JP2005028255A - Method of producing emulsion - Google Patents
Method of producing emulsion Download PDFInfo
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- JP2005028255A JP2005028255A JP2003194777A JP2003194777A JP2005028255A JP 2005028255 A JP2005028255 A JP 2005028255A JP 2003194777 A JP2003194777 A JP 2003194777A JP 2003194777 A JP2003194777 A JP 2003194777A JP 2005028255 A JP2005028255 A JP 2005028255A
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、粒子径分布が狭く均一性が高く微細なエマルションの製造方法に関する。
【０００２】
【従来の技術】
一般に、エマルションはその粒子径が小さくなるほど、水溶液中での分散安定性は高くなると言われている。
【０００３】
従来、微細なエマルションを製造するために種々の方法が知られており、最も一般的な方法は、高圧ホモジナイザーにより、物理的に大きな力を強制的に乳化物に加える方法である。しかし、その方法は製造設備が大がかりになり、コストアップの要因となることに加え、エマルションに与えるエネルギーが大きいため乳化時の温度上昇が大きく、熱に弱い成分の配合が困難であるなどの欠点があった。
【０００４】
この様な欠点を解決するため、最近では多孔質ガラス膜を用いたエマルションの製造方法が知られている（特許文献１〜３など）。この技術は、従来製造が困難であったＷ／Ｏ／Ｗ型複合エマルションを製造することができるなど優れた特性を持っている。
【０００５】
従来知られている多孔質膜を用いたエマルションの製造方法には、大きく二つの方法があり、一つは多孔質膜を通して分散相を連続相に押し出して製造する方法であり、もう一つはホモミキサーなどを用いて一次乳化し、得られた粒径の大きい乳化物を、多孔質膜を透過させることにより微細なエマルションを得る方法である。前者で製造する方法で、Ｏ／Ｗエマルションを製造する場合、分散相となるべき油を連続相となるべき水に多孔質膜を通して押し出すことにより製造し、また、Ｗ／Ｏ／Ｗ型複合エマルションを製造する場合には、分散相となるべきＷ／Ｏ型エマルションを連続相となるべき水に多孔質膜を通して押し出すことにより製造する。このような多孔質ガラス膜を用いたエマルションの製造方法によれば、粒子に与えるエネルギーが少なくてすみ、均一なエマルションを作ることができ、多孔質ガラス膜の細孔径を小さいものとすれば粒径の小さいエマルションを製造することが可能である。
【０００６】
また、多孔質膜を用いたもう一つのエマルションの製造方法としてはホモミキサーなどを用いて一次乳化し、粒径の大きい乳化物を得て、その後に多孔質膜を透過させることにより微細なエマルションを得る方法もある（特許文献４）。
【特許文献１】特開平０２−０９５４３３号
【特許文献２】特開平０５−２２０３８２号
【特許文献３】特開平０４−１００５３６号
【特許文献４】第２７６８２０５号
【発明が解決しようとする課題】
従来法でエマルションを製造する場合、一次乳化物を直接微細な孔径の多孔質膜を透過させるとエマルションが破壊されてしまうことがわかった。そのため膜透過法により微細なエマルションを得るためには、孔径が段階的に小さくなる複数の多孔質膜に透過させる必要があった。
【０００７】
そのため、作業効率が悪く、大量生産が困難なため工業的な生産ができなかった。
【０００８】
本発明は、均一性が高く粒子径が微細なエマルションを効率よく製造する方法を提供することを目的とする。
【０００９】
【課題を解決するための手段】
本発明者らは、上記目的を達成するため種々検討した結果、比較的粒子径の大きいエマルションを一般的な方法により一次乳化し、これを支持層と細粒層からなる多孔質膜の支持層側から細粒層側へ通過させると、粒子径分布が狭く均一なエマルションが得られることを見出し、本発明を完成した。
【００１０】
すなわち本発明は、一次乳化したエマルションを多孔質膜に透過させることにより微細なエマルションを製造する方法において、多孔質膜として細粒層と支持層からなる多孔質膜を用い、一次乳化したエマルションを支持層側から細粒層側へ透過させることを特徴とするエマルションの製造方法である。
【００１１】
【発明の実施の形態】
本発明で用いる多孔質膜としては、細粒層と支持層からなる多孔質膜を用いる必要がある。
【００１２】
ここで、支持層の孔径は約１〜２０μｍで、細粒層は０．００４〜１μｍの孔径を有するものが好ましく、約１０〜２０μｍの支持体に０．００４〜０．５μｍの超微細なアルミナ粒子を表面に固定化しているものがさらに好ましい。
【００１３】
この様な多孔質膜を用い、本発明の製造方法で製造することにより、従来ほとんど報告されていない平均粒子径０．００４〜０．５μｍの超微細なエマルションを得ることができる。
【００１４】
本発明で用いる多孔質膜としてはセラミック膜が最も好ましい。ここでセラミック膜とは、一般に粘土などを原料に、高温処理された無機系材料を膜状としたもので、各種原料の分離・濃縮や、各種加工液・洗浄液のリサイクル、廃液処理などに一般的に使われるものを使用することができる。
【００１５】
本発明で用いるセラミック膜の構成成分としては、アルミナ（Ａｌ２Ｏ３）、ジルコニア（ＺｒＯ２）、チタニア（ＴｉＯ２）、コーディエライト、ムライト、ゼオライト、チタン酸カリウム、アパタイトなどがあげられるが、それらの中でも本発明においてはアルミナ（Ａｌ２Ｏ３）を構成成分とするものが特に好ましい。
【００１６】
本発明では一次乳化したエマルションを支持層側から細粒層側へ通過させる必要がある。なお、本発明で用いる多孔質膜は、支持層側から細粒層側へ通過させる際に膜切断面（支持層）から漏れ出ないように、膜にはガラス質等でシーリングが施されたものが好ましい。
【００１７】
本発明で行う一次乳化の方法としては、ホモミキサー、スターラーなどによる攪拌の他、超音波処理等により乳化を行ってもよい。
【００１８】
本発明では一次乳化で得られたエマルションは、多孔質膜の細粒層の約５００倍程度という大きなものであっても直接微細なエマルションにすることができる。したがって一次乳化は簡単な攪拌程度でも十分であることから工業的に生産する場合においても問題なく製造することができる。従来の膜乳化法であると透過前の一次乳化物の平均粒子径は細孔径の２０倍程度が限界であるが、本発明の方法では平均粒子径がそれよりも大きいものを直接膜乳化法により微細なエマルションにすることができるという特徴を有する。
【００１９】
膜乳化に使用する多孔質膜の具体的な平均細孔径は目的とするエマルションの粒径により適宜選択することができる。本発明の方法により得られるエマルションの平均粒子径は、細粒層の孔径の０．５〜３倍程度になることからエマルションの使用目的により平均粒子径を変えることができる。
【００２０】
本発明では水相（複合エマルションのときは外水相）に水溶性高分子を配合すると得られるエマルションの安定性が向上する点から好ましい。このときの水溶性高分子としてはポリビニルアルコールが最も好ましい。
【００２１】
本発明はＷ／Ｏ／Ｗ型複合エマルションを工業的に製造する方法として特に好適である。
【００２２】
本発明によりＷ／Ｏ／Ｗ型複合エマルションを製造する場合には、一般的に以下のように製造することができる。
【００２３】
最初に、乳化剤、その他の添加剤等を添加した油相を容器に入れ、これを例えばホモミキサーのような攪拌機にセットし、攪拌しながら５０〜９０℃程度の温度で加熱溶解する。次に封入対象物質および任意の添加物を含む所定量の水相を徐々に添加し、液温を５０〜９０℃程度で一定に維持しながら攪拌乳化し、その後室温程度まで冷却しながら一定時間攪拌し、Ｗ／Ｏ型エマルションを調製する。このＷ／Ｏ型エマルションは０．０１〜０．５μｍ程度の平均油滴径を有するように製造されることが好ましい。さらに、任意の添加物を含む所定の外水相を攪拌機にセットし、５０〜８０℃程度の温度で攪拌しながらＷ／Ｏ型エマルションを徐々に添加し外水相に分散させることにより、まず目的とする油滴径よりも大きい油滴径を有するＷ／Ｏ／Ｗ型複合エマルションを製造する（一次乳化）。このような目的とする油滴径よりも大きい油滴径を有するＷ／Ｏ／Ｗ型複合エマルションは、公知のＷ／Ｏ／Ｗ型複合エマルション製造法により製造することができる。
【００２４】
上記で得られた一次乳化複合エマルションは多孔質膜に通すことにより微細化を行うが、この微細化は通常使用されるろ過・濃縮装置、例えばエマルション容器、多孔質膜モジュール等で構成されるろ過・濃縮装置などを用いて行うことができる。
【００２５】
膜乳化における温度は特に制限されないが、必要に応じて熱を加えることができる。このような膜乳化温度を得るための温度調節の方法も特に制限されず、例えば上記のようなろ過・濃縮装置の全体を恒温状態に保持するか、あるいはジャケット式の温度調節装置等を用いて上記温度範囲にコントロールすることができる。
【００２６】
油相として用いられる油は特に制限されず、エマルション製造用に従来から用いられている天然または合成の油を用いることができる。これらの油性成分は、目的とするエマルションに望まれる特性により、硬化あるいは分別して用いることができ、また２種以上の成分を配合して用いることもできる。
【００２７】
また、本発明では油相に油溶性の薬剤を配合することもできる。これにより油溶性薬剤と水溶性薬剤を同時に摂取することができる製剤とすることができる。
【００２８】
油相に添加する乳化剤としては、公知の親油性乳化剤を使用することができる。例えば、一般的に使用されるグリセリン脂肪酸エステル、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、プロピレングリコール脂肪酸エステル、ポリグリセリン脂肪酸エステル、ポリグリセリン縮合リシノレイン酸エステル、レシチンなどを使用することができる。特に、ポリグリセリン縮合リシノレイン酸エステルが好ましい。さらに、これらは単独で、または２種以上を混合して用いることができる。
【００２９】
これらの親油性乳化剤の添加量は、十分な乳化効果が得られる限り特に制限されないが、通常エマルション全体に対し０．０１〜４５質量％程度である。
【００３０】
また、外水相に添加する乳化剤についても、公知の親水性乳化剤を使用することができる。例えば、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、レシチン、高分子乳化剤等があげられる。特に、ポリグリセリン脂肪酸エステルが好ましい。
【００３１】
これらの親水性乳化剤のＨＬＢ（Ｈｙｄｒｏｐｈｌｉｃ Ｌｉｐｏｐｈｉｌｉｃ Ｂａｌａｎｃｅ）は８．０以上であることが好ましく、１０．０以上であることがより好ましい。これらの親水性乳化剤は、所望の乳化特性に応じて単独で、または２種以上混合して用いることができる。
【００３２】
これらの親水性乳化剤の添加量についても、十分な乳化効果が得られる限り特に制限されないが、通常エマルション全体に対し０．００１〜１０重量％程度である。
【００３３】
また、必要があれば外水相に本発明の効果を損なわない成分、防腐剤、ｐＨ調整剤、矯味剤、香料などを配合できる。
【００３４】
本発明のエマルションの用途は特に限定されないが、医薬品、医薬部外品、化粧品、食品等の用途に好ましく使用できる。製品の形態としては、例えば、液剤、乳液、クリーム等とすることができる。
【００３５】
【実施例】
以下に実施例により本発明をさらに詳細に説明する。
実施例１
［Ｗ／Ｏ型エマルションの調製］
組成
ａ：内水相
シアノコバラミン ０．１７ｇ
クエン酸 ０．１１ｇ
水 １６．７２ｇ
水酸化ナトリウム 適量（ｐＨ５．５）
ｂ：油相
酢酸トコフェロール ５５ｇ
ｃ：乳化剤
ポリグリセリン縮合リシノレイン酸エステル ２８ｇ
ｂ、ｃを７０〜８０℃に加温し、混合溶解した後、攪拌しながらａを徐々に添加し、液温を７０〜８０℃程度で一定に維持しながら攪拌乳化し、その後、２０〜４０℃まで冷却しながら一定時間攪拌し、Ｗ／Ｏ型エマルションを得た。
［Ｗ／Ｏ／Ｗ型複合エマルションの一次乳化物の調製］
１．０質量％ポリビニルアルコール、２０質量％トレハロースを含む水溶液９０ｇに、ホモジナイザーで攪拌しながら上記で得られたＷ／Ｏ型エマルション１０ｇを添加し、まず粒子径の比較的大きいＷ／Ｏ／Ｗ型複合エマルションを得た（一次（予備）乳化物）。得られたＷ／Ｏ／Ｗ型複合エマルションの平均粒子径をレーザー回折・散乱式粒度分布測定装置（ＨＯＲＩＢＡ ＬＡ−９２０）により測定した結果、１４．６３μｍであった。
【００３６】
＜薬物封入率の測定＞
封入対象物質のＷ／Ｏ／Ｗ型複合エマルション中への封入率は次式により算出した。
封入率（％）＝（Ｃｔ−Ｃｏ×Ａ）／Ｃｔ×１００
Ｃｔ：Ｗ／Ｏ／Ｗ型複合エマルション製剤中の薬物濃度
Ｃｏ：外水相中の封入対象薬物濃度
Ａ：外水相重量／Ｗ／Ｏ／Ｗ型複合エマルション重量
Ｗ／Ｏ／Ｗ型複合エマルション製剤中の薬物濃度はエマルションを前処理操作により壊し、また外水相に含まれる封入対象薬物濃度はＷ／Ｏ／Ｗ型複合エマルションを遠心分離（５ｘ１０４Ｇ， ９０分）によりエマルション粒子と外水相を分離する操作を行った後に、ＨＰＬＣ法により測定した。その結果、封入対象薬物として測定したシアノコバラミンの封入率は、９２．７％であった。
【００３７】
［Ｗ／Ｏ／Ｗ型複合エマルションの調製］
次に、このＷ／Ｏ／Ｗ型複合エマルションを表１に示した組成となるように調製し、支持層と細粒層からなり細粒層の平均細孔径が０．２μｍの多孔質セラミック膜の支持層側から細粒層側へ通過させ、膜乳化させることにより、Ｗ／Ｏ／Ｗ型複合エマルションを得た。セラミック膜としては、「セラミック膜フィルター セフィルト（商品名：日本ガイシ（株））」を使用し、膜乳化は清本鐵工社製ろ過・濃縮装置を使用して５ＭＰａ以下の圧力で行った。得られたＷ／Ｏ／Ｗ型複合エマルションの平均粒子径をレーザー回折・散乱式粒度分布測定装置（ＨＯＲＩＢＡ ＬＡ−９２０）により測定した結果、０．２３２μｍであり、油相粒子径の分布のＣＶ（標準偏差／平均粒子径）は０．２９であった。また、薬物封入率を上述に示した方法により算出した結果、封入対象薬物として測定したシアノコバラミンの封入率は、９１．４％であった。
【００３８】
実施例２〜４
表１に示した処方で実施例１と同様にしてＷ／Ｏ／Ｗ型エマルションを調製し薬物封入率を測定した。
【００３９】
比較例１
実施例１と同様にして一次（予備）乳化物を得た。
［Ｗ／Ｏ／Ｗ型複合エマルションの調製］
膜乳化の際に一次乳化物を多孔質セラミック膜の細粒層側から支持層側へ通過させることを除き実施例１と同様にしてＷ／Ｏ／Ｗ型複合エマルションを得た。得られたＷ／Ｏ／Ｗ型複合エマルションの平均粒子径をレーザー回折・散乱式粒度分布測定装置（ＨＯＲＩＢＡ ＬＡ−９２０）により測定した結果、９．１４μｍであり、油相粒子径の分布のＣＶ（標準偏差／平均粒子径）は０．６２であった。しかし、薬物封入率については良好なＷ／Ｏ／Ｗ型複合エマルションが得られなかったため測定を行わなかった。
【００４０】
なお、表中ＦＡＣはクエン酸鉄アンモニウム、ＰＧＣＲはポリグリセリン縮合リシノレイン酸エステル（阪本薬品工業、ＣＲＳ−７５）、ＰＶＡはポリビニルアルコールを示す。
【００４１】
【表１】
表から明らかなように、膜乳化の際に支持層と細粒層からなる多孔質膜の支持層側から細粒層側へ粒子径の大きいＷ／Ｏ／Ｗ型複合エマルションを通過させることにより、粒子径分布の狭い均一性が高く微細で、内水相における封入対象物質の封入率が高いＷ／Ｏ／Ｗ型複合エマルションをダイレクトに得ることができた（実施例１〜４）。
【００４３】
一方、膜乳化の際に多孔質セラミック膜の細粒層側から支持層側へ一次乳化物を通過させた場合、膜孔径に近い微細なＷ／Ｏ／Ｗ型複合エマルションを得ることができなかった（比較例１）。
【００４４】
実施例５〜９
［Ｗ／Ｏ型エマルションの調製］
表２に示した各組成を用い、実施例１の製造法と同様にして調製した。
［Ｗ／Ｏ／Ｗ型複合エマルションの一次乳化物の調製］
表２に示した各組成を用い、外水相９０ｇに、ホモジナイザーで攪拌しながら上記で得られたＷ／Ｏ型エマルション１０ｇを添加し、まず粒子径の比較的大きいＷ／Ｏ／Ｗ型複合エマルションを得た後、多孔質膜を通過させ、次操作で用いる多孔質セラミック膜（細粒層の平均細孔径が０．２μｍ）の３５から４０倍の粒子サイズのＷ／Ｏ／Ｗ型複合エマルションを得た（一次乳化物）。また、Ｗ／Ｏ／Ｗ型複合エマルションの平均粒子径の測定法及び薬物封入率の測定も実施例１と同様に行った。
［Ｗ／Ｏ／Ｗ型複合エマルションの調製］
次に、このＷ／Ｏ／Ｗ型複合エマルションを表２に示した組成で、実施例１に記した製造法と同様に調製してＷ／Ｏ／Ｗ型複合エマルションを得た。また、Ｗ／Ｏ／Ｗ型複合エマルションの平均粒子径の測定法及び薬物封入率の測定も実施例１と同様に行った。
【００４５】
【表２】
表から明らかなように、ＰＶＡ濃度を変化させた場合でも、膜乳化の際に支持層と細粒層からなる多孔質膜の支持層側から細粒層側へ粒子径の大きいＷ／Ｏ／Ｗ型複合エマルションを通過させることにより、粒子径分布の狭い均一性が高く微細で、内水相における封入対象物質の封入率が高いＷ／Ｏ／Ｗ型複合エマルションをダイレクトに得ることができた。
【００４７】
実施例１０〜１７
［Ｗ／Ｏ型エマルションの調製］
表３に示した各処方で、実施例１の製造法と同様にして調製した。
［Ｗ／Ｏ／Ｗ型複合エマルションの一次乳化物の調製］
表３に示した各組成を用い、外水相９０ｇに、ホモジナイザーで攪拌しながら上記で得られたＷ／Ｏ型エマルション１０ｇを添加し、まず粒子径の比較的大きいＷ／Ｏ／Ｗ型複合エマルションを得た後、多孔質膜を通過させ、次操作で用いる多孔質セラミック膜（細粒層の平均細孔径が０．２μｍ）の１．８から２．９倍の粒子サイズのＷ／Ｏ／Ｗ型複合エマルションを得た（一次乳化物）。また、Ｗ／Ｏ／Ｗ型複合エマルションの平均粒子径の測定法及び薬物封入率の測定も実施例１と同様に行った。
［Ｗ／Ｏ／Ｗ型複合エマルションの調製］
次に、得られたＷ／Ｏ／Ｗ型複合エマルションを表３に示した組成で、実施例１に記した製造法と同様に調製してＷ／Ｏ／Ｗ型複合エマルションを得た。また、Ｗ／Ｏ／Ｗ型複合エマルションの平均粒子径の測定法及び薬物封入率の測定も実施例１と同様に行った。
【００４８】
【表３】
比較例２〜６
［Ｗ／Ｏ型エマルションの調製］
表４に示した各組成を用い、実施例１の製造法と同様にして調製した。
［Ｗ／Ｏ／Ｗ型複合エマルションの一次乳化物の調製］
表４に示した各組成を用い、外水相９０ｇに、ホモジナイザーで攪拌しながら上記で得られたＷ／Ｏ型エマルション１０ｇを添加し、まず粒子径の比較的大きいＷ／Ｏ／Ｗ型複合エマルションを得た後、多孔質膜を通過させ、次操作で用いる多孔質セラミック膜（細粒層の平均細孔径が０．２μｍ）の１．８から２．９倍の粒子サイズのＷ／Ｏ／Ｗ型複合エマルションを得た（一次乳化物）。また、Ｗ／Ｏ／Ｗ型複合エマルションの平均粒子径の測定法及び薬物封入率の測定も実施例１と同様に行った。
［Ｗ／Ｏ／Ｗ型複合エマルションの調製］
次に、このＷ／Ｏ／Ｗ型複合エマルションを表４に示した組成で、比較例１と同様に細粒層側から支持層側へ通過させＷ／Ｏ／Ｗ型複合エマルションを得た。また、Ｗ／Ｏ／Ｗ型複合エマルションの平均粒子径の測定法及び薬物封入率の測定も実施例１と同様に行った。
【００５０】
比較例７
［Ｗ／Ｏ型エマルションの調製］
表４に示した各組成を用い、実施例１の製造法と同様にして調製した。
［Ｗ／Ｏ／Ｗ型複合エマルションの一次乳化物の調製］
表４に示した各組成を用い、外水相９０ｇに、ホモジナイザーで攪拌しながら上記で得られたＷ／Ｏ型エマルション１０ｇを添加し、まず粒子径の比較的大きいＷ／Ｏ／Ｗ型複合エマルションを得た後、多孔質膜を通過させ、次操作で用いる多孔質セラミック膜（細粒層の平均細孔径が０．２μｍ）の２．７倍の粒子サイズのＷ／Ｏ／Ｗ型複合エマルションを得た（一次乳化物）。また、Ｗ／Ｏ／Ｗ型複合エマルションの平均粒子径の測定法及び薬物封入率の測定も実施例１と同様に行った。
［Ｗ／Ｏ／Ｗ型複合エマルションの調製］
次に、このＷ／Ｏ／Ｗ型複合エマルションを表４に示した組成で、平均細孔径０．２μｍの多孔質ガラス膜で膜乳化させる操作を行ったところ、透明な液（外水相）のみ通過して、エマルションは膜を通過しなかった。多孔質ガラス膜としては、シラス多孔質ガラスを用い、サイジングは清本鐵工社製ろ過・濃縮装置を使用して５ＭＰａ以下の圧力で行ったところ、透明な液（外水相）のみ通過して、エマルションは膜を通過しなかった。
【００５１】
【表４】
表３、４から明らかなように、Ｗ／Ｏ型エマルションの組成や膜乳化時のＷ／Ｏ型エマルションと外水相の比率を変化させた場合にも、膜乳化の際に支持層と細粒層からなる多孔質膜の支持層側から細粒層側へ粒子径の大きいＷ／Ｏ／Ｗ型複合エマルションを通過させることにより、粒子径分布の狭い均一性の高い微細で、しかも内水相における封入対象物質の封入率が高いＷ／Ｏ／Ｗ型複合エマルションが得られた。
【００５３】
一方、膜乳化の際に多孔質セラミック膜の細粒層側から支持層側へ比較的膜孔径に近いＷ／Ｏ／Ｗ型複合エマルションを通過させた場合には、粒子径分布の狭い均一性の高い微細なＷ／Ｏ／Ｗ型複合エマルションが得られたものの、内水相における封入対象物質の封入率が高い良好なＷ／Ｏ／Ｗ型複合エマルションを得ることはできなかった（比較例２〜６）。また、平均細孔径０．２μｍの多孔質ガラス膜で乳化させる操作を行ったところ、透明な液（外水相）のみ通過して、エマルションは膜を通過しなかった（比較例７）。
【００５４】
【発明の効果】
本発明により、微細なエマルションを工業的に大量生産することが可能になった。そのため、医薬品、医薬部外品、化粧品、食品等の液剤、乳液、クリームなどとすることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a fine emulsion having a narrow particle size distribution and high uniformity.
[0002]
[Prior art]
Generally, it is said that the dispersion stability in an aqueous solution increases as the particle size of the emulsion decreases.
[0003]
Conventionally, various methods are known for producing a fine emulsion, and the most common method is a method in which a physically high force is forcibly applied to an emulsion by a high-pressure homogenizer. However, this method has a large manufacturing facility and causes a cost increase. In addition, since the energy given to the emulsion is large, the temperature rise during emulsification is large, and it is difficult to blend heat-sensitive components. was there.
[0004]
In order to solve such drawbacks, recently, a method for producing an emulsion using a porous glass film is known (Patent Documents 1 to 3, etc.). This technique has excellent characteristics such as the ability to produce a W / O / W type composite emulsion that has been difficult to produce.
[0005]
There are two main methods for producing emulsions using a porous membrane known in the art, one is a method in which a dispersed phase is extruded into a continuous phase through a porous membrane, and the other is a method. In this method, a fine emulsion is obtained by first emulsifying using a homomixer or the like, and allowing the obtained emulsion having a large particle size to pass through a porous membrane. In the case of producing an O / W emulsion by the former method, it is produced by extruding oil to be a dispersed phase through water to be a continuous phase through a porous membrane, and a W / O / W type composite emulsion. Is produced by extruding a W / O type emulsion to be a dispersed phase into water to be a continuous phase through a porous membrane. According to the method for producing an emulsion using such a porous glass membrane, less energy is given to the particles, a uniform emulsion can be made, and if the porous glass membrane has a small pore diameter, It is possible to produce an emulsion with a small diameter.
[0006]
As another method for producing an emulsion using a porous membrane, a fine emulsion is obtained by first emulsifying using a homomixer or the like to obtain an emulsion having a large particle size, and then allowing the porous membrane to permeate. There is also a method of obtaining (Patent Document 4).
[Patent Document 1] Japanese Patent Laid-Open No. 02-095433 [Patent Document 2] Japanese Patent Laid-Open No. 05-220382 [Patent Document 3] Japanese Patent Laid-Open No. 04-10000536 [Patent Document 4] 2768205 [Problems to be Solved by the Invention]
In the case of producing an emulsion by a conventional method, it has been found that if the primary emulsion is directly permeated through a porous membrane having a fine pore size, the emulsion is destroyed. Therefore, in order to obtain a fine emulsion by the membrane permeation method, it was necessary to permeate through a plurality of porous membranes whose pore diameters are reduced stepwise.
[0007]
Therefore, work efficiency is bad and mass production is difficult, so industrial production cannot be performed.
[0008]
An object of the present invention is to provide a method for efficiently producing an emulsion having a high uniformity and a fine particle size.
[0009]
[Means for Solving the Problems]
As a result of various studies to achieve the above-mentioned object, the inventors of the present invention primarily emulsified an emulsion having a relatively large particle size by a general method, and this was supported by a porous membrane support layer comprising a support layer and a fine particle layer. It was found that a uniform emulsion having a narrow particle size distribution can be obtained by passing from the side to the fine particle layer side, and the present invention has been completed.
[0010]
That is, the present invention relates to a method for producing a fine emulsion by allowing a primary emulsified emulsion to permeate through a porous membrane, and using a porous membrane comprising a fine particle layer and a support layer as the porous membrane, It is a method for producing an emulsion, characterized by allowing permeation from the support layer side to the fine particle layer side.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
As the porous membrane used in the present invention, it is necessary to use a porous membrane comprising a fine particle layer and a support layer.
[0012]
Here, the support layer has a pore size of about 1 to 20 μm, and the fine-grained layer preferably has a pore size of 0.004 to 1 μm, and a support of about 10 to 20 μm has an ultrafine size of 0.004 to 0.5 μm. More preferably, alumina particles are immobilized on the surface.
[0013]
By using such a porous membrane and producing it by the production method of the present invention, it is possible to obtain an ultrafine emulsion having an average particle size of 0.004 to 0.5 μm, which has hardly been reported so far.
[0014]
The porous membrane used in the present invention is most preferably a ceramic membrane. Here, ceramic membranes are generally made from clay and other raw materials and made from inorganic materials that have been treated at high temperature, and are generally used for separation and concentration of various raw materials, recycling of various processing and cleaning fluids, and waste fluid treatment. You can use what is used for the purpose.
[0015]
Constituent components of the ceramic film used in the present invention include alumina (Al 2 O 3 ), zirconia (ZrO 2 ), titania (TiO 2 ), cordierite, mullite, zeolite, potassium titanate, apatite and the like. Of these, those containing alumina (Al 2 O 3 ) as a constituent component are particularly preferred in the present invention.
[0016]
In the present invention, it is necessary to pass the primary emulsified emulsion from the support layer side to the fine particle layer side. The porous membrane used in the present invention was sealed with a glassy material so that the membrane would not leak from the cut surface (support layer) when passing from the support layer side to the fine particle layer side. Those are preferred.
[0017]
As a method of primary emulsification performed in the present invention, emulsification may be performed by ultrasonic treatment or the like in addition to stirring with a homomixer or a stirrer.
[0018]
In the present invention, the emulsion obtained by the primary emulsification can be directly made into a fine emulsion even if it is as large as about 500 times the fine particle layer of the porous membrane. Therefore, the primary emulsification is sufficient even with simple stirring, so that it can be produced without problems even in industrial production. In the case of the conventional membrane emulsification method, the average particle size of the primary emulsion before permeation is limited to about 20 times the pore size, but in the method of the present invention, those having an average particle size larger than that are directly membrane emulsification methods. It has the feature that it can be made into a finer emulsion.
[0019]
The specific average pore diameter of the porous membrane used for membrane emulsification can be appropriately selected depending on the particle size of the target emulsion. Since the average particle size of the emulsion obtained by the method of the present invention is about 0.5 to 3 times the pore size of the fine-grained layer, the average particle size can be changed depending on the intended use of the emulsion.
[0020]
In this invention, it is preferable from the point which improves the stability of the emulsion obtained when a water-soluble polymer is mix | blended with an aqueous phase (in the case of a composite emulsion, an external aqueous phase). In this case, polyvinyl alcohol is most preferable as the water-soluble polymer.
[0021]
The present invention is particularly suitable as a method for industrially producing a W / O / W type composite emulsion.
[0022]
When producing a W / O / W type composite emulsion according to the present invention, it can generally be produced as follows.
[0023]
First, an oil phase to which an emulsifier and other additives are added is placed in a container, and this is set in a stirrer such as a homomixer, and heated and dissolved at a temperature of about 50 to 90 ° C. while stirring. Next, a predetermined amount of an aqueous phase containing a substance to be encapsulated and optional additives is gradually added, and the mixture is stirred and emulsified while keeping the liquid temperature constant at about 50 to 90 ° C., and then cooled to about room temperature for a certain period of time. Stir to prepare a W / O emulsion. This W / O type emulsion is preferably produced so as to have an average oil droplet diameter of about 0.01 to 0.5 μm. Furthermore, by setting a predetermined outer water phase containing an arbitrary additive in a stirrer and gradually adding a W / O emulsion while stirring at a temperature of about 50 to 80 ° C. and dispersing it in the outer water phase, A W / O / W type composite emulsion having an oil droplet size larger than the target oil droplet size is produced (primary emulsification). A W / O / W type composite emulsion having an oil droplet size larger than the intended oil droplet size can be produced by a known W / O / W type composite emulsion production method.
[0024]
The primary emulsified composite emulsion obtained above is refined by passing through a porous membrane. This refinement is a filtration / concentration device that is usually used, such as an emulsion container, a porous membrane module, and the like. -It can be performed using a concentrator.
[0025]
The temperature in the membrane emulsification is not particularly limited, but heat can be applied as necessary. The temperature control method for obtaining such a membrane emulsification temperature is not particularly limited. For example, the entire filtration / concentration device as described above is maintained at a constant temperature, or a jacket type temperature control device or the like is used. It can be controlled within the above temperature range.
[0026]
The oil used as the oil phase is not particularly limited, and natural or synthetic oils conventionally used for emulsion production can be used. These oily components can be used after being cured or fractionated depending on the properties desired for the intended emulsion, and can also be used by blending two or more components.
[0027]
Moreover, in this invention, an oil-soluble chemical | medical agent can also be mix | blended with an oil phase. Thereby, it can be set as the formulation which can take an oil-soluble chemical | medical agent and a water-soluble chemical | medical agent simultaneously.
[0028]
A known lipophilic emulsifier can be used as an emulsifier to be added to the oil phase. For example, generally used glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, polyglycerin fatty acid ester, polyglycerin condensed ricinoleic acid ester, lecithin and the like can be used. In particular, polyglycerol condensed ricinoleic acid ester is preferable. Furthermore, these can be used individually or in mixture of 2 or more types.
[0029]
The addition amount of these lipophilic emulsifiers is not particularly limited as long as a sufficient emulsification effect is obtained, but is usually about 0.01 to 45% by mass with respect to the whole emulsion.
[0030]
Moreover, a well-known hydrophilic emulsifier can be used also about the emulsifier added to an external water phase. Examples thereof include glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, lecithin, and polymer emulsifier. In particular, polyglycerol fatty acid ester is preferable.
[0031]
These hydrophilic emulsifiers preferably have an HLB (Hydrophilic Lipophilic Balance) of 8.0 or more, and more preferably 10.0 or more. These hydrophilic emulsifiers can be used alone or in combination of two or more depending on the desired emulsification characteristics.
[0032]
The addition amount of these hydrophilic emulsifiers is not particularly limited as long as a sufficient emulsification effect is obtained, but is usually about 0.001 to 10% by weight with respect to the whole emulsion.
[0033]
Further, if necessary, the outer water phase can be blended with components that do not impair the effects of the present invention, preservatives, pH adjusters, flavoring agents, fragrances and the like.
[0034]
Although the use of the emulsion of this invention is not specifically limited, It can use preferably for uses, such as a pharmaceutical, a quasi-drug, cosmetics, and a foodstuff. As a form of a product, it can be set as a liquid agent, emulsion, cream, etc., for example.
[0035]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1
[Preparation of W / O type emulsion]
Composition a: Inner aqueous phase cyanocobalamin 0.17 g
Citric acid 0.11g
16.72 g of water
Sodium hydroxide appropriate amount (pH 5.5)
b: 55 g of oil phase tocopherol acetate
c: Emulsifier polyglycerin condensed ricinoleate 28g
b and c are heated to 70 to 80 ° C., mixed and dissolved, and then a is gradually added with stirring, followed by stirring and emulsification while maintaining the liquid temperature constant at about 70 to 80 ° C. While cooling to 40 ° C., the mixture was stirred for a certain time to obtain a W / O type emulsion.
[Preparation of primary emulsion of W / O / W type composite emulsion]
To 90 g of an aqueous solution containing 1.0% by mass polyvinyl alcohol and 20% by mass trehalose, 10 g of the W / O emulsion obtained above was added while stirring with a homogenizer. First, W / O / W having a relatively large particle size. A mold composite emulsion was obtained (primary (preliminary) emulsion). It was 14.63 micrometers as a result of measuring the average particle diameter of the obtained W / O / W type | mold composite emulsion with the laser diffraction and the scattering type particle size distribution measuring apparatus (HORIBA LA-920).
[0036]
<Measurement of drug encapsulation rate>
The encapsulation rate of the substance to be encapsulated in the W / O / W type composite emulsion was calculated by the following formula.
Encapsulation rate (%) = (Ct−Co × A) / Ct × 100
Ct: Drug concentration in W / O / W type composite emulsion formulation Co: Concentration of drug to be encapsulated in outer aqueous phase A: Weight of outer aqueous phase / W / O / W type composite emulsion Weight W / O / W type composite emulsion The drug concentration in the preparation is broken by pretreatment of the emulsion, and the concentration of the drug to be encapsulated contained in the outer aqueous phase is separated from the emulsion particles by centrifuging the W / O / W type composite emulsion (5 × 10 4 G, 90 minutes). After performing the operation of separating the aqueous phase, it was measured by the HPLC method. As a result, the encapsulation rate of cyanocobalamin measured as a drug to be encapsulated was 92.7%.
[0037]
[Preparation of W / O / W type composite emulsion]
Next, this W / O / W type composite emulsion was prepared so as to have the composition shown in Table 1, and was composed of a support layer and a fine particle layer, and the fine pore layer had an average pore diameter of 0.2 μm. The W / O / W type composite emulsion was obtained by passing from the support layer side to the fine particle layer side and emulsifying the membrane. As the ceramic membrane, “Ceramic Membrane Filter Cefilt (trade name: NGK Co., Ltd.)” was used, and membrane emulsification was performed using a filtration / concentration device manufactured by Kiyomoto Seiko Co., Ltd. at a pressure of 5 MPa or less. The average particle size of the obtained W / O / W type composite emulsion was measured by a laser diffraction / scattering type particle size distribution measuring device (HORIBA LA-920). As a result, it was 0.232 μm, and CV of oil phase particle size distribution The standard deviation / average particle size was 0.29. Moreover, as a result of calculating the drug encapsulation rate by the method described above, the encapsulation rate of cyanocobalamin measured as the drug to be encapsulated was 91.4%.
[0038]
Examples 2-4
A W / O / W type emulsion was prepared in the same manner as in Example 1 with the formulation shown in Table 1, and the drug encapsulation rate was measured.
[0039]
Comparative Example 1
A primary (preliminary) emulsion was obtained in the same manner as in Example 1.
[Preparation of W / O / W type composite emulsion]
A W / O / W composite emulsion was obtained in the same manner as in Example 1 except that the primary emulsion was passed from the fine particle layer side of the porous ceramic membrane to the support layer side during membrane emulsification. The average particle size of the obtained W / O / W type composite emulsion was measured by a laser diffraction / scattering type particle size distribution analyzer (HORIBA LA-920). As a result, it was 9.14 μm, and CV of oil phase particle size distribution The standard deviation / average particle diameter was 0.62. However, the drug encapsulation rate was not measured because a good W / O / W type composite emulsion could not be obtained.
[0040]
In the table, FAC represents ammonium iron citrate, PGCR represents polyglycerin condensed ricinoleic acid ester (Sakamoto Pharmaceutical Co., Ltd., CRS-75), and PVA represents polyvinyl alcohol.
[0041]
[Table 1]
As is apparent from the table, by passing a W / O / W composite emulsion having a large particle diameter from the support layer side to the fine particle layer side of the porous membrane comprising the support layer and the fine particle layer during membrane emulsification. In addition, it was possible to directly obtain a W / O / W type composite emulsion in which the particle size distribution is narrow and highly uniform, and the encapsulation rate of the target substance in the inner aqueous phase is high (Examples 1 to 4).
[0043]
On the other hand, when the primary emulsion is passed from the fine-grained layer side to the support layer side of the porous ceramic membrane during membrane emulsification, a fine W / O / W type composite emulsion close to the membrane pore diameter cannot be obtained. (Comparative Example 1).
[0044]
Examples 5-9
[Preparation of W / O type emulsion]
Each composition shown in Table 2 was used in the same manner as in the production method of Example 1.
[Preparation of primary emulsion of W / O / W type composite emulsion]
Using each composition shown in Table 2, 10 g of the W / O emulsion obtained above was added to 90 g of the outer water phase while stirring with a homogenizer. First, a W / O / W composite having a relatively large particle size was added. After obtaining the emulsion, it is passed through the porous membrane and a W / O / W type composite having a particle size 35 to 40 times that of the porous ceramic membrane (average pore diameter of the fine particle layer is 0.2 μm) used in the next operation. An emulsion was obtained (primary emulsion). Moreover, the measurement method of the average particle diameter of W / O / W type | mold composite emulsion and the measurement of a drug encapsulation rate were also performed similarly to Example 1.
[Preparation of W / O / W type composite emulsion]
Next, this W / O / W type composite emulsion was prepared in the same manner as in the production method described in Example 1 with the composition shown in Table 2 to obtain a W / O / W type composite emulsion. Moreover, the measurement method of the average particle diameter of W / O / W type | mold composite emulsion and the measurement of a drug encapsulation rate were also performed similarly to Example 1.
[0045]
[Table 2]
As is clear from the table, even when the PVA concentration was changed, W / O / having a large particle diameter from the support layer side to the fine particle layer side of the porous membrane composed of the support layer and the fine particle layer during membrane emulsification. By passing the W-type composite emulsion, it was possible to directly obtain a W / O / W-type composite emulsion having a narrow and uniform uniformity of particle size distribution and a high encapsulation rate of the target substance in the inner aqueous phase. .
[0047]
Examples 10-17
[Preparation of W / O type emulsion]
Each formulation shown in Table 3 was prepared in the same manner as the production method of Example 1.
[Preparation of primary emulsion of W / O / W type composite emulsion]
Using each composition shown in Table 3, 10 g of the W / O emulsion obtained above was added to 90 g of the outer aqueous phase while stirring with a homogenizer. First, a W / O / W composite having a relatively large particle size was added. After obtaining the emulsion, the porous membrane is passed through the porous membrane, and a W / O having a particle size 1.8 to 2.9 times that of the porous ceramic membrane (the fine pore layer has an average pore size of 0.2 μm) used in the next operation. / W type composite emulsion was obtained (primary emulsion). Moreover, the measurement method of the average particle diameter of W / O / W type | mold composite emulsion and the measurement of a drug encapsulation rate were also performed similarly to Example 1.
[Preparation of W / O / W type composite emulsion]
Next, the obtained W / O / W type composite emulsion was prepared in the same manner as in the production method described in Example 1 with the composition shown in Table 3 to obtain a W / O / W type composite emulsion. Moreover, the measurement method of the average particle diameter of W / O / W type | mold composite emulsion and the measurement of a drug encapsulation rate were also performed similarly to Example 1.
[0048]
[Table 3]
Comparative Examples 2-6
[Preparation of W / O type emulsion]
Each composition shown in Table 4 was prepared in the same manner as in the production method of Example 1.
[Preparation of primary emulsion of W / O / W type composite emulsion]
Using each composition shown in Table 4, 10 g of the W / O emulsion obtained above was added to 90 g of the outer aqueous phase while stirring with a homogenizer, and first a W / O / W type composite having a relatively large particle size. After obtaining the emulsion, the porous membrane is passed through the porous membrane, and a W / O having a particle size 1.8 to 2.9 times that of the porous ceramic membrane (the fine pore layer has an average pore size of 0.2 μm) used in the next operation. / W type composite emulsion was obtained (primary emulsion). Moreover, the measurement method of the average particle diameter of W / O / W type | mold composite emulsion and the measurement of a drug encapsulation rate were also performed similarly to Example 1.
[Preparation of W / O / W type composite emulsion]
Next, this W / O / W type composite emulsion having the composition shown in Table 4 was passed from the fine particle layer side to the support layer side in the same manner as in Comparative Example 1 to obtain a W / O / W type composite emulsion. Moreover, the measurement method of the average particle diameter of W / O / W type | mold composite emulsion and the measurement of a drug encapsulation rate were also performed similarly to Example 1.
[0050]
Comparative Example 7
[Preparation of W / O type emulsion]
Each composition shown in Table 4 was prepared in the same manner as in the production method of Example 1.
[Preparation of primary emulsion of W / O / W type composite emulsion]
Using each composition shown in Table 4, 10 g of the W / O emulsion obtained above was added to 90 g of the outer aqueous phase while stirring with a homogenizer, and first a W / O / W type composite having a relatively large particle size. After obtaining the emulsion, it is passed through the porous membrane and a W / O / W type composite having a particle size 2.7 times that of the porous ceramic membrane (average pore size of the fine particle layer is 0.2 μm) used in the next operation. An emulsion was obtained (primary emulsion). Moreover, the measurement method of the average particle diameter of W / O / W type | mold composite emulsion and the measurement of a drug encapsulation rate were also performed similarly to Example 1.
[Preparation of W / O / W type composite emulsion]
Next, when this W / O / W type composite emulsion was emulsified with a porous glass membrane having an average pore size of 0.2 μm with the composition shown in Table 4, a transparent liquid (outer aqueous phase) was obtained. Only passed through and the emulsion did not pass through the membrane. Shirasu porous glass is used as the porous glass membrane, and sizing is performed at a pressure of 5 MPa or less using a filtration / concentration device manufactured by Kiyomoto Seiko Co., Ltd., and only a transparent liquid (outer aqueous phase) passes through. The emulsion did not pass through the membrane.
[0051]
[Table 4]
As is apparent from Tables 3 and 4, even when the composition of the W / O emulsion and the ratio of the W / O emulsion and the external water phase during membrane emulsification are changed, the support layer and the fine layer are finely divided during membrane emulsification. By passing a W / O / W composite emulsion having a large particle size from the support layer side to the fine particle layer side of the porous membrane composed of a particle layer, the particle size distribution is narrow and highly uniform, and the internal water A W / O / W type composite emulsion having a high encapsulation rate of the substance to be encapsulated in the phase was obtained.
[0053]
On the other hand, when a W / O / W composite emulsion having a relatively close pore size is passed from the fine-grained layer side to the support layer side of the porous ceramic membrane during membrane emulsification, the uniformity of the particle size distribution is narrow. Although a fine W / O / W type composite emulsion having a high density was obtained, it was not possible to obtain a good W / O / W type composite emulsion in which the encapsulation rate of the substance to be encapsulated in the inner aqueous phase was high (Comparative Example) 2-6). Further, when an operation of emulsifying with a porous glass membrane having an average pore diameter of 0.2 μm was performed, only a transparent liquid (outer aqueous phase) passed through, and the emulsion did not pass through the membrane (Comparative Example 7).
[0054]
【The invention's effect】
The present invention has made it possible to industrially mass produce fine emulsions. Therefore, it can be set as liquid medicines, emulsions, creams, etc., such as pharmaceuticals, quasi drugs, cosmetics, and foods.
Claims (4)
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2006346565A (en) * | 2005-06-15 | 2006-12-28 | Spg Techno Kk | Method for preparing emulsion using porous body and its apparatus |
| JP2007125535A (en) * | 2005-11-01 | 2007-05-24 | Kiyomoto Iron & Machinery Works Co Ltd | Emulsification process and emulsification apparatus |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006346565A (en) * | 2005-06-15 | 2006-12-28 | Spg Techno Kk | Method for preparing emulsion using porous body and its apparatus |
| JP2007125535A (en) * | 2005-11-01 | 2007-05-24 | Kiyomoto Iron & Machinery Works Co Ltd | Emulsification process and emulsification apparatus |
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