JP6524744B2 - Method of producing solid dispersion containing poorly water-soluble substance - Google Patents
Method of producing solid dispersion containing poorly water-soluble substanceInfo
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本発明は難水溶性物質含有固体分散体の製造方法に係り、詳しくは、親水性物質の固体マトリクス中に、ニフェジピンなどの難水溶性物質を、界面活性剤や両親媒性高分子を用いることなく、分子レベルで安定的に分散させた固体分散体を製造する方法に関する。
本発明はまた、この方法により製造された難水溶性物質含有固体分散体と、この難水溶性物質含有固体分散体を含む食品及び医薬品に関する。
The present invention relates to a method for producing a poorly water-soluble substance-containing solid dispersion, and more specifically, using a poorly water-soluble substance such as nifedipine, a surfactant and an amphiphilic polymer in a solid matrix of a hydrophilic substance. The present invention also relates to a method for producing a solid dispersion stably dispersed at the molecular level.
The present invention also relates to a poorly water-soluble substance-containing solid dispersion produced by this method, and to food and medicine containing the poorly water-soluble substance-containing solid dispersion.
医薬品・食品における機能性成分の中には、極めて水溶性に乏しいものが多く、機能性成分の体内吸収や保存性、ハンドリング性の改善の観点から、従来より、これらを親水性物質を用いて固体分散体とする技術の研究が盛んに行われ、いくつかの提案がなされている。 Many functional ingredients in pharmaceuticals and foods are extremely poor in water solubility, and from the viewpoint of improving internal absorption and preservation of functional ingredients and handling properties, they have been conventionally used hydrophilic substances. The research on the technology to make a solid dispersion has been actively conducted, and several proposals have been made.
例えば、難水溶性物質と水溶性を有する高分子の両方が溶解する溶媒に溶解し、乾燥する方法が挙げられる。この方法では、溶媒としては、極性の有機溶媒や有機溶媒と水の混合溶媒が用いられている。また、薬物などの難水溶性物質の非晶質状態を安定化するため水溶性高分子としてグラフト重合体や架橋高分子などの両親媒性物質が用いられたり、難水溶性物質の水溶液中における溶出性を高めるため、界面活性剤や崩壊剤が添加される場合もある。
しかし、両親媒性物質は、再溶解（人体が摂取する）時に難水溶性物質の放出を阻害する可能性がある。また、界面活性剤は高価な上に人体に及ぼす影響も懸念される。
For example, there is a method of dissolving in a solvent in which both the poorly water-soluble substance and the water-soluble polymer are soluble and drying. In this method, a polar organic solvent or a mixed solvent of an organic solvent and water is used as the solvent. In addition, amphiphilic substances such as graft polymers and cross-linked polymers are used as water-soluble polymers to stabilize the amorphous state of poorly water-soluble substances such as drugs, or in aqueous solutions of poorly water-soluble substances. Surfactants and disintegrants may be added to enhance the dissolution.
However, amphiphilic substances may inhibit the release of poorly water-soluble substances upon reconstitution (to be consumed by the human body). In addition, surfactants are expensive and are also concerned about their effects on the human body.
一方、溶媒として賦形剤を溶解した水を用い、水溶液中に懸濁した難水溶性物質を加熱・溶解した上で噴霧乾燥を行うことで、固体分散体を得る方法もある（特許文献１）。これに対し、難水溶性物質と賦形剤成分を別々の溶媒に溶解し、それらの溶液を混合した上で噴霧乾燥したり（特許文献２）、両液を同時に噴霧することで、難水溶性物質と水溶性賦形成分の両方を含むミストを作り出し、これを乾燥することで固体分散体を得る方法もある（特許文献３）。 On the other hand, there is also a method of obtaining a solid dispersion by performing spray drying after heating and dissolving a poorly water-soluble substance suspended in an aqueous solution using water in which an excipient is dissolved as a solvent (Patent Document 1) ). On the other hand, the poorly water-soluble substance and the excipient component are dissolved in different solvents, and the solutions are mixed and spray-dried (Patent Document 2), or both solutions are simultaneously sprayed, There is also a method of producing a solid dispersion by producing a mist containing both a sex substance and a water-soluble excipient and drying it (Patent Document 3).
また、難水溶性物質を融解状態にした上で固体分散化する技術もある。すなわち、難水溶性物質と賦形成分を加熱しながら混練し、十分混合後、冷却・固化することで固体分散体を得ることができる（特許文献４）。このときニルバジピンとセルロース誘導体のように難水溶性物質と賦形成分の組み合わせによっては、融点以下で溶解性が高い固体分散体を作成できる（特許文献５）。また、難水溶性物質をエアロゾルや活性炭などの高比表面積を有する材料と粉砕・混合すれば、固体粒子表面に難水溶性物質が吸着することで、非晶質に準じた状態を作り出すことができる（特許文献６）。 In addition, there is also a technology in which a poorly water-soluble substance is melted and then dispersed into a solid. That is, it is possible to obtain a solid dispersion by kneading while heating the poorly water-soluble substance and the formation component while heating, sufficiently mixing and then cooling and solidifying (Patent Document 4). At this time, depending on the combination of a poorly water-soluble substance and an excipient component, such as nilvadipine and a cellulose derivative, a solid dispersion having high solubility at or below the melting point can be prepared (Patent Document 5). In addition, when a poorly water-soluble substance is crushed and mixed with a material having a high specific surface area such as aerosol or activated carbon, the poorly water-soluble substance is adsorbed on the solid particle surface to create an amorphous state. It can do (patent document 6).
しかしながら、上記従来の方法では、難水溶性物質を親水性物質の固体マトリクス中に分子レベルで十分に分散させることはできなかった。 However, according to the above-mentioned conventional method, the poorly water-soluble substance can not be sufficiently dispersed at the molecular level in the solid matrix of the hydrophilic substance.
本発明は、親水性物質の固体マトリクス中に、ニフェジピンなどの難水溶性物質を、界面活性剤や両親媒性高分子を用いることなく、分子レベルで安定的に分散させた固体分散体を製造する方法を提供することを課題とする。 The present invention produces a solid dispersion in which a poorly water-soluble substance such as nifedipine is stably dispersed at the molecular level in a solid matrix of a hydrophilic substance without using a surfactant or an amphiphilic polymer. The task is to provide a way to
本発明者らは、上記課題を解決すべく、鋭意検討を重ねた結果、糖、糖アルコール及びアミノ酸からなる群から選ばれる親水性物質を用いて非晶質の親水性物質を製造し、この非晶質の親水性物質と、難水溶性物質を分散させた有機溶媒とを混合後、乾燥させることにより、上記課題が解決できることを見出した。
即ち、予め非晶質化した親水性物質は有機溶媒に一時的に分散するため、難水溶性物質と親水性物質が同一溶媒内で分子レベルで分散した混合溶液を得ることができる。この混合溶液を乾燥すれば、親水性物質の非晶質固体マトリクス内に難水溶性物質が分子レベルで分散した固体を得ることができる。
As a result of intensive studies to solve the above problems, the present inventors produced an amorphous hydrophilic substance using a hydrophilic substance selected from the group consisting of sugars, sugar alcohols and amino acids. It has been found that the above problems can be solved by mixing an amorphous hydrophilic substance and an organic solvent in which a poorly water-soluble substance is dispersed and drying the mixture.
That is, since the hydrophilic substance which has been made amorphous in advance is temporarily dispersed in the organic solvent, it is possible to obtain a mixed solution in which the poorly water-soluble substance and the hydrophilic substance are dispersed at the molecular level in the same solvent. By drying this mixed solution, it is possible to obtain a solid in which the poorly water-soluble substance is dispersed at the molecular level in the amorphous solid matrix of the hydrophilic substance.
本発明はこのような知見に基づいて達成されたものであり、以下を要旨とする。 The present invention has been achieved based on such findings, and the gist of the present invention is as follows.
［１］ 親水性物質と難水溶性物質を含有する難水溶性物質含有固体分散体の製造方法であって、該親水性物質は、糖、糖アルコール及びアミノ酸からなる群から選ばれる物質であり、該親水性物質を含有する親水性物質含有液を乾燥させて、非晶質の親水性物質を得る工程、有機溶媒に該難水溶性物質を分散させた分散液を得る工程、該非晶質の親水性物質と、該分散液とを混合して難水溶性物質含有分散液を得る工程、該難水溶性物質含有分散液を乾燥させて難水溶性物質含有固体分散体を得る工程を有することを特徴とする、難水溶性物質含有固体分散体の製造方法。 [1] A method for producing a poorly water-soluble substance-containing solid dispersion containing a hydrophilic substance and a poorly water-soluble substance, wherein the hydrophilic substance is a substance selected from the group consisting of sugar, sugar alcohol and amino acid Drying the hydrophilic substance-containing liquid containing the hydrophilic substance to obtain an amorphous hydrophilic substance, obtaining a dispersion in which the poorly water-soluble substance is dispersed in an organic solvent, the amorphous substance And mixing the dispersion with the dispersion to obtain a poorly water-soluble substance-containing dispersion, and drying the poorly water-soluble substance-containing dispersion to obtain a poorly water-soluble substance-containing solid dispersion. A method for producing a poorly water-soluble substance-containing solid dispersion, characterized in that
［２］ 該難水溶性物質が、水（２５℃）に対する飽和溶解度が１００００μｇ／ｍＬ以下の物質である、［１］に記載の難水溶性物質含有固体分散体の製造方法。 [2] The method for producing a poorly water-soluble substance-containing solid dispersion according to [1], wherein the poorly water-soluble substance is a substance having a saturated solubility in water (25 ° C.) of 10000 μg / mL or less.
［３］ 糖、糖アルコール及びアミノ酸からなる群から選ばれる親水性物質の固体マトリクス中に、難水溶性物質を、界面活性剤及び両親媒性高分子を用いることなく分散させた難水溶性物質含有固体分散体。
［４］ 親水性物質と難水溶性物質を含有する難水溶性物質含有固体分散体であって、該親水性物質は、糖、糖アルコール及びアミノ酸からなる群から選ばれる物質であり、難水溶性物質含有固体分散体は、該親水性物質を含有する親水性物質含有液の乾燥物である非晶質の親水性物質と、有機溶媒に該難水溶性物質を分散させた分散液との混合物からなる難水溶性物質含有分散液の乾燥物である、難水溶性物質含有固体分散体。
[3] A poorly water-soluble substance obtained by dispersing a poorly water-soluble substance in a solid matrix of a hydrophilic substance selected from the group consisting of sugars, sugar alcohols and amino acids without using surfactants and amphiphilic polymers Containing solid dispersion.
[4] A poorly water-soluble substance-containing solid dispersion containing a hydrophilic substance and a poorly water-soluble substance, wherein the hydrophilic substance is a substance selected from the group consisting of sugar, sugar alcohol and amino acid, which is poorly water-soluble Substance-containing solid dispersion comprises an amorphous hydrophilic substance which is a dried product of a hydrophilic substance-containing liquid containing the hydrophilic substance, and a dispersion liquid in which the poorly water-soluble substance is dispersed in an organic solvent A poorly water-soluble substance-containing solid dispersion which is a dried product of a poorly water-soluble substance-containing dispersion comprising a mixture.
［５］ ［３］又は［４］に記載の難水溶性物質含有固体分散体を含む食品。 [ 5 ] A food comprising the poorly water-soluble substance-containing solid dispersion according to [3] or [4] .
［６］ ［３］又は［４］に記載の難水溶性物質含有固体分散体を含む医薬品。 [ 6 ] A medicine comprising the poorly water-soluble substance-containing solid dispersion according to [3] or [4] .
本発明によれば、親水性物質の固体マトリクス中に、ニフェジピンなどの難水溶性物質を、界面活性剤や両親媒性高分子を用いることなく、分子レベルで安定的に分散させた固体分散体を製造することができる。
しかも、本発明で用いる親水性物質、即ち、製造された固体分散体の固体マトリクスを構成する親水性物質は、糖、糖アルコール、アミノ酸という安全性の高いものであり、食品や医薬品としての固体分散体の製造に好適である。
According to the present invention, a solid dispersion in which a poorly water-soluble substance such as nifedipine is stably dispersed at a molecular level without using a surfactant or an amphiphilic polymer in a solid matrix of a hydrophilic substance Can be manufactured.
Moreover, the hydrophilic substance used in the present invention, that is, the hydrophilic substance constituting the solid matrix of the manufactured solid dispersion, is a highly safe substance such as sugar, sugar alcohol or amino acid, and it is solid as food or medicine. Suitable for the preparation of dispersions.
以下に本発明の難水溶性物質含有固体分散体の製造方法の実施の形態を詳細に説明するが、以下に記載する構成要件の説明は、本発明の実施態様の一例（代表例）であり、本発明はその要旨を超えない限り、これらの内容に特定はされない。 The embodiment of the method for producing the hardly water-soluble substance-containing solid dispersion of the present invention will be described in detail below, but the description of the constituent requirements described below is an example (representative example) of the embodiment of the present invention The present invention is not specified in these contents unless it exceeds the gist.
本発明の難水溶性物質含有固体分散体の製造方法は、親水性物質として、糖、糖アルコール及びアミノ酸からなる群から選ばれる物質を用い、親水性物質を含有する親水性物質含有液を乾燥させて、非晶質の親水性物質を得（非晶化工程）、一方、有機溶媒に難水溶性物質を分散させた分散液を得（分散工程）、該非晶質の親水性物質と、該分散液とを混合して難水溶性物質含有分散液を得（混合工程）、この難水溶性物質含有分散液を乾燥させて難水溶性物質含有固体分散体を得る（乾燥工程）ことを特徴とする。 The method for producing the poorly water-soluble substance-containing solid dispersion of the present invention uses a substance selected from the group consisting of sugar, sugar alcohol and amino acid as the hydrophilic substance, and dries the hydrophilic substance-containing liquid containing the hydrophilic substance. To obtain an amorphous hydrophilic substance (amorphization step), while obtaining a dispersion in which a poorly water-soluble substance is dispersed in an organic solvent (dispersion step), the amorphous hydrophilic substance, Mixing with the dispersion to obtain a sparingly water-soluble substance-containing dispersion (mixing step), drying the sparingly water-soluble substance-containing dispersion to obtain a sparingly water-soluble substance-containing solid dispersion (drying step) It features.
＜親水性物質＞
本発明で用いる親水性物質、即ち、得られる難水溶性物質含有固体分散体の固体マトリクスを構成する親水性物質は、糖、糖アルコール、及びアミノ酸から選ばれる物質である。
親水性物質としては、後述の凍結乾燥時に非晶質状態が生じるものであればよく、特に制限されるものではないが、例えば、グルコース、フルクトース等の単糖類、マルトース、ラクトース、スクロース、トレハロース等の二糖類を用いることができる。また、糖アルコールとしては、マルチトール、イノシトール、ソルビット等を用いることができる。また、アミノ酸としては、グリシン、アラニン、アルギニン、アスパラギン酸、ヒスチジン等を用いることができる。
これらは１種を単独で用いてもよく、２種以上を混合して用いてもよい。
<Hydrophilic substance>
The hydrophilic substance used in the present invention, that is, the hydrophilic substance constituting the solid matrix of the obtained poorly water-soluble substance-containing solid dispersion, is a substance selected from sugars, sugar alcohols, and amino acids.
The hydrophilic substance is not particularly limited as long as it causes an amorphous state at the time of lyophilization described later, and examples thereof include monosaccharides such as glucose and fructose, maltose, lactose, sucrose and trehalose Disaccharides can be used. Moreover, maltitol, inositol, sorbite etc. can be used as sugar alcohol. Moreover, as an amino acid, glycine, alanine, arginine, aspartic acid, histidine etc. can be used.
One of these may be used alone, or two or more may be mixed and used.
親水性物質としては、これらのうち、マルトース（特にα−マルトース）、トレハロース、マルチトールが好ましく、マルチトールがより好ましい。 Among these, maltose (especially α-maltose), trehalose and maltitol are preferable as the hydrophilic substance, and maltitol is more preferable.
＜難水溶性物質＞
本発明で固体分散体とする難水溶性物質としては、例えば、水（２５℃）に対する飽和溶解度が通常１００００μｇ／ｍＬ以下、好ましくは１０００μｇ／ｍＬ以下、より好ましくは１００μｇ／ｍＬ以下であるような、水に難溶性のものであればよく、特に制限はないが、得られる難水溶性物質含有固体分散体の用途において、難水溶性の薬剤や食品用、香粧品用または嗜好品用の油溶性成分、例えば、色素、抗酸化剤、栄養成分、香料などが挙げられる。具体的には、レスベラロトール、インドメタシン、ニフェジピン、グリクラジド等の難水溶性の薬剤や、シンナムアルデヒド、ラズベリーケトン、バニリン酸メチルエステル、オイゲノール、アニソール等の食品用香料などの香料、β−カロチン、パプリカ色素等のカロテノイドやクロロフィル、クルクミン等のクルクミノイドなどの色素、ビタミンＥ、ローズマリー抽出物などの抗酸化剤、ビタミンＡ、ビタミンＤ３、コエンザイムＱ１０、α−リポ酸などの栄養成分、などが挙げられるが、何らこれらに限定されるものではなく、前掲の特許文献１〜６において、固体分散体の製造に適用した難水溶性物質等、あらゆる難水溶性物質を用いることができる。また、特許５２５２８２５号公報、国際公開ＷＯ２０１２／１０５５４６号公報、特開２０１３−１５５１１９号公報、特表２０１０−５１５４４７号公報などに記載の難水溶性物質を用いることができる。
<Water-insoluble substances>
As the poorly water-soluble substance to be used as a solid dispersion in the present invention, for example, the saturated solubility in water (25 ° C.) is usually 10000 μg / mL or less, preferably 1000 μg / mL or less, more preferably 100 μg / mL or less And those which are sparingly soluble in water and are not particularly limited, but in the use of the poorly water-soluble substance-containing solid dispersion to be obtained, oils for poorly water-soluble drugs, foods, cosmetics, or luxury goods Soluble ingredients such as dyes, antioxidants, nutritional ingredients, perfumes and the like can be mentioned. Specifically, poorly water-soluble drugs such as resveratrol, indomethacin, nifedipine, gliclazide, and flavors such as cinnamaldehyde, raspberry ketone, vanillic acid methyl ester, eugenol, anisole, etc. food flavors, β-carotene, paprika dyes etc. And carotenoids such as chlorophyll and curcumin, vitamin E, antioxidants such as rosemary extract, vitamin A, vitamin D3, coenzyme Q10, and nutritional components such as α-lipoic acid, etc. The present invention is not limited to these, and in the above-mentioned Patent Documents 1 to 6, any poorly water-soluble substance such as the poorly water-soluble substance applied to the production of the solid dispersion can be used. In addition, it is possible to use the poorly water-soluble substances described in Patent 5522825, International Publication WO 2012/105546, Japanese Patent Application Laid-Open No. 2013-155119, Japanese Patent Application Publication No. 2010-515447, and the like.
これらの難水溶性物質は、１種を単独で用いてもよく、２種以上を混合して用いてもよい。 These poorly water-soluble substances may be used alone or in combination of two or more.
＜非晶化工程＞
前述の親水性物質を含有する親水性物質含有液を乾燥させて非晶質の親水性物質を得るには、例えば、親水性物質を純水等の水に溶解させて親水性物質の水溶液とし、これを凍結乾燥させることにより非晶質の親水性物質（以下、「アモルファス物質」という。）を得る。
アモルファス物質を得る方法は、非晶化が可能であれば、何ら凍結乾燥法に限定されるものではないが、凍結乾燥が簡便で工業的にも有利である。
また、親水性物質が非晶質となったことは、後述の実施例のように示差走査熱量分析により確認することができる。
<Decrystallization process>
In order to obtain an amorphous hydrophilic substance by drying the hydrophilic substance-containing liquid containing the aforementioned hydrophilic substance, for example, the hydrophilic substance is dissolved in water such as pure water to form an aqueous solution of the hydrophilic substance. By freeze-drying this, an amorphous hydrophilic substance (hereinafter referred to as "amorphous substance") is obtained.
The method for obtaining the amorphous substance is not limited to the lyophilization method as long as it can be decrystallized, but the lyophilization is convenient and industrially advantageous.
In addition, the fact that the hydrophilic substance has become amorphous can be confirmed by differential scanning calorimetry as in Examples described later.
凍結乾燥に供する親水性物質水溶液の親水性物質濃度は、０．１〜５０重量％が好ましく、０．５〜２０重量％がより好ましく、特に１〜１０重量％とすることが好ましい。親水性物質濃度が過度に高いと水分を除去（例えば２重量％以下程度まで）することが難しく、過度に低いと一回の乾燥操作で得られる材料が不十分となる場合がある。
凍結乾燥の方法及び条件には特に制限はなく、常法に従って行うことができる。
The concentration of the hydrophilic substance in the aqueous solution of the hydrophilic substance to be subjected to lyophilization is preferably 0.1 to 50% by weight, more preferably 0.5 to 20% by weight, and particularly preferably 1 to 10% by weight. If the concentration of the hydrophilic substance is excessively high, it is difficult to remove water (for example, to about 2% by weight or less). If the concentration is excessively low, the material obtained in one drying operation may be insufficient.
There are no particular limitations on the method and conditions of lyophilization, and the lyophilization can be performed according to a conventional method.
＜分散工程＞
一方、難水溶性物質は適当な有機溶媒に分散、溶解させて分散液を得る。
<Dispersion process>
On the other hand, the poorly water-soluble substance is dispersed and dissolved in a suitable organic solvent to obtain a dispersion.
ここで用いる有機溶媒としては、難水溶性物質を安定に分散、溶解させるものであればよく、特に制限はないが、例えば、メタノール、エタノール等のアルコール、アセトン等のケトンを用いることができる。
これらの有機溶媒は、１種を単独で用いてもよく、２種以上を混合して用いてもよい。
The organic solvent used here is not particularly limited as long as it disperses and dissolves a poorly water-soluble substance stably, and there is no particular limitation. For example, alcohols such as methanol and ethanol, and ketones such as acetone can be used.
One of these organic solvents may be used alone, or two or more thereof may be mixed and used.
有機溶媒への難水溶性物質の添加量は、有機溶媒１Ｌ当たり、難水溶性物質１〜５００ｇが好ましく、１〜１００ｇがより好ましく、特に１〜１０ｇ程度とすることが好ましい。上記範囲よりも難水溶性物質量が少なく、相対的に有機溶媒量が多いと、後工程で乾燥除去する有機溶媒量が多くなり好ましくない。逆に、上記範囲よりも難水溶性物質量が多く、相対的に有機溶媒量が少ないと、均一な分散液を得ることができず、また、次工程の混合工程においても均一な分散液を得ることができない場合がある。 The addition amount of the poorly water-soluble substance to the organic solvent is preferably 1 to 500 g of the poorly water-soluble substance, more preferably 1 to 100 g, and particularly preferably about 1 to 10 g, per 1 L of the organic solvent. If the amount of the hardly water-soluble substance is smaller than the above range and the amount of the organic solvent is relatively large, the amount of the organic solvent to be dried and removed in the subsequent step is undesirably large. Conversely, if the amount of poorly water-soluble substance is larger than the above range and the amount of organic solvent is relatively small, a uniform dispersion can not be obtained, and a uniform dispersion can be obtained in the mixing step of the next step. Sometimes you can not get it.
＜混合工程＞
上記の分散工程で得られた難水溶性物質含有分散液に、前述の非晶化工程で得られたアモルファス物質を添加して均一に混合することにより、アモルファス物質／難水溶性物質分散液を得る。
ここで、親水性物質は有機溶媒には溶解し難いものであるが、アモルファス物質であれば、有機溶媒に対して速やかに分散、溶解する。
<Mixing process>
The amorphous substance / slightly water-soluble substance dispersion is obtained by adding the amorphous substance obtained in the amorphization step described above to the poorly water-soluble substance-containing dispersion obtained in the above dispersion step and uniformly mixing it. obtain.
Here, the hydrophilic substance is hardly soluble in the organic solvent, but if it is an amorphous substance, it is rapidly dispersed and dissolved in the organic solvent.
この工程におけるアモルファス物質の添加量は、難水溶性物質に対して、１〜５００重量倍が好ましく、１〜１００重量倍がより好ましく、特に２〜１０重量倍とすることが好ましい。アモルファス物質の添加量が上記範囲よりも少ないと、安定な固体分散体を得ることができないおそれがあり、上記範囲よりも多いと相対的に難水溶性物質の量が少なくなって、得られる固体分散体の機能性が十分でないものとなるおそれがある。 The amount of the amorphous substance added in this step is preferably 1 to 500 times by weight, more preferably 1 to 100 times by weight, and particularly preferably 2 to 10 times by weight, the amount of the poorly water-soluble substance. If the addition amount of the amorphous substance is less than the above range, a stable solid dispersion may not be obtained, and if it is more than the above range, the amount of the hardly water-soluble substance is relatively small, and the obtained solid is obtained The functionality of the dispersion may not be sufficient.
また、この工程において、分散液中のアモルファス物質と難水溶性物質の合計の含有量は、前述の分散工程で用いた有機溶媒１Ｌに対して１〜５００ｇが好ましく、１〜１００ｇがより好ましく、特に５〜１０ｇであることが、分散安定性と、生産性の面で好ましい。 In this step, the total content of the amorphous substance and the hardly water-soluble substance in the dispersion is preferably 1 to 500 g, more preferably 1 to 100 g, per 1 L of the organic solvent used in the above-mentioned dispersion step. In particular, it is preferable that the amount is 5 to 10 g in terms of dispersion stability and productivity.
＜乾燥工程＞
上記の混合工程で得られたアモルファス物質／難水溶性物質分散液を乾燥処理し、有機溶媒を揮発除去して難水溶性物質含有固体分散体を得る。
この乾燥工程は、２５〜２００℃、好ましくは２５〜９０℃程度の加熱処理下で行うこともできるが、難水溶性物質の変質等を防止するために、室温（１５〜３５℃）での真空乾燥で行うことが好ましい。
<Drying process>
The amorphous substance / slightly water-soluble substance dispersion obtained in the above mixing step is subjected to drying treatment to volatilize and remove the organic solvent to obtain a hardly water-soluble substance-containing solid dispersion.
This drying step can also be performed under a heat treatment of about 25 to 200 ° C., preferably about 25 to 90 ° C., but at a room temperature (15 to 35 ° C.) to prevent deterioration or the like of poorly water-soluble substances. It is preferable to carry out by vacuum drying.
本発明においては、難水溶性物質と親水性物質のアモルファス物質とを有機溶媒中で混合分散するためこれらが極めて均一に混合分散される。そして、この分散液から有機溶媒を乾燥除去することで、得られた難水溶性物質含有固体分散体は、親水性物質のアモルファス物質を固体マトリクスとして、難水溶性物質が分子レベルで均一に分散したものとなる。 In the present invention, since the poorly water-soluble substance and the amorphous substance of the hydrophilic substance are mixed and dispersed in the organic solvent, they are mixed and dispersed very uniformly. Then, by removing the organic solvent from the dispersion by drying, the poorly water-soluble substance-containing solid dispersion is obtained by uniformly dispersing the poorly water-soluble substance at the molecular level, using the amorphous substance of the hydrophilic substance as the solid matrix. It will be done.
このようにして得られる固体分散体は、親水性物質の非晶質固体マトリクス中に難水溶性物質が分子レベルで均一に分散したものであるため、例えば、これを水に添加すると、内包されている難水溶性物質が、本来の溶解度よりも高濃度に速やかに溶解するものとなる。
また、難水溶性物質として揮発性の物質を内包した固体分散体であれば、この物質が固体マトリクス中で均一に分散している結果、揮発性成分の徐放性が得られる。
The solid dispersion thus obtained is obtained by uniformly dispersing the poorly water-soluble substance at the molecular level in an amorphous solid matrix of a hydrophilic substance, so for example, when it is added to water, it is encapsulated The poorly water-soluble substance is rapidly dissolved at a higher concentration than the original solubility.
In addition, in the case of a solid dispersion containing a volatile substance as a poorly water-soluble substance, as a result of the substance being uniformly dispersed in the solid matrix, sustained release of volatile components can be obtained.
以下に、本発明を実施例によって更に具体的に説明するが、本発明はその要旨を超えない限り、以下の実施例の記載に限定されるものではない。 EXAMPLES Hereinafter, the present invention will be more specifically described by way of examples. However, the present invention is not limited to the descriptions of the following examples as long as the gist thereof is not exceeded.
以下の実施例においては、親水性物質として、糖アルコールも用いたが、便宜上、すべて「糖」と総称する。
また、以下において、液中の糖の溶解濃度は、フィルター濾過後、フェノール−硫酸法により定量した。
In the following examples, although sugar alcohol was also used as a hydrophilic substance, all are collectively called "sugar" for convenience.
Also, in the following, the dissolved concentration of sugar in the solution was quantified by the phenol-sulfuric acid method after filter filtration.
［参考例１］
スクロース、α−マルトース、α−ラクトースの１００ｍｇ／ｍＬ水溶液をそれぞれ調製し、これを凍結乾燥させた後、Ｐ２Ｏ５共存下の真空ラジケータ内で３日間絶乾することにより、それぞれ糖のアモルファス粉末を調製した。
得られた糖のアモルファス粉末をメタノール（２５℃）に添加、撹拌し、得られた液中での糖濃度の経時変化を調べ、結果を図１に示した。
図１より、糖のアモルファス粉末は、以下に示すそれぞれの結晶状態におけるメタノール（２５℃）に対する溶解度よりも高濃度に溶解し、過溶解状態をある程度維持することが確認された。
スクロース結晶のメタノール溶解度：１．６ｍｇ／ｍＬ
α−マルトース結晶のメタノール溶解度：２．０ｍｇ／ｍＬ
α−ラクトース結晶のメタノール溶解度：１．５μｇ／ｍＬ
[Reference Example 1]
Prepare an aqueous solution of 100 mg / mL of sucrose, α-maltose and α-lactose, freeze-dry it, and then dry for 3 days in a vacuum radiator in the presence of P 2 O 5 to make the sugar amorphous A powder was prepared.
The obtained amorphous powder of sugar was added to methanol (25 ° C.) and stirred, and the change with time of the sugar concentration in the obtained liquid was examined, and the result is shown in FIG.
It was confirmed from FIG. 1 that the amorphous powder of sugar is dissolved at a higher concentration than the solubility in methanol (25 ° C.) in each of the crystalline states shown below, and maintains the over-dissolved state to some extent.
Solubility of sucrose crystals in methanol: 1.6 mg / mL
Solubility of α-maltose crystals in methanol: 2.0 mg / mL
Solubility of α-lactose crystals in methanol: 1.5 μg / mL
［実施例１〜５、比較例１］
以下に示す親水性物質の１００ｍｇ／ｍＬの水溶液を調製し、これを凍結乾燥させた後、Ｐ２Ｏ５共存下の真空デシケータ内で３日間絶乾することにより各々アモルファス粉末を得た。
実施例１：α−マルトース
実施例２：スクロース
実施例３：マルチトール
実施例４：トレハロース
実施例５：α−ラクトース
[Examples 1 to 5, Comparative Example 1]
Preparing an aqueous solution of 100 mg / mL of the hydrophilic material described below, after freeze-dried, to give the respective amorphous powder by bone dry for 3 days in a vacuum desiccator P 2 O 5 coexistence.
Example 1: α-maltose Example 2: sucrose Example 3: maltitol Example 4: trehalose Example 5: α-lactose
一方、シンナムアルデヒドをメタノール（２５℃）に溶解させたシンナムアルデヒド溶液を調製し、ここへ、上記の糖のアモルファス粉末をシンナムアルデヒドの１０倍量添加して十分に撹拌し、シンナムアルデヒド濃度１０ｍｇ／ｍＬ、糖濃度１００ｍｇ／ｍＬの混合液を得た。
この混合液をそれぞれ真空乾燥（室温，１時間）することで、固体分散体試料を得た（実施例１〜５）。
On the other hand, a cinnamaldehyde solution was prepared by dissolving cinnamaldehyde in methanol (25 ° C.), to which an amorphous powder of the above sugar was added 10 times the amount of cinnamaldehyde and thoroughly stirred to give a cinnamaldehyde concentration of 10 mg / A mixture of mL and a sugar concentration of 100 mg / mL was obtained.
The mixed solution was dried under vacuum (room temperature, 1 hour) to obtain a solid dispersion sample (Examples 1 to 5).
比較のため、シンナムアルデヒドを界面活性剤（Ｔｗｅｅｎ２０）共存下でＯ／Ｗエマルション化し、これを凍結乾燥した試料も調製した（比較例１）。 For comparison, cinnamaldehyde was subjected to O / W emulsification in the presence of a surfactant (Tween 20), and a lyophilized sample was also prepared (Comparative Example 1).
実施例１〜５及び比較例１で得られた試料を減圧下（２５℃，１００Ｐａ以下）で０〜７日間保存し、この間、適当な時間間隔で試料を取り出し、メタノール中に分散、溶解させてメタノール中のシンナムアルデヒド濃度をＵＶ−ｖｉｓ分光光度計（２８５ｎｍ）により測定し、この測定値から、各試料中のシンナムアルデヒドの保持率を算出した。
この結果を図２に示す。
The samples obtained in Examples 1 to 5 and Comparative Example 1 are stored under reduced pressure (25 ° C., 100 Pa or less) for 0 to 7 days, while the samples are taken out at appropriate time intervals, dispersed and dissolved in methanol The concentration of cinnamaldehyde in methanol was measured with a UV-vis spectrophotometer (285 nm), and from this measurement value, the retention of cinnamaldehyde in each sample was calculated.
The results are shown in FIG.
図２に示されるように、実施例１〜５の固体分散体試料では、香気成分であるシンナムアルデヒドの経時による保持率の低下を抑制することができ、特に、α−マルトース、スクロースを用いた場合は、界面活性剤によりＯ／Ｗエマルション化して凍結乾燥した比較例１の試料より高い保持率を示した。
この結果から、本発明によれば、香気成分であるシンナムアルデヒドを固体分散体とすることができると共に、香気成分の徐放性を有する機能性材料を提供することができることが分かる。
As shown in FIG. 2, in the solid dispersion samples of Examples 1 to 5, the decrease in retention rate with time of the cinnamaldehyde which is an aroma component can be suppressed, and in particular, α-maltose and sucrose were used. In the case, it showed higher retention than the sample of Comparative Example 1 which was O / W emulsified with a surfactant and lyophilized.
From this result, it can be seen that according to the present invention, cinnamaldehyde which is an aroma component can be made into a solid dispersion, and a functional material having sustained release of the aroma component can be provided.
［実施例６〜８、比較例２，３］
以下の実施例においては、難水溶性物質として次のものを用いた。
[Examples 6-8, Comparative Examples 2 and 3]
In the following examples, the following were used as poorly water-soluble substances.
［難水溶性物質］
ニフェジピン（狭心症治療薬）：水（２５℃）に対する飽和溶解度８μｇ／ｍＬ
グリクラジド（糖尿病治療薬）：水（２５℃）に対する飽和溶解度６μｇ／ｍＬ
インドメタシン（抗炎症剤）：水（２５℃）に対する飽和溶解度４０μｇ／ｍＬ
レスベラロトール（抗酸化剤）：水（２５℃）に対する飽和溶解度１９μｇ／ｍＬ
[Water-insoluble substances]
Nifedipine (angina drug): saturated solubility in water (25 ° C) 8 μg / mL
Glyclazide (diabetic agent): saturated solubility in water (25 ° C) 6 μg / mL
Indomethacin (anti-inflammatory agent): saturated solubility in water (25 ° C) 40 μg / mL
Resveratrol (antioxidant): saturated solubility in water (25 ° C) 19 μg / mL
＜試料の調製＞
以下に示す親水性物質の１００ｍｇ／ｍＬの水溶液を調製し、これを凍結乾燥させた後、Ｐ２Ｏ５共存下の真空デシケータ内で３日間絶乾することにより各々アモルファス粉末を得た。
実施例６：α−マルトース
実施例７：マルチトール
実施例８：トレハロース
<Preparation of sample>
Preparing an aqueous solution of 100 mg / mL of the hydrophilic material described below, after freeze-dried, to give the respective amorphous powder by bone dry for 3 days in a vacuum desiccator P 2 O 5 coexistence.
Example 6: α-maltose Example 7: maltitol Example 8: trehalose
一方、ニフェジピンをメタノール（２５℃）に溶解させたニフェジピン溶液を調製し、ここへ、上記の糖のアモルファス粉末をニフェジピンの４倍量添加して十分に撹拌し、ニフェジピン濃度２５ｍｇ／ｍＬ、糖濃度１００ｍｇ／ｍＬの混合液を得た。
この混合液を真空乾燥（室温，１時間）することで、固体分散体試料を得た（実施例６〜８）。
On the other hand, nifedipine solution in which nifedipine is dissolved in methanol (25 ° C) is prepared, to which an amorphous powder of the above sugar is added 4 times amount of nifedipine and stirred sufficiently, nifedipine concentration 25 mg / mL, sugar concentration A mixture of 100 mg / mL was obtained.
The mixture was dried under vacuum (room temperature, 1 hour) to obtain a solid dispersion sample (Examples 6 to 8).
比較のため、ニフェジピンを両親媒性高分子（ポリビニルピロリドン：ＰＶＰ）共存下でＯ／Ｗエマルション化し、これを凍結乾燥した試料も調製した（比較例２）。
また、ニフェジピン単体（ニフェジピン結晶）を真空乾燥したものを比較例３の試料とした。
For comparison, nifedipine was subjected to O / W emulsification in the presence of an amphiphilic polymer (polyvinylpyrrolidone: PVP), and a freeze-dried sample was also prepared (Comparative Example 2).
A sample of Comparative Example 3 was obtained by vacuum drying nifedipine alone (nifedipine crystal).
＜熱分析＞
実施例６〜８で得られた試料約３ｍｇをアルミニウムパンに密閉し、示差走査熱量計（ＴＡ instruments Ｑ２０）を用いて−２０〜２００℃の温度範囲を昇温速度１０℃／ｍｉｎで走査して熱分析を行ったところ、いずれの固体分散体試料においても、結晶の融解に伴う吸熱ピークは検出されなかった。
また、固体分散体試料のガラス転移温度は、いずれも糖単体のガラス転移温度の値よりやや低下しているものの、ガラス転移に伴う比熱変化は明確に認められた。
これらのことから、調製した固体分散体ではニフェジピン、糖とも非晶質状態にあることが分かった。
Thermal analysis
About 3 mg of the sample obtained in Examples 6 to 8 is sealed in an aluminum pan, and a temperature range of −20 to 200 ° C. is scanned at a heating rate of 10 ° C./min using a differential scanning calorimeter (TA instruments Q20). As a result of thermal analysis, no endothermic peak associated with melting of crystals was detected in any of the solid dispersion samples.
Moreover, although the glass transition temperature of the solid dispersion sample was slightly lower than the value of the glass transition temperature of the single saccharide, the specific heat change associated with the glass transition was clearly observed.
From these facts, it was found that in the prepared solid dispersion, both nifedipine and sugar are in an amorphous state.
＜溶解実験＞
実施例６〜８及び比較例２，３で得られた試料を３７℃のイオン交換水に添加し、スターラーで十分撹拌しながら、適当な時間間隔でサンプルを採取した。採取したサンプルをフィルター濾過後、ＵＶ−ｖｉｓ分光光度計により、溶出したニフェジピンによる吸光度変化を測定し、この測定値から、ニフェジピンの溶解濃度の経時変化を求めた。
結果を図３に示す。
図３より明らかなように、ニフェジピンは、いずれの糖を用いた場合も、数分〜数時間、飽和溶解度の５〜８倍の溶解濃度を示した。
<Dissolution experiment>
The samples obtained in Examples 6 to 8 and Comparative Examples 2 and 3 were added to ion-exchanged water at 37 ° C., and samples were taken at appropriate time intervals while sufficiently stirring with a stirrer. The collected sample was subjected to filter filtration, and the change in absorbance due to the eluted nifedipine was measured with a UV-vis spectrophotometer, and from this measurement value, the change with time of the dissolution concentration of nifedipine was determined.
The results are shown in FIG.
As is clear from FIG. 3, nifedipine showed a dissolution concentration of 5 to 8 times the saturation solubility for several minutes to several hours, regardless of which sugar was used.
なお、ニフェジピンの代りに、グリクラジド、インドメタシン、レスベラロトールをそれぞれ用いて実施例６〜８と同様に固体分散体試料を調製し、同様に熱分析を行ったところ、同様の結果が得られた。
また、これらの試料について、同様に溶解実験を行ったところ、レスベラロトールについては固体分散化による溶解濃度の上昇は認められなかったものの、インドメタシンについては、ニフェジピンと同様の溶解濃度の上昇が認められた。また、グリクラジドでは、１０分程度、飽和溶解度の３倍の溶解濃度を示した。
A solid dispersion sample was prepared in the same manner as in Examples 6 to 8 using gliclazide, indomethacin and resveratrol in place of nifedipine, and the same thermal analysis was carried out, and similar results were obtained.
In addition, when the dissolution experiment was similarly performed on these samples, although the increase in dissolution concentration by solid dispersion was not observed for resveratrol, the increase in dissolution concentration similar to that of nifedipine was observed for indomethacin. . In addition, gliclazide showed a dissolution concentration of 3 times the saturation solubility for about 10 minutes.
［実施例９〜１２、比較例４，５］
実施例１と同様にして、α−マルトースのアモルファス粉末を得た。
[Examples 9 to 12, Comparative Examples 4 and 5]
In the same manner as in Example 1, an amorphous powder of α-maltose was obtained.
一方、以下に示す香気成分である難水溶性物質をメタノール（２５℃）に溶解させた溶液を調製し、ここへ、上記のα−マルトースのアモルファス粉末を難水溶性物質の１０倍量添加して十分に撹拌し、難水溶性物質濃度１０ｍｇ／ｍＬ、α−マルトース濃度１００ｍｇ／ｍＬの混合液を得た。
この混合液をそれぞれ真空乾燥（室温，１時間）することで、固体分散体試料を得た（実施例９〜１２）。
On the other hand, a solution was prepared by dissolving a poorly water-soluble substance, which is an aroma component shown below, in methanol (25 ° C.), and to this, 10 times amount of the above amorphous powder of α-maltose was added as compared to the poorly water-soluble substance. The mixture was sufficiently stirred to obtain a mixed solution of a poorly water-soluble substance concentration of 10 mg / mL and an α-maltose concentration of 100 mg / mL.
The liquid mixture was dried under vacuum (room temperature, 1 hour) to obtain a solid dispersion sample (Examples 9 to 12).
＜難水溶性物質＞
実施例９：ラズベリーケトン
実施例１０：バニリン酸メチルエステル
実施例１１：オイゲノール
実施例１２：アニソール
<Water-insoluble substances>
Example 9 Raspberry Ketone Example 10 Vanillic Acid Methyl Ester Example 11 Eugenol Example 12 Anisole
比較のため、オイゲノール（比較例４）、アニソール（比較例５）を、それぞれ界面活性剤（Ｔｗｅｅｎ２０）共存下でＯ／Ｗエマルション化し、これを凍結乾燥した試料も調製した。なお、室温で固体であるラズベリーケトンとバニリン酸メチルエステルは、Ｏ／Ｗエマルションを経由した凍結乾燥粉末を作成することは不可能であった。 For comparison, eugenol (comparative example 4) and anisole (comparative example 5) were respectively O / W emulsified in the presence of surfactant (Tween 20), and a freeze-dried sample was also prepared. Raspberry ketone and vanillic acid methyl ester, which are solid at room temperature, were unable to produce a lyophilized powder via the O / W emulsion.
実施例９〜１２及び比較例４、５で得られた試料を、メタノール中に分散、溶解させてメタノール中の難水溶性物質濃度をＵＶ−ｖｉｓ分光光度計（２８５ｎｍ）により測定し、この測定値から、凍結乾燥後の各固体分散体試料中の難水溶性物質の保持率を算出した。結果を表１に示す。 The samples obtained in Examples 9 to 12 and Comparative Examples 4 and 5 are dispersed and dissolved in methanol, and the concentration of the poorly water-soluble substance in methanol is measured by a UV-vis spectrophotometer (285 nm), and this measurement is made. From the values, the retention rate of the poorly water-soluble substance in each solid dispersion sample after lyophilization was calculated. The results are shown in Table 1.
表１に示したように、実施例９〜１２の固体分散体試料では、難水溶性物質の凍結乾燥後の保持率が高く、オイゲノールおよびアニソールについては、界面活性剤によりＯ／Ｗエマルション化して凍結乾燥した比較例４、５の試料より高い保持率を示した。
この結果から、本発明によれば、香気成分である複数の難水溶性物質を固体分散体とすることができると共に、乾燥時の散逸を防ぎ、香気成分の保持率の高い粉末化香料を提供できることが分かった。
As shown in Table 1, in the solid dispersion samples of Examples 9 to 12, the retention rate of the poorly water-soluble substance after lyophilization is high, and for eugenol and anisole, O / W emulsification is carried out with a surfactant. It showed higher retention than the lyophilized samples of Comparative Examples 4 and 5.
From this result, according to the present invention, a plurality of slightly water-soluble substances which are aroma components can be made into solid dispersion, and dissipation during drying can be prevented, and a powdered fragrance having a high retention ratio of aroma components can be provided. It turned out that it can be done.
［実施例１３、比較例６，７］
トレハロースの１００ｍｇ／ｍＬの水溶液を調製し、これを凍結乾燥させた後、Ｐ２Ｏ５共存下の真空デシケータ内で３日間絶乾することにより、トレハロースのアモルファス粉末を得た。
[Example 13, Comparative Examples 6, 7]
An aqueous solution of 100 mg / mL trehalose prepared, after freeze-dried, by bone dry for 3 days in a vacuum desiccator P 2 O 5 presence to give an amorphous powder of trehalose.
一方、クルクミノイドの１種であるクルクミン（和光特級クルクミン、和光純薬工業社製）をメタノール（２５℃）に溶解させた溶液を調製し、ここへ、上記のトレハロースのアモルファス粉末をクルクミノイドの１００倍量添加して十分に撹拌し、クルクミノイド濃度０．９ｍｇ／ｍＬ、トレハロース濃度９０ｍｇ／ｍＬの混合液を得た。
この混合液を真空乾燥（室温，１時間）することで、クルクミノイド含有量が１重量％である固体分散体試料を得た（実施例１３）。
On the other hand, a solution of curcumin (Wako special grade curcumin, manufactured by Wako Pure Chemical Industries, Ltd.), which is a kind of curcuminoid, dissolved in methanol (25 ° C.) is prepared. The amount was added and the mixture was stirred sufficiently to obtain a mixed solution of a curcuminoid concentration of 0.9 mg / mL and a trehalose concentration of 90 mg / mL.
The liquid mixture was vacuum dried (room temperature, 1 hour) to obtain a solid dispersion sample having a curcuminoid content of 1% by weight (Example 13).
比較のため、市販の食品用界面活性剤を含有するクルクミン水分散液（横浜油脂工業社製「クルクミン水分散液２０％」、クルクミノイド含有量：２０重量％）（比較例６）と、クルクミン原体（ＣＯＡＣＨ ＩＮＤＵＳＴＲＥＩＳ社製「クルクミン９５％」、クルクミノイド含有量：９５重量％）（比較例７）を用いた。
For comparison, a curcumin aqueous dispersion containing a commercially available surfactant for food (“curcumin
実施例１３、比較例６、７の試料を、脱塩水に対し、クルクミノイドとして０．００１重量％となるようにそれぞれ計量して添加し、総量を４０ｇとした。これを、遮光下、５分間マグネチックスターラーで撹拌した後、１００ｍｅｓｈのステンレスフィルターで濾過し、水への溶解性を以下の基準で評価した。
○：フィルター上に溶け残りなし
×：フィルター上に溶け残りあり
The samples of Example 13 and Comparative Examples 6 and 7 were respectively weighed and added so as to be 0.001% by weight as curcuminoid with respect to demineralized water, and the total amount was 40 g. This was stirred with a magnetic stirrer for 5 minutes under light shielding, then filtered with a 100 mesh stainless steel filter, and the solubility in water was evaluated based on the following criteria.
○: no residue on the filter ×: no residue on the filter
次に、実施例１３と比較例６における上記濾過後の液をマグネチックスターラーで撹拌しながら、中鎖脂肪酸トリグリセリド（日清オイリオ社製「スコレー６４Ｇ」、以下「ＭＣＴ」）を４０ｇ添加し、遮光下で１５分間マグネチックスターラーで撹拌後、遮光下で１５分間静置した。静置後、分離した上層（ＭＣＴ相）と下層（水相）を、それぞれ分取し、紫外可視分光光度計（島津製作所社製、ＵＶ−１８００）を用い、波長３５０〜７８０ｎｍでの吸収スペクトルを、それぞれの溶媒（ＭＣＴ、または脱塩水）をブランクとして測定した。各相のスペクトルのピーク波長における吸光度から、以下の式を用い、ＭＣＴ相へのクルクミノイドの分配率を求めた。
分配率（％）＝｛ＭＣＴ相のピーク波長における吸光度÷（水相のピーク波長における吸光度＋ＭＣＴ相のピーク波長における吸光度）｝×１００
Next, while stirring the solution after the above filtration in Example 13 and Comparative Example 6 with a magnetic stirrer, 40 g of medium-chain fatty acid triglyceride (“Scoley 64G”, hereinafter “MCT” manufactured by Nisshin Oillio, Inc.) is added. After stirring with a magnetic stirrer for 15 minutes under light shielding, it was allowed to stand for 15 minutes under light shielding. After standing, separate the upper layer (MCT phase) and the lower layer (water phase) which were separated, and use an ultraviolet-visible spectrophotometer (UV-1800 manufactured by Shimadzu Corp.) to obtain an absorption spectrum at a wavelength of 350 to 780 nm. Was measured with each solvent (MCT or demineralized water) as a blank. From the absorbance at the peak wavelength of the spectrum of each phase, the distribution ratio of curcuminoid to the MCT phase was determined using the following equation.
Distribution ratio (%) = {Absorbance at peak wavelength of MCT phase 相 (Absorbance at peak wavelength of aqueous phase + absorbance at peak wavelength of MCT phase)} × 100
溶解性およびＭＣＴ相への分配率の評価結果を、表２に示す。 The evaluation results of solubility and distribution rate to MCT phase are shown in Table 2.
表２に示したように、実施例１３の固体分散体試料は、市販の界面活性剤を含有する水分散液と同等の水への溶解性を示しており、また、試料中の難水溶性物質は、疎水性溶媒との接触により、疎水性溶媒にほぼ完全に分配することがわかった。
この結果から、本発明によれば、一旦難水溶性物質を水に容易に溶解させた後、その水溶液を目的とする疎水性溶媒と接触、混合することで、界面活性剤などに阻害されることなく、難水溶性物質を効率よく、疎水性溶媒に選択的に分配することができることが分かった。
このことは、難水溶性物質を用いる上で、機能性成分としては体内へ吸収の面で、食品用、香粧品用、嗜好品用油溶性成分としては、添加時の分散、溶解性、並びに、添加後の対象物の疎水性領域に対する着色・酸化防止等の機能の発揮といったハンドリング性の面で、界面活性剤や両親媒性高分子を用いた公知の技術より、より効率的であることを示している。
As shown in Table 2, the solid dispersion sample of Example 13 shows the same solubility in water as the aqueous dispersion containing a commercially available surfactant, and the poor water solubility in the sample. The substance was found to partition almost completely to the hydrophobic solvent upon contact with the hydrophobic solvent.
From this result, according to the present invention, once the poorly water-soluble substance is easily dissolved in water, the aqueous solution is inhibited by the surfactant etc. by being brought into contact with and mixing with the target hydrophobic solvent. It has been found that poorly water-soluble substances can be efficiently distributed selectively to hydrophobic solvents.
This means that when using a poorly water-soluble substance, in terms of absorption into the body as a functional ingredient, dispersion, solubility, and addition at the time of addition as an oil-soluble ingredient for food, cosmetic, and luxury goods. More efficient than known techniques using surfactants or amphiphilic polymers in terms of handling properties such as coloring, oxidation prevention, etc. to the hydrophobic area of the object after addition. Is shown.
本発明の難水溶性物質含有固体分散体の製造方法は、安全性の高い固体マトリクスを用いるものであり、難水溶性薬剤を内包した粉末剤や錠剤といった医薬品、香気成分を固体内に内包した固体食品や消臭剤、香粧品、嗜好品、疎水性栄養成分を内包した栄養補助食品といった分野における難水溶性物質含有固体分散体の製造に好適であるが、本発明により製造される難水溶性物質含有固体分散体の用途は何らこれらに限定されるものではない。 The method for producing a poorly water-soluble substance-containing solid dispersion according to the present invention uses a highly safe solid matrix, and it comprises a drug such as a powder or tablet containing a poorly water-soluble drug, and an aroma component in solid. It is suitable for the production of solid dispersions containing poorly water-soluble substances in the fields of solid foods, deodorants, cosmetics, luxury foods, and nutraceuticals containing hydrophobic nutritional components, but it is difficult to be water-soluble according to the present invention The application of the solid substance-containing solid dispersion is not limited to these.
Claims (6)
該親水性物質は、糖、糖アルコール及びアミノ酸からなる群から選ばれる物質であり、
該親水性物質を含有する親水性物質含有液を乾燥させて、非晶質の親水性物質を得る工程、
有機溶媒に該難水溶性物質を分散させた分散液を得る工程、
該非晶質の親水性物質と、該分散液とを混合して難水溶性物質含有分散液を得る工程、
該難水溶性物質含有分散液を乾燥させて難水溶性物質含有固体分散体を得る工程
を有し、
該難水溶性物質が、水（２５℃）に対する飽和溶解度が１００００μｇ／ｍＬ以下の物質である、難水溶性物質含有固体分散体の製造方法。 A method for producing a poorly water-soluble substance-containing solid dispersion containing a hydrophilic substance and a poorly water-soluble substance,
The hydrophilic substance is a substance selected from the group consisting of sugar, sugar alcohol and amino acid,
Drying the hydrophilic substance-containing liquid containing the hydrophilic substance to obtain an amorphous hydrophilic substance;
Obtaining a dispersion in which the poorly water-soluble substance is dispersed in an organic solvent,
Mixing the amorphous hydrophilic substance with the dispersion to obtain a poorly water-soluble substance-containing dispersion,
The flame-soluble substance-containing dispersion was dried to have a step of obtaining a poorly water-soluble substance-containing solid dispersion,
Flame-soluble substance, the saturation solubility Ru following substances der 10000 / mL in water (25 ° C.), the manufacturing method of the poorly water-soluble substance-containing solid dispersion.
該親水性物質は、糖、糖アルコール及びアミノ酸からなる群から選ばれる物質であり、
該難水溶性物質が、水（２５℃）に対する飽和溶解度が１００００μｇ／ｍＬ以下の物質であり、
難水溶性物質含有固体分散体は非晶質固体であり、該非晶質固体マトリクス内で該難溶性物質が分子状態で分散している、難水溶性物質含有固体分散体。 A poorly water-soluble substance-containing solid dispersion comprising a hydrophilic substance and a poorly water-soluble substance, wherein
The hydrophilic substance is a substance selected from the group consisting of sugar, sugar alcohol and amino acid,
The poorly water-soluble substance is a substance having a saturated solubility in water (25 ° C.) of 10000 μg / mL or less,
A poorly water-soluble substance-containing solid dispersion, wherein the poorly water-soluble substance-containing solid dispersion is an amorphous solid, and the poorly water- soluble substance is dispersed in a molecular state in the amorphous solid matrix .
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