JP4117119B2 - Fat-soluble substance solubilizing solution - Google Patents
Fat-soluble substance solubilizing solution Download PDFInfo
- Publication number
- JP4117119B2 JP4117119B2 JP2001204280A JP2001204280A JP4117119B2 JP 4117119 B2 JP4117119 B2 JP 4117119B2 JP 2001204280 A JP2001204280 A JP 2001204280A JP 2001204280 A JP2001204280 A JP 2001204280A JP 4117119 B2 JP4117119 B2 JP 4117119B2
- Authority
- JP
- Japan
- Prior art keywords
- tocopherol
- vitamin
- weight
- solution
- fatty acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Description
【０００１】
【発明の属する技術分野】
本発明は、脂溶性物質を含有する、味質と服用感に優れ、且つ、安定性に優れた透明性の高い可溶化液剤およびその製造方法に関する。
【０００２】
【従来の技術】
一般に脂溶性物質は水に対して難溶性であり、脂溶性物質を内服液剤や水性注射剤等の可溶化液剤とするために、種々の試みがなされている。
【０００３】
例えば、特公平４ー７７２２号には、脂溶性物質のビタミンＥを用いて、(A)ビタミンＥ、(B)ビタミンＥに対し１００〜５００重量％の硬化ヒマシ油ポリオキシエチレン誘導体、及び(C)ビタミンＥに対し１０〜５０重量％のソルビタン脂肪酸エステル、ポリオキシエチレンソルビット脂肪酸エステル、ポリグリセリン脂肪酸エステル及びポリオキシエチレングリセリン脂肪酸エステルからなる群から選ばれた１種又は２種以上の安定剤を含有する安定なビタミンＥの可溶化液が開示されている。
【０００４】
しかし、このビタミンＥ可溶化液は、特にビタミンＥに対し１００〜５００重量％の硬化ヒマシ油ポリオキシエチレン誘導体を添加するという極めて多量の界面活性剤（硬化ヒマシ油ポリオキシエチレン誘導体）を必要とする為、製造コストや消費者の添加剤摂取量の少量志向等の観点から、望ましいとは言い難い。また、該可溶化液は、透明性は優れているものの、硬化ヒマシ油ポリオキシエチレン誘導体に由来する不快な味が強く感じられ、内服液剤としての味質と服用感は良好ではない。
【０００５】
【発明が解決しようとする課題】
脂溶性物質を含有する可溶化液剤において、安定性に優れ、透明性が高く、且つ、味質と服用感に優れる可溶化液剤、特にドリンク剤等の内服水溶性液剤の開発が求められている。また、ドリンク剤は、滋養強壮剤として服用されることが多い為、脂溶性物質として、脂溶性ビタミン、特にビタミンＥ類、ビタミンＡ類、ビタミンＤ類及び／又はビタミンＫ類を含有する不快な味を有さない可溶化液剤が要望されている。
【０００６】
【課題を解決するための手段】
本発明は、脂溶性物質と、(1)脂溶性物質に対して５０重量％以上１００重量％未満のポリオキシエチレン硬化ヒマシ油及びポリオキシエチレンヒマシ油から選ばれる１種又は２種以上と、(2)脂溶性物質に対して５〜１００重量％のポリグリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレングリセリン脂肪酸エステル、ショ糖脂肪酸エステル及びポリオキシエチレンアルキルエーテルからなる群から選ばれる１種又は２種以上と、(3)可溶化液剤全量に対して１０〜８０重量％の多価アルコールとを含有してなる、脂溶性物質の可溶化液剤及びその製造方法、並びにこの可溶化液剤を、精製水、緩衝液又は水性液剤で希釈してなる、脂溶性物質を０．０１〜０．３重量％含有する可溶化液剤希釈液である。
【０００７】
【発明の実施の形態】
本発明の可溶化液剤において、(1)のポリオキシエチレン硬化ヒマシ油及び／又はポリオキシエチレンヒマシ油としては、エチレンオキサイド平均付加モル数４０〜６０のものが好ましい。このポリオキシエチレン硬化ヒマシ油及び／又はポリオキシエチレンヒマシ油の配合量は、十分な透明性と、優れた味質や服用感を得るために、脂溶性物質に対し５０重量％以上１００重量％未満であり、好ましくは７０重量％以上１００重量％未満であり、さらに好ましくは８０重量％以上１００重量％未満である。
【０００８】
また、本発明の可溶化液剤において、(2)の脂肪酸エステル類としては、炭素数１４〜２２の飽和又は不飽和脂肪酸のエステルが好ましく、部分エステルでも、完全にエステル化したものでもよい。またポリグリセリン脂肪酸エステルのグリセリン縮合度は２〜１０が好ましく、ポリオキシエチレンソルビタン脂肪酸エステル及びポリオキシエチレングリセリン脂肪酸エステルのエチレンオキサイド平均付加モル数は６〜４０が好ましい。またポリオキシエチレンアルキルエーテルのアルキル基の炭素数は１２〜２２が好ましく、エチレンオキサイドの平均付加モル数は６〜４０が好ましい。
【０００９】
これら(2)成分の配合量は、十分な透明性と、優れた味質や服用感を得る観点から、脂溶性物質に対して５〜１００重量％であり、好ましくは１０〜５０重量％である。
【００１０】
本発明に係る脂溶性物質は、特に限定されず、例えば、ビタミンＥ類、ビタミンＡ類、βーカロチン、ビタミンＤ類及び／又はビタミンＫ類等の脂溶性ビタミン、クロタミトン、テプレノン、インドメタシン、プレドニゾロン、タンニン酸等が挙げられるが、好ましくは、ビタミンＥ類、ビタミンＡ類、ビタミンＤ類及び／又はビタミンＫ類であり、さらに好ましくは、ビタミンＥ類である。
【００１１】
ビタミンＥ類としては、例えば、ｄｌ―α―トコフェロール、ｄ―α―トコフェロール、酢酸ｄｌ―α―トコフェロール、酢酸ｄ―α―トコフェロール、コハク酸ｄｌ―α―トコフェロール、コハク酸ｄ―α―トコフェロール、ニコチン酸ｄｌ―α―トコフェロール、ニコチン酸ｄ―α―トコフェロール、ｄｌ―β―トコフェロール、ｄ―β―トコフェロール、酢酸ｄｌ―β―トコフェロール、酢酸ｄ―β―トコフェロール、コハク酸ｄｌ―β―トコフェロール、コハク酸ｄ―β―トコフェロール、ニコチン酸ｄｌ―β―トコフェロール、ニコチン酸ｄ―β―トコフェロール、ｄｌ―γ―トコフェロール、ｄ―γ―トコフェロール、酢酸ｄｌ―γ―トコフェロール、酢酸ｄ―γ―トコフェロール、コハク酸ｄｌ―γ―トコフェロール、コハク酸ｄ―γ―トコフェロール、ニコチン酸ｄｌ―γ―トコフェロール、ニコチン酸ｄ―γ―トコフェロール、ｄｌ―δ―トコフェロール、ｄ―δ―トコフェロール、酢酸ｄｌ―δ―トコフェロール、酢酸ｄ―δ―トコフェロール、コハク酸ｄｌ―δ―トコフェロール、コハク酸ｄ―δ―トコフェロール、ニコチン酸ｄｌ―δ―トコフェロール、ニコチン酸ｄ―δ―トコフェロール、トコトリエノール等が挙げられ、酢酸ｄ―α―トコフェロールが好ましい。ビタミンＤ類としては、例えば、ビタミンＤ1、ビタミンＤ2、ビタミンＤ3が、ビタミンＫ類としては、ビタミンＫ1、ビタミンＫ2、ビタミンＫ3、ビタミンＫ4等が挙げられる。
【００１２】
本発明に係る可溶化液剤中の脂溶性物質の含有量は、特に限定されないが、好ましくは、可溶化液剤全量に対して３〜１５重量％である。
【００１３】
本発明に係る多価アルコールとしては、例えば、グリセリン、ジグリセリン、トリグリセリン、ポリグリセリン、プロピレングリコール、ジプロピレングリコール、1,3−ブチレングリコール、エチレングリコール、ポリエチレグリコール、ソルビトール、マンニトール、キシリトール等が挙げられる。多価アルコールの配合量は、十分な透明性の確保、及び脂溶性物質や(1)及び(2)成分の至適配合量の確保の観点から、可溶化液剤全量に対して１０〜８０重量％であり、好ましくは３０〜８０重量％である。
【００１４】
本発明に係る可溶化液剤は、精製水の配合の有無にかかわらず製造可能である。精製水の配合により可溶化液剤の粘度が低下する為、精製水を加えることにより、可溶化液剤の製造時の作業性は良好となる。
【００１５】
本発明に係る脂溶性物質の可溶化液剤は、１）ドリンク剤、液剤、シロップ剤、含漱剤、洗口液等の内服の医薬品・医薬部外品、２）エリキシル剤、ローション剤、点眼剤、点鼻剤、点耳剤、経膣剤、経腸剤等の外用の医薬品・医薬部外品や、化粧品配合剤、又は、３）通常の賦形剤を加えて、錠剤、チュアブル剤、顆粒剤、カプセル剤等の固形製剤として使用することができる。
【００１６】
本発明に係る脂溶性物質の可溶化液剤は、そのまま服用しても良いが、特にドリンク剤等の内服液剤として使用する場合には、さらに、精製水、緩衝液又はドリンク剤等の水性液剤で任意の濃度に希釈して可溶化液剤希釈液として用いることができる。可溶化液剤希釈液中の脂溶性物質の濃度は、特に限定されないが、好ましくは０．０１〜０．３重量％である。
【００１７】
本発明に係る可溶化液剤を製造するには、上記各成分を混合して、各成分を含有する混合物を調製すればよいが、各成分を含有する混合物を更に高圧処理してもよい。
【００１８】
したがって、本発明は、脂溶性物質に、(1)脂溶性物質に対して５０重量％以上１００重量％未満のポリオキシエチレン硬化ヒマシ油及びポリオキシエチレンヒマシ油からなる群から選ばれる１種又は２種以上と、(2)脂溶性物質に対して５〜１００重量％のポリグリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレングリセリン脂肪酸エステル、ショ糖脂肪酸エステル及びポリオキシエチレンアルキルエーテルからなる群から選ばれる１種又は２種以上を配合し、更に、(3)可溶化液剤全量に対して１０〜８０重量％の多価アルコールを配合するか、あるいは配合した混合物を、高圧処理することを特徴とする脂溶性物質の可溶化液剤の製造方法をも提供する。
【００１９】
上記各成分を配合する際の温度は、６０〜９０℃が好ましく、７０〜８５℃が更に好ましい。また各成分を混合する際には、プロペラ式、アンカー式等の単純攪拌機、及び／又はホモジナイザー、ホモミキサー等の高剪断乳化機等を用いることができる。
【００２０】
高圧処理は、通常、高圧ホモジナイザー、高速加圧乳化機等を使用して行なう。高圧処理時の液剤温度は、通常は常温から約９０℃であり、好ましくは６０〜８０℃である。また、高圧処理時の圧力は特に限定されないが、通常は１００〜５０００ｋｇ／ｃｍ2（９８０７〜４９０３５０ｋＰａ）であり、好ましくは１５０〜２０００ｋｇ／ｃｍ2（１９６１４〜１９６１４０ｋＰａ）であり、さらに好ましくは２００〜１８００ｋｇ／ｃｍ2（２９４２１〜１７６５６ｋＰａ）である。
【００２１】
本発明に係る脂溶性物質の可溶化液剤は、安定性に優れた透明性の高い液剤である。特に、界面活性剤のポリオキシエチレン硬化ヒマシ油及び／又はポリオキシエチレンヒマシ油の添加量が、脂溶性物質に対して５０重量％以上１００重量％未満という極めて少量で、透明性の高い液剤が得られるという驚くべき特徴を有している。また、本発明に係る脂溶性物質の可溶化液剤は、内服服用時における不快な味をほとんど感じることなく、味質と服用感に極めて優れるという、際立った特性を有している。
【００２２】
脂溶性物質の可溶化液剤に関する従来技術では、十分な透明性を有する透過率の高い液剤を得る為に、ポリオキシエチレン硬化ヒマシ油等の界面活性剤を多量に配合せざるを得ず、またその配合量が多い為に該界面活性剤に由来する不快な味質及び服用感を強く感じるという問題があった。本発明に係る脂溶性物質の可溶化液剤は、ポリオキシエチレン硬化ヒマシ油等の界面活性剤の配合量を特定の範囲幅まで減らすことにより、上記問題を解決し、透過率９０％以上の十分な液剤透明性と良好な味質・服用感の両立という驚くべき効果を達成したものである。
【００２３】
したがって、本発明に係る脂溶性物質の可溶化液剤、及び可溶化液剤を精製水、緩衝液又は水性液剤で希釈した可溶化液剤希釈液は、ドリンク剤、液剤、シロップ剤、含漱剤、洗口液等の内服の医薬品・医薬部外品に使用する場合に、特に有用である。
【００２４】
本発明に係る脂溶性物質の可溶化液剤及び可溶化液剤希釈液は、例えば、次の方法により製造することができる。
【００２５】
例えば、酢酸ｄ−α−トコフェロール１００ｇ、ポリオキシエチレン硬化ヒマシ油８５ｇ、ポリグリセリン脂肪酸エステル３０ｇ、グリセリン６３５ｇ及び精製水１５０ｇを入れて混合し、約70℃に加温しながら、ホモミキサーで10000 rpm×５分間撹拌混合して、均一な水性液剤を調製することにより、酢酸ｄ−α−トコフェロールの可溶化液剤を製造することができる。また、さらにこの水性液剤を高圧ホモジナイザーを使用して、１０００ｋｇ／ｃｍ2（９８０７０ｋＰａ）で高圧処理を行い、酢酸ｄ−α−トコフェロールの可溶化液剤を製造することもできる。また、これらの可溶化液剤１ｇに、ｐＨ３に調整した緩衝液を加えて希釈することにより、酢酸ｄ−α−トコフェロールを0．1重量％含有する可溶化液剤希釈液を製造することができる。
【００２６】
【実施例】
以下に実施例を挙げて本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。
【００２７】
実施例１〜実施例８
脂溶性物質として、酢酸ｄ−α−トコフェロールを用い、表１に示した処方で、各成分を混合し、約70℃に加温しながら、ホモミキサーで10000rpm×５分間撹拌混合して、均一な可溶化液剤を調製した。この水性液剤を高圧ホモジナイザーを使用して１０００ｋｇ／ｃｍ2（９８０７０ｋＰａ）で高圧処理を行い、酢酸ｄ−α−トコフェロールの可溶化液剤を得た。
【００２８】
得られた可溶化液剤に水を加えて、粒子数として100000〜1000000個／ｍＬになるように希釈し、所定のセルに入れサブミクロン粒子測定装置(Coulter社製、MODEL Ｎ４ ＳＤ）を用いて平均粒子径（ｎｍ）を測定した。
【００２９】
また、上記の高圧処理した可溶化液剤１ｇに、市販品ドリンク剤（Ａ）１００ｍＬ（ニコチン酸アミド２０ｍｇ、アミノエチルスルホン酸１ｇ、硝酸チアミン５ｍｇ、リン酸リボフラビンナトリウム５ｍｇ、塩酸ピリドキシン５ｍｇ、塩酸カルニチン１００ｍｇ、イノシトール５０ｍｇ、無水カフェイン５０ｍｇを１瓶１００ｍＬ中に含有）を加えて希釈し、酢酸ｄ−α−トコフェロール含量１００ｍｇとなるように可溶化液剤希釈液を得た。
【００３０】
比較例１
脂溶性物質として、酢酸ｄ−α−トコフェロールを用い、表１に示した処方（脂溶性物質に対して２００重量％のポリオキシエチレン硬化ヒマシ油を添加）で、各成分を混合する以外は実施例１〜８と同様にして、酢酸ｄ−α−トコフェロールの可溶化液剤、及び酢酸ｄ−α−トコフェロール含量１００ｍｇとなるように可溶化液剤希釈液を得、同様に平均粒子径を測定した。
【００３１】
実施例１〜８で得られた可溶化液剤希釈液を、比較例１で得られた可溶化液剤希釈液と比較して、物性評価を行なった。評価は、製造直後、７0℃で１日及び７日の保存を行った後の640nmにおける透過率（％）を測定し、製造直後のそれぞれの可溶化液剤希釈液を口腔内に５秒間含んだ時の味質及び服用感を官能検査により、下記の基準で評価した。処方と各試験結果を表１に示した。
【００３２】
＜味質及び服用感の評価基準＞
○：味質及び服用感は良好である。
△：やや、味質及び服用感に不快感を感じる。
×：味質及び服用感に不快感を感じる。
【００３３】
【表１】
表１から明らかなように、実施例１〜８ではいずれも、「液剤の味質及び服用感は良好」であった。一方、ポリオキシエチレン硬化ヒマシ油の配合比率が脂溶性物質に対して２００重量％である比較例１では、「液剤の味質及び服用感に不快感」が感じられた。
【００３５】
また可溶化液剤希釈液の640nmにおける透過率（％）は、表１に示したように、製造直後において、いずれの実施例も９０％以上であり、良好な透明性を有しており、また、７０℃で１日及び７日の保存を行っても透過率の顕著な低下は認められなかった。また、ポリオキシエチレン硬化ヒマシ油やポリグリセリン脂肪酸エステル（デカグリセリンモノステアリン酸エステル）の配合比率による差はほとんどなく、若干、配合比率が大きいほど透過率は若干高くなる傾向が認められたが大きな差は認められなかった。尚、通常、液剤の透過率は９０％以上であれば、外観上十分な透明性を有していると判断でき、ポリグリセリン脂肪酸エステルの配合比率が最も小さい実施例５（脂溶性物質に対して１０重量％）でも、製造直後の透過率が９２．３％、７0℃で１日及び７日の保存後の透過率が、各々９４．１％、９１．９％で、外観上比較例１と同程度の透明性であったことから、良好な透明性を有していると言える。
【００３６】
以上から、本発明により、脂溶性物質を含有する味質と服用感に優れ、且つ、安定性に優れた透明性の高い可溶化液剤が得られることは明白である。
【００３７】
実施例９〜実施例１３
脂溶性物質として、酢酸ｄ−α−トコフェロールを用い、表２に示した処方で、各成分を混合し、約70℃に加温しながら、ホモミキサーで10000rpm×５分間撹拌混合して、均一な可溶化液剤を調製した。この水性液剤を高圧ホモジナイザーを使用して３００ｋｇ／ｃｍ2（２９４２１ｋＰａ）で高圧処理を行い、酢酸ｄ−α−トコフェロールの可溶化液剤を得た。得られた可溶化液剤の平均粒子径を実施例１〜８と同様に測定した。
【００３８】
また、これらの高圧処理した可溶化液剤１ｇに、市販品ドリンク剤（Ａ）１００ｍＬ（ニコチン酸アミド２０ｍｇ、アミノエチルスルホン酸１ｇ、硝酸チアミン５ｍｇ、リン酸リボフラビンナトリウム５ｍｇ、塩酸ピリドキシン５ｍｇ、塩酸カルニチン１００ｍｇ、イノシトール５０ｍｇ、無水カフェイン５０ｍｇを１瓶１００ｍＬ中に含有）を加えて希釈し、酢酸ｄ−α−トコフェロール含量１００ｍｇとなるように可溶化液剤希釈液を得た。得られた可溶化液剤希釈液について、実施例１〜８と同様に透過率を測定し、味質及び服用感を官能検査した。処方と試験結果を表２に示した。
【００３９】
【表２】
表２から明らかなように、いずれの実施例も製造直後において、９０％以上の透過率であり、良好な透明性を有しており、また、７０℃で保存しても透過率の顕著な低下は認めなかった。さらに、味質及び服用感は良好であった。
【００４１】
実施例１４〜実施例１６
脂溶性物質として、酢酸ｄ−α−トコフェロールを用い、表３に示した処方で、各成分を混合し、約70℃に加温しながら、ホモミキサーで10000rpm×５分間撹拌混合して、均一な可溶化液剤を調製した。この水性液剤を高圧ホモジナイザーを使用して、２００ｋｇ／ｃｍ2（１９６１４ｋＰａ）で高圧処理を行い、酢酸ｄ−α−トコフェロールの可溶化液剤を得た。得られた可溶化液剤の平均粒子径を実施例１〜８と同様に測定した。
【００４２】
また、これらの高圧処理した可溶化液剤１ｇに、市販品ドリンク剤（Ａ）１００ｍＬ（ニコチン酸アミド２０ｍｇ、アミノエチルスルホン酸１ｇ、硝酸チアミン５ｍｇ、リン酸リボフラビンナトリウム５ｍｇ、塩酸ピリドキシン５ｍｇ、塩酸カルニチン１００ｍｇ、イノシトール５０ｍｇ、無水カフェイン５０ｍｇを１瓶１００ｍＬ中に含有）を加えて希釈し、酢酸ｄ−α−トコフェロール含量1２０ｍｇ（実施例１４）、1５０ｍｇ（実施例１５〜実施例１６）である可溶化液剤希釈液を得た。得られた可溶化液剤希釈液について、実施例１〜８と同様に透過率を測定し、味質及び服用感を官能検査した。処方と試験結果を表３に示した。
【００４３】
【表３】
表３から明らかなように、トコフェロールの濃度に関係なく、実施例１４、１５及び１６の可溶化液剤希釈液の透過率は、製造直後において、いずれも９０％以上であり良好な透明性を有しており、また、７０℃で保存しても透過率の顕著な低下は認めなかった。さらに、味質及び服用感は良好であった。
【００４５】
実施例１７〜１９
脂溶性物質として、酢酸ｄ−α−トコフェロールを用い、表４に示した処方で、各成分を約80℃に加温しながら、ホモミキサーで10000rpm×10分間撹拌混合して、均一な可溶化液剤を調製した。この水性液剤を高圧乳化機を使用して、9000 psiで高圧処理を行い、室温まで冷却して、酢酸ｄ−α−トコフェロールの可溶化液剤を得た。さらに、実施例１〜８と同様に市販品ドリンク剤（Ａ）を加えて希釈し、酢酸ｄ−α−トコフェロール含量１００ｍｇとなるように可溶化液剤希釈液を得た。
【００４６】
得られた可溶化液剤希釈液について、実施例１〜８と同様に透過率、平均粒子径を測定し、味質及び服用感を官能検査した。処方と試験結果を表４に示した。
【００４７】
【表４】
表４の結果から明らかなように、グリセリン濃度に関係なく、透過率90％以上の澄明な液体が得られた。また、この希釈液を７０℃で７日間保存しても、透過率及び平均粒子径にほとんど変化は認められなかった。
【００４９】
実施例２０〜２２
脂溶性物質として、酢酸ｄ−α−トコフェロールを用い、表５に示した処方で、各成分を単純撹拌機（90rpm）を用いて、85±５℃で製剤が澄明になるまで加温撹拌したのち、室温まで冷却し、可溶化液剤を得た。この液剤を５℃、45℃、−10℃／40℃（昇降時間12時間、各保温時間12時間の48時間サイクル）で２ヶ月保存、又は４５℃で２ヶ月保存したのち、精製水を添加して酢酸ｄ−α−トコフェロール含量１００ｍｇの可溶化液剤希釈液として、実施例１〜８と同様に透過率を測定した。その結果を表５に示す。この結果から、製造直後の初期値と同様に、保存後も透過率90％以上の澄明な液体を得ることができ、この可溶化液剤は保存性が良いことが確認された。
【００５０】
また、この可溶化液剤を、前記市販品ドリンク剤（Ａ）100ｍＬまたは市販品ドリンク剤（Ｂ）100ｍＬ（タウリン1000ｍｇ、イノシトール50ｍｇ、ニコチン酸アミド20ｍｇ、ビタミンＢ1硝酸塩５ｍｇ、ビタミンＢ2リン酸エステル５ｍｇ、ビタミンＢ6 ５ｍｇ、無水カフェイン50ｍｇを１瓶100ｍＬ中に含有）に１本あたり酢酸ｄ−α−トコフェロール100ｍｇとなるように添加して可溶化液剤希釈液を得た。これらの希釈液について、実施例１〜８と同様に透過率を測定し、味質及び服用感を官能検査した。結果を表５に示した。この結果から、可溶化液剤を添加しない市販品と比較して、味質及び服用感に差は認められず、良好であった。また、希釈液を、７０℃で１日及び７日保存後の透過率は、製造直後の透過率とほとんど変化せず、澄明な液体であった。
【００５１】
【表５】
実施例２３
表６に示す処方で、80重量％の精製水（約80℃）中に、メチルパラベン、安息香酸ナトリウムを溶解させた後、ポリエチレングリコール（PEG4000）、粉末還元麦芽糖水飴、グリセリンを投入撹拌し、室温まで冷却し澄明な液体を得た。さらに、Ｌ−アルギニン及びビタミンＣ誘導体、実施例２１で調製した可溶化液剤及び精製水（残部）を添加して、均一な澄明な液体となるまで撹拌し、ビタミンＥ及びビタミンＣ含有ローション剤を得た。このローション剤は、透過率97.1％の澄明な液体であり、ｐＨ4.7であった。使用感は、べたつきは認められず、さっぱりとして良好であった。
【００５３】
また、同様に実施例２１の可溶化液剤を、０．５、３又は５％添加したローション剤を調製したところ、べたつきのない、さっぱりした使用感のローション剤であった。
【００５４】
実施例２４
表６に示す処方で、80重量％の精製水（約80℃）中に、メチルパラベン、安息香酸ナトリウム、イプシロンアミノカプロン酸、グリセリンを溶解させた後、カルボキシビニルポリマーを徐々に添加し、撹拌し、均一な分散液を得た。この分散液を50℃付近まで冷却し、撹拌下、トリエタノールアミン水溶液（処方中５％の精製水）を添加し、澄明なゲル剤を得た。さらに、実施例２１で調製した可溶化液剤及び精製水（残部）を添加し、均一になるまで撹拌し、ビタミンＥ含有ゲル剤を得た。このゲル剤は、べたつきのないさっぱりとした使用感であった。
【００５５】
また、同様に実施例２１の可溶化液剤を、０．５、３又は５％添加したゲル剤を調製したところ、濃度に依らず、べたつきは認められず、さっぱりとした使用感であった。
【００５６】
【表６】
実施例２５〜２６
表７に示す処方で、80重量％の精製水（約80℃）中に、メチルパラベン、安息香酸ナトリウム、キサンタンガムを溶解させた後、PEG4000、キシリトール、グリセリンを投入撹拌し、室温まで冷却し澄明な液体を得た。さらに、Ｌ−アルギニン及びビタミンＣ誘導体、実施例２１で調製した可溶化液剤を添加して、均一な澄明な液体となるまで撹拌し、ビタミンＥ及びビタミンＣ含有ローション剤を得た。これらのローション剤を、冷所で２ヶ月保存するか、実施例２０〜２２のサイクル試験と同様のサイクルで２ヶ月保存するか、あるいは４５℃で２ヶ月保存し、その性状を評価した。その結果、初期ｐＨに依存せず、安定であり、性状（澄明性、におい）に変化は認められなかった。使用感も、べたつきは認められず、良好であった。
【００５８】
【表７】
【発明の効果】
本発明によると、脂溶性物質を含有する、味質と服用感に優れ、且つ、安定性に優れた透明性の高い可溶化液剤を提供することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a highly transparent solubilized liquid agent containing a fat-soluble substance, excellent in taste and feeling of taking, and having excellent stability, and a method for producing the same.
[0002]
[Prior art]
In general, a fat-soluble substance is hardly soluble in water, and various attempts have been made to make the fat-soluble substance a solubilized solution such as an internal solution or an aqueous injection.
[0003]
For example, Japanese Patent Publication No. 4-7722 uses (A) vitamin E, (B) 100 to 500% by weight of hydrogenated castor oil polyoxyethylene derivative based on vitamin E, and fat-soluble substance vitamin E, and ( C) One or more stabilizers selected from the group consisting of 10 to 50% by weight of sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyglycerin fatty acid ester and polyoxyethylene glycerin fatty acid ester relative to vitamin E A stable solubilizing solution of vitamin E is disclosed.
[0004]
However, this vitamin E solubilized solution requires an extremely large amount of surfactant (hardened castor oil polyoxyethylene derivative) in which 100 to 500% by weight of hardened castor oil polyoxyethylene derivative is added to vitamin E in particular. Therefore, it is difficult to say that it is desirable from the viewpoint of manufacturing cost and consumer-oriented additive intake. Moreover, although the solubilized solution is excellent in transparency, an unpleasant taste derived from the hardened castor oil polyoxyethylene derivative is strongly felt, and the taste quality and feeling of taking as an internal solution are not good.
[0005]
[Problems to be solved by the invention]
In solubilizing liquids containing fat-soluble substances, development of solubilized liquids that are excellent in stability, high transparency, and excellent in taste and feeling of ingestion, particularly internal water-soluble liquids such as drinks, is required. . In addition, since the drink is often taken as a nourishing tonic, it is unpleasant to contain fat-soluble vitamins, particularly vitamin Es, vitamins A, vitamins D and / or vitamins K as fat-soluble substances. There is a need for a solubilizing solution that does not have a taste.
[0006]
[Means for Solving the Problems]
The present invention comprises a fat-soluble substance, and (1) one or more selected from polyoxyethylene hydrogenated castor oil and polyoxyethylene castor oil in an amount of 50% by weight or more and less than 100% by weight based on the fat-soluble substance, (2) selected from the group consisting of 5 to 100% by weight of polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, sucrose fatty acid ester and polyoxyethylene alkyl ether with respect to the fat-soluble substance 1 or 2 or more types, and (3) 10-80 weight% of polyhydric alcohol with respect to the total amount of solubilization liquid agent, the solubilization liquid agent of a fat-soluble substance, its manufacturing method, and this solubilization A diluted solubilized solution containing 0.01 to 0.3% by weight of a fat-soluble substance obtained by diluting a solution with purified water, a buffer solution or an aqueous solution. .
[0007]
DETAILED DESCRIPTION OF THE INVENTION
In the solubilizing solution of the present invention, the polyoxyethylene hydrogenated castor oil and / or polyoxyethylene castor oil (1) preferably has an ethylene oxide average added mole number of 40 to 60. The blending amount of this polyoxyethylene hydrogenated castor oil and / or polyoxyethylene castor oil is 50% by weight to 100% by weight with respect to the fat-soluble substance in order to obtain sufficient transparency and excellent taste and feeling of taking. It is less than, Preferably it is 70 weight% or more and less than 100 weight%, More preferably, it is 80 weight% or more and less than 100 weight%.
[0008]
In the solubilizing solution of the present invention, the fatty acid esters (2) are preferably esters of saturated or unsaturated fatty acids having 14 to 22 carbon atoms, and may be partially esterified or completely esterified. The degree of glycerol condensation of the polyglycerol fatty acid ester is preferably 2 to 10, and the average number of moles of ethylene oxide added to the polyoxyethylene sorbitan fatty acid ester and the polyoxyethylene glycerol fatty acid ester is preferably 6 to 40. Moreover, 12-22 are preferable and, as for the carbon number of the alkyl group of polyoxyethylene alkyl ether, the average added mole number of ethylene oxide has preferable 6-40.
[0009]
The blending amount of these components (2) is 5 to 100% by weight, preferably 10 to 50% by weight, based on the fat-soluble substance, from the viewpoint of obtaining sufficient transparency and excellent taste and feeling of taking. is there.
[0010]
The fat-soluble substance according to the present invention is not particularly limited. For example, fat-soluble vitamins such as vitamin E, vitamin A, β-carotene, vitamin D and / or vitamin K, crotamiton, teprenone, indomethacin, prednisolone, Although tannic acid etc. are mentioned, Preferably it is vitamin E, vitamin A, vitamin D, and / or vitamin K, More preferably, it is vitamin E.
[0011]
Examples of vitamin E include dl-α-tocopherol, d-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol acetate, dl-α-tocopherol succinate, d-α-tocopherol succinate, Nicotinic acid dl-α-tocopherol, nicotinic acid d-α-tocopherol, dl-β-tocopherol, d-β-tocopherol, dl-β-tocopherol acetate, d-β-tocopherol acetate, dl-β-tocopherol succinate, D-β-tocopherol succinate, dl-β-tocopherol nicotinate, d-β-tocopherol nicotinate, dl-γ-tocopherol, d-γ-tocopherol, dl-γ-tocopherol acetate, d-γ-tocopherol acetate, Succinic acid dl-γ-tocopherol, succinic acid d-γ-tocopherol Errol, nicotinic acid dl-γ-tocopherol, nicotinic acid d-γ-tocopherol, dl-δ-tocopherol, d-δ-tocopherol, dl-δ-tocopherol acetate, d-δ-tocopherol acetate, dl-δ-succinate Examples include tocopherol, d-δ-tocopherol succinate, dl-δ-tocopherol nicotinate, d-δ-tocopherol nicotinate, tocotrienol and the like, and d-α-tocopherol acetate is preferred. Examples of vitamin Ds include vitamin D 1 , vitamin D 2 , and vitamin D 3 , and examples of vitamin Ks include vitamin K 1 , vitamin K 2 , vitamin K 3 , vitamin K 4, and the like.
[0012]
The content of the fat-soluble substance in the solubilized liquid according to the present invention is not particularly limited, but is preferably 3 to 15% by weight with respect to the total amount of the solubilized liquid.
[0013]
Examples of the polyhydric alcohol according to the present invention include glycerin, diglycerin, triglycerin, polyglycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, ethylene glycol, polyethylene glycol, sorbitol, mannitol, xylitol and the like. Can be mentioned. The blending amount of the polyhydric alcohol is 10 to 80 weights with respect to the total amount of the solubilized liquid from the viewpoint of securing sufficient transparency and securing the optimal blending amount of the fat-soluble substance and the components (1) and (2). %, Preferably 30 to 80% by weight.
[0014]
The solubilized solution according to the present invention can be produced regardless of the presence or absence of purified water. Since the viscosity of the solubilized liquid agent is reduced by adding purified water, the workability during the production of the solubilized liquid agent is improved by adding purified water.
[0015]
The fat-soluble substance solubilizing solution according to the present invention includes: 1) internal medicines such as drinks, liquids, syrups, mouthwashes, mouthwashes, etc. 2) elixirs, lotions, eye drops Preparations, nasal drops, ear drops, vaginal preparations, enteral preparations and other external medicines and quasi-drugs, cosmetic preparations, or 3) ordinary excipients, tablets, chewable preparations , And can be used as solid preparations such as granules and capsules.
[0016]
The solubilized solution of the fat-soluble substance according to the present invention may be taken as it is, but particularly when used as an internal solution such as a drink, it may be further added with an aqueous solution such as purified water, a buffer solution or a drink. It can be diluted to an arbitrary concentration and used as a solubilizing liquid diluent. The concentration of the fat-soluble substance in the solubilizing liquid diluent is not particularly limited, but is preferably 0.01 to 0.3% by weight.
[0017]
In order to produce the solubilized liquid preparation according to the present invention, the above-described components may be mixed to prepare a mixture containing each component, but the mixture containing each component may be further subjected to high-pressure treatment.
[0018]
Therefore, the present invention provides the fat-soluble substance as follows: (1) one kind selected from the group consisting of polyoxyethylene hydrogenated castor oil and polyoxyethylene castor oil in an amount of 50% by weight or more and less than 100% by weight based on the fat-soluble substance. 2 or more, and (2) 5 to 100% by weight of polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, sucrose fatty acid ester, and polyoxyethylene alkyl ether with respect to the fat-soluble substance 1 type or 2 types or more selected from the group consisting of the above, and (3) 10 to 80% by weight of polyhydric alcohol based on the total amount of the solubilizing solution, or a high pressure treatment of the blended mixture. There is also provided a method for producing a solubilized liquid agent of a fat-soluble substance.
[0019]
60-90 degreeC is preferable and the temperature at the time of mix | blending each said component has more preferable 70-85 degreeC. In addition, when mixing each component, a simple agitator such as a propeller type or an anchor type and / or a high shear emulsifier such as a homogenizer or a homomixer can be used.
[0020]
The high-pressure treatment is usually performed using a high-pressure homogenizer, a high-speed pressure emulsifier, or the like. The liquid agent temperature during the high-pressure treatment is usually from room temperature to about 90 ° C, preferably 60 to 80 ° C. The pressure during the high-pressure treatment is not particularly limited, but is usually 100 to 5000 kg / cm 2 (9807 to 490350 kPa), preferably 150 to 2000 kg / cm 2 (19614 to 196140 kPa), and more preferably 200 to 1800 kg / cm 2 (29421 to 17656 kPa).
[0021]
The solubilized liquid agent of the fat-soluble substance according to the present invention is a highly transparent liquid agent having excellent stability. In particular, the addition amount of the surfactant polyoxyethylene hydrogenated castor oil and / or polyoxyethylene castor oil is a very small amount of 50 wt% or more and less than 100 wt% with respect to the fat-soluble substance, and a highly transparent liquid agent is obtained. It has the surprising feature of being obtained. Moreover, the solubilized solution of fat-soluble substances according to the present invention has outstanding characteristics that it is extremely excellent in taste quality and feeling of taking without almost feeling unpleasant taste when taken internally.
[0022]
In the prior art relating to the solubilizing liquid agent of the fat-soluble substance, in order to obtain a liquid agent having sufficient transparency and high transmittance, it is necessary to add a large amount of surfactant such as polyoxyethylene hydrogenated castor oil, There was a problem that unpleasant taste derived from the surfactant and a feeling of taking were strongly felt due to a large amount of the compound. The solubilizing agent of the fat-soluble substance according to the present invention solves the above problems by reducing the blending amount of a surfactant such as polyoxyethylene hydrogenated castor oil to a specific range width, and has a sufficient transmittance of 90% or more. It has achieved the surprising effect of achieving both good liquid transparency and good taste and feeling.
[0023]
Therefore, the solubilized liquid agent of the fat-soluble substance according to the present invention and the solubilized liquid diluted solution obtained by diluting the solubilized liquid solution with purified water, buffer solution or aqueous liquid solution are drinks, liquids, syrups, gargles, washings It is particularly useful when used for oral medicines and quasi drugs such as oral fluids.
[0024]
The solubilizing liquid agent and solubilizing liquid diluent of the fat-soluble substance according to the present invention can be produced, for example, by the following method.
[0025]
For example, 100 g of d-α-tocopherol acetate, 85 g of polyoxyethylene hydrogenated castor oil, 30 g of polyglycerin fatty acid ester, 635 g of glycerin and 150 g of purified water are mixed and heated at about 70 ° C. with a homomixer at 10000 rpm. By stirring and mixing for 5 minutes to prepare a uniform aqueous solution, a solubilized solution of d-α-tocopherol acetate can be produced. Further, this aqueous solution can be subjected to a high-pressure treatment at 1000 kg / cm 2 (98070 kPa) using a high-pressure homogenizer to produce a solubilized solution of d-α-tocopherol acetate. Further, by diluting 1 g of these solubilizing solutions with a buffer adjusted to pH 3, a solubilizing solution diluting solution containing 0.1% by weight of d-α-tocopherol acetate can be produced.
[0026]
【Example】
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
[0027]
Examples 1 to 8
As a fat-soluble substance, acetic acid d-α-tocopherol was used, and the ingredients shown in Table 1 were mixed. While heating to about 70 ° C., the mixture was stirred and mixed with a homomixer at 10000 rpm × 5 minutes. A solubilized solution was prepared. This aqueous solution was subjected to a high pressure treatment at 1000 kg / cm 2 (98070 kPa) using a high pressure homogenizer to obtain a solubilized solution of d-α-tocopherol acetate.
[0028]
Water is added to the obtained solubilized solution, diluted so that the number of particles becomes 10,000 to 100,000 / mL, put in a predetermined cell, and using a submicron particle measuring device (Coulter, MODEL N4 SD). The average particle diameter (nm) was measured.
[0029]
In addition, 1 g of the above-mentioned solubilized solution subjected to high pressure was added to 100 mL of a commercial product (A) (nicotinamide 20 mg, aminoethylsulfonic acid 1 g, thiamine nitrate 5 mg, riboflavin sodium phosphate 5 mg, pyridoxine hydrochloride 5 mg, carnitine hydrochloride 100 mg Inositol 50 mg and anhydrous caffeine 50 mg contained in 100 mL of one bottle) were added and diluted to obtain a solubilizing liquid diluent so that the d-α-tocopherol acetate content was 100 mg.
[0030]
Comparative Example 1
Implemented except that d-α-tocopherol acetate is used as a fat-soluble substance, and the ingredients shown in Table 1 are added (200 wt% polyoxyethylene hydrogenated castor oil is added to the fat-soluble substance) and the components are mixed. In the same manner as in Examples 1 to 8, a solubilizing solution of d-α-tocopherol acetate and a solubilizing solution diluent were obtained so that the d-α-tocopherol acetate content was 100 mg, and the average particle size was measured in the same manner.
[0031]
The solubilized liquid diluent obtained in Examples 1 to 8 was compared with the solubilized liquid diluent obtained in Comparative Example 1, and physical properties were evaluated. Evaluation was made by measuring the transmittance (%) at 640 nm after storage for 1 day and 7 days at 70 ° C. immediately after production, and each solubilized liquid diluent immediately after production was included in the oral cavity for 5 seconds. The taste quality and the feeling of taking were evaluated according to the following criteria by a sensory test. Table 1 shows the prescription and the test results.
[0032]
<Evaluation criteria of taste quality and feeling of taking>
○: Taste quality and feeling of taking are good.
Δ: Slightly uncomfortable in taste and feel.
X: Feeling uncomfortable in taste and feeling of taking.
[0033]
[Table 1]
As is clear from Table 1, in Examples 1 to 8, “taste quality of the liquid preparation and feeling of taking” were good. On the other hand, in Comparative Example 1 in which the blending ratio of the polyoxyethylene hydrogenated castor oil was 200% by weight with respect to the fat-soluble substance, “discomfort in the taste and the feeling of taking the liquid” was felt.
[0035]
Further, as shown in Table 1, the transmittance (%) at 640 nm of the solubilized solution diluted solution was 90% or more in all Examples immediately after production, and had good transparency. Even when stored at 70 ° C. for 1 day and 7 days, no significant decrease in transmittance was observed. In addition, there was almost no difference depending on the blending ratio of polyoxyethylene hydrogenated castor oil or polyglycerin fatty acid ester (decaglycerin monostearic acid ester). There was no difference. In general, if the transmittance of the liquid agent is 90% or more, it can be determined that the liquid has sufficient transparency in appearance, and the blending ratio of the polyglycerin fatty acid ester is the smallest in Example 5 (relative to the fat-soluble substance). 10% by weight), the transmittance immediately after production was 92.3%, and the transmittances after storage at 70 ° C. for 1 day and 7 days were 94.1% and 91.9%, respectively. It can be said that it has favorable transparency since it was as transparent as 1.
[0036]
From the above, it is apparent that a highly transparent solubilized liquid agent having excellent taste and ingestion feeling containing a fat-soluble substance and excellent stability can be obtained by the present invention.
[0037]
Example 9 to Example 13
As a fat-soluble substance, acetic acid d-α-tocopherol was used, and the components shown in Table 2 were mixed. The mixture was stirred and mixed with a homomixer at 10,000 rpm for 5 minutes while heating to about 70 ° C. A solubilized solution was prepared. This aqueous solution was subjected to a high pressure treatment at 300 kg / cm 2 (29421 kPa) using a high pressure homogenizer to obtain a solubilized solution of d-α-tocopherol acetate. The average particle size of the solubilized liquid obtained was measured in the same manner as in Examples 1-8.
[0038]
In addition, 1 g of these high-pressure-treated solubilized solutions was added to 100 mL of a commercially available drink (A) (nicotinamide 20 mg, aminoethylsulfonic acid 1 g, thiamine nitrate 5 mg, riboflavin sodium phosphate 5 mg, pyridoxine hydrochloride 5 mg, carnitine hydrochloride 100 mg. Inositol 50 mg and anhydrous caffeine 50 mg contained in 100 mL of one bottle) were added and diluted to obtain a solubilizing liquid diluent so that the d-α-tocopherol acetate content was 100 mg. About the obtained solubilizing liquid diluent, the transmittance | permeability was measured similarly to Examples 1-8, and the sensory test was carried out about the taste quality and the ingestion feeling. The formulation and test results are shown in Table 2.
[0039]
[Table 2]
As is apparent from Table 2, all the examples had a transmittance of 90% or more immediately after production, had good transparency, and had a remarkable transmittance even when stored at 70 ° C. There was no decline. Furthermore, the taste and feeling of taking were good.
[0041]
Example 14 to Example 16
As a fat-soluble substance, acetic acid d-α-tocopherol was used, and each component was mixed according to the formulation shown in Table 3. The mixture was stirred and mixed with a homomixer at 10,000 rpm for 5 minutes while heating to about 70 ° C. A solubilized solution was prepared. This aqueous solution was subjected to a high pressure treatment at 200 kg / cm 2 (19614 kPa) using a high pressure homogenizer to obtain a solubilized solution of d-α-tocopherol acetate. The average particle size of the solubilized liquid obtained was measured in the same manner as in Examples 1-8.
[0042]
In addition, 1 g of these high-pressure-treated solubilized solutions was added to 100 mL of a commercially available drink (A) (nicotinamide 20 mg, aminoethylsulfonic acid 1 g, thiamine nitrate 5 mg, riboflavin sodium phosphate 5 mg, pyridoxine hydrochloride 5 mg, carnitine hydrochloride 100 mg. , Inositol 50 mg, anhydrous caffeine 50 mg contained in a bottle 100 mL) and diluted, solubilized with d-α-tocopherol acetate content of 120 mg (Example 14), 150 mg (Examples 15 to 16) A liquid diluent was obtained. About the obtained solubilizing liquid diluent, the transmittance | permeability was measured similarly to Examples 1-8, and the sensory test was carried out about the taste quality and the ingestion feeling. The formulation and test results are shown in Table 3.
[0043]
[Table 3]
As is clear from Table 3, the transmittances of the solubilized liquid diluents of Examples 14, 15 and 16 were 90% or more immediately after production, regardless of the tocopherol concentration, and had good transparency. In addition, even when stored at 70 ° C., no significant decrease in transmittance was observed. Furthermore, the taste and feeling of taking were good.
[0045]
Examples 17-19
Using d-α-tocopherol acetate as a fat-soluble substance, with the formulation shown in Table 4, stirring and mixing with a homomixer at 10,000 rpm for 10 minutes while heating each component to about 80 ° C, uniform solubilization A solution was prepared. This aqueous solution was subjected to high pressure treatment at 9000 psi using a high pressure emulsifier and cooled to room temperature to obtain a solubilized solution of d-α-tocopherol acetate. Further, a commercially available drink (A) was added and diluted in the same manner as in Examples 1 to 8 to obtain a solubilized diluent diluted so that the d-α-tocopherol acetate content was 100 mg.
[0046]
About the obtained solubilizing liquid diluent, the transmittance | permeability and the average particle diameter were measured similarly to Examples 1-8, and the sensory test was carried out about the taste quality and the ingestion feeling. The formulation and test results are shown in Table 4.
[0047]
[Table 4]
As is clear from the results in Table 4, a clear liquid having a transmittance of 90% or more was obtained regardless of the glycerin concentration. Further, even when this diluted solution was stored at 70 ° C. for 7 days, almost no change was observed in the transmittance and the average particle size.
[0049]
Examples 20-22
As a fat-soluble substance, d-α-tocopherol acetate was used, and each component was heated and stirred at 85 ± 5 ° C. with a simple stirrer (90 rpm) until the formulation became clear with the formulation shown in Table 5. Then, it cooled to room temperature and obtained the solubilization liquid agent. Store this solution for 2 months at 5 ° C, 45 ° C, -10 ° C / 40 ° C (48 hours cycle with 12 hours of elevating time and 12 hours of incubation time), or store for 2 months at 45 ° C and then add purified water Then, the transmittance was measured in the same manner as in Examples 1 to 8 as a solubilized solution diluent having a d-α-tocopherol acetate content of 100 mg. The results are shown in Table 5. From this result, it was confirmed that a clear liquid having a transmittance of 90% or more could be obtained even after storage, similar to the initial value immediately after production, and that the solubilized liquid preparation had good storage stability.
[0050]
Further, this solubilized solution was prepared by adding 100 mL of the above-mentioned commercial drink (A) or 100 mL of the commercial drink (B) (1000 mg taurine, 50 mg inositol, 20 mg nicotinamide, 5 mg vitamin B 1 nitrate, vitamin B 2 phosphate ester) 5 mg, vitamin B 6 5 mg, and anhydrous caffeine 50 mg contained in 100 mL of a bottle) were added so as to give 100 mg of d-α-tocopherol acetate per bottle to obtain a solubilized diluted solution. About these dilution liquids, the transmittance | permeability was measured similarly to Examples 1-8, and the sensory test was carried out about the taste quality and the feeling of taking. The results are shown in Table 5. From this result, compared with the commercial item which does not add a solubilizing liquid agent, the difference in taste quality and a feeling of taking was not recognized, and it was favorable. Moreover, the transmittance | permeability after preserve | saving a diluted solution at 70 degreeC for 1 day and 7 days was a clear liquid with almost no change with the transmittance | permeability immediately after manufacture.
[0051]
[Table 5]
Example 23
In the formulation shown in Table 6, after dissolving methylparaben and sodium benzoate in 80% by weight of purified water (about 80 ° C.), polyethylene glycol (PEG4000), powdered reduced maltose starch syrup and glycerin were added and stirred. The solution was cooled to a clear liquid. Further, L-arginine and vitamin C derivative, the solubilized solution prepared in Example 21 and purified water (remainder) were added, and the mixture was stirred until a uniform clear liquid was obtained. Obtained. This lotion was a clear liquid with a transmittance of 97.1% and a pH of 4.7. As for the feeling of use, stickiness was not recognized and it was refreshingly good.
[0053]
Similarly, when a lotion preparation containing 0.5%, 3% or 5% of the solubilizing solution of Example 21 was prepared, it was a non-sticky, fresh feeling lotion preparation.
[0054]
Example 24
In the formulation shown in Table 6, after dissolving methylparaben, sodium benzoate, epsilon aminocaproic acid, and glycerin in 80% by weight purified water (about 80 ° C.), carboxyvinyl polymer was gradually added and stirred. A uniform dispersion was obtained. The dispersion was cooled to about 50 ° C., and an aqueous triethanolamine solution (5% purified water in the formulation) was added with stirring to obtain a clear gel. Further, the solubilized solution prepared in Example 21 and purified water (remainder) were added and stirred until uniform to obtain a vitamin E-containing gel. This gel agent had a refreshing feeling without stickiness.
[0055]
Similarly, when a gel was prepared by adding 0.5, 3 or 5% of the solubilizing solution of Example 21, no stickiness was observed regardless of the concentration, and the gel was refreshed.
[0056]
[Table 6]
Examples 25-26
In the formulation shown in Table 7, after dissolving methylparaben, sodium benzoate and xanthan gum in 80% by weight purified water (about 80 ° C.), PEG4000, xylitol and glycerin were added and stirred, cooled to room temperature and clear. A liquid was obtained. Furthermore, L-arginine and a vitamin C derivative and the solubilizing solution prepared in Example 21 were added and stirred until a uniform clear liquid was obtained to obtain a lotion containing vitamin E and vitamin C. These lotions were stored for 2 months in a cold place, stored for 2 months in the same cycle as the cycle test of Examples 20 to 22, or stored for 2 months at 45 ° C., and their properties were evaluated. As a result, it was not dependent on the initial pH and was stable, and no change was observed in the properties (clearness, odor). The feeling of use was also good with no stickiness.
[0058]
[Table 7]
【The invention's effect】
According to the present invention, it is possible to provide a highly-solubilized solubilizing agent containing a fat-soluble substance, having excellent taste and feeling of taking, and having excellent stability.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2001204280A JP4117119B2 (en) | 2000-07-05 | 2001-07-05 | Fat-soluble substance solubilizing solution |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000203394 | 2000-07-05 | ||
| JP2000-203394 | 2000-07-05 | ||
| JP2001204280A JP4117119B2 (en) | 2000-07-05 | 2001-07-05 | Fat-soluble substance solubilizing solution |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2002080365A JP2002080365A (en) | 2002-03-19 |
| JP2002080365A5 JP2002080365A5 (en) | 2008-01-24 |
| JP4117119B2 true JP4117119B2 (en) | 2008-07-16 |
Family
ID=26595408
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001204280A Expired - Fee Related JP4117119B2 (en) | 2000-07-05 | 2001-07-05 | Fat-soluble substance solubilizing solution |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4117119B2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002020268A (en) * | 2000-07-10 | 2002-01-23 | Takeda Chem Ind Ltd | Internal liquid containing fat-soluble substance |
| WO2005034913A1 (en) * | 2003-10-10 | 2005-04-21 | Eisai Co., Ltd. | Novel liquid preparation composition |
| JP2007277207A (en) * | 2006-03-15 | 2007-10-25 | Rohto Pharmaceut Co Ltd | Preparation for internal use |
| JP6131522B2 (en) * | 2011-03-25 | 2017-05-24 | 大正製薬株式会社 | Loxoprofen-containing external preparation |
| JP6420969B2 (en) * | 2014-05-22 | 2018-11-07 | 株式会社 沖縄リサーチセンター | Polymethoxyflavonoid-dissolving composition and method for producing the same |
| JP7268012B2 (en) * | 2017-12-20 | 2023-05-02 | フイルメニツヒ ソシエテ アノニム | oral care composition |
| JP6904289B2 (en) * | 2018-03-19 | 2021-07-14 | ライオン株式会社 | Aqueous ophthalmic composition |
-
2001
- 2001-07-05 JP JP2001204280A patent/JP4117119B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002080365A (en) | 2002-03-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3903061B2 (en) | Nanoparticles containing drug, method for producing the same, and preparation for parenteral administration comprising the nanoparticles | |
| CN100463670C (en) | Microemulsion concentrate for oral administration of water-insoluble anti-cold drug and method for preparing same | |
| CN101366696B (en) | Medicament composition for water-soluble injection of paclitaxel, preparation method and uses thereof | |
| WO2010139278A1 (en) | Preparation method of drug loaded emulsion | |
| US20170216224A1 (en) | Solid particulate compositions comprising coenzyme q10 | |
| JPS63150221A (en) | Emulsified composition containing crystalline drug | |
| US20230398072A1 (en) | Concentrate containing poorly soluble drug and emulsion prepared therefrom | |
| JP2014133764A (en) | Taxol submicroemulsion with steroidal compound as intermediate carrier | |
| JP4117119B2 (en) | Fat-soluble substance solubilizing solution | |
| EP0600395B1 (en) | Antinflammatory and analgesic diclofenac gel preparation | |
| JPH11255640A (en) | Emulsified preparation for external use for skin | |
| US11160780B2 (en) | Pharmaceutical composition of ivermectin and process for preparation thereof | |
| EP0893121B1 (en) | Oral liquid medicine solution | |
| KR100722326B1 (en) | Solubilized liquid formulation of fat-soluble material | |
| JPH05139955A (en) | Stable instillation | |
| CN114522142A (en) | Nano stabilizer and preparation method and application thereof | |
| CN114642635A (en) | Oral emulsion of terpene medicinal composition, its preparation method and application | |
| JPH04235925A (en) | Stable multivitamin injection | |
| CN113679664B (en) | Resveratrol polymer aqueous solution and preparation method thereof | |
| JP2003012497A (en) | Urea-containing composition for external use | |
| WO2023101252A1 (en) | Ophthalmic nanoemulsion composition for treating macular degeneration and method for preparing same | |
| JP2003012496A (en) | Stable urea-containing composition for external use | |
| JP3438264B2 (en) | Method for preparing stable vitamin A solubilized aqueous eye drops | |
| JPS62106018A (en) | Water-based preparation containing vitamin e in high concentration | |
| JP6084579B2 (en) | Oil-in-water cream composition containing tacrolimus |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A712 Effective date: 20060808 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20071130 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20071130 |
|
| A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20071130 |
|
| A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20080104 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20080108 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20080306 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20080401 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20080421 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110425 Year of fee payment: 3 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 4117119 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110425 Year of fee payment: 3 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120425 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130425 Year of fee payment: 5 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130425 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140425 Year of fee payment: 6 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313117 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313115 |
|
| R360 | Written notification for declining of transfer of rights |
Free format text: JAPANESE INTERMEDIATE CODE: R360 |
|
| R360 | Written notification for declining of transfer of rights |
Free format text: JAPANESE INTERMEDIATE CODE: R360 |
|
| R371 | Transfer withdrawn |
Free format text: JAPANESE INTERMEDIATE CODE: R371 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313115 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |