JP7557705B2 - Composition for suppressing blood glucose rise immediately after meals - Google Patents
Composition for suppressing blood glucose rise immediately after meals Download PDFInfo
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- JP7557705B2 JP7557705B2 JP2020042688A JP2020042688A JP7557705B2 JP 7557705 B2 JP7557705 B2 JP 7557705B2 JP 2020042688 A JP2020042688 A JP 2020042688A JP 2020042688 A JP2020042688 A JP 2020042688A JP 7557705 B2 JP7557705 B2 JP 7557705B2
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Description
特許法第３０条第２項適用 第３３回日本キチン・キトサン学会大会，Ｖｏｌ．２５，Ｎｏ．２，２０１９，第１７７頁（Ｐ－２０）、令和１年８月１日発行 Ｔｈｅ Ｗｏｒｋｓｈｏｐ ｏｎ Ｃｈｉｔｉｎ Ｂｉｏｌｏｇｙ ａｎｄ Ｂｅｙｏｎｄ，第３２頁（Ｐ１５）、令和１年９月５日発行Application of Article 30, Paragraph 2 of the Patent Act 33rd Japan Chitin and Chitosan Society Conference, Vol. 25, No. 2, 2019, page 177 (P-20), published on August 1, 2020 The Workshop on Chitin Biology and Beyond, page 32 (P15), published on September 5, 2021
本発明は、食直後血糖値上昇抑制組成物に関する。 The present invention relates to a composition for suppressing postprandial blood glucose rise.
キトサンは、カニ、エビ等の甲殻類の甲皮などから単離されるキチンをアルカリ処理することにより脱アセチル化を行い、得られる食物繊維物質である。前記キトサンは、経口摂取することによりコレステロール調整機能、脂肪吸収阻害機能、血圧上昇抑制機能などの様々な生理活性機能を有することが知られている。そこで健康食品分野において、これらの機能に関連する生活習慣病を予防する機能性食品素材として前記キトサンは用いられている。 Chitosan is a dietary fiber material obtained by deacetylating chitin, which is isolated from the shells of crustaceans such as crabs and shrimp, through alkaline treatment. It is known that chitosan has various physiologically active functions, such as cholesterol regulation, fat absorption inhibition, and blood pressure elevation suppression, when taken orally. Therefore, in the field of health foods, chitosan is used as a functional food material that prevents lifestyle-related diseases related to these functions.
健康食品としては、手軽に摂取できるキトサンを含有するサプリメント製剤が知られている。前記サプリメント製剤として、錠剤、ハードカプセル剤、ソフトカプセル剤、顆粒剤などの様々な製剤形で用いられる。サプリメントとしてのキトサンの用量と服用し易さを考慮すると、キトサンを高含量化できる製剤形とすることが望まれている。 As health foods, supplement formulations containing chitosan that can be easily ingested are known. The supplement formulations are used in various dosage forms such as tablets, hard capsules, soft capsules, and granules. Considering the dosage of chitosan as a supplement and ease of administration, it is desirable to have a dosage form that can increase the chitosan content.
現在、キトサンを高含量化できる製剤形としては、キトサン、又は、キトサン及び水からなり、嵩密度が０．２５ｇ／ｍＬ以上０．４０ｇ／ｍＬ以下であり、体積平均粒径が、２００μｍ以上４４０μｍ以下であり、かつ体積粒径５０μｍ以下の含有率が３体積％以下である造粒したキトサン粉末を用いたキトサン含有製剤が提案されている（例えば、特許文献１参照）。
しかしながら、造粒したキトサン粉末を用いたキトサン含有製剤の生体内における、食直後血糖値上昇抑制効果については明らかとなっていない。
食直後の血糖値の上昇を抑制する意義としては、食直後の高血糖により引き起こされる、がん、動脈硬化、認知障害などの重大疾病を予防できることが知られている（例えば、非特許文献１参照）。
Currently, a chitosan-containing formulation that can achieve a high chitosan content is a chitosan-containing formulation that uses granulated chitosan powder composed of chitosan or chitosan and water, which has a bulk density of 0.25 g/mL to 0.40 g/mL, a volume average particle size of 200 μm to 440 μm, and a content of volume particles of 50 μm or less of 3 vol% or less (see, for example, Patent Document 1).
However, the in vivo effect of chitosan-containing preparations using granulated chitosan powder in suppressing postprandial blood glucose rise has not been clarified.
The significance of suppressing the rise in blood glucose level immediately after a meal is known to be that it can prevent serious diseases such as cancer, arteriosclerosis, and cognitive impairment caused by hyperglycemia immediately after a meal (see, for example, Non-Patent Document 1).
本発明は、キトサンを高含量で含み、食直後２時間以内の血糖値上昇抑制効果を有する食直後血糖値上昇抑制組成物を提供することを目的とする。 The present invention aims to provide a composition that contains a high content of chitosan and has the effect of suppressing an increase in blood glucose level immediately after a meal within two hours.
前記課題を解決するための手段としては、以下の通りである。即ち、
＜１＞ キトサン、又は、キトサン及び水からなり、嵩密度が０．２５ｇ／ｍＬ以上０．４０ｇ／ｍＬ以下であり、かつ体積粒径５０μｍ以下の含有率が３体積％以下である、キトサン粉末を含むことを特徴とする食直後血糖値上昇抑制組成物である。
＜２＞ 前記キトサン粉末の体積平均粒径が２００μｍ以上４４０μｍ以下である、前記＜１＞に記載の食直後血糖値上昇抑制組成物である。
＜３＞ 前記キトサン粉末が、内径８ｍｍの臼と、杵とを備えた単発式打錠機により２，５００ｋｇ／ｃｍ２の打錠圧で打錠して得られた、２００ｍｇ錠の第十四改正日本薬局方崩壊試験の錠剤の評価方法に従った第１液（ｐＨ１．２水溶液）による崩壊時間が、３０分間以内である、前記＜１＞から＜２＞のいずれかに記載の食直後血糖値上昇抑制組成物である。
＜４＞ 前記キトサン粉末の含有率が３０質量％以上である、前記＜１＞から＜３＞のいずれかに記載の食直後血糖値上昇抑制組成物である。
＜５＞ 食前３０分以内又は食後３０分以内に経口投与されて用いられる、前記＜１＞から＜４＞のいずれかに記載の食直後血糖値上昇抑制組成物である。
The means for solving the above problems are as follows.
<1> A composition for suppressing an increase in blood glucose level immediately after a meal, comprising chitosan or chitosan and water, and containing chitosan powder having a bulk density of 0.25 g/mL or more and 0.40 g/mL or less and a content of particles having a volume particle size of 50 μm or less of 3 vol% or less.
<2> The composition for suppressing immediate postprandial blood glucose rise according to <1>, wherein the chitosan powder has a volume average particle size of 200 μm or more and 440 μm or less.
<3> The composition for suppressing immediate postprandial blood glucose rise according to any one of <1> to <2>, wherein the chitosan powder is obtained by tableting a 200 mg tablet obtained by tableting at a tableting pressure of 2,500 kg/ cm2 using a single-punch tablet press equipped with a mortar having an inner diameter of 8 mm and a pestle, and the disintegration time in first liquid (pH 1.2 aqueous solution) according to the tablet evaluation method of the Disintegration Test of the Japanese Pharmacopoeia, Fourteenth Edition, of the tablet is within 30 minutes.
<4> The composition for suppressing immediate postprandial blood glucose rise according to any one of <1> to <3>, wherein the chitosan powder content is 30% by mass or more.
<5> The composition for suppressing immediate postprandial blood glucose rise according to any one of <1> to <4>, which is orally administered within 30 minutes before or within 30 minutes after a meal.
本発明によれば、キトサンを高含量で含み、食直後２時間以内の血糖値上昇抑制効果を有する食直後血糖値上昇抑制組成物を提供することができる。 According to the present invention, it is possible to provide a composition that contains a high content of chitosan and has the effect of suppressing an increase in blood glucose level immediately after a meal within two hours.
（食直後血糖値上昇抑制組成物）
本発明の食直後血糖値上昇抑制組成物は、キトサン、又は、キトサン及び水からなり、嵩密度が０．２５ｇ／ｍＬ以上０．４０ｇ／ｍＬ以下であり、かつ体積粒径５０μｍ以下の含有率が３体積％以下である、キトサン粉末を含み、添加剤、賦形剤などを含んでもよく、更に必要に応じて、その他の成分を含む。
従来の造粒したキトサン粉末を用いた錠剤は、未造粒のキトサン粉末を用いた錠剤よりも水中における分散性が向上することが知られているが、生体内における、造粒したキトサン粉末を用いた錠剤の食直後２時間以内の血糖値上昇抑制作用については明らかとなっていない。
そこで、本発明者らは、造粒したキトサン粉末を用いた錠剤は、分散性が向上することで、消化管内の移行が速く、食直後２時間以内の血糖値の上昇を抑制できることを知見した。なお、本発明における「食直後」とは、食後から２時間以内を意味する。
前記食直後血糖値上昇抑制組成物としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、医薬品、食品などが挙げられる。
(Composition for suppressing elevation of blood glucose level immediately after a meal)
The composition for suppressing blood glucose rise immediately after a meal of the present invention contains chitosan powder consisting of chitosan or chitosan and water, having a bulk density of 0.25 g/mL or more and 0.40 g/mL or less and a content of particles having a volume particle size of 50 μm or less of 3 vol% or less, and may contain additives, excipients, etc., and further contains other ingredients as necessary.
It is known that tablets made with conventional granulated chitosan powder have better dispersibility in water than tablets made with ungranulated chitosan powder, but the effect of tablets made with granulated chitosan powder in inhibiting blood glucose levels from increasing in the body within two hours after ingestion has not been clarified.
The present inventors have found that tablets using granulated chitosan powder have improved dispersibility, and therefore can be rapidly transferred through the digestive tract, thereby suppressing the rise in blood glucose level within 2 hours after a meal. In the present invention, "immediately after a meal" means within 2 hours after a meal.
The composition for suppressing immediate postprandial blood glucose rise is not particularly limited and can be appropriately selected depending on the purpose. Examples of the composition include medicines and foods.
＜キトサン粉末＞
前記キトサン粉末は、キトサン、又は、キトサン及び水からなる造粒物であり、後述するキトサン粉末の製造方法によって好適に製造することができる。
<Chitosan powder>
The chitosan powder is a granulated product of chitosan or chitosan and water, and can be suitably produced by the method for producing chitosan powder described below.
＜＜キトサン＞＞
「キトサン」とは、グルコサミンの１，４－重合体、又はグルコサミンとＮ－アセチルグルコサミンとの１，４－共重合体（ランダム共重合体）であり、直鎖状の多糖類である。
キトサンは、経口摂取することによりコレステロール調整機能、脂肪吸収阻害機能、血圧上昇阻害機能等の種々の生理的調整機能を有し、健康維持や体調改善のための機能性素材として知られている。キトサンの生理活性機能は、経口摂取の後、胃酸によりキトサンが溶解し、脂質、胆汁酸、糖質、塩化物イオンなどの生活習慣病に関連する原因物質を吸着して消化吸収を阻害することで発揮されると考えられている。
工業的には、主として、カニ、エビ、イカ、昆虫等の甲殻中に多量に含まれるキチン（Ｎ－アセチルグルコサミンの１，４－重合体）を抽出し、これをアルカリ中で加水分解して脱アセチル化することにより得られる。分子量、脱アセチル化の割合（％ＤＡ）、粘度等において、様々な物性及び品質の市販品のキトサンを入手することができる。
以下に、キチン及びキトサンの構造式を示す。
<<Chitosan>>
"Chitosan" is a 1,4-polymer of glucosamine or a 1,4-copolymer (random copolymer) of glucosamine and N-acetylglucosamine, and is a linear polysaccharide.
Oral ingestion of chitosan has various physiological regulating functions, such as cholesterol regulation, fat absorption inhibition, and blood pressure elevation inhibition, and it is known as a functional material for maintaining health and improving physical condition. It is believed that the physiological activity of chitosan is exerted when, after oral ingestion, chitosan is dissolved by gastric acid and adsorbs substances that cause lifestyle-related diseases, such as lipids, bile acids, sugars, and chloride ions, thereby inhibiting digestion and absorption.
Industrially, chitosan is obtained by extracting chitin (1,4-polymer of N-acetylglucosamine) contained in large quantities in the shells of crabs, shrimp, squid, insects, etc., and hydrolyzing and deacetylating it in an alkali. Commercially available chitosan products with various physical properties and qualities, such as molecular weight, deacetylation rate (% DA), and viscosity, are available.
The structural formulas of chitin and chitosan are shown below.
前記キトサンの脱アセチル化の割合（％ＤＡ）としては、酸性の水溶液に溶解すれば特に限定はなく、目的に応じて適宜選択することができるが、６０％以上１００％以下が好ましく、８０％以上１００％以下がより好ましい。
なお、前記脱アセチル化の割合（％ＤＡ）は、前記キトサンの構造式中、ｍ／（ｍ＋ｎ）×１００に相当する。
The deacetylation ratio (% DA) of the chitosan is not particularly limited as long as it is soluble in an acidic aqueous solution and can be appropriately selected depending on the purpose, but is preferably 60% or more and 100% or less, and more preferably 80% or more and 100% or less.
The percentage of deacetylation (% DA) corresponds to m/(m+n)×100 in the structural formula of chitosan.
＜＜水＞＞
前記水としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、工業用水、水道水、ミネラル水、蒸留水、精製水などが挙げられる。
前記キトサン粉末における水の含有率としては、２０質量％以下が好ましく、１２質量％以下がより好ましく、８質量％以下がさらに好ましく、５質量％以下が特に好ましい。
<<Water>>
The water is not particularly limited and can be appropriately selected depending on the purpose. Examples of the water include industrial water, tap water, mineral water, distilled water, and purified water.
The water content in the chitosan powder is preferably 20% by mass or less, more preferably 12% by mass or less, further preferably 8% by mass or less, and particularly preferably 5% by mass or less.
前記キトサン粉末の嵩密度としては、０．２５ｇ／ｍＬ以上０．４０ｇ／ｍＬ以下であり、０．２８ｇ／ｍＬ以上０．３５ｇ／ｍＬ以下が好ましく、０．２８ｇ／ｍＬ以上０．３４ｇ／ｍＬ以下がより好ましい。
前記嵩密度が、０．２５ｇ／ｍＬ以上であると、胃内崩壊性が良好となり、０．４０ｇ／ｍＬ以下であると、硬度及び耐摩損性が良好となる。
The bulk density of the chitosan powder is from 0.25 g/mL to 0.40 g/mL, preferably from 0.28 g/mL to 0.35 g/mL, and more preferably from 0.28 g/mL to 0.34 g/mL.
When the bulk density is 0.25 g/mL or more, the gastric disintegration property is good, and when the bulk density is 0.40 g/mL or less, the hardness and abrasion resistance are good.
前記キトサン粉末の嵩密度は、例えば、顔料用嵩密度測定器(ＪＩＳ Ｋ ５１０１型、筒井理化学器械株式会社製)を用い、キトサン原料を測定カップ容積３０ｍＬ（直径２２ｍｍ）に自由落下させ、測定カップ内のキトサンの質量（ｇ）を容積３０ｍＬで割ることにより算出することができる。 The bulk density of the chitosan powder can be calculated, for example, by using a pigment bulk density measuring device (JIS K 5101 type, manufactured by Tsutsui Rikagaku Kikai Co., Ltd.), allowing the chitosan raw material to freely fall into a measuring cup with a volume of 30 mL (diameter 22 mm), and dividing the mass (g) of chitosan in the measuring cup by the volume of 30 mL.
前記キトサン粉末の体積粒径５０μｍ以下の含有率としては、３体積％以下であり、２体積％以下が好ましく、１体積％以下がより好ましい。
前記含有率が、３体積％以下であると、硬度及び耐摩損性が良好となる。
The content of the chitosan powder having a volume particle size of 50 μm or less is 3 vol % or less, preferably 2 vol % or less, and more preferably 1 vol % or less.
When the content is 3% by volume or less, the hardness and abrasion resistance are good.
前記キトサン粉末の体積平均粒径としては、２００μｍ以上４４０μｍ以下が好ましく、２００μｍ以上２９０μｍ以下がより好ましい。
前記体積平均粒径が、４４０μｍを超えると、粒子が粗く、打錠した場合、摩損の可能性が高まることがあり、２００μｍ未満であると、打錠した場合、酸性水溶液下での崩壊性が悪くなることがある。一方、前記体積平均粒径が、２００μｍ以上４４０μｍ以下であると、硬度及び耐摩損性が良好となる。
The volume average particle size of the chitosan powder is preferably 200 μm or more and 440 μm or less, and more preferably 200 μm or more and 290 μm or less.
When the volume average particle size is more than 440 μm, the particles are coarse and the possibility of wear may increase when tableted, and when it is less than 200 μm, the disintegration property in an acidic aqueous solution may be deteriorated when tableted. On the other hand, when the volume average particle size is 200 μm or more and 440 μm or less, the hardness and wear resistance are good.
前記キトサン粉末の体積平均粒径、及び体積粒径（体積基準の粒度分布における粒径）５０μｍ以下の含有率は、例えば、レーザー回折－散乱式粒度分析計（レーザーマイクロンサイザーＬＭＳ２０００ｅ型、株式会社セイシン企業製）を用いて、適当な溶媒（例えば、メタノール）にキトサン粉末（例えば、１０ｍｇ以上３０ｍｇ以下／溶媒１ｍＬ）を分散し、その粒子にレーザー光を照射して生じた回析折／散乱光の角度により異なる強度パターン（強度分布）を観測し、Ｆｒａｕｎｈｏｆｅｒ（フランホーファ）回折理論やＭｉｅ（ミー）散乱理論を用いて、粒径分布を求めることにより、測定することができる。 The volume average particle size and the content of volume particle sizes (particle size in volume-based particle size distribution) of 50 μm or less of the chitosan powder can be measured, for example, by dispersing chitosan powder (e.g., 10 mg to 30 mg/mL of solvent) in a suitable solvent (e.g., methanol) using a laser diffraction-scattering particle size analyzer (Laser Micronsizer LMS2000e type, manufactured by Seishin Enterprise Co., Ltd.), irradiating the particles with laser light, observing the intensity pattern (intensity distribution) that varies depending on the angle of the diffracted/scattered light, and determining the particle size distribution using the Fraunhofer diffraction theory or Mie scattering theory.
なお、キトサン粉末の粒度分布の測定は、従来は振動篩を用いた篩別法を用いていたが、本発明においては、平均粒径を評価することが不可欠であり、篩別法では設置する篩の目開きにより平均粒径の測定結果が異なる恐れがある。したがって、粒度分布の測定は全てレーザー回折－散乱法を用いた。
レーザー回折－散乱法は、篩別法による段階的な粒度分布の値と比較すると比較的連続した分布結果となり測定粒子の幅も広いことが特徴である。また、コンピューターを用いた解析も可能であるため、容易に平均粒径や任意の粒度の割合を計算することができる。前記体積平均粒径は、レーザー回折－散乱式粒度分析計における測定粒径（ｄ）を小さい順から、ｄ１，ｄ２，・・・・ｄｉ，・・・ｄｋ、それぞれの粒径を持つ粒子の個数をそれぞれｎ１，ｎ２，・・・・ｎｉ，・・・ｎｋ個、粒子１個当りの表面積をａｉ、体積をｖｉとしたときに以下の式で計算される粒子平均値のことである。
体積平均粒径＝Σ（Ｖｉ・Ｄｉ）÷Σ（Ｖｉ）
また、体積粒径５０μｍ以下の含有率は、レーザー回折－散乱式粒度分析計のアウトプットより、体積粒径５０μｍ以下の頻度を測定粒度毎に累計することにより求めることができる。
In the past, the particle size distribution of chitosan powder was measured by a sieving method using a vibrating sieve, but in the present invention, it is essential to evaluate the average particle size, and the measurement results of the average particle size may differ depending on the opening of the sieve installed in the sieving method. Therefore, the particle size distribution was measured by a laser diffraction-scattering method.
The laser diffraction-scattering method is characterized by a relatively continuous distribution result and a wide range of measured particles compared to the stepped particle size distribution value obtained by the sieving method. In addition, since analysis using a computer is also possible, the average particle size and the ratio of any particle size can be easily calculated. The volume average particle size is the particle average value calculated by the following formula when the particle sizes (d) measured by the laser diffraction-scattering particle size analyzer are d1, d2, ... di, ... dk in ascending order, the number of particles having each particle size is n1, n2, ... ni, ... nk, the surface area per particle is ai, and the volume is vi.
Volume average particle size = Σ(Vi · Di) ÷ Σ(Vi)
The content of particles having a volume particle size of 50 μm or less can be determined by accumulating the frequency of particles having a volume particle size of 50 μm or less for each measured particle size from the output of a laser diffraction-scattering particle size analyzer.
前記キトサン粉末を打錠した際の胃液等の酸性水溶液における崩壊時間としては、３０分間以内が好ましく、１０分間以内がより好ましく、５分間以内が特に好ましい。
従来のキトサン粉末を含むキトサン含有製剤は、胃液等の酸性水溶液中において、錠剤表面が水分を吸収してゲル状になり、錠剤の崩壊を妨げる現象が生じるという問題があった。しかしながら、当該キトサン粉末によれば、食直後血糖値上昇抑制組成物を製造する際に、所望の崩壊時間に設定することができ、高含量であっても優れた崩壊性を発揮することができる。
前記キトサン粉末を打錠した際の酸性水溶液における崩壊時間（以下、「胃内崩壊性」ということがある）は、前記キトサン粉末が、内径８ｍｍＣＲの臼と、杵とを備えた単発式打錠機（例えば、ＫＴ２型、岡田精工株式会社製）により限界まで硬度を上げた２，５００ｋｇ／ｃｍ２の打錠圧で打錠して得られた２００ｍｇ錠を用い、「第十四改正日本薬局方、崩壊試験法」の「（１）錠剤」の評価方法に準じて、第１液（塩化ナトリウム２.０ｇに塩酸７．０ｍＬ及び水を加えて溶かして１，０００ｍＬとしたｐＨ１．２の水溶液）を用いて崩壊性を評価した際の、崩壊までに要した時間である。
The disintegration time in an acidic aqueous solution such as gastric juice when the chitosan powder is compressed into tablets is preferably within 30 minutes, more preferably within 10 minutes, and particularly preferably within 5 minutes.
Conventional chitosan-containing preparations containing chitosan powder have a problem that the tablet surface absorbs water and becomes gel-like in an acidic aqueous solution such as gastric juice, which hinders tablet disintegration. However, when the chitosan powder is used, a desired disintegration time can be set when producing a composition for suppressing postprandial blood glucose rise, and excellent disintegrability can be achieved even at a high chitosan content.
The disintegration time in an acidic aqueous solution when the chitosan powder is compressed into tablets (hereinafter, sometimes referred to as "intragastric disintegrability") is the time required for disintegration when the disintegrability is evaluated using 200 mg tablets obtained by compressing the chitosan powder into tablets at a tableting pressure of 2,500 kg/ cm2 , which increases the hardness to the limit, using a single-punch tablet press (e.g., KT2 type, manufactured by Okada Seiko Co., Ltd.) equipped with a die having an inner diameter of 8 mm CR and a pestle, in accordance with the evaluation method of "(1) Tablets" in "Disintegration Test Method, Japanese Pharmacopoeia, Fourteenth Edition," using a first fluid (a pH 1.2 aqueous solution prepared by dissolving 2.0 g of sodium chloride with 7.0 mL of hydrochloric acid and water to make 1,000 mL).
＜＜キトサン粉末の製造方法＞＞
前記キトサン粉末の製造方法は、加水工程、乾燥工程を含む。
前記キトサン粉末は、粉末状のキトサン原料に加水工程、乾燥工程を施すことにより製造できる。
前記キトサン粉末の製造方法は、前記加水工程の後に、回転運動付与工程を含むことが好ましく、更に必要に応じて、整粒工程などのその他の工程を含んでもよい。
<<Method of manufacturing chitosan powder>>
The method for producing the chitosan powder includes a hydration step and a drying step.
The chitosan powder can be produced by subjecting a powdered chitosan raw material to a hydration step and a drying step.
The method for producing the chitosan powder preferably includes a step of imparting a rotational motion after the hydration step, and may further include other steps such as a particle size adjustment step, if necessary.
－キトサン原料－
前記キトサン原料は、粉末状のキトサンであり、キトサン、又は、キトサン及び水からなり、体積平均粒径は５０μｍ以上１５０μｍ以下が好ましく、体積粒径５０μｍ以下の含有率は２０体積％以上であり、かつ嵩密度は０．２５ｇ／ｍＬ以下である。
-Chitosan raw material-
The chitosan raw material is powdered chitosan, and is composed of chitosan or chitosan and water, and preferably has a volume average particle size of 50 μm or more and 150 μm or less, a content of particles with a volume particle size of 50 μm or less being 20 volume % or more, and a bulk density of 0.25 g/mL or less.
前記キトサン原料の体積平均粒径としては、５０μｍ以上１５０μｍ以下が好ましく、７５μｍ以上１５０μｍ以下がより好ましく、７５μｍ以上１２５μｍ以下が特に好ましい。
前記体積平均粒径が５０μｍ以上１５０μｍ以下であると、嵩密度が０．２５ｇ／ｍＬ以上０．４０ｇ／ｍＬ以下であり、体積粒径５０μｍ以下の含有率が３体積％以下であるキトサン粉末を得ることができ、前記キトサン粉末を含有するキトサン含有組成物は、硬度及び耐摩損性が良好となる。
The volume average particle size of the chitosan raw material is preferably from 50 μm to 150 μm, more preferably from 75 μm to 150 μm, and particularly preferably from 75 μm to 125 μm.
When the volume average particle size is 50 μm or more and 150 μm or less, a chitosan powder can be obtained having a bulk density of 0.25 g/mL or more and 0.40 g/mL or less and a content of volume particle sizes of 50 μm or less of 3 volume % or less, and the chitosan-containing composition containing the chitosan powder has good hardness and abrasion resistance.
前記キトサン原料の体積粒径５０μｍ以下の含有率としては、２０体積％以上であり、２０体積％以上５０体積％以下が好ましく、２０体積％以上４５体積％以下がより好ましい。
前記キトサン粉末を調製するためには、体積粒径５０μｍ以下の含有率が２０体積％以上を含む前記キトサン原料を用いることが重要である。このような粒度分布を有する前記キトサン原料を用いることで、適切な嵩密度と体積粒径５０μｍ以下含有率を有するキトサン粉末を得ることができる。
The content of particles having a volume particle size of 50 μm or less in the chitosan raw material is 20% by volume or more, preferably 20% by volume or more and 50% by volume or less, and more preferably 20% by volume or more and 45% by volume or less.
In order to prepare the chitosan powder, it is important to use the chitosan raw material having a volume particle size of 50 μm or less of 20% by volume or more. By using the chitosan raw material having such a particle size distribution, it is possible to obtain chitosan powder having an appropriate bulk density and a volume particle size of 50 μm or less.
前記キトサン原料の嵩密度としては、０．２５ｇ／ｍＬ以下であり、０．１５ｇ／ｍＬ以下であることが好ましく、前記嵩密度の数値範囲としては、０．０８ｇ／ｍＬ以上０．２５ｇ／ｍＬ以下が好ましく、０．１０ｇ／ｍＬ以上０．１５ｇ／ｍＬ以下がより好ましい。
前記嵩密度が０．２５ｇ／ｍＬ以下であると、体積粒径５０μｍ以下の含有率が３体積％以下であるキトサン粉末を得ることができ、前記キトサン粉末を含有するキトサン含有組成物は、硬度及び耐摩損性が良好となる。
The bulk density of the chitosan raw material is 0.25 g/mL or less, and preferably 0.15 g/mL or less. The numerical range of the bulk density is preferably 0.08 g/mL or more and 0.25 g/mL or less, and more preferably 0.10 g/mL or more and 0.15 g/mL or less.
When the bulk density is 0.25 g/mL or less, a chitosan powder having a content of particles with a volume particle size of 50 μm or less of 3 volume % can be obtained, and a chitosan-containing composition containing the chitosan powder has good hardness and abrasion resistance.
－－キトサン－－
前記キトサン原料となるキトサンは、カニ、エビ、イカ、昆虫等の甲殻中に多量に含まれるキチン（Ｎ－アセチルグルコサミンの１，４－重合体）を抽出し、これをアルカリ中で加水分解して脱アセチル化することにより得られる。前記キトサンは、すでに工業化されており安価に入手できる。分子量、脱アセチル化度、粘度等において、様々な物性及び品質のキトサンを入手することができ、製造コストを抑えることが可能であり、工業上利用可能性が高い。前記キトサン原料としては、粒径を制御したキトサンを用いる必要があるが、粒径制御前のキトサンとしては、特に限定されるものではなく、工業的に入手できるキトサンをそのまま用いることができる。
--Chitosan--
The chitosan raw material is obtained by extracting chitin (1,4-polymer of N-acetylglucosamine) contained in large amounts in the shells of crabs, shrimp, squid, insects, etc., and hydrolyzing and deacetylating it in an alkali. The chitosan has already been industrialized and is available at low cost. Chitosan with various physical properties and qualities, such as molecular weight, degree of deacetylation, and viscosity, is available, making it possible to reduce production costs and providing high industrial applicability. It is necessary to use chitosan with a controlled particle size as the chitosan raw material, but the chitosan before particle size control is not particularly limited, and industrially available chitosan can be used as it is.
前記キトサンは、中性下で水不溶性、酸性下で水溶性を有する物性であれば特に限定なく用いることができる。
前記キトサンの重量平均分子量としては、５，０００以上５００，０００以下が好ましく、１０，０００以上２００，０００以下がより好ましい。
前記キトサンの重量平均分子量は、被験キトサン試料を０．５体積％酢酸水溶液に溶解した分析試料を調製し、ゲル浸透クロマトグラフ（ＧＰＣ）法によりプルラン標準品を用いて測定した重量平均分子量により規定される。
前記キトサンの重量平均分子量の調整は、原料キチン質としてカニ殻を使用する場合、塩酸を用いてカルシウムを取り除く工程の塩酸濃度、反応時間、及び反応温度、並びに濃水酸化ナトリウムを用いてキチンを脱アセチル化する工程における水酸化ナトリウム濃度、反応時間、及び反応温度のいずれかをコントロールすることで所望の重量平均分子量のキトサンを調製することができる。
The chitosan can be used without any particular limitation as long as it has physical properties of being water-insoluble under neutral conditions and water-soluble under acidic conditions.
The weight average molecular weight of the chitosan is preferably from 5,000 to 500,000, and more preferably from 10,000 to 200,000.
The weight average molecular weight of chitosan is defined as follows: a test chitosan sample is dissolved in a 0.5% by volume aqueous acetic acid solution to prepare an analytical sample, and the weight average molecular weight is measured by gel permeation chromatography (GPC) using a pullulan standard.
When crab shells are used as the raw chitin, the weight-average molecular weight of the chitosan can be adjusted by controlling any one of the hydrochloric acid concentration, reaction time, and reaction temperature in the step of removing calcium using hydrochloric acid, and the sodium hydroxide concentration, reaction time, and reaction temperature in the step of deacetylating chitin using concentrated sodium hydroxide, thereby preparing chitosan of the desired weight-average molecular weight.
前記キトサンとしては、キチンを脱アセチル化処理して調製され、少なくとも５０％以上が脱アセチル化されたものであれば特に問題なく使用することができるが、前記キトサンのアセチル化度としては、７０％以上が好ましく、８０％以上がより好ましく、８５％以上が特に好ましい。
なお、前記キトサンの脱アセチル化度は、例えば、キトサンを０．５体積％酢酸水溶液で溶解し、トルイジンブルーを指示薬として１／４００Ｎポリビニル硫酸カリウム（和光純薬工業株式会社製）を用いてコロイド滴定を行い、遊離のアミノ基のモル数を測定することにより算出することができる。
The chitosan is prepared by subjecting chitin to a deacetylation treatment, and can be used without any problem as long as it is at least 50% deacetylated. The degree of acetylation of the chitosan is preferably 70% or more, more preferably 80% or more, and particularly preferably 85% or more.
The degree of deacetylation of chitosan can be calculated, for example, by dissolving chitosan in a 0.5% by volume aqueous solution of acetic acid, performing colloidal titration using 1/400N potassium polyvinyl sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) with toluidine blue as an indicator, and measuring the number of moles of free amino groups.
［キトサン原料の製造方法］
前記キトサン原料の製造方法としては、特に限定はなく、目的に応じて適宜選択することができる。例えば、前記キトサンを、摩砕式粉砕機、凍結粉砕機、衝撃式粉砕機、エアージェット式粉砕機、遠心カッター式粉砕機等の粉砕機で機械的に粉砕し、任意に所定の目開きのメッシュを装着した篩別機で篩分けすることで、様々な粒径及び嵩密度のキトサン原料を得る方法が挙げられる。
なお、キトサン原料の粒径制御としては、粉砕機運転条件、篩別条件、粉砕時間などを調整することにより、粒径及び粒度分布を調整することができる。嵩密度については、キトサンの分子量が大きいほど粉砕負荷が強くなり、粉砕物の嵩密度が低下するため、キトサンの分子量により調整することができる。粉砕原理的には、摩砕式粉砕機、衝撃式粉砕機、エアージェット式粉砕機は、嵩密度が小さくなる傾向にあり、ボールミル粉砕機、カッター式粉砕機は、比較的嵩密度が大きくなる傾向にある。しかしながら、本発明においては複数の粉砕機で粉砕したキトサンを混合して、粒度分布において粒径５０μｍ以下のキトサンを２０体積％以上含有し、かつ嵩密度が０．２５ｇ／ｍＬ以下のキトサン原料が得られればよく、その意味では、粉砕機の種別としては、特に限定なく、目的に応じて適宜選択することができる。
[Method of manufacturing chitosan raw material]
The method for producing the chitosan raw material is not particularly limited and can be appropriately selected depending on the purpose. For example, the chitosan raw material may be mechanically crushed by a crusher such as a grinding crusher, a freeze crusher, an impact crusher, an air jet crusher, or a centrifugal cutter crusher, and then sieved by a sieving machine equipped with a mesh having a predetermined opening size to obtain chitosan raw material with various particle sizes and bulk densities.
In addition, the particle size of the chitosan raw material can be controlled by adjusting the pulverizer operating conditions, sieving conditions, pulverization time, etc. to adjust the particle size and particle size distribution. The bulk density can be adjusted by the molecular weight of chitosan, because the larger the molecular weight of chitosan, the stronger the pulverization load becomes, and the bulk density of the pulverized product decreases. In principle, the bulk density tends to be small with a friction pulverizer, an impact pulverizer, and an air jet pulverizer, while the bulk density tends to be relatively large with a ball mill pulverizer and a cutter pulverizer. However, in the present invention, it is sufficient to mix chitosan pulverized by multiple pulverizers to obtain a chitosan raw material containing 20% by volume or more of chitosan with a particle size distribution of 50 μm or less and having a bulk density of 0.25 g/mL or less, and in that sense, the type of pulverizer is not particularly limited and can be appropriately selected according to the purpose.
前記キトサン原料は、例えば、衝撃式微粉砕機等により粒度分布の広いキトサン粉体を調製する方法；ボールミル粉砕機を用いてキトサンを粉砕した後、さらにジェットミル粉砕を行うこと等により粒度分布が異なる複数のキトサン粉体を得、これらを混合する方法；篩（例えば、８０メッシュ）を装着した衝撃式微粉砕機を用い、キトサンチップ（例えば、３ｍｍ角）を粉砕する方法などにより得ることができる。
なお、ジェットミルによるキトサンの粉砕は、粉砕熱が発生しないため安定した品質の粉砕物が得られるが、３ｍｍ角のチップのような大きな粒子を粉砕することには適さない場合がある。その際、予め衝撃式微粉砕機などで粗粉砕を行うことで、ジェットミルで微粉砕は可能となるが、ジェットミルによる粉砕で得られる粉砕物は、体積平均粒径２０μｍ程度の非常に細かい物性の粉砕物となる。これを体積平均粒径の比較的大きな粉砕物と混合することで、前記キトサン原料に調整してもよい。
The chitosan raw material can be obtained, for example, by a method of preparing chitosan powder having a wide particle size distribution using an impact type fine grinder or the like; a method of grinding chitosan using a ball mill grinder, and then grinding it with a jet mill or the like to obtain a plurality of chitosan powders having different particle size distributions, and mixing these; a method of grinding chitosan chips (e.g., 3 mm square) using an impact type fine grinder equipped with a sieve (e.g., 80 mesh), and the like.
In addition, the jet mill can grind chitosan to obtain a ground product of stable quality because no grinding heat is generated, but it may not be suitable for grinding large particles such as chips of 3 mm square. In this case, fine grinding with a jet mill is possible by performing coarse grinding in advance with an impact type fine grinder, but the ground product obtained by grinding with a jet mill is a ground product with very fine physical properties with a volume average particle size of about 20 μm. This may be mixed with ground product with a relatively large volume average particle size to prepare the chitosan raw material.
＜＜＜加水工程＞＞＞
前記加水工程は、キトサン原料に水を加える工程である。
<<<Hydration process>>>
The hydration step is a step of adding water to a chitosan raw material.
－水－
前記水としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、工業用水、水道水、ミネラル水、蒸留水、精製水などが挙げられる。前記水は、水蒸気の形態で前記キトサン原料に添加されてもよく、含水溶媒の形態で前記キトサン原料に添加されてもよい。前記水としては、廃水の問題や、回収工程の有無の点で、工業用水、水道水、ミネラル水、蒸留水、精製水が好ましく、健康食品用の有効成分として使用することを考慮すると、蒸留水、精製水がより好ましい。
前記含水溶媒における溶媒としては、水と任意の割合で混合できる有機溶媒であれば特に限定はなく、目的に応じて適宜選択することができるが、アセトン、エタノールなどのキトサンを溶解しない溶媒を用いることが好ましい。また、前記溶媒としては、経口摂取において認容されている有機溶媒が好ましい。
前記含水溶媒における含水率としては、５体積％であれば特に限定はなく、目的に応じて適宜選択することができるが、４０体積％以上が好ましい。
-water-
The water is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include industrial water, tap water, mineral water, distilled water, purified water, etc. The water may be added to the chitosan raw material in the form of steam, or may be added to the chitosan raw material in the form of a water-containing solvent. In terms of wastewater problems and the presence or absence of a recovery process, the water is preferably industrial water, tap water, mineral water, distilled water, or purified water, and more preferably distilled water or purified water when the water is used as an active ingredient for health foods.
The solvent in the water-containing solvent is not particularly limited as long as it is an organic solvent that can be mixed with water in any ratio and can be appropriately selected depending on the purpose, but it is preferable to use a solvent that does not dissolve chitosan, such as acetone, ethanol, etc. In addition, the solvent is preferably an organic solvent that is accepted for oral intake.
The water content of the water-containing solvent is not particularly limited as long as it is 5% by volume and can be appropriately selected depending on the purpose, but is preferably 40% by volume or more.
前記キトサン原料に水を加える方法としては、例えば、前記キトサン原料５０ｇあたり２０ｍＬ以上２００ｍＬ以下（例えば、１００ｍＬ）の水を加え、均一になるまで練合する方法、前記キトサン原料５０ｇあたり２０ｍＬ以上２００ｍＬ以下（例えば、１００ｍＬ）の水を噴霧器等を用いて霧状に水分を吹き付けながら撹拌することにより、前記キトサン原料に均一に水を浸透させる方法、前記キトサン原料５０ｇあたり４０ｍＬ以上４００ｍＬ以下（例えば、２００ｍＬ）の５０体積％エタノール水溶液を、前記練合、噴霧等の方法により加えて均質化した後、熱を加えてエタノールを蒸発させる方法などが挙げられる。
これにより、均一な含水キトサン原料が得られる。
Examples of the method for adding water to the chitosan raw material include a method of adding 20 mL to 200 mL (e.g., 100 mL) of water per 50 g of the chitosan raw material and kneading until uniform; a method of spraying 20 mL to 200 mL (e.g., 100 mL) of water per 50 g of the chitosan raw material in a mist form using a sprayer or the like while stirring to uniformly permeate the chitosan raw material with water; and a method of adding 40 mL to 400 mL (e.g., 200 mL) of a 50 volume% aqueous ethanol solution per 50 g of the chitosan raw material by the kneading, spraying, or other method, homogenizing the mixture, and then applying heat to evaporate the ethanol.
This makes it possible to obtain a uniform hydrated chitosan raw material.
＜＜＜回転運動付与工程＞＞＞
前記回転運動付与工程は、前記水を加えたキトサン原料（含水キトサン原料）に対し、回転運動を与える工程である。
前記回転運動を与える方法としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、Ｖ型混合機、混合パン、リボンミキサー、ナウター混合機、コニカル混合機などの粉体混合機を用いて前記キトサン原料に回転運動を与える方法が挙げられる。回転運動を与える時の温度としては、水が凍結しない温度であれば特に限定はないが、１０℃以上８０℃以下が好ましい。回転運動を行う時間としては、前記含水キトサン原料が目視で均一な粉状物（造粒物）になったことを確認できれば、特に限定はなく適宜選択することができるが、粉体混合機を用いた回転運動時間として、１分間以上が好ましく、１分間以上１２０分間以下がより好ましく、１分間以上６０分間以下が特に好ましく、５分間以上３０分間以下が最も好ましい。なお、前記含水キトサン原料が１ｋｇ以下の少量である場合には、前記含水キトサン原料を気体（例えば、空気）と共に容器（例えば、ビニール袋）に封入し、手動で混合しながら回転運動を与えてもよい。
<<<Rotational motion imparting step>>>
The rotational motion imparting step is a step of imparting a rotational motion to the chitosan raw material to which water has been added (hydrous chitosan raw material).
The method of applying the rotational motion is not particularly limited and can be appropriately selected depending on the purpose. For example, a method of applying a rotational motion to the chitosan raw material using a powder mixer such as a V-type mixer, a mixing pan, a ribbon mixer, a Nauter mixer, or a conical mixer can be mentioned. The temperature when applying the rotational motion is not particularly limited as long as the temperature is such that water does not freeze, but is preferably 10°C or more and 80°C or less. The time for performing the rotational motion is not particularly limited and can be appropriately selected as long as it is possible to visually confirm that the hydrated chitosan raw material has become a uniform powder (granulated product). The time for the rotational motion using a powder mixer is preferably 1 minute or more, more preferably 1 minute to 120 minutes, particularly preferably 1 minute to 60 minutes, and most preferably 5 minutes to 30 minutes. In addition, when the amount of the hydrated chitosan raw material is a small amount of 1 kg or less, the hydrated chitosan raw material may be sealed in a container (e.g., a plastic bag) together with a gas (e.g., air) and applied with a rotational motion while being mixed manually.
＜＜＜乾燥工程＞＞＞
前記乾燥工程は、前記含水キトサン原料、又は回転運動を与えた含水キトサン原料を、乾燥する工程である。これにより、本発明に用いるキトサン粉末が得られる。
前記乾燥する方法としては、例えば、乾燥機を用いる方法が挙げられる。
前記乾燥機としては、例えば、棚式乾燥機、透過式乾燥機、凍結乾燥機、減圧乾燥機等の静置状態で乾燥する乾燥機；コニカル乾燥機、ナウター乾燥機、スクリュー式乾燥機等の一般の健康食品製造工場に設置され、混合機能を有する乾燥機などが挙げられる。これらの中でも、混合機能を有する乾燥機が好ましい。
前記乾燥の温度（前記乾燥機内の温度）としては、キトサン粉末が変質しない温度であれば特に限定はなく、目的に応じて適宜選択することができるが、効率等の点から３０℃以上が好ましく、６０℃以上がより好ましく、８０℃以上が特に好ましく、１８０℃以下が好ましく、１５０℃以下がより好ましく、１２０℃以下が特に好ましい。
前記乾燥工程は、得られるキトサン粉末の含水量が規定の値になるまで乾燥を継続すればよい。前記含水量としては、２０質量％以下であれば特に限定はなく、目的に応じて適宜選択することができるが、１２質量％以下が好ましく、８質量％以下がより好ましく、５質量％以下が特に好ましい。
<<<Drying process>>>
The drying step is a step of drying the hydrated chitosan raw material or the hydrated chitosan raw material subjected to the rotational motion, thereby obtaining the chitosan powder used in the present invention.
The drying method may be, for example, a method using a dryer.
Examples of the dryer include a dryer that dries in a stationary state, such as a shelf dryer, a permeation dryer, a freeze dryer, or a reduced pressure dryer; a dryer that dries in a stationary state, such as a conical dryer, a Nauta dryer, or a screw dryer; Dryers having a mixing function, which are installed in general health food manufacturing factories, etc. Among these, dryers having a mixing function are preferred.
The drying temperature (temperature inside the dryer) is not particularly limited as long as the chitosan powder does not deteriorate, and can be appropriately selected depending on the purpose. From the viewpoint of efficiency, a temperature of 30° C. or higher is preferable. The temperature is preferably 60° C. or higher, and particularly preferably 80° C. or higher, and is preferably 180° C. or lower, more preferably 150° C. or lower, and particularly preferably 120° C. or lower.
In the drying step, drying may be continued until the moisture content of the resulting chitosan powder reaches a specified value. The moisture content is not particularly limited as long as it is 20% by mass or less, and may be appropriately selected depending on the purpose. However, it is preferably 12% by mass or less, more preferably 8% by mass or less, and particularly preferably 5% by mass or less.
＜＜＜その他の工程＞＞＞
－整粒工程－
前記整粒工程は、乾燥中又は乾燥後のキトサン粉末を整粒する工程である。
前記整粒する方法としては、例えば、篩（例えば、目開き２．０ｍｍのステンレス製篩）を通過させることにより整粒する方法などが挙げられる。
<<<Other processes>>>
- Particle size adjustment process -
The granulation step is a step of granulating the chitosan powder during or after drying.
The method for sizing the particles may be, for example, a method of sizing the particles by passing them through a sieve (for example, a stainless steel sieve with a mesh size of 2.0 mm).
［食直後血糖値上昇抑制組成物の用法及び剤形］
前記食直後血糖値上昇抑制組成物の用法としては、食前３０分以内又は食後３０分以内に経口投与されて用いられることが好ましく、これにより食直後（例えば、食後２時間以内）の血糖値の上昇を抑制することができる。
[Method of use and dosage form of the composition for suppressing postprandial blood glucose rise]
The composition for suppressing an increase in blood glucose level immediately after a meal is preferably orally administered within 30 minutes before or within 30 minutes after a meal, thereby suppressing an increase in blood glucose level immediately after a meal (e.g., within 2 hours after a meal).
前記食直後血糖値上昇抑制組成物の剤形としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、錠剤、ハードカプセル剤、ソフトカプセル剤、散剤、チュアブル錠、フィルムコート錠、ゼリー剤、水溶性剤、顆粒剤などが挙げられる。これらの中でも、推奨されるキトサンの用量が０．５ｇ／日以上２．０ｇ／日以下であることから、キトサン含量を高含有量化でき、また服用しやすい点で、錠剤が好ましい。
前記錠剤としては、例えば、素錠、多層錠、コーティング錠などが挙げられる。
前記コーティング錠は、コーティング基剤でコーティングされており、前記コーティング基剤としては、例えば、ゼラチン、デキストリン、アルギン酸ナトリウム、カルボキシメチルエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロ－ス、シェラック、ツェインなどが挙げられる。
The dosage form of the composition for suppressing an increase in blood glucose level immediately after a meal is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include tablets, hard capsules, soft capsules, powders, chewable tablets, film-coated tablets, jellies, water-soluble agents, granules, etc. Among these, tablets are preferred because the recommended chitosan dose is 0.5 g/day or more and 2.0 g/day or less, allowing a high chitosan content and making it easy to take.
Examples of the tablets include plain tablets, multi-layer tablets, and coated tablets.
The coated tablets are coated with a coating base, and examples of the coating base include gelatin, dextrin, sodium alginate, carboxymethylethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, and zein.
前記錠剤としては、前記キトサン粉末に、必要に応じて添加剤を添加し、更に必要に応じて賦形剤、その他の成分等を配合した製剤配合物を調製し、これを圧縮成形することで調製することができる。
前記錠剤の形状、構造、大きさ、重さ、硬さなどとしては、特に制限はなく、目的に応じて適宜選択することができる。
The tablets can be prepared by adding additives to the chitosan powder as necessary, and further adding excipients and other ingredients as necessary to prepare a formulation, and compressing and molding the formulation.
The shape, structure, size, weight, hardness, etc. of the tablet are not particularly limited and can be appropriately selected depending on the purpose.
前記キトサン粉末の含有率としては、特に限定はなく、目的に応じて適宜選択することができるが、キトサンを高含有量化させる観点から、３０質量％以上が好ましく、４０質量％以上がより好ましく、５０質量％以上が特に好ましい。
前記キトサン粉末を含有することにより、キトサンを高含有量化（例えば、３０質量％以上）することができ、かつ硬度、崩壊性及び耐摩損性に優れる食直後血糖値上昇抑制組成物を得ることができる。また、前記キトサン粉末が１００質量％であっても、硬度、崩壊性及び耐摩損性に優れる食直後血糖値上昇抑制組成物を得ることができる。
The content of the chitosan powder is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of increasing the chitosan content, however, it is preferably 30% by mass or more, more preferably 40% by mass or more, and particularly preferably 50% by mass or more.
By containing the chitosan powder, it is possible to obtain a composition for suppressing an increase in blood glucose level immediately after meals that has a high chitosan content (e.g., 30% by mass or more) and is excellent in hardness, disintegrability and abrasion resistance. Even if the chitosan powder is 100% by mass, it is possible to obtain a composition for suppressing an increase in blood glucose level immediately after meals that has excellent hardness, disintegrability and abrasion resistance.
前記添加剤としては、経口投与用製剤として通常用いられている添加剤であれば特に限定はなく、目的に応じて適宜選択することができ、例えば、塩化ナトリウム、炭酸カルシウム、リン酸カルシウム、炭酸マグネシウム等の無機塩類；結晶セルロース、メチルセルロース、エチルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース等のセルロース類などが挙げられる。
前記添加剤の含有率としては、特に制限はなく、目的に応じて適宜選択することができるが、０％以上８０％以下が好ましく、０％以上５０％以下がより好ましい。
The additives are not particularly limited as long as they are additives that are commonly used in preparations for oral administration and can be appropriately selected depending on the purpose. Examples of the additives include inorganic salts such as sodium chloride, calcium carbonate, calcium phosphate, and magnesium carbonate; and celluloses such as crystalline cellulose, methyl cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, and hydroxyethyl cellulose.
The content of the additives is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 0% or more and 80% or less, and more preferably 0% or more and 50% or less.
前記賦形剤としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、乳糖、麦芽糖、還元乳糖、還元麦芽糖、デンプン、マルチトール、デキストリン、ソルビトール、マンニトール、エリスリトール、キシリトール、トレハロース、白糖等の糖類；グアーガム、キサンタンガム、アルギン酸ナトリウム、アラビアガム、トラガントガム、プルラン、カラギーナン、寒天、ゼラチン、大豆食物繊維、ヒドロキシプロピルスターチ、ポリビニルピロリドン、カルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウムなどが挙げられる。これらは、結合剤や崩壊剤としても機能する。
前記賦形剤の含有率としては、特に制限はなく、目的に応じて適宜選択することができるが、０％以上１５％以下が好ましく、０％以上１０％以下がより好ましく、０％以上５％以下が特に好ましい。
The excipient is not particularly limited and may be appropriately selected depending on the purpose, and examples thereof include sugars such as lactose, maltose, reduced lactose, reduced maltose, starch, maltitol, dextrin, sorbitol, mannitol, erythritol, xylitol, trehalose, and sucrose; guar gum, xanthan gum, sodium alginate, gum arabic, tragacanth gum, pullulan, carrageenan, agar, gelatin, soybean dietary fiber, hydroxypropyl starch, polyvinylpyrrolidone, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, and carboxymethyl starch sodium. These also function as binders and disintegrants.
The content of the excipient is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 0% to 15%, more preferably 0% to 10%, and particularly preferably 0% to 5%.
前記その他の成分としては、結合剤、崩壊剤、甘味料、酸味料、香料、界面活性剤、滑沢剤などが挙げられる。その他、食品業界や医薬品業界において使用可能な全ての製剤添加物は、その効果を妨げない範囲内で添加することができる。
前記結合剤としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、カルボキシメチルセルロース、澱粉、ガム質（例えば、ローカストビーンガム等）、コラーゲンペプチドなどが挙げられる。
前記崩壊剤としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、澱粉、セルロースパウダー、崩壊寒天などが挙げられる。
前記甘味料としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、スクラロース、アスパルテームなどが挙げられる。
前記酸味料としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、クエン酸、リンゴ酸などが挙げられる。
前記香料としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、バニラフレーバー、メントール、シナモン、ハーブ（例えば、ローズマリー抽出物等）などが挙げられる。
前記界面活性剤としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、グリセリン脂肪酸エステル、ショ糖脂肪酸エステルなどが挙げられる。
前記滑沢剤としては、特に限定はなく、目的に応じて適宜選択することができ、例えば、ステアリン酸マグネシウム、ステアリン酸アルミニウム、ステアリン酸カルシウム、二酸化ケイ素、タルク、ケイ酸アルミニウムなどが挙げられる。
The other components include binders, disintegrants, sweeteners, acidulants, flavorings, surfactants, lubricants, etc. In addition, all formulation additives that can be used in the food and pharmaceutical industries can be added within the range that does not impair their effects.
The binder is not particularly limited and can be appropriately selected depending on the purpose. Examples of the binder include carboxymethylcellulose, starch, gums (for example, locust bean gum, etc.), and collagen peptides.
The disintegrant is not particularly limited and can be appropriately selected depending on the purpose. Examples of the disintegrant include starch, cellulose powder, and disintegrating agar.
The sweetener is not particularly limited and can be appropriately selected depending on the purpose. Examples of the sweetener include sucralose and aspartame.
The acidulant is not particularly limited and can be appropriately selected depending on the purpose. Examples of the acidulant include citric acid and malic acid.
The flavoring is not particularly limited and can be appropriately selected depending on the purpose. Examples of the flavoring include vanilla flavor, menthol, cinnamon, and herbs (e.g., rosemary extract).
The surfactant is not particularly limited and can be appropriately selected depending on the purpose. Examples of the surfactant include glycerin fatty acid esters and sucrose fatty acid esters.
The lubricant is not particularly limited and can be appropriately selected depending on the purpose. Examples of the lubricant include magnesium stearate, aluminum stearate, calcium stearate, silicon dioxide, talc, and aluminum silicate.
以下、実施例に基づいて本発明をより具体的に説明するが、本発明は以下の実施例に限定されるものではない。 The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.
－キトサン原料の調製－
キトサン原料（造粒前の粉砕物）として、下記の通り、キトサン原料１～５及びａ～ｄを調製した。
- Preparation of chitosan raw material -
As chitosan raw materials (pulverized materials before granulation), chitosan raw materials 1 to 5 and a to d were prepared as follows.
－－キトサン原料１～５及びａの調製－－
３ｍｍ角のチップ状に粉砕したキトサンを、サイクロン分級機（ホソカワミクロン株式会社製）を併設した衝撃式微粉砕機（装置名：ＡＣＭ－１０、ホソカワミクロン株式会社製）を用い、１６Ａ～２０Ａの運転条件、内蔵篩８０メッシュの分級条件にて粉砕して、表１に示す物性値を有する各種キトサン原料１～５及びキトサン原料ａを得た。
--Preparation of chitosan raw materials 1 to 5 and a--
Chitosan pulverized into chips of 3 mm square was pulverized using an impact type fine pulverizer (device name: ACM-10, manufactured by Hosokawa Micron Corporation) equipped with a cyclone classifier (manufactured by Hosokawa Micron Corporation) under operating conditions of 16A to 20A and classification conditions with a built-in sieve of 80 mesh to obtain various chitosan raw materials 1 to 5 and chitosan raw material a having the physical properties shown in Table 1.
－－キトサン原料ｂの調製－－
３ｍｍ角のチップ状に粉砕したキトサンを、セラミックボールを用いたボールミル（装置名：ＢＭ（７００Ｌ）、セイシン企業株式会社製）を用い、セラミックボール（直径１０ｍｍ～１００ｍｍ、仕込み量：４０ｋｇ／７００Ｌ）、２６時間乾式で粉砕して、キトサン原料ｂを得た。
--Preparation of chitosan raw material b--
Chitosan pulverized into chips of 3 mm square was dry-pulverized for 26 hours using a ball mill (machine name: BM (700 L), manufactured by Seishin Enterprise Co., Ltd.) with ceramic balls (diameter 10 mm to 100 mm, charge amount: 40 kg/700 L) to obtain chitosan raw material b.
－－キトサン原料ｃの調製－－
３ｍｍ角のチップ状に粉砕したキトサンを、剪断粉砕機（装置名：ＶＭＢ－６０型、槇野産業株式会社製）を用い、３００ｒｐｍの剪断条件にて粉砕して、キトサン原料ｃを得た。
--Preparation of chitosan raw material c--
The chitosan crushed into chips of 3 mm square was crushed using a shear crusher (device name: VMB-60, manufactured by Makino Sangyo Co., Ltd.) under shear conditions of 300 rpm to obtain chitosan raw material c.
－－キトサン原料ｄの調製－－
３ｍｍ角のチップ状に粉砕したキトサンを、粉砕機とスクリーンを一体型したカッターミル（装置名：ＲＣＭ－２５０型、株式会社奈良機械製作所製）を用い、７００ｒｐｍの粉砕条件にて粉砕して、キトサン原料ｄを得た。
--Preparation of chitosan raw material d--
The chitosan crushed into chips of 3 mm square was crushed at 700 rpm using a cutter mill (device name: RCM-250 type, manufactured by Nara Machinery Co., Ltd.) which is an integrated crusher and screen, to obtain chitosan raw material d.
－キトサン原料の物性－
下記表１－１及び表１－２に記載した通り、キトサン原料１～５及びキトサン原料ａ～ｄについて、嵩密度、体積平均粒径、及び体積粒径５０μｍ以下の含有率を測定した。結果を表１－１及び表１－２に示す。
- Properties of chitosan raw material -
As shown in Tables 1-1 and 1-2 below, the bulk density, volume average particle size, and content of volume particle size of 50 μm or less were measured for chitosan raw materials 1 to 5 and chitosan raw materials a to d. The results are shown in Tables 1-1 and 1-2.
－－嵩密度の測定方法－－
顔料用嵩密度測定器(ＪＩＳ Ｋ ５１０１型、筒井理化学器械株式会社製)を用い、キトサン原料を測定カップ容積３０ｍＬ（直径２２ｍｍ）に自由落下させ、測定カップ内のキトサンの質量（ｇ）を容積３０ｍＬで割ることにより算出した。
--Method of measuring bulk density--
Using a pigment bulk density meter (JIS K 5101 type, manufactured by Tsutsui Rikagaku Kikai Co., Ltd.), the chitosan raw material was allowed to freely fall into a measuring cup with a volume of 30 mL (diameter 22 mm), and the bulk density was calculated by dividing the mass (g) of chitosan in the measuring cup by the volume of 30 mL.
－－体積平均粒径、及び粒径５０μｍ以下の割合の測定方法－－
体積平均粒径、及び体積粒径５０μｍ以下の含有率は、レーザー回折－散乱式粒度分析計（レーザーマイクロンサイザーＬＭＳ２０００ｅ型、株式会社セイシン企業製）を用いて、メタノール１ｍＬあたり、キトサン１０ｍｇ以上３０ｍｇ以下を分散した分散液を試験サンプルとして測定した。
なお、体積粒径５０μｍ以下のキトサン含有率は、粒径５０μｍ以下の頻度を測定粒度毎に累計することにより求めた。
--Method of measuring volume average particle size and the proportion of particles with particle sizes of 50 μm or less--
The volume average particle size and the content of volume particle sizes of 50 μm or less were measured using a laser diffraction-scattering particle size analyzer (Laser Micronsizer LMS2000e, manufactured by Seishin Enterprise Co., Ltd.) by dispersing 10 mg to 30 mg of chitosan per mL of methanol as a test sample.
The chitosan content by volume of particle diameter of 50 μm or less was determined by accumulating the frequency of particles having a particle diameter of 50 μm or less for each measured particle size.
（実施例１）
＜キトサン粉末の調製＞
５０ｇのキトサン原料１に蒸留水１００ｍＬを加え、乳鉢で均一になるまで練合した後、９０℃の乾燥機で３０分間乾燥した。次いで、目開き２．０ｍｍのステンレス製篩を通過させることにより整粒を行い、その後、２時間乾燥することにより造粒物である実施例１のキトサン粉末を調製した。なお、実施例１のキトサン粉末における水の含有率は、６．３質量％であった。
Example 1
<Preparation of chitosan powder>
100 mL of distilled water was added to 50 g of chitosan raw material 1, and the mixture was kneaded in a mortar until homogeneous, and then dried in a dryer at 90° C. for 30 minutes. The mixture was then passed through a stainless steel sieve with a mesh size of 2.0 mm to size the mixture, and then dried for 2 hours to prepare the chitosan powder of Example 1, which is a granulated product. The water content in the chitosan powder of Example 1 was 6.3% by mass.
＜キトサン粉末の物性＞
キトサン原料に代えて、キトサン粉末を用いたこと以外は、上記「キトサン原料の物性」と同様に、キトサン粉末について、嵩密度、体積平均粒径、及び体積粒径５０μｍ以下の含有率を測定した。結果を表１－１に示す。
<Physical properties of chitosan powder>
Except for using chitosan powder instead of chitosan raw material, the bulk density, volume average particle size, and content of volume particle size of 50 μm or less were measured for the chitosan powder in the same manner as in the above "Physical properties of chitosan raw material". The results are shown in Table 1-1.
＜キトサン含有組成物の調製＞
実施例１のキトサン粉末を、内径８ｍｍＣＲの臼と、杵とを備えた単発式打錠機（ＫＴ２型、岡田精工株式会社製）で、限界まで硬度を上げた条件である２，５００ｋｇ／ｃｍ２に相当する打錠圧で１粒２００ｍｇになるように打錠し、実施例１のキトサン含有組成物を調整した。なお、キトサン粉末自体の特性、及び高含量のキトサン錠剤における加工性を比較するため、賦形剤、滑沢剤、結着剤などの添加物は加えずにキトサン粉末自体を打錠に供した。
Preparation of chitosan-containing composition
The chitosan powder of Example 1 was compressed into tablets of 200 mg per tablet using a single punch tablet press (KT2 type, manufactured by Okada Seiko Co., Ltd.) equipped with a mortar with an inner diameter of 8 mm CR and a pestle at a tableting pressure equivalent to 2,500 kg/cm2, which is the condition for increasing hardness to the limit, to prepare the chitosan-containing composition of Example 1. In order to compare the characteristics of the chitosan powder itself and the processability of high-content chitosan tablets, the chitosan powder itself was subjected to tableting without adding additives such as excipients, lubricants, and binders.
＜評価＞
作製したキトサン粉末及びキトサン含有組成物について、以下のように評価した。結果を表１－１に示す。
<Evaluation>
The prepared chitosan powder and chitosan-containing composition were evaluated as follows, and the results are shown in Table 1-1.
＜＜硬度＞＞
キトサン含有組成物の硬度について、モンサント型錠剤硬度計（装置名：Ｂ型、富士理化工業株式会社製）を用いて、６個のキトサン含有組成物の平均硬度を測定し、以下の評価基準に基づき評価した。
［評価基準］
○：９．０ｋｇ以上、良好
△：４．０ｋｇ以上、９．０ｋｇ未満、硬度不足
×：４．０ｋｇ未満、打錠不可
<<Hardness>>
The hardness of the chitosan-containing composition was measured using a Monsanto tablet hardness tester (device name: Type B, manufactured by Fuji Rika Kogyo Co., Ltd.) to measure the average hardness of six chitosan-containing compositions, and evaluated based on the following evaluation criteria.
[Evaluation Criteria]
○: 9.0 kg or more, good △: 4.0 kg or more, less than 9.0 kg, insufficient hardness ×: Less than 4.0 kg, not tabletable
＜＜耐摩損性＞＞
キトサン含有組成物の耐摩損性について、「第十四改正日本薬局方、錠剤の摩損度試験法」に準じてキトサン含有組成物を日本薬局方錠剤摩損度試験機(萱垣医理科工業株式会社製）を用い、２５回転／分間にて、４分間(１００回転)処理し、処理後（摩損度試験後）のキトサン含有組成物の外観を観察することによって評価を行った。
評価は、図１中、パネルａ～ｄに示すように、以下の４段階で行った。
［評価基準］
◎：摩損なし（図１中、パネルａ）、良好
○：摩損を僅かに認める（図１中、パネルｂ）
△：摩損を認める（図１中、パネルｃ）、実用範囲内
×：摩損を激しく認める（図１中、パネルｄ）、実用不可
<<Abrasion resistance>>
The abrasion resistance of the chitosan-containing composition was evaluated in accordance with the "Japanese Pharmacopoeia, 14th Edition, Testing Method for Tablet Friability", by treating the chitosan-containing composition with a Japanese Pharmacopoeia Tablet Friability Tester (manufactured by Kayagaki Irika Kogyo Co., Ltd.) at 25 rotations/minute for 4 minutes (100 rotations), and observing the appearance of the chitosan-containing composition after treatment (after the friability test).
The evaluation was carried out on the following four-point scale, as shown in panels a to d in FIG.
[Evaluation Criteria]
⊚: No wear (panel a in FIG. 1), good ◯: Slight wear (panel b in FIG. 1)
△: Abrasion was observed (panel c in FIG. 1), within the practical range. ×: Abrasion was observed severely (panel d in FIG. 1), not practical.
＜＜崩壊性＞＞
＜＜＜胃内崩壊性＞＞＞
前記キトサン粉末の胃内崩壊性は、前記キトサン粉末を、内径８ｍｍＣＲの臼と、杵とを備えた単発式打錠機（ＫＴ２型、岡田精工株式会社製）により２，５００ｋｇ／ｃｍ２に相当する打錠圧で打錠して得られた、２００ｍｇ錠について、「第十四改正日本薬局方、崩壊試験法」の「（１）錠剤」の評価方法に準じて、第１液（塩化ナトリウム２.０ｇに塩酸７．０ｍＬ及び水を加えて溶かして１，０００ｍＬとしたｐＨ１．２の水溶液）を用いて崩壊性を下記評価基準に基づき評価した。
なお、図２は、実施例における崩壊性試験の評価基準を示す図である。図２中、符号ａで示す写真は崩壊した状態を示し、符号ｂで示す写真は未崩壊の状態を示す。また、符号ｃで示す写真は、崩壊した錠剤（符号ａ）を崩壊試験機より取り出したときの状態を示し、符号ｄで示す写真は、未崩壊の錠剤（符号ｂ）を崩壊試験機より取り出したときの状態を示す。
［評価基準］
◎：１０分間以内
○：１０分間超、３０分間以内
△：３０分間超、かつ３０分間後の時点で錠剤の破片の残留を認める
×：３０分間超、かつ３０分間後の時点で錠剤の原形を留める（錠剤の表面がゲル化したものも含む）
<<Disintegrability>>
<<<<Gastric disintegration>>>
The intragastric disintegrability of the chitosan powder was evaluated for 200 mg tablets obtained by compressing the chitosan powder at a compression pressure equivalent to 2,500 kg/ cm2 using a single punch tableting machine (KT2 type, manufactured by Okada Seiko Co., Ltd.) equipped with a die having an inner diameter of 8 mm CR and a pestle, in accordance with the evaluation method of "(1) Tablets" in "Disintegration Test Method, Japanese Pharmacopoeia, Fourteenth Edition," using a first liquid (a pH 1.2 aqueous solution obtained by dissolving 2.0 g of sodium chloride with 7.0 mL of hydrochloric acid and water to make 1,000 mL) based on the following evaluation criteria.
Fig. 2 shows the evaluation criteria for the disintegration test in the examples. In Fig. 2, the photograph indicated by the symbol a shows the disintegrated state, and the photograph indicated by the symbol b shows the undisintegrated state. The photograph indicated by the symbol c shows the state of the disintegrated tablet (symbol a) when it is taken out of the disintegration tester, and the photograph indicated by the symbol d shows the state of the undisintegrated tablet (symbol b) when it is taken out of the disintegration tester.
[Evaluation Criteria]
◎: Within 10 minutes ○: More than 10 minutes, within 30 minutes △: More than 30 minutes, and tablet fragments were found to remain after 30 minutes ×: More than 30 minutes, and the tablet retains its original shape after 30 minutes (including tablets with gelled surfaces)
（実施例２～５）
実施例１において、下記表１－１に記載した通り、キトサン原料を変更したこと以外は、実施例１と同様にして、実施例２～５のキトサン粉末及びキトサン含有組成物を作製し、これらの評価を実施した。結果を表１－１に示す。
(Examples 2 to 5)
Chitosan powders and chitosan-containing compositions of Examples 2 to 5 were prepared and evaluated in the same manner as in Example 1, except that the chitosan raw material was changed as shown in Table 1-1 below. The results are shown in Table 1-1.
（比較例１～４）
実施例１において、下記表１－１及び表１－２に記載した通り、キトサン原料の種類を変更したこと以外は、実施例１と同様にして、比較例１～４のキトサン粉末及びキトサン含有組成物を作製し、これらの評価を実施した。結果を表１－１及び表１－２に示す。
(Comparative Examples 1 to 4)
Chitosan powders and chitosan-containing compositions of Comparative Examples 1 to 4 were prepared and evaluated in the same manner as in Example 1, except that the type of chitosan raw material was changed as shown in Tables 1-1 and 1-2 below. The results are shown in Tables 1-1 and 1-2.
（実施例６～１２）
下記表２－１に記載した通りの質量比で、実施例２のキトサン粉末、乳糖（商品名：フローラック１００、メグレジャパン株式会社製）、及び結晶セルロース（商品名：セオラスＳＴ－１００、旭化成ケミカルズ株式会社製）をローリングミキサー(ＲＭ－１０型、愛知電機商事株式会社製)目盛５にて５分間混合し、内径８ｍｍＣＲの臼と、杵とを備えた単発式打錠機（ＫＴ２型、岡田精工株式会社製）で、２，５００ｋｇ／ｃｍ２に相当する打錠圧で１粒２００ｍｇになるように打錠し、実施例６～１２の食直後血糖値上昇抑制組成物を調整し、実施例１と同様に胃内崩壊性を評価した。結果を表２－１に示す。
(Examples 6 to 12)
The chitosan powder of Example 2, lactose (product name: Flowlac 100, manufactured by Meglee Japan Co., Ltd.), and crystalline cellulose (product name: CEOL ST-100, manufactured by Asahi Kasei Chemicals Corporation) were mixed for 5 minutes at the scale 5 of a rolling mixer (RM-10 type, manufactured by Aichi Denki Shoji Co., Ltd.) in the mass ratios shown in Table 2-1 below, and compressed into tablets of 200 mg per tablet at a tableting pressure equivalent to 2,500 kg/ cm2 using a single-punch tablet press (KT2 type, manufactured by Okada Seiko Co., Ltd.) equipped with a mortar with an inner diameter of 8 mm CR and a pestle, to prepare compositions for suppressing postprandial blood glucose rise of Examples 6 to 12, and their gastric disintegration properties were evaluated in the same manner as in Example 1. The results are shown in Table 2-1.
（比較例５～１８）
実施例６～１２において、実施例２のキトサン粉末に代えて、比較例２又は比較例４のキトサン粉末を用いたこと以外は、実施例６～１２と同様にして、比較例５～１１及び比較例１２～１８のキトサン含有組成物を調整し、実施例１と同様に胃内崩壊性を評価した。結果を表２－１及び表２－２に示す。
(Comparative Examples 5 to 18)
In Examples 6 to 12, except that the chitosan powder of Comparative Example 2 or Comparative Example 4 was used instead of the chitosan powder of Example 2, chitosan-containing compositions of Comparative Examples 5 to 11 and Comparative Examples 12 to 18 were prepared in the same manner as in Examples 6 to 12, and their gastric disintegration properties were evaluated in the same manner as in Example 1. The results are shown in Tables 2-1 and 2-2.
（参考例１）
また、参考例１として、実施例６において、実施例２のキトサン粉末を用いずに、乳糖を増量したこと以外は、実施例６と同様の操作により、参考例１のキトサンを含有しない製剤を調整し、実施例１と同様に胃内崩壊性を評価した。結果を表２－２に示す。
(Reference Example 1)
In addition, as Reference Example 1, a chitosan-free preparation of Reference Example 1 was prepared in the same manner as in Example 6, except that the chitosan powder of Example 2 was not used and the amount of lactose was increased, and the gastric disintegration property was evaluated in the same manner as in Example 1. The results are shown in Table 2-2.
実施例１２及び比較例１８のキトサン含有組成物の消化管内移行性、食直後の血糖値の上昇抑制を評価した。 The chitosan-containing compositions of Example 12 and Comparative Example 18 were evaluated for their ability to be transported into the digestive tract and their ability to inhibit the rise in blood glucose level immediately after eating.
＜消化管内移行性＞
前記消化管内移行性は、胃内移行性及び腸内移行性を評価した。
＜＜胃内移行性＞＞
Ｇｄ－ＤＴＰＡ（商品名：マグネビスト静注（登録商標）、バイエル薬品株式会社製）２．５質量％を含有する実施例１２及び比較例１８のキトサン含有組成物２０ｍｇ（錠剤）を、ＳＤラット（４週齢、雄、供給源：日本エスエルシー株式会社）に経口投与し、投与してから２時間後のラットの胃内をＭＲＩ（ＭＲ ＶｉｖｏＬＡ １．５Ｔ ｃｏｍｐａｃｔ ＭＲＩ ｓｙｓｔｅｍ、ＤＳファーマバイオメディカル社製）を用いて撮影し、ＭＲＩ画像を得た。ＭＲＩ画像を図３に示す。図３の白く囲った部分が胃から小腸に続く消化管であり、キトサン含有組成物が崩壊している場合は、この部分に白い影が確認される。図３における比較例１８では、胃から小腸に続く消化管内でキトサン含有組成物の崩壊が確認されなかったのに対して、実施例１２では、胃から小腸に続く消化管内でキトサン含有組成物の崩壊が確認された。このことから、本発明の食直後血糖値上昇抑制組成物は、高い胃内移行性を有することが確認された。
＜＜腸内移行性＞＞
エバンスブルー（商品名：エバンスブルー、和光純薬株式会社製）を含有する実施例１２及び比較例１８のキトサン含有組成物２０ｍｇ（錠剤）を、ＳＤラット（４週齢、雄、供給源：日本エスエルシー株式会社）に経口投与し、投与してから８時間後のラットの消化管を摘出した。摘出した消化管の画像を図４に示す。キトサン含有組成物は、エバンスブルーを含有しているため、エバンスブルーが確認された消化管の部位に、キトサン含有組成物が存在していることが確認できる。図４における比較例１８では、キトサン含有組成物が小腸の上部で滞留しているのに対して、実施例１２では、キトサン含有組成物が小腸の下部まで移行している。このことから、本発明の食直後血糖値上昇抑制組成物は、高い腸内移行性を有することが確認された。
<Gastrointestinal transfer>
The gastrointestinal transferability was evaluated by evaluating the gastric transferability and the intestinal transferability.
<<Gastric transfer>>
20 mg (tablets) of the chitosan-containing compositions of Example 12 and Comparative Example 18 containing 2.5% by mass of Gd-DTPA (trade name: Magnevist Intravenous Injection (registered trademark), manufactured by Bayer Yakuhin, Ltd.) were orally administered to SD rats (4 weeks old, male, source: Japan SLC Co., Ltd.), and the inside of the rat's stomach was photographed 2 hours after administration using an MRI (MR VivoLA 1.5T compact MRI system, manufactured by DS Pharma Biomedical Co., Ltd.) to obtain MRI images. The MRI images are shown in FIG. 3. The white-circled area in FIG. 3 is the digestive tract continuing from the stomach to the small intestine, and if the chitosan-containing composition has disintegrated, a white shadow is observed in this area. In Comparative Example 18 in FIG. 3, disintegration of the chitosan-containing composition was not observed in the digestive tract continuing from the stomach to the small intestine, whereas disintegration of the chitosan-containing composition was observed in the digestive tract continuing from the stomach to the small intestine in Example 12. From this, it was confirmed that the composition of the present invention for suppressing postprandial blood glucose rise has high gastric transferability.
<<Intestinal transfer>>
20 mg (tablets) of the chitosan-containing compositions of Example 12 and Comparative Example 18 containing Evans Blue (trade name: Evans Blue, manufactured by Wako Pure Chemical Industries, Ltd.) were orally administered to SD rats (4 weeks old, male, source: Japan SLC Co., Ltd.), and the rats' digestive tracts were excised 8 hours after administration. An image of the excised digestive tract is shown in FIG. 4. Since the chitosan-containing composition contains Evans Blue, it can be confirmed that the chitosan-containing composition is present in the digestive tract where Evans Blue was confirmed. In Comparative Example 18 in FIG. 4, the chitosan-containing composition is retained in the upper part of the small intestine, whereas in Example 12, the chitosan-containing composition is transferred to the lower part of the small intestine. From this, it was confirmed that the postprandial blood glucose level rise suppressing composition of the present invention has high intestinal transferability.
＜食直後の血糖値の上昇抑制＞
２ｇ／ｋｇ／ｍＬのブドウ糖と、実施例１２又は比較例１８のキトサン含有組成物４０ｍｇ／匹を、ＳＤラット（４週齢、雄、供給源：日本エスエルシー株式会社）に同時に経口投与し、投与後１８分間において６分毎に採血を行い、血清グルコース（ブドウ糖）濃度（ｍｇ／ｄＬ）を測定した。測定結果を図６に示す。図６における比較例１８では、ブドウ糖とキトサン含有組成物を経口投与してから１８分後の血清グルコース濃度が低下していないのに対して、実施例１２では、ブドウ糖とキトサン含有組成物を経口投与してから１２分後には血清グルコース濃度が低下していた。このことから、本発明の食直後血糖値上昇抑制組成物は、食直後の血糖値の上昇を抑制する作用を有することが確認された。
<Suppression of blood sugar rise immediately after meals>
2 g/kg/mL glucose and 40 mg/rat of the chitosan-containing composition of Example 12 or Comparative Example 18 were orally administered simultaneously to SD rats (4 weeks old, male, source: Japan SLC Co., Ltd.), blood was collected every 6 minutes for 18 minutes after administration, and serum glucose (glucose) concentration (mg/dL) was measured. The measurement results are shown in FIG. 6. In Comparative Example 18 in FIG. 6, the serum glucose concentration did not decrease 18 minutes after the oral administration of the glucose and chitosan-containing composition, whereas in Example 12, the serum glucose concentration decreased 12 minutes after the oral administration of the glucose and chitosan-containing composition. From this, it was confirmed that the composition for suppressing blood glucose level rise immediately after a meal of the present invention has an effect of suppressing blood glucose level rise immediately after a meal.
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| JP2017082102A (en) | 2015-10-28 | 2017-05-18 | 日本化薬フードテクノ株式会社 | Chitosan powder and method for producing the same, and chitosan containing formulation |
| CN108125978A (en) | 2017-12-29 | 2018-06-08 | 广州润虹医药科技股份有限公司 | A kind of chitin fiber composition and preparation method thereof |
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| JP2017082102A (en) | 2015-10-28 | 2017-05-18 | 日本化薬フードテクノ株式会社 | Chitosan powder and method for producing the same, and chitosan containing formulation |
| CN108125978A (en) | 2017-12-29 | 2018-06-08 | 广州润虹医药科技股份有限公司 | A kind of chitin fiber composition and preparation method thereof |
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