JP6893650B2 - Release-controlled film containing water-soluble polysaccharides as the main component - Google Patents
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本発明は，水溶性多糖類を主たる成分とする放出制御型フィルムに関する。さらに詳しくいうと本発明は，水溶性多糖類としてこんにゃくグルコマンナンを主たる成分として作製されたフィルムであり，このフィルムに有用成分を含有させ，嚥下が困難な患者や投与が困難な動物の口腔内に付着して用いるなどすることにより，フィルムの崩壊とともに有用成分の放出等のコントロールが可能な，放出制御型フィルムならびに有用成分放出システムに関する。 The present invention relates to a release-controlled film containing a water-soluble polysaccharide as a main component. More specifically, the present invention is a film prepared by using konjac glucomannan as a main component as a water-soluble polysaccharide, and the film contains useful components in the oral cavity of patients who have difficulty swallowing or animals who have difficulty in administration. The present invention relates to a release-controlled film and a useful component release system that can control the release of useful components as the film collapses by using the film by adhering to the film.
こんにゃくは，古くから日本の食文化に根付いた食物であり，近年では，低カロリーであり食物繊維も豊富なことから，ダイエット食品としての認知度が高い。
しかるに，日本人の食生活の変化や天候不順による原材料の高騰など，種々の事情により，近年，こんにゃくの消費は大きく落ち込んでいるのが現状である。結果として，多くのこんにゃく製造企業は廃業や倒産を余儀なくされており，日本の伝統的産業であるこんにゃく産業の衰退に，歯止めが掛からない状況である。
Konjac is a food that has been rooted in Japanese food culture for a long time. In recent years, it is highly recognized as a diet food because it is low in calories and rich in dietary fiber.
However, the current situation is that the consumption of konjac has dropped significantly in recent years due to various circumstances such as changes in the eating habits of Japanese people and soaring prices of raw materials due to unseasonable weather. As a result, many konjac manufacturing companies have been forced to go out of business or go bankrupt, and the decline of the konjac industry, which is a traditional Japanese industry, cannot be stopped.
こんにゃくについて，科学的には，こんにゃくグルコマンナン（以下，「KGM」）と呼ばれる水溶性多糖類を豊富に含むものであり，こんにゃくを成分として含んだフィルムに関する技術が開示されている（特許文献１）。 Scientifically, konjac is rich in water-soluble polysaccharides called konjac glucomannan (hereinafter, "KGM"), and a technique relating to a film containing konjac as a component is disclosed (Patent Document 1). ).
先行技術は，こんにゃくを成分として含んだフィルム技術を提供する点で有用であるものの，用途として単にフィルムとしての用途にとどまるにすぎない。
このように，こんにゃく粉を原料とするフィルムは，食品用ラップ，有機EL薄膜の表面保護膜などへの応用が研究されているが，こんにゃくそのものが有する，可食性かつ生分解性であるという特徴を活かしきれていないのが現状である。
Although the prior art is useful in providing a film technology containing konjac as a component, it is merely used as a film.
In this way, films made from konjac flour have been studied for application to food wraps, surface protective films for organic EL thin films, etc., but the characteristics of konjac itself are that it is edible and biodegradable. The current situation is that we have not fully utilized.
こんにゃくは古くから「腹中の砂下ろし」などと言われ，生理作用は科学的に明らかではないが，経験的に体に良いものとして伝えられてきた。こんにゃくという日本独自の伝統的な農産物を使い，こんにゃく由来の新規製品を開発することは，こんにゃくの需要を高め，こんにゃく農家の飛躍を支える一助となると考えられる。 Konjac has long been referred to as "sanding down the abdomen," and although its physiological effects are not scientifically clear, it has been empirically reported to be good for the body. Using konjac, a traditional Japanese agricultural product, to develop new products derived from konjac is thought to help increase the demand for konjac and support the leap of konjac farmers.
上記事情を背景として本発明では，こんにゃくを用いた新規な技術開発を課題とする。 Against the background of the above circumstances, an object of the present invention is the development of a new technique using konjac.
発明者らは，鋭意研究の結果，酸加水分解によってKGMの平均分子量の調整を行い，かかる調製されたKGMを用いたフィルムの作製を行った。かかるフィルムが，口腔内において崩壊することにより，フィルム内から有用成分を放出することを実験的に確認し，発明を完成させたものである。 As a result of diligent research, the inventors adjusted the average molecular weight of KGM by acid hydrolysis, and produced a film using the prepared KGM. The invention was completed by experimentally confirming that such a film releases useful components from the film when it disintegrates in the oral cavity.
本発明は，以下の構成からなる。
本発明の第一の構成は，水溶性多糖類を主たる組成成分とし，有用成分を含有することを特徴とする放出制御型フィルムである。
The present invention has the following configuration.
The first constitution of the present invention is a release-controlled film characterized by containing a water-soluble polysaccharide as a main composition component and a useful component.
本発明の第二の構成は，前記水溶性多糖類が，こんにゃく由来であることを特徴とする第一の構成に記載の放出制御型フィルムである。
本発明の第三の構成は，皮膚もしくは口腔内に付着して用いられることを特徴とする第一又は第二の構成に記載の放出制御型フィルムである。
本発明の第四の構成は，さらに，組成成分として，可塑剤を含むことを特徴とする第一から第三の構成に記載の放出制御型フィルムである。
本発明の第五の構成は，前記可塑剤が，グリセリン，ヒアルロン酸のいずれか又は複数から選択されることを特徴とする第四の構成に記載の放出制御型フィルムである。
The second configuration of the present invention is the release-controlled film according to the first configuration, wherein the water-soluble polysaccharide is derived from konjac.
The third configuration of the present invention is the release-controlled film according to the first or second configuration, which is used by adhering to the skin or the oral cavity.
The fourth configuration of the present invention is the release-controlled film according to the first to third configurations, which further contains a plasticizer as a composition component.
The fifth configuration of the present invention is the release-controlled film according to the fourth configuration, wherein the plasticizer is selected from one or more of glycerin and hyaluronic acid.
本発明の第六の構成は，前記有用成分が，薬物成分，栄養成分，活性炭のいずれか又は複数から選択されることを特徴とする第一から第五の構成に記載の放出制御型フィルムである。
本発明の第七の構成は，前記有用成分として，Ambroxol Hydrochloride，Bromhexine Hydrochlorideのいずれか又は複数を含み，嚥下困難な患者の去痰薬として用いられることを特徴とする第六の構成に記載の放出制御型フィルムである。
本発明の第八の構成は，前記有用成分に少なくとも活性炭を含み，動物腎***の治療に用いられることを特徴とする第六の構成に記載の放出制御型フィルムである。
本発明の第九の構成は，前記活性炭を極性有機溶媒で前処理したうえで，水溶性多糖類溶液に添加することにより作製されたことを特徴とする第八の構成に記載の放出制御型フィルムである。
本発明の第十の構成は，前記極性有機溶媒が，エタノールであることを特徴とする第九の構成に記載の放出制御型フィルムである。
本発明の第十一の構成は，前記水溶性多糖類の分子量が，約40万であることを特徴とする第一から第十の構成に記載の放出制御型フィルムである。
本発明の第十二の構成は，口腔内に有用成分を含んだフィルムを付着させ，フィルムが経時的に崩壊することにより，有用成分を，口腔内を含む消化管に放出することを特徴とする有用成分放出システムである。
The sixth configuration of the present invention is the release-controlled film according to the first to fifth configurations, wherein the useful component is selected from one or more of a drug component, a nutritional component, and activated carbon. is there.
The release according to the sixth configuration, wherein the seventh configuration of the present invention contains one or more of Ambroxol Hydrochloride and Bromhexine Hydrochloride as the useful component and is used as an expectorant for patients who have difficulty swallowing. It is a control type film.
The eighth configuration of the present invention is the release-controlled film according to the sixth configuration, which contains at least activated carbon in the useful component and is used for the treatment of animal renal uremia.
The release-controlled type according to the eighth configuration, wherein the ninth configuration of the present invention is prepared by pretreating the activated carbon with a polar organic solvent and then adding it to a water-soluble polysaccharide solution. It is a film.
The tenth configuration of the present invention is the release-controlled film according to the ninth configuration, wherein the polar organic solvent is ethanol.
The eleventh configuration of the present invention is the release-controlled film according to the first to tenth configurations, wherein the water-soluble polysaccharide has a molecular weight of about 400,000.
The twelfth configuration of the present invention is characterized in that a film containing a useful component is attached to the oral cavity, and the film disintegrates over time to release the useful component into the digestive tract including the oral cavity. It is a useful component release system.
本発明により，こんにゃくを用いた新規な技術の提供が可能となった。すなわち本発明の放出制御型フィルムによれば，こんにゃくをはじめとする水溶性多糖類を主たる組成物として含有するものであり，口腔内に貼付等して用いることにより，有用成分の放出をコントロールすることが可能である。これにより本発明の放出制御型フィルムは，こんにゃくの新たな有用性を展開するものである。 INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a new technique using konjac. That is, according to the release-controlled film of the present invention, a water-soluble polysaccharide such as konjac is contained as a main composition, and the release of useful components is controlled by attaching it to the oral cavity or the like. It is possible. As a result, the release-controlled film of the present invention develops a new usefulness of konjac.
本発明の放出制御型フィルム等について説明を行う。 The emission control type film and the like of the present invention will be described.
本発明の放出制御型フィルムは，水溶性多糖類を主たる組成成分とし，有用成分を含有することを特徴とする。 The release-controlled film of the present invention is characterized in that it contains a water-soluble polysaccharide as a main composition component and contains a useful component.
水溶性多糖類は，グルコースやマンノースなどの単糖類の重合体であり，水などを加えることによりゲル化が可能な化合物として定義される。このような水溶性多糖類として，典型的には，グルコマンナンを用いることができる。また，水溶性多糖類はゲル化が可能であれば，適宜，部分的にその化学構造を修飾ないし置換したものであっても構わない。
加えて，本発明の趣旨に鑑みれば，水溶性多糖類は，天然由来のものを用いてもよいし，化学的に合成したものを用いてもかまわない。すなわち，グルコマンナン自体は，(C6H10O5)nで表さる分子であり，かかる化合物や類する化合物を化学合成して，水溶性多糖類として用いることができる。
A water-soluble polysaccharide is a polymer of monosaccharides such as glucose and mannose, and is defined as a compound that can be gelled by adding water or the like. Glucomannan can typically be used as such a water-soluble polysaccharide. Further, the water-soluble polysaccharide may be a partially modified or substituted chemical structure as long as it can be gelled.
In addition, in view of the gist of the present invention, the water-soluble polysaccharide may be a naturally derived polysaccharide or a chemically synthesized polysaccharide. That is, glucomannan itself is a molecule represented by (C 6 H 10 O 5 ) n , and such a compound or a similar compound can be chemically synthesized and used as a water-soluble polysaccharide.
天然由来のものとしてこんにゃく由来のグルコマンナンを用いる場合は，所定のpH溶液にてKGMを加水分解処理し，分子量を調整してから用いればよい。分子量については，用いる有用成分の量や種類，適用する対象に応じて適宜調整することができる。
すなわち，本発明の放出制御型フィルムにおいては，水溶性多糖類の含有量が同じ場合，平均分子量が減少するほど，有用成分の溶出が速くなる傾向にある。このことから，一つの目安として，活性炭のように経時的かつ徐々に放出を行う場合はKGMの平均分子量を大きく，去痰薬のように比較的速やかに放出を行う場合は平均分子量を小さくすればよい。
When konjac-derived glucomannan is used as a naturally-derived substance, KGM may be hydrolyzed with a predetermined pH solution to adjust the molecular weight before use. The molecular weight can be appropriately adjusted according to the amount and type of useful components used and the target to be applied.
That is, in the release-controlled film of the present invention, when the content of the water-soluble polysaccharide is the same, the elution of useful components tends to be faster as the average molecular weight decreases. From this, as a guide, the average molecular weight of KGM should be increased when it is released over time and gradually like activated carbon, and it should be decreased when it is released relatively quickly like expectorant. Good.
平均分子量としては，約40万程度のものを用いることが好ましい。これにより，フィルムとしての崩壊性を最適化することが可能となり，本発明の放出制御型フィルムの性能を向上させる効果を有する。
KGMでこの範囲の平均分子量に調整する場合，こんにゃく粉10.0gに70% エタノール100mLを加えて1Mクエン酸溶液でpH2.7に調整，130℃で2時間還流した後，ろ過洗浄し，105℃で1時間乾燥することにより，調整することができる。
このように，天然由来の水溶性多糖類を用いる場合，加水分解をして調整を行うことが好ましい。これにより，KGM平均分子量の調整が可能となるとともに，夾雑物の除去が可能となり，本発明の放出制御型フィルムの品質を向上させる効果を有する。
It is preferable to use an average molecular weight of about 400,000. This makes it possible to optimize the disintegration property of the film, and has the effect of improving the performance of the emission control type film of the present invention.
When adjusting to an average molecular weight in this range with KGM, add 100 mL of 70% ethanol to 10.0 g of konjac flour, adjust to pH 2.7 with a 1 M citric acid solution, reflux at 130 ° C for 2 hours, filter and wash, and then filter and wash at 105 ° C. It can be adjusted by drying in 1 hour.
As described above, when a naturally occurring water-soluble polysaccharide is used, it is preferable to hydrolyze it for adjustment. This makes it possible to adjust the average molecular weight of KGM and remove impurities, which has the effect of improving the quality of the emission-controlled film of the present invention.
本発明において有用成分とは，人体もしくは動物において，何らかの有用性をもたらす成分として定義される。また，有用成分は，成分分子そのものが有用性を発揮する場合に限定されるものではなく，腸管もしくは経皮，経粘膜により吸収された後，分解された分子が有用性を発揮する，いわゆるDDS化された分子を含むものとして定義される。
このような有用成分として，例えば，薬物成分，糖やアミノ酸などの栄養成分，活性炭などが挙げられる。すなわち，腸管もしくは経皮，経粘膜により吸収される有用成分を用いてもよいし，それらから吸収されない，活性炭のような有用成分を用いることもできる。
In the present invention, a useful component is defined as a component that brings some usefulness to the human body or an animal. In addition, the useful component is not limited to the case where the component molecule itself exerts its usefulness, but the so-called DDS in which the molecule that is decomposed after being absorbed by the intestinal tract, the transdermal, or the transmucosa exerts its usefulness. It is defined as containing a modified molecule.
Examples of such useful components include drug components, nutritional components such as sugars and amino acids, and activated carbon. That is, useful components that are absorbed by the intestinal tract, transdermal, or transmucosa may be used, or useful components that are not absorbed by them, such as activated carbon, may be used.
本発明の有用成分において，活性炭を用いることが好ましい。これにより，腸管内への経時的な活性炭の放出により，インドールの吸着ならびに体外***が可能となり，動物腎***の治療に用いることが期待できる。 It is preferable to use activated carbon in the useful components of the present invention. As a result, the release of activated carbon into the intestinal tract over time enables adsorption of indole and excretion from the body, and is expected to be used for the treatment of animal renal uremia.
活性炭を用いる場合，これを極性有機溶媒で前処理したうえで，水溶性多糖類を含む溶液に添加することが好ましい。
すなわち，かかる前処理により，疎水性の極めて高い活性炭に極性有機溶媒を吸着させ，水溶性多糖類を含む水溶液への親和性を高めることができる。これにより，活性炭を効率よく放出制御型フィルム内に均一に分散させることが可能となり，本発明の放出制御型フィルムの製造効率ないし性能を向上させる効果を有する。
When activated carbon is used, it is preferable to pretreat it with a polar organic solvent and then add it to a solution containing a water-soluble polysaccharide.
That is, by such pretreatment, the polar organic solvent can be adsorbed on the activated carbon having extremely high hydrophobicity, and the affinity for the aqueous solution containing the water-soluble polysaccharide can be enhanced. This makes it possible to efficiently and uniformly disperse the activated carbon in the release-controlled film, and has the effect of improving the production efficiency or performance of the release-controlled film of the present invention.
極性有機溶媒としては，特に限定する必要はなく，用いる有用成分やフィルムの用途などを考慮し，適宜選択することができる。極性有機溶媒として，エタノールを用いることが好ましい。これにより，安価かつ効率的に活性炭を分散することが可能となるとともに，フィルムの安全性を高めることができ，本発明の放出制御型フィルムの性能を向上させる効果を有する。
前処理を行う場合，典型的には，活性炭を極性有機溶媒に十分浸した後，これをろ過などにより極性有機溶媒を除去したものを，水溶性多糖類溶液に添加すればよい。
The polar organic solvent is not particularly limited and can be appropriately selected in consideration of useful components to be used, the use of the film, and the like. It is preferable to use ethanol as the polar organic solvent. This makes it possible to disperse activated carbon inexpensively and efficiently, enhance the safety of the film, and have the effect of improving the performance of the release-controlled film of the present invention.
In the case of pretreatment, typically, activated carbon is sufficiently immersed in a polar organic solvent, and then the polar organic solvent is removed by filtration or the like, and the solution is added to a water-soluble polysaccharide solution.
本発明の放出制御型フィルムは，可塑剤を組成成分として含むことが好ましい。これにより，製造時の放出制御型フィルムの取扱性を向上させることが可能となるという効果を有する。
可塑剤としては，用いる水溶性多糖類の種類や有用成分，フィルムの使用用途，安全性等を考慮して適宜選択することができるが，典型的には，グリセリンやヒアルロン酸を用いることができる。
添加するグリセリンまたはヒアルロン酸については，用いる水溶性多糖類の種類や有用成分，フィルムの柔軟性等を考慮して，適宜調整できるが，典型的には，0.1%から0.3%前後とすることができる。
The release-controlled film of the present invention preferably contains a plasticizer as a composition component. This has the effect of improving the handleability of the release-controlled film during manufacturing.
The plasticizer can be appropriately selected in consideration of the type and useful component of the water-soluble polysaccharide to be used, the intended use of the film, safety, etc., but typically, glycerin or hyaluronic acid can be used. ..
The amount of glycerin or hyaluronic acid to be added can be adjusted as appropriate in consideration of the type of water-soluble polysaccharide used, useful components, film flexibility, etc., but is typically around 0.1% to 0.3%. it can.
本発明の放出制御型フィルムは，皮膚もしくは口腔内に付着して用いられることが好ましい。これにより，フィルムを通じて，腸管もしくは経皮，経粘膜への有用成分の放出またはそれらからの吸収を図ることが可能となる。
特に，本発明の放出制御型フィルムは，口腔内粘膜に付着して用いることが好ましい。これにより，嚥下が困難なヒトや服用をコントロールすることが難しい動物などに，経粘膜もしくはフィルムの崩壊とともに口腔内を含む消化管に経時的に有用成分を放出することが可能となる。その結果，比較的安全にこれら被験者に用いることができ，本発明の放出制御型フィルムの有用性を向上させる効果を有する。
さらにいうと本発明は，上記の放出制御型フィルムにより具現化される，有用成分放出システムないし方法としての権利を主張するものである。
すなわち，本発明の有用成分放出システムは，口腔内に有用成分を含んだフィルムを付着させ，フィルムが短時間または経時的に崩壊することにより，有用成分を，口腔内を含む消化管に放出することを特徴とするものである。
The release-controlled film of the present invention is preferably used by adhering to the skin or the oral cavity. This makes it possible to release or absorb useful components into the intestinal tract, transdermally, and transmucosa through the film.
In particular, the release-controlled film of the present invention is preferably used by adhering to the oral mucosa. This makes it possible to release useful components over time to the digestive tract including the oral cavity along with the collapse of the transmucosa or film to humans who have difficulty swallowing or animals whose administration is difficult to control. As a result, it can be used relatively safely for these subjects, and has the effect of improving the usefulness of the release-controlled film of the present invention.
Furthermore, the present invention asserts the right as a useful component release system or method embodied by the release controlled film described above.
That is, the useful component release system of the present invention attaches a film containing a useful component to the oral cavity, and the film disintegrates in a short time or over time to release the useful component into the digestive tract including the oral cavity. It is characterized by that.
実施例を挙げて，本発明の放出制御型フィルムについて説明を行う。 The emission control type film of the present invention will be described with reference to Examples.
＜＜I．活性炭含有こんにゃくフィルムの調製＞＞
種々の条件で作成した活性炭含有こんにゃくフィルムについて，放出制御型フィルムとしての製造条件を調べることを目的として検討を行った。
<< I. Preparation of konjac film containing activated carbon >>
The activated carbon-containing konjac film prepared under various conditions was examined for the purpose of investigating the production conditions as a release-controlled film.
１．各実験に用いる所定pHに調整した溶液40mLに，平均分子量を調整したこんにゃく粉所定量を添加し，冷蔵庫内で一日放置し，膨潤させた。(A液)
２．各実験に用いる所定の活性炭を，過剰量のエタノールに浸し，室温で一日放置した。(B液)
３．A液に所定量のグリセリンを加え，氷冷しながら12分間超音波処理を行い，吸引ろ過を行った。
４．B液をろ過後，ろ取した活性炭をA液に加え，真空ポンプで脱気した。
５．上記溶液10gを，直径4cmのステンレス製シャーレに流し込み，50℃で15時間乾燥した。
1. 1. A predetermined amount of konjac flour having an adjusted average molecular weight was added to 40 mL of a solution adjusted to a predetermined pH used in each experiment, and the mixture was left in a refrigerator for one day to swell. (Liquid A)
2. The prescribed activated carbon used in each experiment was immersed in an excess amount of ethanol and left at room temperature for one day. (Liquid B)
3. 3. A predetermined amount of glycerin was added to Solution A, and sonication was performed for 12 minutes while cooling with ice, and suction filtration was performed.
4. After filtering the liquid B, the activated carbon collected by filtration was added to the liquid A and degassed with a vacuum pump.
5. 10 g of the above solution was poured into a stainless steel petri dish having a diameter of 4 cm, and dried at 50 ° C. for 15 hours.
＜＜II．こんにゃくフィルムの物性＞＞
こんにゃくフィルムの基礎的物性を明らかにするため，フィルムを作製し，検討を行った。
<< II. Physical characteristics of konjac film >>
In order to clarify the basic physical properties of konjac film, a film was prepared and examined.
１．こんにゃくフィルムの外観等を図１に示す。
(1) 図１aは，活性炭を含まないこんにゃくフィルム（実験例１），図１bは，活性炭を含んだこんにゃくフィルム（実験例２）である。いずれのフィルムも，直径約3.5cmの円状フィルムとして形成している。
(2) 実験例１では，無色半透明の外観であった（図１a）。一方，実験例２では，フィルム内に分散された活性炭を反映して黒色の外観であった（図１b）。
(3) これらを水に濡らしたのち，皮膚に付着させたところ，ともに，ぴったりと皮膚に付着し，逆さまにしても剥がれ落ちることはなかった（図１c，図１d）。
1. 1. The appearance of the konjac film is shown in FIG.
(1) FIG. 1a is a konjac film containing no activated carbon (Experimental Example 1), and FIG. 1b is a konjac film containing activated carbon (Experimental Example 2). Both films are formed as circular films with a diameter of about 3.5 cm.
(2) In Experimental Example 1, the appearance was colorless and translucent (Fig. 1a). On the other hand, in Experimental Example 2, the appearance was black reflecting the activated carbon dispersed in the film (Fig. 1b).
(3) When these were wetted with water and then adhered to the skin, both adhered to the skin exactly and did not peel off even when turned upside down (Fig. 1c, Fig. 1d).
３．各フィルムについて，破断強度を測定した結果を図２に示す。比較としてオブラート（比較例１）を用いた。
(1) それぞれの最大応力は，実験例１が8.13N，実験例２が2.42N，比較例１が0.78Nであった。
(2) また，最大変形距離は，実験例１が3.78mm，実験例２が2.80mm，比較例１が0.87mmであった。
(3) これらより，実験例１が最も強度があり，しなやかで伸びやすいものであった。
(4) 一方，実験例２は，オブラートより伸びやすかったが，実験例１より強度は小さく伸びにくいものであった。これについては，実験例２が不溶性の活性炭を含んでいたためと考えられ，活性炭ではなく，有用成分として水溶性成分を含んだフィルムであれば，実験例１と同様の物性を有するフィルムが作製できるものと思われた。
3. 3. The results of measuring the breaking strength of each film are shown in FIG. Oblate (Comparative Example 1) was used for comparison.
(1) The maximum stress of each was 8.13N in Experimental Example 1, 2.42N in Experimental Example 2, and 0.78N in Comparative Example 1.
(2) The maximum deformation distance was 3.78 mm in Experimental Example 1, 2.80 mm in Experimental Example 2, and 0.87 mm in Comparative Example 1.
(3) From these, Experimental Example 1 was the strongest, supple and easy to stretch.
(4) On the other hand, Experimental Example 2 was easier to stretch than oblate, but its strength was smaller than that of Experimental Example 1 and it was hard to stretch. It is considered that this is because Experimental Example 2 contained insoluble activated carbon, and if the film contained a water-soluble component as a useful component instead of activated carbon, a film having the same physical characteristics as Experimental Example 1 was produced. I thought I could do it.
＜＜III．インドール吸着の最適化＞＞
インドールは，***毒素インドキシル硫酸の前駆体である。加えて，活性炭は，腸管から吸収されず，糞便として体外に***される。
これらより，本発明における有用成分として活性炭を用いることにより，腸管中のインドールを体外へ排出し，***を防止・抑制することが期待される。そのため，インドール吸着に最適な活性炭種を選定するとともに，選定された活性炭を用いたフィルムが，どのような吸着性能を示すかについて検討を行った。
<< III. Optimization of indole adsorption >>
Indole is a precursor of the uremic toxin indoxyl sulfate. In addition, activated carbon is not absorbed from the intestinal tract and is excreted outside the body as feces.
From these, it is expected that by using activated carbon as a useful component in the present invention, indole in the intestinal tract is excreted from the body and uremia is prevented / suppressed. Therefore, we selected the most suitable activated carbon type for indole adsorption, and examined what kind of adsorption performance the film using the selected activated carbon shows.
１．球形吸着炭（クレメジン（登録商標），粒径：2〜4mm，以下，実験例３），ならびに黒色粉末活性炭（粒径150μm，以下，実験例４），これら2種類の活性炭を用いて検討を行った。
２．それぞれ67mgを，30mg/Lインドール溶液（pH7.4PBS）100mL中に入れ，撹拌を行い，溶液中の遊離インドールの濃度を，紫外可視分光光度計（269nm）で180分間経時的に測定し，下記式に従い，インドール吸着除去率を算出した。
1. 1. Spherical adsorption carbon (Kremezin (registered trademark), particle size: 2-4 mm, hereinafter, Experimental Example 3), and black powder activated carbon (
2. 67 mg of each was placed in 100 mL of a 30 mg / L indole solution (pH 7.4PBS), stirred, and the concentration of free indole in the solution was measured over time for 180 minutes with an ultraviolet-visible spectrophotometer (269 nm). The indole adsorption removal rate was calculated according to the formula.
３．結果を図３に示す。
(1) 実験例３では，緩やかにインドールの吸着が進み，90分後からはほぼ一定値となり，180分後では98.6%の吸着除去率であった。
(2) 一方，実験例４では速やかにインドールの吸着が進み，15分後でほとんど飽和に達し，最終的な吸着除去率は96.1%であった。
４．これらの結果から，いずれの活性炭についても十分な吸着能を有することが確認されたが，実験例４の黒色粉末活性炭の方が，粒子径が小さく，フィルムを作製する際に液中に分散しやすいことから，以降の検討では，黒色粉末活性炭を用いた。
3. 3. The results are shown in FIG.
(1) In Experimental Example 3, the adsorption of indole proceeded slowly, and after 90 minutes, the value became almost constant, and after 180 minutes, the adsorption removal rate was 98.6%.
(2) On the other hand, in Experimental Example 4, the adsorption of indole proceeded rapidly, and after 15 minutes, it almost reached saturation, and the final adsorption removal rate was 96.1%.
4. From these results, it was confirmed that all activated carbons have sufficient adsorptive capacity, but the black powder activated carbon of Experimental Example 4 has a smaller particle size and is dispersed in the liquid when the film is produced. Since it is easy, black powder activated carbon was used in the subsequent studies.
５．黒色活性炭67mgを含有するフィルム（実験例５），または活性炭のみ67mg（比較例２）を，30mg/Lインドール溶液（pH7.4PBS）100mL中に入れ，溶液中の遊離インドールの濃度を，紫外可視分光光度計（269nm）で180分間経時的に測定し，前述の式に従い，インドール吸着除去率を算出した。 5. A film containing 67 mg of black activated carbon (Experimental Example 5) or 67 mg of activated carbon only (Comparative Example 2) was placed in 100 mL of a 30 mg / L indole solution (pH 7.4PBS) to show the concentration of free indole in the solution in ultraviolet visibility. It was measured over time for 180 minutes with a spectrophotometer (269 nm), and the indole adsorption removal rate was calculated according to the above formula.
６．結果を図４に示す。
(1) 比較例２では速やかにインドールの吸着が進み，15分後でほとんど飽和に達し，最終的な吸着除去率は96.1%であった。
(2) 一方，実験例５では，穏やかにインドールの吸着が進み，180分後で84.0%の吸着除去率であった。
6. The results are shown in FIG.
(1) In Comparative Example 2, the adsorption of indole proceeded rapidly, and after 15 minutes, it almost reached saturation, and the final adsorption removal rate was 96.1%.
(2) On the other hand, in Experimental Example 5, the adsorption of indole proceeded gently, and the adsorption removal rate was 84.0% after 180 minutes.
７．これらの結果より，黒色活性炭を含んだ徐放性フィルムは，フィルム崩壊に伴い活性炭が徐々に放出され，十分なインドール吸着能を有することが示された。よって，黒色活性炭を含んだフィルムは，***の予防ないし治療に期待できることが示された。 7. From these results, it was shown that the sustained release film containing black activated carbon has sufficient indole adsorption ability because the activated carbon is gradually released as the film collapses. Therefore, it was shown that the film containing black activated carbon can be expected to prevent or treat uremia.
＜＜IV．調製条件によるフィルム性能の変化＞＞
フィルムについて，製造を行う際の各種条件を変化させ，インドール吸着除去率にどのような影響を及ぼすかについて，検討を行った。なお，各実験例における概容と除去速度定数（k値）を表１に示す。
<< IV. Changes in film performance depending on preparation conditions >>
For the film, various conditions during manufacturing were changed, and the effect on the indole adsorption removal rate was investigated. Table 1 shows the outline and removal rate constant (k value) in each experimental example.
１．フィルムについて，各pHで作製した外観を図５に，インドール吸着除去率を比較した結果を図６に示す。なお，その他の条件については，黒色活性炭の添加量を0.5%，グリセリンの添加量を0.3％，こんにゃく粉の添加量を1.0%に調整した。
(1) 実験例６ならびに実験例７では，黒色粉末活性炭が比較的均一に分散している一方，実験例８では分散状態に偏りが見られた（図５）。また，フィルムの柔軟性については，実験例６が最も柔軟性が高かった。
(2) インドール吸着については，実験例８が最も高い吸着除去率とk値を示した。一方，実験例６と実験例７は同様の吸着曲線であった。
(3) これらの結果より，いずれのpHについても十分な吸着除去能を示すことが示された。以降の検討においては，フィルムとしての取扱性に優れるpH３でフィルムを作製した。
1. 1. The appearance of the film prepared at each pH is shown in FIG. 5, and the result of comparing the indole adsorption removal rate is shown in FIG. Regarding other conditions, the amount of black activated carbon added was adjusted to 0.5%, the amount of glycerin added was adjusted to 0.3%, and the amount of konjac flour added was adjusted to 1.0%.
(1) In Experimental Example 6 and Experimental Example 7, the black powder activated carbon was dispersed relatively uniformly, while in Experimental Example 8, the dispersed state was biased (Fig. 5). As for the flexibility of the film, Experimental Example 6 had the highest flexibility.
(2) Regarding indole adsorption, Experimental Example 8 showed the highest adsorption removal rate and k value. On the other hand, Experimental Example 6 and Experimental Example 7 had similar adsorption curves.
(3) From these results, it was shown that sufficient adsorption and removal ability was exhibited at any pH. In the subsequent studies, a film was prepared at
２．フィルムについて，こんにゃく粉の比率で比較した結果を図７に示す。
(1) インドール吸着について，実験例１０が最も高い吸着除去率とk値を示した。
(2) また，吸着除去率の立ち上がりについても早く，実験例３（クレメジン）と類似の挙動を示したため，こんにゃく粉については，0.5%の比率が最も適していると考えられた。
2. The results of comparing the films with the ratio of konjac flour are shown in FIG.
(1) Regarding indole adsorption, Experimental Example 10 showed the highest adsorption removal rate and k value.
(2) In addition, the adsorption removal rate started quickly, and the behavior was similar to that of Experimental Example 3 (Kremezin). Therefore, it was considered that the ratio of 0.5% was the most suitable for konjac flour.
３．フィルムについて，グリセリンの比率で比較した結果を図８に示す。
(1) 実験例１２ならびに実験例１３について，インドール吸着除去率ならびにk値はほとんど変わらなかった。同様に，実験例１４と１５について，インドール吸着除去率はほとんど変わらず，実験例１２等と比較すると，低い吸着除去率であった。
(2) これらの結果より，グリセリンについては比率の少ない0.3%で，十分と考えられる。
3. 3. The results of comparing the films with the ratio of glycerin are shown in FIG.
(1) The indole adsorption removal rate and k value were almost the same for Experimental Example 12 and Experimental Example 13. Similarly, the indole adsorption removal rate was almost the same for Experimental Examples 14 and 15, which was lower than that of Experimental Example 12 and the like.
(2) From these results, it is considered that 0.3%, which is a small ratio of glycerin, is sufficient.
＜＜Ｖ．薬物含有こんにゃくフィルムからの薬物溶出率の変化＞＞
速放性フィルムの利用可能性として，去痰薬である2種類の薬物を有用成分として添加し，各種条件を変化させて薬物溶出率がどのように変化するかを調べることを目的として検討を行った。なお，各実験例における概容と溶出速度定数（kd値）を表２に示す。
<< V. Changes in drug elution rate from drug-containing konjac film >>
As the possibility of using a quick-release film, two kinds of drugs, which are expectorants, were added as useful ingredients, and the purpose of the study was to investigate how the drug elution rate changes by changing various conditions. It was. Table 2 shows the outline and elution rate constant (kd value) in each experimental example.
１．去痰薬であるAmbroxol Hydrochloride（以下，「AMBX」），Bromhexine Hydrochloride （以下，「BRMH」）を有用成分として，フィルム１枚につき各薬物を約10mgずつ添加し，表２に示す条件にて，フィルムの作製を行った。
２．作製したフィルムについて，精製水に浸し，ゆっくりと撹拌を行った。
３．撹拌後，溶液を適時採取し，採取した溶液を0.45μｍフィルターにてろ過し，HPLCにて分析を行った。
４．HPLCによる分析で各有用成分のピーク面積値を算出した。このピーク面積値を，精製水に完全に溶解させた各有用成分のHPLC分析から算出したピーク面積値で割ることにより，溶出率として算出を行った。
1. 1. Ambroxol Hydrochloride (hereinafter, "AMBX") and Bromhexine Hydrochloride (hereinafter, "BRMH"), which are expectorants, are used as useful ingredients, and about 10 mg of each drug is added to each film under the conditions shown in Table 2. Was produced.
2. The prepared film was immersed in purified water and stirred slowly.
3. 3. After stirring, the solution was collected in a timely manner, and the collected solution was filtered through a 0.45 μm filter and analyzed by HPLC.
4. The peak area value of each useful component was calculated by analysis by HPLC. The elution rate was calculated by dividing this peak area value by the peak area value calculated from the HPLC analysis of each useful component completely dissolved in purified water.
１．こんにゃく粉比率を変化させて検討した各薬物の溶出結果を図９（AMBX），１０（BRMH）に示す。
(1) AMBX，BRMHともに，こんにゃく粉の量が増加するほど，薬物溶出速度定数（kd）は小さくなり，フィルムからの薬物溶出速度は遅くなる傾向であった。
(2) 加えて，実験例１９と２３を除き，いずれのフィルムにおいても溶出率は，錠剤における溶出試験の判定基準（AMBX:20分で80%以上，BRMH:30分で75%以上）を満たしていた。
２．この結果から，こんにゃく粉の比率を変化させることにより，フィルムからの薬物溶出速度をコントロールできる可能性が示された。さらに，こんにゃく粉については，0.1%の含有率が速放性フィルムとして最も適していると考えられた。
1. 1. The dissolution results of each drug examined by changing the konjac flour ratio are shown in FIGS. 9 (AMBX) and 10 (BRMH).
(1) In both AMBX and BRMH, the drug elution rate constant (kd) tended to decrease and the drug elution rate from the film tended to decrease as the amount of konjac flour increased.
(2) In addition, except for Experimental Examples 19 and 23, the dissolution rate of all films is based on the criteria for dissolution test in tablets (AMBX: 80% or more at 20 minutes, BRMH: 75% or more at 30 minutes). Was satisfied.
2. From this result, it was shown that the drug elution rate from the film could be controlled by changing the ratio of konjac flour. Furthermore, for konjac flour, a content of 0.1% was considered to be the most suitable as a quick-release film.
３．こんにゃく粉の添加量を0.1%とし，グリセリン比率を変化させて検討を行った結果を図１１（AMBX），１２（BRMH）に示す。
(1) AMBX，BRMHともに，速やかな薬物溶出を示し，グリセリンの添加量による大きな変化は見られなかった。
(2) 加えて，いずれの薬物においても溶出率は，5分以内に80%以上となった。
４．この結果から，グリセリン添加量については，0.05%と0.10%では薬物溶出にほとんど影響を及ぼさないことが示された。
５．可塑剤であるグリセリン量が少なすぎると，フィルムが硬くなったため，口腔内速放性フィルムの作製にはこんにゃく粉量0.1％およびグリセリン量0.1％が適していると考えられた。
3. 3. The results of the study in which the amount of konjac flour added was 0.1% and the glycerin ratio was changed are shown in FIGS. 11 (AMBX) and 12 (BRMH).
(1) Both AMBX and BRMH showed rapid drug elution, and no significant change was observed depending on the amount of glycerin added.
(2) In addition, the dissolution rate of all drugs was 80% or more within 5 minutes.
4. From this result, it was shown that the amount of glycerin added was 0.05% and 0.10%, which had almost no effect on drug elution.
5. If the amount of glycerin, which is a plasticizer, was too small, the film became hard. Therefore, it was considered that 0.1% of konjac flour and 0.1% of glycerin were suitable for producing a quick-release film in the oral cavity.
＜＜VI．こんにゃく粉処理による分子量の変化＞＞
放出制御型フィルムを作製する際に用いるこんにゃく粉の基礎的性質を確認するため，こんにゃく粉処理方法により，KGMの平均分子量がどのように変化するかについて調べることを目的に検討を行った。
<< VI. Changes in molecular weight due to konjac flour treatment >>
In order to confirm the basic properties of the konjac flour used when producing the release-controlled film, we investigated how the average molecular weight of KGM changes depending on the konjac flour treatment method.
１．こんにゃく粉について，そのエタノール溶液をクエン酸酸性下で還流し，加水分解を行った。なお，KGMの平均分子量については，JP16粘度測定法第１法毛細管粘度計法により測定を行った。 1. 1. The ethanol solution of konjac flour was refluxed under citric acid acidity and hydrolyzed. The average molecular weight of KGM was measured by the JP16 viscosity measurement method, the first method, the capillary viscometer method.
２．加水分解の回数を変化させた結果を図１３に示す。加水分解を繰り返すごとに平均分子量は徐々に低下していった。
３．還流時間を変化させた結果を図１４に示す。還流時間によっても平均分子量は低下していった。
2. The result of changing the number of hydrolysiss is shown in FIG. The average molecular weight gradually decreased with each repeated hydrolysis.
3. 3. The result of changing the reflux time is shown in FIG. The average molecular weight also decreased with the reflux time.
４．これらの結果から，こんにゃく粉の加水分解回数や還流時間を変化させることにより，こんにゃく粉のKGM分子量の調整が可能であることが示された。 4. From these results, it was shown that the KGM molecular weight of konjac flour can be adjusted by changing the number of hydrolysis and reflux time of konjac flour.
＜＜VII．KGMの平均分子量とフィルムの崩壊速度定数の変化＞＞
こんにゃく粉のKGM平均分子量の調整が可能なことから，フィルム中のKGM平均分子量が，薬物の溶出速度にどのような影響をもたらすかの基礎的知見を得ることを目的に検討を行った。
<< VII. Changes in KGM average molecular weight and film decay rate constant >>
Since the average molecular weight of KGM in konjac flour can be adjusted, the purpose of this study was to obtain a basic understanding of how the average molecular weight of KGM in the film affects the dissolution rate of the drug.
１．こんにゃく粉 0.3%，グリセリン 0.3%，pH3.0 調製液で作成したフィルムを50℃，20時間乾燥した。なお，それぞれのサンプルについては，加水分解回数を変えて，KGM平均分子量の調整を行った。
２．メチレンブルー（0.005%）で染色し，水溶液中でフィルムから溶出するメチレンブルーの濃度から，フィルムの崩壊速度定数（kdis）を求めた。
1. 1. The film prepared with konjac flour 0.3%, glycerin 0.3%, and pH3.0 preparation solution was dried at 50 ° C. for 20 hours. For each sample, the average molecular weight of KGM was adjusted by changing the number of hydrolysiss.
2. The film decay rate constant (kdis) was determined from the concentration of methylene blue eluted from the film in an aqueous solution after dyeing with methylene blue (0.005%).
３．結果を図１５に示す。
(1) 図１５中，右からそれぞれ加水分解数が0回，1回，3回，5回，7回，8回，10回であり，加水分解数が増えるほど，KGM平均分子量（Mw）が小さくなっていくことが確認された。
(2) また，Mwが減少するほど，崩壊速度定数（kdis）が大きくなっていった。このことは，KGMの平均分子量が減少するほど，同量のこんにゃく粉で作製するフィルムは柔らかくなるとともに，フィルム崩壊速度が速くなり，含有物質の溶出速度が増加することを意味する。
3. 3. The results are shown in FIG.
(1) In Fig. 15, the number of hydrolysis is 0, 1, 3, 5, 7, 8 and 10 from the right, respectively. As the number of hydrolysis increases, the average molecular weight of KGM (Mw) Was confirmed to be getting smaller.
(2) In addition, the decay rate constant (kdis) increased as Mw decreased. This means that as the average molecular weight of KGM decreases, the film made from the same amount of konjac flour becomes softer, the film disintegration rate increases, and the elution rate of the contained substances increases.
４．これらの結果から，KGMの平均分子量を調整することにより，薬物溶出速度のコントロールが可能なことが示された。 4. From these results, it was shown that the drug elution rate can be controlled by adjusting the average molecular weight of KGM.
＜＜VIII．考察＞＞
１．今回，実験例で使用したこんにゃく粉は，もともと，KGMの平均分子量が80万から100万である。
２．水溶性多糖類としてこんにゃく粉を用いる場合，こんにゃく臭の原因である窒素含有物等の夾雑物が含まれる場合も多い。そのため，１回は加水分解をして夾雑物を除去することが好ましい。
３．今回の実験例において加水分解した後のこんにゃく粉は，元素分析により窒素原子が含まれていないこと，およびKGMの理論値と合致していることを確かめてフィルム作製に用いた。
４．加水分解を行う場合，加水分解の回数を繰り返してKGMの分子量を減少させるのも良いが，それほど時間と労力を掛けなくとも，１回の加水分解で約40万程度の分子量のKGMを調製することができる。また，放出制御型フィルムとして用いる場合，KGMの平均分子量は，30万以上が好ましく，フィルムとしての性能を効果的に発揮しうると考えられる。
５．これらより，放出制御型フィルムは，有用物質の物性を踏まえ，主としてこんにゃく粉量および調整液のpHを変えることにより，放出制御が可能となるものである。
<< VIII. Consideration >>
1. 1. The konjac flour used in this experimental example originally has an average molecular weight of KGM of 800,000 to 1,000,000.
2. When konjac flour is used as a water-soluble polysaccharide, it often contains impurities such as nitrogen-containing substances that cause the konjac odor. Therefore, it is preferable to hydrolyze once to remove impurities.
3. 3. In this experimental example, the hydrolyzed konjac flour was used for film production after confirming that it did not contain nitrogen atoms by elemental analysis and that it was consistent with the theoretical value of KGM.
4. When hydrolyzing, it is good to reduce the molecular weight of KGM by repeating the number of hydrolysis, but it is possible to prepare KGM with a molecular weight of about 400,000 by one hydrolysis without spending too much time and effort. be able to. When used as a release-controlled film, the average molecular weight of KGM is preferably 300,000 or more, and it is considered that the performance as a film can be effectively exhibited.
5. From these, the release control type film can control the release mainly by changing the amount of konjac flour and the pH of the adjusting liquid based on the physical characteristics of useful substances.
Claims (8)
前記活性炭を極性有機溶媒で前処理したうえで，平均分子量を調整したグルコマンナン溶液に添加して乾燥することにより，有用成分の放出を制御することを特徴とする放出制御型フィルムの製造方法。
A method for producing a release-controlled film containing konjac-derived glucomannan as a main composition component and at least activated carbon as a useful component.
A method for producing a release-controlled film, which comprises controlling the release of useful components by pretreating the activated carbon with a polar organic solvent, adding it to a glucomannan solution having an adjusted average molecular weight, and drying the activated carbon.
The method for producing a release-controlled film according to claim 1, wherein the release-controlled film is used by adhering to the skin or the oral cavity.
The method for producing a release-controlled film according to claim 1 or 2, wherein the release-controlled film further contains a plasticizer as a composition component.
The method for producing a release-controlled film according to claim 3, wherein the plasticizer is selected from any one or a plurality of glycerin and hyaluronic acid.
The method for producing a release-controlled film according to any one of claims 1 to 4, further comprising any or a plurality of a drug component and a nutritional component as the useful component.
The method for producing a release-controlled film according to any one of claims 1 to 5, wherein the release-controlled film is used for the treatment of animal renal uremia.
The method for producing a release-controlled film according to any one of claims 1 to 6, wherein the polar organic solvent is ethanol.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS5542210A (en) * | 1978-09-12 | 1980-03-25 | Koichi Ogawa | Special activated carbon |
| JPS62129052A (en) * | 1985-11-29 | 1987-06-11 | ユニコロイド株式会社 | Wound covering material |
| JPH05221862A (en) * | 1992-02-12 | 1993-08-31 | Otsuka Pharmaceut Co Ltd | Medical composition for suppository |
| JPH10179045A (en) * | 1996-12-25 | 1998-07-07 | Osaka Kagaku Gokin Kk | Sheet-like edible molding |
| US6596298B2 (en) * | 1998-09-25 | 2003-07-22 | Warner-Lambert Company | Fast dissolving orally comsumable films |
| KR20060016245A (en) * | 2004-08-17 | 2006-02-22 | 윤용만 | Method of manufacturing hydrogel sheet |
| CN102846581A (en) * | 2012-09-28 | 2013-01-02 | 天津市聚星康华医药科技有限公司 | Ambroxol hydrochloride oral fast-dissolving film and preparation method thereof |
| CN106236807B (en) * | 2016-07-20 | 2020-08-14 | 深圳神农特医食品有限公司 | Composition for preventing and treating influenza virus and traditional Chinese medicine compound oral instant membrane preparation |
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