Ｄ１〜Ｄ６、比較例１〜３で作成したＥ１〜Ｅ３、及び市販のヒドロキシアパタイト、合成シリカ及び、珪酸カルシウムのそれぞれ１０ｇを担体として、２−メルカプトベンゾチアゾール及びキトサン−２、５−アンヒドロマンノースを噴霧添加し、各担体に対して２−メルカプトベンゾチアゾール及びキトサン−２、５−アンヒドロマンノースが５重量％の徐放体組成物を得た。これら徐放体の抗菌効果を下記の方法で確認した。結果を表８に示す。
表８より、本発明の徐放体組成物は優れた抗菌効果を有することが確認できる。
（試験方法）
日本製薬（株）製のＳＣＤＬＰ寒天培地（細菌用）を溶解し、４５℃に保温しながら一般雑菌を含む汚水を溶解培地１００ml当たり３ml添加した培地１０mlに上記実施例及び比較例資料を所定量添加しよく攪拌する。これをシャーレに入れ、培地が固まった後、蓋をして裏返しにした状態で培養する。培養条件は３０℃、５日間とする。
【００３７】
【表８】
実施例３１〜３６ 比較例２８〜３３
実施例１〜６で作成した本発明の徐放体用花弁状多孔質基材Ｄ１〜Ｄ６、比較例１〜３で作成したＥ１〜Ｅ３、及び市販のヒドロキシアパタイト、合成シリカ及び、珪酸カルシウムのそれぞれ１０ｇを担体として、脱臭剤（タンニン酸）の４０％水溶液を５ｇ噴霧添加し、タンニン酸２ｇを担持させた徐放体組成物を得た。これら徐放体の脱臭性能を確認するために、１０％のアンモニア水１５０mlを入れた洗気瓶（容量３０００ml）の一方から窒素ガスを５００ml／分で流しながら、もう一方の流出口に該脱臭剤を詰めたカラムを取り付け、そのカラムを通過するアンモニアをpH４の塩酸水溶液中に導き、該徐放体組成物の脱臭能力が低下してアンモニアを脱臭しなくなるまでの時間をpHが１０以上となるまで時間として求め、脱臭能力を調べた。結果を表９に示す。
表９より、本発明の徐放体組成物は持続性のある優れた脱臭性能を有することが確認できる。
【００３９】
【表９】
実施例３７〜４２ 比較例３４〜３９
実施例１〜６で作成した本発明の徐放体用花弁状多孔質基材Ｄ１〜Ｄ６、比較例１〜３で作成したＥ１〜Ｅ３、及び市販のヒドロキシアパタイト、合成シリカ及び、珪酸カルシウムのそれぞれ６ｇを担体として、香料（アセト酢酸エチル）に２時間含浸させ、香料を担持させた徐放体組成物を得た。これら徐放体の芳香性能を確認するために、常温の室内に放置し、持続性を測定した。結果を表１０に示す。
表１０より、本発明の徐放体組成物は持続性のある優れた芳香性能を有することが確認できる。
【００４１】
【表１０】
Ａ：芳香性の低下が殆どない
Ｂ：芳香性が若干低下している
Ｃ：芳香性が半減している
Ｄ：芳香性が殆どない
【００４２】
実施例４３〜４８ 比較例４０〜４５
実施例１〜６で作成した本発明の徐放体用花弁状多孔質基材Ｄ１〜Ｄ６、比較例１〜３で作成したＥ１〜Ｅ３、及び市販のヒドロキシアパタイト、合成シリカ及び、珪酸カルシウムのそれぞれ２５ｇを担体として、２−エチルヘキシル−２−シアノ−３，３−ジフェニルアクリレートを５ｇ添加し、紫外線吸収剤を担持させた徐放体組成物を得た。これら徐放体の紫外線吸収性能を確認するために、該徐放体３０ｇとポリプロピレン樹脂ペレット５００ｇをブレンドしたものを混練押し出し機で混練し、該徐放体を配合したポリプロピレン樹脂ペレットを得た。このペレットを射出成形法にて、ポリプロピレン成型品を得た。この成型品を用いてＡＳＴＭ−Ｄ−１４９９の試験法により、カーボンアーク型ウェザーメーターにて６００時間促進耐候性試験を行い、該成型品の表面状態を調べた。結果を表１１に示す。
表１１より、本発明の徐放対組成物は持続性の高い紫外線吸収効果を有することが確認できる。
【００４３】
【表１１】
Ａ：変化なし
Ｂ：若干亀裂あり
Ｃ：多数亀裂あり
【００４４】
【発明の効果】
叙上の通り、特定の粒子形状、特定の細孔径と比表面積、特定の粒子径と分散度を有する本発明の徐放体用花弁状多孔質基材は用途に応じて徐放性のコントロールが可能で、該基材に薬剤を担持してなる本発明の徐放体組成物は各種用途に優れた徐放効果を発揮する。
【図面の簡単な説明】
【図１】実施例１で得られた粒子Ｄ１の粒子構造を示す電子顕微鏡写真（１０００倍）である。
【図２】実施例１で得られた粒子Ｄ１の粒子構造を示す電子顕微鏡写真（１００００倍）である。
【図３】市販のヒドロキシアパタイトの粒子構造を示す電子顕微鏡写真（１０００倍）である。
【図４】市販のヒドロキシアパタイトの粒子構造を示す電子顕微鏡写真（１００００倍）である。
【図５】実施例１で得られた粒子Ｄ１の粉末Ｘ線回折図である。
【図６】実施例３で得られた粒子Ｄ３の粉末Ｘ線回折図である。
【図７】実施例５で得られた粒子Ｄ５の粉末Ｘ線回折図である。
【図８】市販のヒドロキシアパタイトの粉末Ｘ線回折図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to calcium carbonateRaw material particlesThe petal-like porous substrate for sustained release, which is a calcium phosphate-based compound having a petal-like porous structure, and a sustained-release composition comprising various drugs supported thereon, in detail, agricultural chemicals, antibacterial agents, Controlled release is possible according to various chemicals such as deodorizers, fragrances, and UV absorbers, and exhibits excellent sustained release effects for various applications such as plastic molded products, synthetic resin films, synthetic resin fibers, paints, etc. The present invention relates to a petal-like porous substrate for sustained release and a sustained release composition comprising a drug supported thereon.
[0002]
[Prior art]
Conventionally, various methods have been studied in which a drug is supported on various substrates and the drug is released from the substrate surface. Advantages of using the base material include that the diffusion of the drug can be adjusted, and that the liquid drug can be made into a solid state, so that the handling property is improved. Widely used as the base material is activated carbon, felt, sawdust, zeolite, synthetic silica, alumina, calcium silicate, hydroxyapatite, starch, cellulose acetate and the like. Commonly used are pesticides such as insect repellents and herbicides, antibacterial agents, deodorants, fragrances, ultraviolet absorbers and the like.
[0003]
[Problems to be solved by the invention]
However, it has been difficult to sufficiently control the elution of the supported active ingredient with the conventional base as described above. If it elutes in a short period of time, the sustainability will decrease, and a large amount of the drug will act temporarily, causing a problem of phytotoxicity. Conversely, the active ingredient will not be eluted well. Almost no effect is recognized. As a method for controlling the elution of the active ingredient, it is carried out by increasing / decreasing the amount of the drug carried, but depending on the nature of the drug used, etc., it is impossible to sufficiently control it. Therefore, there has been a demand for a sustained release body that can be freely set depending on the use of the fast-acting and slow-acting controls and the kind of the drug.
[0004]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have a specific particle shape, a specific surface area and pore diameter, a particle having a specific particle diameter and dispersity, and a drug supported on the particle. It was found that the sustained-release composition had the intended function, and the present invention was completed.
Hereinafter, the present invention will be described in detail.
[0005]
In the first aspect of the present invention, calcium carbonateRaw material particlesA calcium phosphate compound having a petal-like porous structure, and the atomic ratio of Ca / P is5.56It is a petal-like porous substrate for sustained release, characterized in that it satisfies the following formulas (a) to (g).
(A) 0.2 ≦ dx1 ≦ 20 (μm)
(B) 0.01 ≦ dx2 ≦0.20(Μm)
(C) 50 ≦ Sw1 ≦165(M2/ G)
(D) 95 ≦ ω1 ≦ 99
(E) 70 ≦ ω2 ≦ 95
(F) 1 ≦ α ≦2 However, α = d50 / dx1
(G) 0 ≦ β ≦1.1 However, β = (d90−d10) / d50
However,
dx1: average particle diameter (μm) of particles measured by electron micrograph.
dx2: average pore diameter (μm) of particles determined by pore distribution measured by mercury porosimetry.
Sw1: BET specific surface area by nitrogen adsorption method (m2/ G)
ω1: JISK5101-91 20.1 The apparent specific volume (ml / g) of the pigment test method by the static method was measured, and the static void ratio (%) calculated by the following formula (h)
1
(H) ω1 = {1 ----------------------- x 100 (%)
2.9 × [apparent specific volume]
ω2: 0.5 g of sample 2 cm cross-sectional area2Filled in a cylinder of 30kg /
0.5
(I) ω2 = {1 ------------------------ x 100 (%)
2.9 x 2 x [thickness]
α: Dispersion coefficient
d50: 50% average particle diameter (μm) of particles measured by Microtrac FRA laser particle size distribution analyzer.
β: Sharpness.
d90: 90% of particle diameter (μm) on the sieving pass side of particles measured with a Microtrac FRA laser particle size distribution analyzer.
d10: 10% particle diameter (μm) on the sieving pass side of particles measured with a Microtrac FRA laser particle size distribution meter.
[0006]
BEST MODE FOR CARRYING OUT THE INVENTION
An important feature of the petal-like porous substrate for sustained release of the present invention is in the shape of particles, and is that it is composed of a porous calcium phosphate-based compound having a petal-like structure, not a simple calcium phosphate-based compound. The petal-like porous substrate for sustained release of the present invention has a high specific surface area because of its petal-like structure, and has excellent carrying performance, as well as the use of quick-acting and slow-acting controls. It is possible to set freely according to the type of drug or drug.
A second aspect of the present invention is a sustained release composition comprising a variety of drugs supported on the petal-like porous substrate for sustained release. By using the petal-like porous substrate for sustained release, It is possible to release drugs suitable for various applications. Moreover, since the sustained release composition of the present invention is excellent in dispersibility and particle uniformity, it can be blended in any application. For example, synthetic resin films and synthetic resin fibers can be cited as applications requiring dispersibility and particle uniformity. The sustained-release composition of the present invention is a powder that can be used sufficiently for these applications. Has physical properties.
[0007]
Factors that control the sustained release include the particle shape and particle size content of the sustained release particles, and among these, it depends on the balance between the average pore diameter and the specific surface area in the porous shape. Most conventional sustained-release bodies have a porous shape and a high specific surface area, but it is difficult to freely adjust the average pore diameter and specific surface area, and it is difficult to control the sustained-release performance. . The petal-like porous substrate for sustained release of the present invention is not only porous and has a high specific surface area, but has pores and a specific surface area that are adjusted according to the active ingredient used and the application. Yes, it has an excellent sustained release performance that has never existed before.
The present invention is described in detail below.
[0008]
The petal-like porous calcium phosphate compound constituting the petal-like porous substrate for sustained release of the present invention is not particularly limited, but amorphous calcium phosphate [abbreviation ACP, chemical formula CaThree(POFour)2・ NH2O], fluorapatite [abbreviation FAP, chemical formula CaTen(POFour)6F2], Chloroapatite [abbreviation CAP, chemical formula CaTen(POFour)6Cl2], Hydroxyapatite [abbreviation HAP, chemical formula CaTen(POFour)6(OH)2], Octacalcium phosphate [abbreviation OCP, chemical formula Ca8H2(POFour)6・ 5H2O], tricalcium phosphate [abbreviation TCP, chemical formula CaThree(POFour)2], Calcium hydrogen phosphate (abbreviation DCP, chemical formula CaHPOFour), Calcium hydrogen phosphate dihydrate (abbreviation DCPD, chemical formula CaHPO)Four・ 2H2O) and the like can be exemplified, and may be one or two or more. Among them, hydroxyapatite, octacalcium phosphate, tricalcium phosphate, and calcium hydrogenphosphate are preferable, and hydroxyapatite is particularly preferable. . In terms of the content of hydroxyapatite having the highest stability, the content is preferably 10% by weight or more, more preferably 50% by weight, and most preferably 90% by weight based on the total calcium phosphate compound.
[0009]
The atomic ratio of Ca / P in the particles of the petal-like porous substrate for sustained release of the present invention is as follows:5.56From the viewpoint of efficiently carrying and releasing a drug,3.33The following is preferred:1.85More preferredNew. The atomic ratio of Ca / P is5.56If it exceeds, the drug is not sufficiently loaded. The lower limit of the atomic ratio is preferably about 1.60 from the viewpoint of maintaining the stability of the particles. Also,Raw material particlesAll of the calcium carbonate used as a calcium phosphate compoundRaw material particlesThere is no problem if 100% of the particle weight (Ca / P atomic ratio is 1-1.67) is changed to a petal-like porous calcium phosphate compound.
[0010]
The average particle diameter dx1 of the sustained-release petal-like porous substrate in the present invention is 0.2 ≦ dx1 ≦ 20 (μm), preferably 0.2 ≦ dx1 ≦ 10 (μm), more preferably 0.8. 5 ≦ dx1 ≦ 5 (μm). . When the average particle diameter is less than 0.2 μm, the aggregated particles are remarkably deteriorated and the sustained release performance is lowered. In addition, when the particle diameter exceeds 20 μm, for example, when the pesticide is supported and sprayed over a wide area on a field or the like, the scattering property is reduced. The effective area (area where the drug is diffused) is reduced, and the sustained release performance is reduced.
[0011]
The average pore diameter dx2 of the petal-like porous substrate for sustained release of the present invention is 0.01 ≦ dx2 ≦.0.20(Μm). When the average pore diameter is less than 0.01 μm, the supported drug is not diffused well because the pore diameter is small, and the sustained release effect is not exhibited. On the other hand, when the diameter exceeds 1 μm, the supported drug is released in a short time because the pore diameter is large, and the sustainability of the sustained release effect is lowered.
[0012]
The specific surface area Sw1 of the petal-like porous substrate for sustained release of the present invention is 50 ≦ Sw1 ≦.165(M2/ G), preferably 100 ≦ Sw1 ≦165(M2/ G). Sw1 is 50m2Less than / g, good drug loading and sustained release performance cannot be obtained, and165m2When the amount exceeds / g, the carrying performance is high, but the carrying material does not diverge well, and good sustained release performance cannot be obtained.
[0013]
The stationary porosity ω1 and the pressurized porosity ω2 of the petal-like porous substrate for sustained release of the present invention are 95 ≦ ω1 ≦ 99 and 70 ≦ ω2 ≦ 95, respectively. When ω1 is less than 95 and ω2 is less than 70, since the porosity is small, the carrying amount becomes insufficient. When ω1 exceeds 99 and ω2 exceeds 95, the carrying amount is sufficient, but the effective area of the particles having sustained release becomes small.
[0014]
The dispersibility α and particle uniformity β of the petal-like porous substrate for sustained release of the present invention are 1 ≦ α ≦, respectively.2, 0 ≦ β ≦1.1And preferably 1 ≦ α ≦1.60 ≦ β ≦ 1. α is2In the case of exceeding the ratio, the proportion of coarse aggregates increases, and the effective area of particles having sustained release performance decreases. When α is less than 1, the proportion of fine particles increases, the cohesiveness of the particles increases, and the effective area of the particles having sustained release performance decreases. Β is1.1When the particle size exceeds the range, the particle size is not uniform, and at the same time, the sustained release effect also varies.
[0015]
The sustained-release composition of the present invention is obtained by carrying a drug on the petal-like porous substrate for sustained-release of the present invention, and the drug to be carried is not particularly limited, but is an agrochemical that requires high sustained-release performance. It is preferable to use an antibacterial agent, a deodorizing agent, a fragrance, an ultraviolet absorber, etc., because excellent sustained release performance is exhibited. These are supported alone or in combination of two or more. For example, the following are illustrated about an agrochemical, an antibacterial agent, a deodorizing agent, a fragrance | flavor, and an ultraviolet absorber.
(Pesticide)
Organophosphorus insecticides such as isoxathione, diazinon, pyracrofos, disulfotone, prothiophos, carbofuran insecticides such as carbosulfan, furthiocarb, carbofuran, pyrethroid insecticides such as allethrin, flucitrinate, tefluthrin, aldrin, DCIP, hepta Chlorine-based insecticides such as chlor, herbicide ingredients such as pretilachlor, metolachlor, and bencho curve
(Antimicrobial agent)
Quaternary ammonium such as benzalkonium chloride and cetylpyridinium chloride, alcohol such as ethanol and isopropanol, aldehyde such as formalin and glyoxal, phenol such as cresol and xylenol, carboxylic acid such as sorbic acid and benzoic acid, Guanidines such as chlorhexidine and n-dodecylguanidine acetate, thiazoles such as 2-mercaptobenzothiazole and 2-methyl-4-isothiazolin-3-one, (1,4) -2-amino-2-deoxy-β- Chitosans such as D-glucan, N-carboxymethylchitosan, glycol chitosan, phosphorylated chitosan, chitosan-2, 5-anhydromannose
(Deodorant)
Tannic acid, turpentine oil, show brain oil, natural fulvic acid
(Fragrance)
Natural fragrances such as potato, abies oil, bergamot oil, boroaz oil, rosewood oil, rosemary oil, etc., synthetic fragrances such as ethyl acetoacetate, anethole, amylcinamic aldehyde, ethyl isovalerate, isoamyl acetate, rose oil, Blended fragrances such as jasmine and lira
(UV absorber)
2-ethylhexyl-2-cyano-3,3-diphenyl acrylate, 2,4-dihydroxybenzophenone, phenyl salicylate, 2- (2'-hydroxy-5'-methyl-phenyl) -benzotriazole
[0016]
The method for preparing the petal-like porous substrate for sustained release of the present invention is not particularly limited. For example, in a water system in which calcium carbonate is dispersed, water-soluble phosphoric acid or water-soluble phosphate is gradually added. ReactRaw material particlesIt is prepared by generating a petal-like porous calcium phosphate compound on the surface. Specifically, a specificRaw material particlesAn aqueous suspension dispersion of calcium carbonate and a dilute aqueous solution of phosphoric acid and / or an aqueous suspension dispersion of specific calcium dihydrogen phosphate and / or an aqueous suspension dispersion of specific calcium hydrogen phosphate dihydrate Examples of the method include mixing at a specific ratio under specific mixing conditions, aging under specific aging conditions, and then drying.
[0017]
The preparation method in the case where the main component is a petal-like porous hydroxyapatite that can be particularly preferably used among the calcium phosphate compounds having a petal-like porous structure for sustained-release bodies according to the present invention is more specifically described below. Illustrate.
[0018]
An aqueous suspension dispersion of calcium carbonate having a mean particle size of 0.1 to 5 μm and a diluted aqueous solution of phosphoric acid and / or a particle size distribution measuring device (SA-CP3 manufactured by Shimadzu Corporation) An aqueous suspension dispersion of calcium dihydrogen phosphate and / or a particle size distribution measuring instrument (SA-CP3 manufactured by Shimadzu Corporation) having an average particle diameter of 2 to 10 μm measured by SA-CP3 manufactured by Shimadzu Corporation. An aqueous suspension dispersion of calcium hydrogenphosphate dihydrate having an average particle diameter of 2 to 10 μm measured by the method described above is used.1.60~5.56After mixing in water at the following ratio under the following mixing conditions, aging is further performed under the following aging conditions, followed by dehydration and washing with water, drying in a dry atmosphere of 300 ° C. or less, and crushing finish.
[0019]
Mixing conditions
The petal-like porous substrate for sustained release of the present invention is a coupling agent such as a silane coupling agent or a titanate coupling agent, an organic acid such as a fatty acid, in order to further improve the dispersibility, stability, etc. of the particles. Α, β monoethylenically unsaturated carboxylic acids and their esters such as resin acids and acrylic acids, organic acids such as oxalic acid and citric acid, inorganic acids such as tartaric acid and hydrofluoric acid, polymers and copolymers thereof, Surface treatment agents such as salts thereof or esters thereof, surfactants, sodium hexametaphosphate, pyrophosphoric acid, sodium pyrophosphate, tripolyphosphoric acid, sodium tripolyphosphate, condensed metaphosphoric acid such as trimetaphosphoric acid, high polyphosphoric acid, and salts thereof Etc. may be added or surface-treated according to a conventional method.
[0021]
There are no particular limitations on the method for supporting various drugs on the petal-like porous substrate for sustained release of the present invention, and conventional methods may be used. For example, the following method is mentioned. (A) A drug is added to the aqueous suspension of the petal-like porous base material for sustained release, which is powdered. (B) A powder obtained by dissolving a drug in a solvent is sprayed and added to the powder of the petal-like porous substrate for sustained release. (C) The petal-like porous substrate for sustained release is immersed in a drug dissolved in a solvent.
[0022]
The other components to be blended in the sustained-release composition of the present invention are not particularly limited, but if necessary, inorganic particles such as calcium carbonate, synthetic silica, calcium silicate and the like may be used alone or in combination of two or more. Amorphous calcium phosphate that can be blended and does not have a petal-like structure [abbreviation ACP, chemical formula CaThree(POFour)2・ NH2O], fluorapatite [abbreviation FAP, chemical formula CaTen(POFour)6F2], Chloroapatite [abbreviation CAP, chemical formula CaTen(POFour)6Cl2], Hydroxyapatite [abbreviation HAP, chemical formula CaTen(POFour)6(OH)2], Octacalcium phosphate [abbreviation OCP, chemical formula Ca8H2(POFour)6・ 5H2O], tricalcium phosphate [abbreviation TCP, chemical formula CaThree(POFour)2], Calcium hydrogen phosphate (abbreviation DCP, chemical formula CaHPOFour), Calcium hydrogen phosphate dihydrate (abbreviation DCPD, chemical formula CaHPO)Four・ 2H2Depending on the purpose, one or more calcium phosphate compounds having no petal-like structure different from the petal-like porous substrate for sustained release of the present invention such as O) may be used.
[0023]
【Example】
Examples The present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.
[0024]
Preparation method of aqueous suspensions a and b of calcium carbonate to be used.
Preparation of an aqueous suspension dispersion a of calcium carbonate:
24 m of furnace gas with a carbon dioxide concentration of 27% by weight is applied to 7000 liters of lime milk (calcium hydroxide aqueous suspension) with a specific gravity of 1.055 and a temperature of 8 ° C.ThreeThe average particle size measured from an electron micrograph was obtained by conducting a carbonation reaction up to pH 9 and conducting a carbonation reaction until pH 9 followed by stirring and aging at 40 to 50 ° C. for 5 hours to elute alkali between particles and disperse them as pH 10.8. An aqueous suspension of calcium carbonate having an average particle size of 0.48 μm measured by a particle size distribution analyzer (SA-CP3 manufactured by Shimadzu Corporation) at 0.05 μm was prepared.
Preparation of aqueous dispersion b of calcium carbonate:
Heavy calcium carbonate "Super SSS" manufactured by Maruo Calcium Co., Ltd. (1.2m2/ G), after adding and mixing water, the mixture was stirred and dispersed with a TK homomixer (5000 rpm, 15 minutes) and measured with an average particle size of 3 μm measured by an electron micrograph having a solid concentration of 25% (Shimadzu Corporation) An aqueous suspension b of calcium carbonate having an average particle diameter of 3.4 μm measured by SA-CP3 manufactured by Seisakusho was prepared.
[0025]
Examples 1-6, Comparative Examples 1-3
In accordance with the raw materials and mixing conditions described in Tables 1 and 2, 0.4 m with a stirrer with one turbine blade having a diameter of 0.6 m in a stainless steel tank with baffle platesThreeAn aqueous suspension of calcium carbonate adjusted to a diluted concentration and adjusted in temperature was added to a stainless steel tank, and a dilute aqueous solution of phosphoric acid was added dropwise with stirring, and aged with stirring according to the described aging conditions. After ripening, adjust the solid content to 8% and spray-dry the calcium carbonate.Raw material particlesThe petal-like porous substrates D1 to D6 and E1 to E3 for sustained release, which are calcium phosphate compounds having a petal-like porous structure, were prepared. The total weight of the raw material and water was 400 kg.
The spray-drying conditions were such that the particle size at spraying was about 0.1 mm, the hot air temperature at the entrance was 250 ° C., the drying time was about 10 seconds, and the heat loss at 200 ° C. for 2 hours immediately after drying was 5-8%. It was. Tables 3 and 4 show the powder physical properties of the petal-like porous substrates D1 to D6 for sustained release prepared in Examples 1 to 6 and E1 to E3 prepared in Comparative Examples 1 to 3, respectively.
From Table 3, it can be confirmed that the petal-like porous base material for sustained release body of the present invention can freely adjust the specific surface area, pore diameter and particle diameter, and has excellent dispersibility and particle diameter uniformity.
Electron micrographs showing the particle structure of D1 are shown in FIG. 1 (1000 times) and FIG. 2 (10000 times). 1 and 2, it can be confirmed that the petal-like porous substrate for sustained release of the present invention has a petal-like structure. Further, powder X-ray diffraction diagrams of D1, D3, and D5 are shown in FIGS. From the powder X-ray diffraction results of FIGS.D3No other than calcium phosphate compounds and calcium carbonate (calcite) were observed. It can be confirmed that the main component of the calcium phosphate compound is hydroxyapatite (HAP) and contains a small amount of octacalcium phosphate (OCP).D5About FIG. 7, calcium carbonate was not recognized but other than the calcium phosphate type compound was not recognized. It can be confirmed that the main component of the calcium phosphate compound is hydroxyapatite (HAP) and contains a small amount of octacalcium phosphate (OCP).
For comparison with the petal-like porous substrate for sustained release of the present invention, electron micrographs showing the particle structure of commercially available hydroxyapatite described later are shown in FIG. 3 (1000 times) and FIG. 4 (10000 times). FIG. 8 shows a powder X-ray diffraction diagram.
3 and 4, it can be confirmed that commercially available hydroxyapatite is a fine particle and an aggregate of the particle and does not have a petal-like porous structure. Further, from FIG. 8, it can be confirmed that the commercially available hydroxyapatite contains a trace amount of calcium hydrogen phosphate dihydrate (DCPD) in addition to the main component hydroxyapatite (HAP).
[0026]
[Table 1]
[Table 2]
[Table 3]
[Table 4]
[0030]
Examples 7-12 Comparative Examples 4-9
Petal-like porous substrates D1 to D6 for sustained release bodies of the present invention prepared in Examples 1 to 6, E1 to E3 prepared in Comparative Examples 1 to 3 and commercially available hydroxyapatite (trade name: tricalcium phosphate, 5 g each of Yoneyama Chemical Co., Ltd., synthetic silica (trade name: Aerosil # 130, Nippon Aerosil Co., Ltd.) and calcium silicate (trade name: Florite R, Tokuyama Soda Co., Ltd.) After being immersed in a carbon tetrachloride solution, the carbon tetrachloride was volatilized to obtain a sustained release composition carrying 2 g of naphthalene. In order to confirm the sustained release properties of these sustained release compositions, they were placed in a thermostatic bath at a temperature of 30 ° C., and the residual rate of naphthalene was measured from the change in weight after the lapse of a certain period. Table 5 shows the powder physical properties of commercially available hydroxyapatite, synthetic silica, and calcium silicate. Table 6 shows the measurement results of the naphthalene residual ratio.
From Table 6, the sustained release composition of the present invention can be controlled for sustained release by using the petal-like porous substrate for sustained release of the present invention, and has excellent sustainability. I can confirm.
[0031]
[Table 5]
[Table 6]
Examples of the sustained-release composition of the present invention include cases where agricultural chemicals, antibacterial agents, deodorants, fragrances, and ultraviolet absorbers are used as various drugs.
[0034]
Examples 13-18 Comparative Examples 10-15
Petal-like porous base materials D1 to D6 for sustained release of the present invention prepared in Examples 1 to 6, E1 to E3 prepared in Comparative Examples 1 to 3, and commercially available hydroxyapatite, synthetic silica, and calcium silicate Using each as a carrier, pyracrofos, a soil insecticidal component, was mixed with a mixer to obtain a sustained-release composition having 5% by weight of pyracrofos for each carrier. The effects of these sustained release bodies were confirmed by the following test methods. The results are shown in Table 7.
From Table 7, it can be confirmed that the sustained release composition of the present invention has a highly durable insecticidal effect. (Test method)
Target plant: tomato
Target pest: Sweet potato root nematode
Test scale: 400cm2
Addition amount: 3mg / cm2
Measurement method: Confirm
[0035]
[Table 7]
A: You can see many roots
B: You can check several roots
C: Almost no root can be confirmed
[0036]
Examples 19-30 Comparative Examples 16-27
Petal-like porous base materials D1 to D6 for sustained release of the present invention prepared in Examples 1 to 6, E1 to E3 prepared in Comparative Examples 1 to 3, and commercially available hydroxyapatite, synthetic silica, and calcium silicate 2-mercaptobenzothiazole and chitosan-2,5-anhydromannose were spray-added using 10 g each as a carrier, and 5-mercaptobenzothiazole, chitosan-2,5-anhydromannose was 5% by weight with respect to each carrier. A sustained-release composition was obtained. The antibacterial effect of these sustained release bodies was confirmed by the following method. The results are shown in Table 8.
From Table 8, it can confirm that the sustained release body composition of this invention has the outstanding antimicrobial effect.
(Test method)
Dissolve the SCDLP agar medium (for bacteria) manufactured by Nippon Pharmaceutical Co., Ltd., and keep the temperature at 45 ° C and add 3 ml of sewage containing general bacteria to 100 ml of the dissolution medium. Add and stir well. This is put into a petri dish, and after the medium has hardened, it is cultured with the lid turned upside down. The culture conditions are 30 ° C. and 5 days.
[0037]
[Table 8]
Examples 31-36 Comparative Examples 28-33
Petal-like porous base materials D1 to D6 for sustained release of the present invention prepared in Examples 1 to 6, E1 to E3 prepared in Comparative Examples 1 to 3, and commercially available hydroxyapatite, synthetic silica, and calcium silicate Using 10 g each as a carrier, 5 g of a 40% aqueous solution of a deodorant (tannic acid) was added by spraying to obtain a sustained release composition carrying 2 g of tannic acid. In order to confirm the deodorizing performance of these sustained-release bodies, nitrogen gas was allowed to flow from one side of a washing bottle (capacity 3000 ml) containing 150 ml of 10% ammonia water to the other outlet while flowing nitrogen gas at 500 ml / min. A column packed with an agent is attached, the ammonia passing through the column is led into a hydrochloric acid aqueous solution of pH 4, and the time until the deodorizing ability of the sustained-release composition is reduced and ammonia is not deodorized is set to 10 or more. It was calculated as time until it was, and the deodorizing ability was examined. The results are shown in Table 9.
From Table 9, it can confirm that the sustained release body composition of this invention has the outstanding deodorizing performance with persistence.
[0039]
[Table 9]
Examples 37-42 Comparative Examples 34-39
Petal-like porous substrates D1 to D6 for sustained release bodies of the present invention prepared in Examples 1 to 6, E1 to E3 prepared in Comparative Examples 1 to 3, and commercially available hydroxyapatite, synthetic silica, and calcium silicate Using 6 g of each as a carrier, a perfume (ethyl acetoacetate) was impregnated for 2 hours to obtain a sustained release composition carrying the perfume. In order to confirm the fragrance performance of these sustained-release bodies, they were left in a room temperature room to measure the sustainability. The results are shown in Table 10.
From Table 10, it can confirm that the sustained release body composition of this invention has the outstanding fragrance performance with persistence.
[0041]
[Table 10]
A: Almost no decrease in fragrance
B: Aroma is slightly lowered
C: The aromaticity is halved
D: Almost no fragrance
[0042]
Examples 43-48 Comparative Examples 40-45
Petal-like porous substrates D1 to D6 for sustained release bodies of the present invention prepared in Examples 1 to 6, E1 to E3 prepared in Comparative Examples 1 to 3, and commercially available hydroxyapatite, synthetic silica, and calcium silicate Using each 25 g as a carrier, 5 g of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate was added to obtain a sustained-release composition carrying an ultraviolet absorber. In order to confirm the ultraviolet-absorbing performance of these sustained-release bodies, a blend of 30 g of the sustained-release body and 500 g of polypropylene resin pellets was kneaded with a kneading extruder to obtain polypropylene resin pellets containing the sustained-release body. A polypropylene molded product was obtained from this pellet by an injection molding method. This molded product was subjected to an accelerated weathering test for 600 hours with a carbon arc type weather meter according to ASTM-D-1499 test method, and the surface state of the molded product was examined. The results are shown in Table 11.
From Table 11, it can be confirmed that the sustained-release composition of the present invention has a highly durable UV absorption effect.
[0043]
[Table 11]
A: No change
B: Some cracks
C: Many cracks
[0044]
【The invention's effect】
As mentioned above, the petal-like porous substrate for sustained release of the present invention having a specific particle shape, a specific pore size and specific surface area, a specific particle size and dispersity is controlled for controlled release according to the application. The sustained-release composition of the present invention having a drug supported on the substrate exhibits excellent sustained-release effects for various uses.
[Brief description of the drawings]
1 is an electron micrograph (magnification 1000 times) showing the particle structure of particles D1 obtained in Example 1. FIG.
2 is an electron micrograph (10,000 magnifications) showing the particle structure of particles D1 obtained in Example 1. FIG.
FIG. 3 is an electron micrograph (1000 ×) showing the particle structure of commercially available hydroxyapatite.
FIG. 4 is an electron micrograph (magnification 10,000 times) showing the particle structure of commercially available hydroxyapatite.
5 is a powder X-ray diffraction pattern of particles D1 obtained in Example 1. FIG.
6 is a powder X-ray diffraction pattern of particles D3 obtained in Example 3. FIG.
7 is a powder X-ray diffraction pattern of particles D5 obtained in Example 5. FIG.
FIG. 8 is a powder X-ray diffraction pattern of commercially available hydroxyapatite.
Claims (10)
（ａ）０．２≦ｄｘ１≦２０（μｍ）
（ｂ）０．０１≦ｄｘ２≦０．２０（μｍ）
（ｃ）５０≦Ｓｗ１≦１６５（m2／ｇ）
（ｄ）９５≦ω１≦９９
（ｅ）７０≦ω２≦９５
（ｆ）１≦α≦２ 但し、α＝ｄ５０／ｄｘ１
（ｇ）０≦β≦１．１ 但し、β＝（ｄ９０−ｄ１０）／ｄ５０
但し、
ｄｘ１：電子顕微鏡写真により測定した粒子の平均粒子径（μｍ）。
ｄｘ２：水銀圧入法により測定した細孔分布により求めた粒子の平均細孔径（μｍ）。
Ｓｗ１：窒素吸着法によるＢＥＴ比表面積（m2／ｇ）
ω１ ：ＪＩＳＫ５１０１−９１ ２０．１ 顔料試験方法の静置法による見掛け比容（ ml／ｇ）を測定し、下記の式（ｈ）により計算した静置空隙率（％）
１
（ｈ）ω１＝｛１−─────────────｝×１００（％）
２．９×［見掛け比容］
ω２：試料０．５ｇを断面積２cm2 の円筒に充填、３０kg／cm2 の圧力で３０秒間加圧、 その厚みをノギスで測定し、下記の式（ｉ）より計算した３０kg／cm2 の加圧空隙 率（％）
０．５
（ｉ）ω２＝｛１−─────────────｝×１００（％）
２．９×２×［厚さ］
α ：分散係数
ｄ５０：マイクロトラックＦＲＡレーザー式粒度分布計により測定した粒子の５０％平 均粒子径（μｍ）。
β ：シャープネス。
ｄ９０：マイクロトラックＦＲＡレーザー式粒度分布計により測定した粒子のふるい通 過側累計９０％粒子径（μｍ）。
ｄ１０：マイクロトラックＦＲＡレーザー式粒度分布計により測定した粒子のふるい通 過側累計１０％粒子径（μｍ）。It consists of a calcium phosphate compound having a petal-like porous structure using calcium carbonate as a raw material particle , the Ca / P atomic ratio is 5.56 or less, and the following formulas (a) to (g) are satisfied. A petal-like porous substrate for sustained release.
(A) 0.2 ≦ dx1 ≦ 20 (μm)
(B) 0.01 ≦ dx2 ≦ 0.20 (μm)
(C) 50 ≦ Sw1 ≦ 165 (m 2 / g)
(D) 95 ≦ ω1 ≦ 99
(E) 70 ≦ ω2 ≦ 95
(F) 1 ≦ α ≦ 2, where α = d50 / dx1
(G) 0 ≦ β ≦ 1.1 where β = (d90−d10) / d50
However,
dx1: average particle diameter (μm) of particles measured by electron micrograph.
dx2: average pore diameter (μm) of particles determined by pore distribution measured by mercury porosimetry.
Sw1: BET specific surface area by nitrogen adsorption method (m 2 / g)
ω1: JISK5101-91 20.1 The apparent specific volume (ml / g) of the pigment test method by the static method was measured, and the static void ratio (%) calculated by the following formula (h)
1
(H) ω1 = {1 ----------------------- x 100 (%)
2.9 × [apparent specific volume]
.omega.2: filling the sample 0.5g of cylindrical cross-sectional area 2 cm 2, the pressure for 30 seconds under pressure of 30kg / cm 2, the thickness was measured with calipers, the 30kg / cm 2 was calculated from the equation (i) below Pressurized porosity (%)
0.5
(I) ω2 = {1 ----------------------- x 100 (%)
2.9 x 2 x [thickness]
α: Dispersion coefficient d50: 50% average particle diameter (μm) of particles measured by Microtrac FRA laser particle size distribution meter.
β: Sharpness.
d90: 90% of particle diameter (μm) on the sieving pass side of particles measured with a Microtrac FRA laser particle size distribution analyzer.
d10: 10% particle diameter (μm) on the sieving pass side of particles measured with a Microtrac FRA laser particle size distribution meter.
（ｊ）０．２≦ｄｘ１≦１０（μｍ）The petal-like porous substrate for sustained release according to claim 1, wherein the average particle diameter dx1 satisfies the following formula (j).
(J) 0.2 ≦ dx1 ≦ 10 (μm)
（ｋ）０．５≦ｄｘ１≦５（μｍ）The petal-like porous substrate for sustained release according to claim 2, wherein the average particle diameter dx1 satisfies the following formula (k).
(K) 0.5 ≦ dx1 ≦ 5 (μm)
（ｌ）１００≦Ｓｗ１≦１６５（m2／ｇ）The petal-like porous substrate for sustained release according to any one of claims 1 to 3, wherein the BET specific surface area Sw1 satisfies the following formula (1).
(L) 100 ≦ Sw1 ≦ 165 (m 2 / g)
（ｍ）１≦α≦１．６
（ｎ）０≦β≦１．０The petal-like porous substrate for sustained release according to any one of claims 1 to 4, wherein the dispersion coefficient α and the sharpness β satisfy the following formulas (m) and (n) simultaneously.
(M) 1 ≦ α ≦ 1.6
(N) 0 ≦ β ≦ 1.0
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP35735796A JP4110235B2 (en) | 1996-12-25 | 1996-12-25 | Petal-like porous substrate for sustained release body and sustained release body composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP35735796A JP4110235B2 (en) | 1996-12-25 | 1996-12-25 | Petal-like porous substrate for sustained release body and sustained release body composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH10182492A JPH10182492A (en) | 1998-07-07 |
| JP4110235B2 true JP4110235B2 (en) | 2008-07-02 |
Family
ID=18453722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP35735796A Expired - Fee Related JP4110235B2 (en) | 1996-12-25 | 1996-12-25 | Petal-like porous substrate for sustained release body and sustained release body composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4110235B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4230558B2 (en) * | 1998-03-11 | 2009-02-25 | 株式会社エルブ | Antibacterial ceramics and manufacturing method thereof |
| JP4664571B2 (en) * | 2002-06-06 | 2011-04-06 | 丸尾カルシウム株式会社 | Foam stabilizer and foam-molded product comprising the same |
| JP5488778B2 (en) * | 2007-07-02 | 2014-05-14 | 日産化学工業株式会社 | Controlled release particulates and solid agrochemical formulations containing the granules |
| JP5732043B2 (en) * | 2009-04-24 | 2015-06-10 | オムヤ インターナショナル アーゲー | Particulate material for controlled release of active ingredients |
-
1996
- 1996-12-25 JP JP35735796A patent/JP4110235B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH10182492A (en) | 1998-07-07 |
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