JP6018845B2 - Method for producing capsule containing ultrafine powder - Google Patents
Method for producing capsule containing ultrafine powder Download PDFInfo
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Description
本発明は、超微粉末を基材液に懸濁・分散した状態で封入したカプセル剤に関するものである。 The present invention relates to a capsule in which ultrafine powder is encapsulated in a state of being suspended and dispersed in a base liquid.
生体内への健康機能関与成分の吸収率、利用率を上げ、できるだけ少量で有用な医薬品、化粧品、健康食品などを提供することは有益であり、多くの研究が行われている。その一つに粉末成分の超微粉砕、ナノ化がある。粉砕レベルが上がると、これに比例して同じ重量の粉末成分でもその表面積が上がり、胃液、腸液などの体液への溶解速度や溶解量が上がり、また表皮からの経皮吸収も向上する。
粉末を超微粉砕する方法に関しても多くの研究開発が行われているが、医薬品、化粧品、健康食品などの分野において、超微粉砕した粉末含有製品はほとんど市販されていない。この大きな理由の一つは、二次凝集、粉砕及び製剤コストの問題があるためである。医薬品の一般的な製剤としては、顆粒・錠剤があるが、これらの製剤では、一度超微粉砕した粉末を造粒・成形のため、練合や加圧を行っており、むしろ二次凝集を促進する製剤・製品であり、超微粉砕した価値を阻害するものである。粉末をそのまま製剤・製品としたものとしては、散剤・ハードカプセルがある。しかし、超微粉砕した粉末は、表面積が大きくなり、かさ密度が小さくなり、同じ重量でも体積が大きくなることから、製剤・製品も大型化となり飲みにくくなる。また、表面積が増えた分、空気中の酸素、湿度との反応も促進され、安定性の問題も懸念される。ソフトカプセル、液体充填ハードカプセル、シームレスカプセルに粉末を分散させた製剤もあるが、粉末を湿式で超微粉砕した後、スプレードライ、凍結乾燥などにより再固化（液体を固体とする）する過程で、二次凝集が起こり、超微粉砕した粉末をそのまま含むソフトカプセル、液体充填ハードカプセルはない。
It is beneficial to increase the absorption rate and utilization rate of health function-related components in the living body and provide useful pharmaceuticals, cosmetics, health foods, etc. in as little amount as possible, and many studies have been conducted. One of them is ultra-fine pulverization and nano-ization of powder components. When the pulverization level is increased, the surface area of the powder component having the same weight is increased in proportion to this, and the dissolution rate and the amount of dissolution in body fluids such as gastric juice and intestinal fluid are increased, and percutaneous absorption from the epidermis is also improved.
Many researches and developments have also been made on methods for finely pulverizing powders, but in the fields of pharmaceuticals, cosmetics, health foods, and the like, very few finely powdered products are commercially available. One of the major reasons for this is the problem of secondary aggregation, grinding and formulation costs. Common preparations of pharmaceuticals include granules and tablets. In these preparations, powders that have been once finely pulverized are kneaded and pressed for granulation and molding, but rather, secondary agglomeration is performed. It is a formulation / product that promotes, and inhibits the value of ultra-fine grinding. Powders and hard capsules are available as powders and preparations as they are. However, the finely pulverized powder has a large surface area, a small bulk density, and a large volume even with the same weight. Therefore, the preparation / product becomes large and difficult to drink. Further, the reaction with oxygen and humidity in the air is promoted as the surface area increases, and there is a concern about stability problems. There are preparations in which the powder is dispersed in soft capsules, liquid-filled hard capsules, and seamless capsules, but in the process of re-solidifying the liquid by spray drying, freeze drying, etc. There are no soft capsules and liquid-filled hard capsules that contain the finely pulverized powder as it is, and the next aggregation occurs.
それ故、本発明は、上記した課題を解決する、新規且つ有効な超微粉末含有カプセル剤（ソフトカプセル、液体充填ハードカプセル、シームレスカプセル等）を提供することを、その目的とする。 Therefore, an object of the present invention is to provide a novel and effective ultrafine powder-containing capsule (soft capsule, liquid-filled hard capsule, seamless capsule, etc.) that solves the above-described problems.
本発明者は、鋭意検討の結果、前記カプセル剤の基材液を、湿式粉砕による超微粉砕の粉砕媒液として使用して、目的とする成分の粉末を湿式粉砕に供することで、湿式粉砕特有のナノ単位までの超微粉砕を達成でき、しかも、分散剤や安定化剤に安易に頼らずとも、二次凝集のない懸濁及び分散を容易に維持できること、さらに粒度範囲を適切に設定することで粘度も低める方向で調整できることを見出した。また、複数の成分の粉末を一つの工程で超微粉末化、並びに基材油へ懸濁及び分散を達成でき、そのままカプセル剤の内容液として製剤化することにより、不安定かつ面倒な製造工程を省略できることを見出した。
さらに、この直接超微粉砕法に、粉末を０．１ｍｍ以下に揃える整粒工程を加えると、体内吸収が有意的に良くなることを見出した。
従って、本発明者は、上記した知見に基づいて、以下の具体的なカプセル剤を提案するに至った。
As a result of intensive studies, the present inventor has used the capsule base material liquid as a finely pulverized grinding medium liquid by wet pulverization, and subjected to wet pulverization by subjecting the powder of the target component to wet pulverization. Achieving ultra-fine pulverization up to the unique nano-unit, and easily maintaining suspension and dispersion without secondary aggregation without relying on dispersants and stabilizers, and setting the particle size range appropriately By doing so, it was found that the viscosity could be adjusted in the direction of decreasing. In addition, it is possible to achieve ultra-fine powders of multiple components in one step, and to suspend and disperse in base oil, and to formulate the contents as capsules as they are, making the production process unstable and troublesome. It was found that can be omitted.
Furthermore, it has been found that the absorption in the body is significantly improved by adding a sizing step for adjusting the powder to 0.1 mm or less to this direct ultrafine pulverization method.
Accordingly, the present inventor has proposed the following specific capsule based on the above-described findings.
請求項１の発明は、超微粉末含有カプセル剤の製造方法において、基材液としての中鎖脂肪酸トリグリセライドに、目的とする抽出エキスを濃縮・粉末化した粉末成分を含有させ、高圧方式での湿式粉砕に供して超微粉末化した、粘度が５０，０００ｃｐｓ以下のものをカプセル内容液として、この液をそのままあるいはその他の成分、安定化剤などを加えた後、カプセル封入して、１カプセル当たり、カプセル内容液中粉末成分の配合率を６０質量％超のソフトカプセル剤とし、前記湿式粉砕を、二段階に分けて供し、前記粉末成分の一部の量を含有させて一段階目の湿式粉砕に供した後に残りの量を含有させて二段階目の湿式粉砕に供することを特徴とする製造方法である。
請求項２の発明は、請求項１に記載した超微粉末含有カプセル剤の製造方法において、ジェット粉砕式で湿式粉砕を行うことを特徴とする製造方法である。
According to the first aspect of the present invention, in the method for producing a capsule containing ultrafine powder, a medium chain fatty acid triglyceride as a base liquid contains a powder component obtained by concentrating and pulverizing a target extract , Capsule content liquid with a viscosity of 50,000 cps or less that has been subjected to wet pulverization and made into an ultrafine powder, this liquid is added as it is or after adding other components, stabilizers, etc. At first, a soft capsule agent having a blending ratio of the powder component in the capsule content liquid of more than 60% by mass , the wet pulverization is divided into two stages, and a part amount of the powder component is contained to obtain the first stage. It is a manufacturing method characterized by including the remaining amount after being subjected to wet pulverization and subjecting to wet pulverization in the second stage .
A second aspect of the present invention is a method for producing a capsule containing ultrafine powder according to the first aspect, wherein wet pulverization is performed by a jet pulverization method.
請求項３の発明は、請求項１または２に記載した超微粉末含有カプセル剤の製造方法において、１カプセル当たり、カプセル内容液中粉末成分の８０質量％以上が０．１５ｍｍ以下で、５０質量％以上が０．０１ｍｍ以下であることを特徴とする製造方法である。 Invention of Claim 3 is the manufacturing method of the capsule containing ultra fine powder according to Claim 1 or 2 , wherein 80% by mass or more of the powder component in the capsule content liquid is 0.15 mm or less per capsule , and 50% by mass. or% are prepared wherein the at 0.01mm or less.
請求項４の発明は、請求項１から３のいずれかに記載した超微粉末含有カプセル剤の製造方法において、１カプセル当たり、カプセル内容液中粉末成分が０．１０ｍｍ以下となるよう整粒し、体内吸収が高められたことを特徴とする製造方法である。 According to a fourth aspect of the present invention, in the method for producing an ultrafine powder-containing capsule according to any one of the first to third aspects, the size of the capsule is adjusted so that the powder component in the capsule content liquid is 0.10 mm or less per capsule. This is a production method characterized by enhanced absorption in the body.
本発明によれば、従来のカプセル剤より、封入する粉末成分が微粒化されているので、体内吸収を改良することができ、しかも、分散剤や安定化剤の安易な併用を抑えられる。さらに粒度範囲を適切に設定することで粘度も低める方向に調整できるので、ソフトカプセル剤やシームレスカプセル剤にする場合には、カプセル内容液中に占める粉末の量を従来より多くできるので、１カプセルに封入する粉末を従来より多くしたり、カプセルの大きさを従来より小さくしたりできる。また、分散溶媒として基材液をそのまま使用して湿式粉砕することで、製造工程を簡易化、安定化できる。
さらに、超微粉砕及び低粘度化により、ソフトカプセル皮膜のヒートシール面からのカプセル内容液の漏出（ピンホール）を防ぐことができる。
加えて、粉末成分の大きさを揃えることで体内吸収をさらに改善できる。
According to the present invention, since the powder component to be encapsulated is finer than conventional capsules, absorption in the body can be improved, and easy use of a dispersant or a stabilizer can be suppressed. Furthermore, since the viscosity can be adjusted in the direction of lowering the viscosity by setting the particle size range appropriately, the amount of powder in the capsule content liquid can be increased compared to the conventional one when making soft capsules or seamless capsules. The encapsulated powder can be increased more than before, or the capsule can be made smaller than before. Moreover, a manufacturing process can be simplified and stabilized by wet-grinding using a base-material liquid as a dispersion solvent as it is.
Furthermore, leakage of the capsule content liquid (pinhole) from the heat seal surface of the soft capsule film can be prevented by ultrafine pulverization and low viscosity.
In addition, absorption in the body can be further improved by aligning the size of the powder component.
本発明は、カプセルに製剤化することが想定されており、そのカプセルにはソフトカプセル、シームレスカプセル、液体充填ハードカプセル等が含まれる。 The present invention is envisaged to be formulated into capsules, which include soft capsules, seamless capsules, liquid filled hard capsules and the like.
（カプセル内容液）
粉末成分を基材液に懸濁・分散させたものである。
粉末は、カプセル剤用に基材液に懸濁・分散できるものであれば、特に限定されず、従来から使用されているものだけでなく、従来品と同様な特性を有するものであれば、いずれのものでもよい。
例えば、最近では、効用の点から機能性成分としてコエンザイムQ10、ウコン、ブルーベリー、にんにく等があるが、これらの抽出エキスを濃縮・粉末化したものを使用してもよい。
粉末の結晶性は特に限定されず、微細な単結晶体でも、微細な多結晶体でも、微細な非晶質体でもよい。また、粉末はペースト状でもよい。
(Capsule content liquid)
A powder component is suspended and dispersed in a base liquid.
The powder is not particularly limited as long as it can be suspended / dispersed in a base liquid for capsules, not only those conventionally used, but also those having the same characteristics as conventional products, Any one is acceptable.
For example, recently, there are coenzyme Q10, turmeric, blueberry, garlic, and the like as functional components from the viewpoint of utility, but a concentrated and powdered extract of these extracts may be used.
The crystallinity of the powder is not particularly limited, and may be a fine single crystal, a fine polycrystal, or a fine amorphous. The powder may be in the form of a paste.
基材液も、カプセル剤用に粉末を懸濁・分散できるものであれば、特に限定されず、従来から使用されているものだけでなく、従来品と同様な特性を有するものであれば、いずれのものでもよい。
例えば、カプセル剤が食用の場合は食用に適したものとなるが、植物性、動物性いずれの食用油脂でも良く、現在主要な基材油であるＭＣＴ（中鎖脂肪酸トリグリセライド）も当然ながら使用できる。これに１０〜３０％の水やエタノールを加えた液や、親水性のポリエチレングリコール４００〜１０００なども対象となる。
The base liquid is not particularly limited as long as it can suspend and disperse the powder for capsules, not only those conventionally used, but also those having the same characteristics as conventional products, Any one is acceptable.
For example, if the capsule is edible, it will be suitable for edible use, but it may be any vegetable or animal edible fat, and MCT (medium chain fatty acid triglyceride), which is currently the main base oil, can of course be used. . A solution obtained by adding 10 to 30% water or ethanol to this, hydrophilic polyethylene glycol 400 to 1000, and the like are also targeted.
粉末の基材液への分散を助けるために、分散剤を配合してもよい。分散剤の例としては、レシチン、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル等の乳化剤や、グァーガム等の増粘多糖類が挙げられる。
また、粉末の基材液中での安定した懸濁状態を確保するために、安定化剤を配合してもよい。安定化剤の例としては、ミツロウ、グリセリン脂肪酸エステル、硬化油等が挙げられる。
In order to assist the dispersion of the powder into the base material liquid, a dispersant may be blended. Examples of the dispersant include emulsifiers such as lecithin, glycerin fatty acid ester and polyglycerin fatty acid ester, and thickening polysaccharides such as guar gum.
Moreover, in order to ensure the stable suspension state in the base material liquid of a powder, you may mix | blend a stabilizer. Examples of the stabilizer include beeswax, glycerin fatty acid ester, hydrogenated oil, and the like.
（カプセル内容液の製造方法）
粉末を基材液に含ませ、それを湿式粉砕に供することで、粉末を超微粉末化する。
湿式粉砕の方法としては二枚のディスクを回転させた隙間にスラリーを通す石臼式のコロイドミル、ガラスやジルコニアなどのビーズをスラリーに混合し高速で攪拌するビーズミル、高圧、高速で乳化、粉砕を行うジェット粉砕式ではスラリー同士を衝突させるアルティマイザー式、ダイヤモンド板に衝突させるナノマイザー式等があるが、湿式粉砕が可能であればいずれの粉砕方式を採用しても良い。好ましくは、高圧、高速で乳化、粉砕を行うジェット粉砕式である。
(Method for producing capsule content liquid)
By adding the powder to the base material liquid and subjecting it to wet pulverization, the powder is made into an ultrafine powder.
Wet grinding methods include a millstone colloid mill that passes slurry through a gap between two discs, a bead mill that mixes beads such as glass and zirconia into the slurry, and stirs at high speed, emulsification and grinding at high pressure and high speed. As the jet pulverization method to be performed, there are an optimizer method in which the slurry collides with each other, a nanomizer method in which the slurry collides with the diamond plate, and the like, but any pulverization method may be adopted as long as wet pulverization is possible. A jet pulverization method is preferred in which emulsification and pulverization are performed at high pressure and high speed.
湿式粉砕によれば、粉末全量のうち８０質量％以上が０．１５ｍｍ以下で、さらに粉末全量のうち５０質量％以上が０．０１ｍｍ以下に収まるように調整できる。この範囲に揃えることで、カプセル内容液の全量中粉末を５０質量％以上含ませても、その粘度を５０，０００ｃｐｓ以下に抑えることがより容易となる。しかも、安定化剤や分散剤の使用を従来の８０質量％以下に抑えられる。
この粘度は従来品の粉末を最大限配合させたソフトカプセル剤の内容物の粘度と同程度のものであり、従来と同様に、金型が回転式のロータリー方式の製造装置を利用するロータリー方式カプセルを製造できる。また、本製法はシームレスカプセルや液体充填ハードカプセルに製剤化できることも元よりである。
なお、上記の粒度分布は、レーザー回析・散乱式粒度分布測定機（日機装製マイクロトラックＭＴ３３００ＥＸII）による測定結果により規定したものである。
According to the wet pulverization, it can be adjusted so that 80% by mass or more of the total amount of the powder is 0.15 mm or less and 50% by mass or more of the total amount of the powder is 0.01 mm or less. By adjusting to this range, even if the powder in the total amount of the capsule content liquid is contained in an amount of 50% by mass or more, it becomes easier to suppress the viscosity to 50,000 cps or less. In addition, the use of stabilizers and dispersants can be suppressed to 80% by mass or less.
This viscosity is about the same as the viscosity of the contents of soft capsules containing the maximum amount of conventional powder, and as before, rotary type capsules using a rotary type manufacturing device with a rotating mold. Can be manufactured. In addition, this production method can be formulated into a seamless capsule or a liquid-filled hard capsule.
In addition, said particle size distribution is prescribed | regulated by the measurement result by a laser diffraction / scattering type particle size distribution measuring device (Nikkiso Microtrac MT3300EXII).
以下は、本発明の一例である。
（１）粉末（結晶、ペースト状粒子を含む）を、目的とするソフトカプセル剤の基剤液に分散または懸濁し、この液を湿式粉砕機で一次粉砕する。
（２）一次粉砕した懸濁液に、目的とするソフトカプセル剤の内容液の残りの成分を加え、以降はソフトカプセル剤の内容液調合の常法、例えばホモミキサー、アジホモミキサーなどのタンクを用いて撹拌、二次粉砕、脱泡し、調合液とする。
The following is an example of the present invention.
(1) A powder (including crystals and pasty particles) is dispersed or suspended in a base solution of a target soft capsule, and this liquid is first pulverized by a wet pulverizer.
(2) The remaining components of the intended soft capsule content liquid are added to the primary pulverized suspension, and thereafter, a conventional method for preparing the soft capsule content liquid, for example, a tank such as a homomixer or an adihomomixer is used. Then, stir, secondary pulverize, defoam and use as a preparation liquid.
（カプセル剤の製造方法）
上記のようにして製造した懸濁液は、そのままカプセル剤のカプセル内容液とできる。
すなわち、ロータリー方式のソフトカプセル剤を製造する場合には、二枚の皮膜シートの間にその懸濁液をそのまま充填しながら立体成形することでその懸濁液が封入されたソフトカプセル剤を製造することができる。
(Method for producing capsule)
The suspension produced as described above can be used as the capsule content liquid of the capsule as it is.
That is, when producing a rotary type soft capsule, a soft capsule in which the suspension is enclosed is manufactured by three-dimensional molding while filling the suspension as it is between two coating sheets. Can do.
その際に使用する皮膜シートも、カプセル剤用に内容物を封入できるものであれば、特に限定されず、従来から使用されているものだけでなく、従来品と同様な特定を有するものであれば、いずれのものでもよい。ソフトカプセル剤を製造する場合で、代表的なものは、動物系では、ゼラチンを主成分とし、グリセリン等の可塑剤や水を含むものであるが、植物系でも、プルラン、寒天、カラギーナン、デンプン、デンプン分解物、アルギン酸やＨＭＣ（ヒドロキシメチルセルロース）、ＨＰＭＣ（ヒドロキシプロピルメチルセルロース）、ジェランガム、カードラン等や、これらの酸化・アルカリ化した増粘多糖類も使用できる。 The coating sheet used at that time is not particularly limited as long as it can enclose the contents for the capsule, and is not limited to those conventionally used, but may have the same specifications as conventional products. Any of them may be used. In the case of manufacturing soft capsules, typical ones in animal systems are mainly composed of gelatin and contain plasticizers such as glycerin and water, but also in plant systems, pullulan, agar, carrageenan, starch, starch decomposition Products, alginic acid, HMC (hydroxymethylcellulose), HPMC (hydroxypropylmethylcellulose), gellan gum, curdlan, etc., and these oxidized and alkalized thickening polysaccharides can also be used.
（懸濁液の作製）
（１）ブルーベリーエキス粉末
ブルーベリーのエキスを濃縮・粉末化したブルーベリー粉末を６０質量％、ＭＣＴを４０質量％となる配合割合で合わせて混合して、ブルーベリー粉末を、溶媒を構成する大豆レシチンとＭＣＴ中に分散・懸濁させた。
このときの粘度は２０，０００ｃｐｓであった。
この懸濁液を、高圧処理が可能なジェット粉砕式の装置を用いて湿式粉砕に供して、粘度５，０００ｃｐｓ、平均粒子径（メディアン径）を約５μｍとした。
(Preparation of suspension)
(1) Blueberry extract powder Blueberry powder obtained by concentrating and pulverizing the extract of blueberry is mixed at a blending ratio of 60% by mass and MCT is 40% by mass, and the blueberry powder is mixed with soybean lecithin and MCT constituting the solvent. Dispersed and suspended in.
The viscosity at this time was 20,000 cps.
This suspension was subjected to wet pulverization using a jet pulverization apparatus capable of high-pressure treatment to give a viscosity of 5,000 cps and an average particle diameter (median diameter) of about 5 μm.
次に、上記の懸濁液にブルーベリー粉末を追加して懸濁液中に占める粉末を９０質量％とした上で、再度湿式粉砕に供した。最終的には、粉末全量のうち粉末成分の８０質量％以上が０．１５ｍｍ以下で、５０質量％以上が０．０１ｍｍ以下に収まっていた。このときの懸濁液の粘度は５０，０００ｃｐｓであった。
なお、二段階に分けて湿式粉砕に供したのは、１回目の粉砕前に粉末が６１質量％以上になると粘度が高くなり過ぎ、湿式粉砕が出来なくなった失敗例を考慮したためである。
上記の他に、さらに、安定化剤としてミツロウを３質量％配合し、その分だけブルーベリー粉末の量を減らした懸濁液も作製した。
Next, blueberry powder was added to the above suspension to make 90% by mass of the powder in the suspension, and then subjected to wet grinding again. Eventually, 80% by mass or more of the powder component in the total amount of the powder was 0.15 mm or less, and 50% by mass or more was within 0.01 mm or less. At this time, the viscosity of the suspension was 50,000 cps.
The reason why the powder was subjected to wet pulverization in two stages was because a failure example in which wet pulverization could not be performed when the powder became 61 mass% or more before the first pulverization caused the viscosity to be too high.
In addition to the above, a suspension was also prepared in which 3% by weight of beeswax was added as a stabilizer and the amount of blueberry powder was reduced accordingly.
（ソフトカプセル剤の作製）
上記により作製した２種類の懸濁液と、ゼラチン系皮膜液を用いて、金型が回転式のロータリー方式の製造装置にかけたところ、いずれの懸濁液からも従来品と遜色の無い軟カプセル剤が得られた。
(Production of soft capsule)
Using the two types of suspensions prepared above and the gelatin-based coating solution, the mold was put on a rotary type manufacturing apparatus with a rotary mold. An agent was obtained.
〈アントシアニンを指標とした体内吸収性の比較〉
ブルーベリーエキス粉末（アントシアニン含量３６％）を６０質量％、ＭＣＴを４０質量％となる配合割合で混合して、ブルーベリーエキス粉末をＭＣＴに分散・懸濁させた。この懸濁液を、高圧処理が可能なジェット粉砕式の湿式粉砕装置を用いて、粉末成分の８０質量％以上が０．１５ｍｍ以下で、５０質量％以上が０．０１ｍｍ以下収まるまで粉砕し、且つ粉末成分が０．１ｍｍを超す粒径が無いように整粒し、その体内吸収性を調べた（以降は、超微粉砕品と称する）。比較対照には、湿式粉砕処理をしていないものを用いた（以降は、未粉砕品と称する）。
超微粉砕品と未粉砕品の体内吸収性比較試験の詳細は以下のとおりである。
<Comparison of absorption in the body using anthocyanin as an index>
Blueberry extract powder (anthocyanin content 36%) was mixed at a blending ratio of 60% by mass and MCT at 40% by mass to disperse and suspend the blueberry extract powder in MCT. This suspension is pulverized using a jet pulverization type wet pulverizer capable of high-pressure treatment until 80% by mass or more of the powder component is 0.15 mm or less and 50% by mass or more is 0.01 mm or less. The powder component was sized so as not to have a particle size exceeding 0.1 mm, and the absorbability in the body was examined (hereinafter referred to as ultra-fine pulverized product). As a comparative control, a product that was not wet-pulverized was used (hereinafter referred to as an unground product).
Details of the in-vivo absorbability comparison test between the ultra-fine pulverized product and the unground product are as follows.
事前に試験の説明を行い、同意を得た健常人６名を２群（Ａ群、Ｂ群）に分け、Ａ群には超微粉砕品、Ｂ群には未粉砕品を、ブルーベリーエキス粉末として４８０ｍｇとなるよう毎日朝食後に、試験開始日から７日間連続して摂取させた。摂取開始から７日目は、被験者にサンプルを摂取させた後、０、０．５、１、２、４、８時間経過したところで静脈血５ｍＬを採取し、遠心分離により血漿を分取した。７日間の前期試験後、ウォッシュアウトの期間を１４日間設け、その後Ａ群とＢ群の摂取サンプルを入れ替えて、同様に後期試験を実施した。 The test was explained in advance, and 6 healthy individuals who obtained consent were divided into 2 groups (Group A and Group B). Group A was a finely pulverized product, Group B was an unground product, Blueberry Extract Powder As a 480 mg daily after breakfast for 7 consecutive days from the start of the study. On the seventh day from the start of ingestion, 5 mL of venous blood was collected at 0, 0.5, 1, 2, 4, and 8 hours after the subject was ingested, and plasma was collected by centrifugation. After the 7-day early test, a wash-out period was provided for 14 days, after which the ingested samples in Group A and Group B were replaced, and the latter test was conducted in the same manner.
血漿を除タンパク後、濃縮し移動相にて溶解させたものをサンプルとして、高速液体クロマトグラフィー（ＨＰＬＣ）を用いて血漿中のアントシアニン濃度をシアニジン−３−グルコシドを指標として測定した。測定値より、０〜８時間までの血中濃度-時間曲線下面積（ＡＵＣ０−８ｈ）を算出し、まとめた結果を表１に示す。
表１に示されるように、ブルーベリーエキス粉末を湿式粉砕し、粉末成分の８０質量％以上が０．１５ｍｍ以下で、５０質量％以上が０．０１ｍｍ以下で、且つ粉末成分が０．１ｍｍを超す粒径が無いように整粒したものは、ＡＵＣ０−８ｈが未粉砕品に比べて約１．５倍となっており、体内吸収が向上していることが示された。 As shown in Table 1, wet pulverization of the blueberry extract powder is performed, and 80% by mass or more of the powder component is 0.15 mm or less, 50% by mass or more is 0.01 mm or less, and the powder component exceeds 0.1 mm. In the case where the particle size was adjusted so as not to have a particle size, AUC 0-8h was about 1.5 times that of the unmilled product, indicating that the absorption in the body was improved.
ブルーベリー粉末を６０質量％の代わりに、にんにく粉末４０質量％と卵黄粉末２０質量％を使用した以外は、実施例１と同様にして懸濁液を作製し、ソフトカプセル剤に製剤化したところ、いずれの懸濁液からも従来品と遜色の無いソフトカプセル剤が得られた。また、１カプセル中、にんにく粉末は４０質量％で卵黄粉末は２０質量％であった。 A suspension was prepared in the same manner as in Example 1 except that 40% by weight of blueberry powder and 40% by weight of garlic powder and 20% by weight of egg yolk powder were used instead of 60% by weight. From this suspension, soft capsules comparable to conventional products were obtained. Moreover, in 1 capsule, the garlic powder was 40 mass% and the egg yolk powder was 20 mass%.
ブルーベリー粉末を６０質量％の代わりに、ウコン粉末５０質量％と黒コショウ粉末１０質量％を使用した以外は、実施例１と同様にして懸濁液を作製し、軟カプセル剤に製剤化したところ、いずれの懸濁液からも従来品と遜色の無い軟カプセル剤が得られた。また、１カプセル中、ウコン粉末は５０質量％で黒コショウ粉末は１０質量％であった。 A suspension was prepared in the same manner as in Example 1 except that 50% by mass of turmeric powder and 10% by mass of black pepper powder were used instead of 60% by mass of blueberry powder, and formulated into a soft capsule. From these suspensions, soft capsules comparable to the conventional products were obtained. Moreover, in 1 capsule, the turmeric powder was 50 mass% and the black pepper powder was 10 mass%.
（１）黒酢濃縮エキス粉末
黒酢濃縮エキス粉末６０質量％と、ＭＣＴ４０質量％から上記と同様に湿式粉砕に供したところ、粉砕前の粘度１０，０００ｃｐｓが粉砕後には４，０００ｃｐｓまで低下した。
（２）レスベラトール粉末
レスベラトール粉末６０質量％と、ＭＣＴ４０質量％から上記と同様に湿式粉砕に供したところ、粉砕前の粘度１８，０００ｃｐｓが粉砕後には１０，０００ｃｐｓまで低下した。
（３）イチョウ葉エキス粉末
イチョウ葉エキス粉末５０質量％と、ＭＣＴ５０質量％から上記と同様に湿式粉砕に供したところ、粉砕前の粘度２５，０００ｃｐｓが粉砕後には１５，０００ｃｐｓまで低下した。
（４）脱タンパクローヤルゼリー粉末
脱タンパクローヤルゼリー粉末５０質量％と、ＭＣＴ５０質量％から上記と同様に湿式粉砕に供したところ、粉砕前の粘度２０，０００ｃｐｓが粉砕後には１０，０００ｃｐｓまで低下した。
（５）にんにく粉末、唐辛子粉末
にんにく粉末５０質量％と、唐辛子粉末１０質量％、サフラワー油４０質量％から上記と同様に湿式粉砕に供したところ、粉砕前の粘度２５，０００ｃｐｓが粉砕後には１０，０００ｃｐｓまで低下した。
(1) Black vinegar concentrated extract powder 60% by weight of black vinegar concentrated powder and 40% by weight of MCT were subjected to wet pulverization in the same manner as described above, and the viscosity before crushing decreased to 4,000 cps after pulverization. .
(2) Resveratrol powder When subjected to wet pulverization in the same manner as described above from 60% by mass of resveratrol powder and 40% by mass of MCT, the viscosity before pulverization decreased to 10,000 cps after pulverization.
(3) Ginkgo biloba extract powder When subjected to wet pulverization in the same manner as described above from 50% by mass of Ginkgo biloba extract powder and 50% by mass of MCT, the viscosity before pulverization decreased to 15,000 cps after pulverization.
(4) Deproteinized royal jelly powder When subjected to wet pulverization in the same manner as described above from 50% by mass of deproteinized royal jelly powder and 50% by mass of MCT, the viscosity before pulverization decreased to 10,000 cps after pulverization.
(5) Garlic powder, pepper powder Garlic powder 50% by weight, pepper powder 10% by weight, safflower oil 40% by weight were subjected to wet grinding in the same manner as above, and the viscosity before grinding was 25,000 cps after grinding. Reduced to 10,000 cps.
本発明の湿式粉砕で製した粉末成分の８０質量％以上が０．１５ｍｍ以下で、５０質量％以上が０．０１ｍｍ以下の各種ソフトカプセル内容液の粒度を、これと同一処方で従来法で製したソフトカプセル内容液の粒度と比較して表２に示した。 The particle sizes of various soft capsule content liquids of 80% by mass or more and 0.15 mm or less and 50% by mass or more and 0.01 mm or less of the powder component produced by the wet pulverization of the present invention were produced by the conventional method with the same formulation. Table 2 shows the particle size of the soft capsule content liquid.
表２に示されるように、従来法により製したソフトカプセル内容液に比べ、本発明の方法で製した各種ソフトカプセル内容液の粒度は、平均粒子径にして平均２８．５３μｍ、最大６４．７４μｍ低下していた。 As shown in Table 2, the particle size of the various soft capsule content liquids manufactured by the method of the present invention is 28.53 μm on average and 64.74 μm maximum on the average particle diameter as compared to the soft capsule content liquid manufactured by the conventional method. It was.
ソフトカプセルは定量ポンプで液体を１カプセルずつ定量的に注入しているため、ポンプの負荷、界面張力などのため、内容液の粉末含量を高めることは製剤性の悪化につながるが、本発明の方法で製した粉末成分の８０質量％以上が０．１５ｍｍ以下で、５０質量％以上が０．０１ｍｍ以下のソフトカプセル内容液中の目的とする粉末成分の最大配合率を従来法と比較し、表３に示した。 Since soft capsules quantitatively inject liquid one capsule at a time by a metering pump, increasing the powder content of the content liquid due to pump load, interfacial tension, etc. leads to deterioration of the formulation, but the method of the present invention Table 3 compares the maximum blending ratio of the desired powder component in the soft capsule content liquid in which 80% by mass or more of the powder component manufactured in Step 1 is 0.15 mm or less and 50% by mass or more is 0.01 mm or less. It was shown to.
表３に示されるように、従来法により製したソフトカプセルに比べ、粉末成分の８０質量％以上が０．１５ｍｍ以下で、５０質量％以上が０．０１ｍｍ以下のソフトカプセルは目的とする粉末成分を超微粉末化することにより、粘度やピンホールのリスクが減り、粉末配合率を高めることができた。 As shown in Table 3, the soft capsules in which 80% by mass or more of the powder component is 0.15 mm or less and 50% by mass or more is 0.01 mm or less than the soft capsules manufactured by the conventional method exceed the intended powder component. By making the powder fine, the risk of viscosity and pinholes was reduced, and the powder blending ratio could be increased.
ソフトカプセル内容液の粉末成分の安定した懸濁状態を保つためにミツロウ、グリセリン脂肪酸エステル等の分散剤が必要であるが、粉末成分を本発明の湿式粉砕の方法で製したソフトカプセル内容液中の安定化剤の最小含有量を従来法と比較し、表４に示した。 Dispersants such as beeswax and glycerin fatty acid esters are necessary to maintain a stable suspension of the powder component of the soft capsule content liquid. The minimum content of the agent is shown in Table 4 in comparison with the conventional method.
表４に示されるように、従来法により製したソフトカプセルに比べ、本発明のソフトカプセルは、安定化剤の含有量を減らす事が出来、各内容液の粘度は、８，０００ｃｐｓで遠心分離機、７，０００ｒｐｍにて分離状態を確認したところ、分離は起きなかった。 As shown in Table 4, the soft capsule of the present invention can reduce the content of the stabilizer compared to the soft capsule produced by the conventional method, and the viscosity of each content liquid is 8,000 cps. When the separation state was confirmed at 7,000 rpm, no separation occurred.
本発明の製造方法によれば、製造工程数を減らせるので、生産性が向上する。
また、今まで１カプセル（総内容物３００ｍｇ配合）あたり粉末は６０質量％（１８０ｍｇ）未満の配合であったが、本発明では、粉末の配合量の可能な範囲が広がっており、粉末は９０質量％（２７０ｍｇ）まで配合できた例もあるので、摂取するカプセル数の多さが問題となるような場合には配合量を増やすことでカプセル数を減らすこともできる。また、カプセルのサイズが問題となるような場合にはカプセルをサイズダウンできる。
According to the manufacturing method of the present invention, the number of manufacturing steps can be reduced, so that productivity is improved.
Further, until now, the powder was less than 60 mass% (180 mg) per capsule (total content 300 mg), but in the present invention, the possible range of the amount of powder is widened, and the powder is 90 Since there is an example that can be blended up to mass% (270 mg), the number of capsules can be decreased by increasing the blending amount when the number of capsules to be taken in becomes a problem. In addition, when the size of the capsule becomes a problem, the capsule can be reduced in size.
Claims (4)
基材液としての中鎖脂肪酸トリグリセライドに、目的とする抽出エキスを濃縮・粉末化した粉末成分を含有させ、高圧方式での湿式粉砕に供して超微粉末化した、粘度が５０，０００ｃｐｓ以下のものをカプセル内容液として、この液をそのままあるいはその他の成分、安定化剤などを加えた後、カプセル封入して、１カプセル当たり、カプセル内容液中粉末成分の配合率を６０質量％超のソフトカプセル剤とし、
前記湿式粉砕を、二段階に分けて供し、前記粉末成分の一部の量を含有させて一段階目の湿式粉砕に供した後に残りの量を含有させて二段階目の湿式粉砕に供することを特徴とする製造方法。 In the method for producing a capsule containing ultrafine powder,
A medium-chain fatty acid triglyceride as a base liquid contains a powder component obtained by concentrating and pulverizing the target extract, and is subjected to wet pulverization using a high-pressure method to form an ultrafine powder having a viscosity of 50,000 cps or less. The capsule content liquid is used as it is or after adding other components and stabilizers, and then encapsulated. Soft capsules with a blending ratio of powder components in the capsule content liquid of more than 60% by mass per capsule As an agent ,
The wet pulverization is provided in two stages, and a part of the powder component is included and subjected to the first stage wet pulverization, and then the remaining amount is included for the second stage wet pulverization. The manufacturing method characterized by this.
ジェット粉砕式で湿式粉砕を行うことを特徴とする製造方法。 In the manufacturing method of the capsule containing ultra fine powder according to claim 1,
A production method comprising wet pulverization using a jet pulverization method.
１カプセル当たり、カプセル内容液中粉末成分の８０質量％以上が０．１５ｍｍ以下で、５０質量％以上が０．０１ｍｍ以下であることを特徴とする製造方法。80% by mass or more of the powder component in the capsule content liquid is 0.15 mm or less and 50% by mass or more is 0.01 mm or less per capsule.
１カプセル当たり、カプセル内容液中粉末成分が０．１０ｍｍ以下となるよう整粒し、体内吸収が高められたことを特徴とする製造方法。A manufacturing method characterized by sizing so that a powder component in a capsule content liquid is 0.10 mm or less per capsule, and absorption in the body is enhanced.
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