JP2014058502A - Chitosan containing composition and chitosan coating composition - Google Patents
Chitosan containing composition and chitosan coating composition Download PDFInfo
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- JP2014058502A JP2014058502A JP2013112523A JP2013112523A JP2014058502A JP 2014058502 A JP2014058502 A JP 2014058502A JP 2013112523 A JP2013112523 A JP 2013112523A JP 2013112523 A JP2013112523 A JP 2013112523A JP 2014058502 A JP2014058502 A JP 2014058502A
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- chitosan
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- containing composition
- acid
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Abstract
Description
本発明は、キトサン含有組成物、及び当該組成物を用いて製造したキトサンコーティング組成物に関する。 The present invention relates to a chitosan-containing composition and a chitosan coating composition produced using the composition.
キトサンはカニやエビなどの甲殻類の殻の主成分であるキチンから作られる多糖類で、加工が容易なため、繊維や膜などの素材として近年利用されている。キトサンは経口製剤等のコーティングにも使用されているが、酸に溶解しやすいため、経口摂取するとキトサンの被膜は胃酸で溶解してしまう。しかし、キトサンコーティングした製剤に、さらに腸溶性被膜やｐＨ依存性被膜等の他のコーティングを施すことなどにより、所望の部位に薬剤を送達することのできる、いわゆるＤＤＳ（ドラッグデリバリーシステム）製剤化が可能となる。例えば、特許文献１には、有効成分と、該有効成分を含有する中心体と、該中心体を被覆するキトサンを含んでなる内層と、該内層を被覆する胃酸耐性材料を含んでなる外層とを含んでなる、当該有効成分を大腸へ送達するための構造体が記載されている。 Chitosan is a polysaccharide made from chitin, the main component of crustacean shells such as crabs and shrimps, and has been used in recent years as a material for fibers and membranes because it is easy to process. Chitosan is also used in coatings for oral preparations and the like, but it is easily dissolved in acid. Therefore, when taken orally, the chitosan coating dissolves in stomach acid. However, a so-called DDS (drug delivery system) formulation that can deliver a drug to a desired site by applying another coating such as an enteric coating or a pH-dependent coating to the preparation coated with chitosan is available. It becomes possible. For example, Patent Document 1 discloses an active ingredient, a central body containing the active ingredient, an inner layer comprising chitosan covering the central body, and an outer layer comprising a gastric acid resistant material covering the inner layer. A structure for delivering the active ingredient to the large intestine is described.
キトサンは酸性溶液で溶解するが、水や中性溶液には溶解しにくい。またキトサンは分子内にアミノ基を持つ高分子電解質のため、溶液のイオン強度が増大すると粘度が低下し、ｐＨが低下すると粘度が増大する性質がある。そのため、キトサン膜を製造する場合には、一般に、揮発性有機酸である酢酸等を用いてキトサン含有酸性水溶液を調製し、これを材料にしてキトサン膜を製造する。一方、製造されたキトサン膜に酸が多く存在すると、膜の耐水性が低下し、またキトサンの経時的な加水分解が起こり、保管中に膜の着色や物性低下が起こり、分解が進行する。したがって、一旦キトサン膜を製造した後には、酸を膜から除去する必要がある。例えば、製造したキトサン膜の乾燥温度を高めたり乾燥時間を長く保持したりして、膜における酸の含有量を低くすることが行われている。しかしながら、キトサン膜から完全に酸を除去することは難しく、少なからず残存してしまうのが実情である。さらに、キトサンのみでは造膜性は低いため、従来のキトサン膜形成の際には、可塑剤などの添加により造膜性を付与していた。 Chitosan dissolves in an acidic solution, but hardly dissolves in water or a neutral solution. Chitosan is a polyelectrolyte having an amino group in the molecule, and therefore has a property that the viscosity decreases when the ionic strength of the solution increases and increases when the pH decreases. Therefore, when a chitosan film is manufactured, a chitosan-containing acidic aqueous solution is generally prepared using acetic acid or the like which is a volatile organic acid, and the chitosan film is manufactured using this as a material. On the other hand, when a large amount of acid is present in the produced chitosan membrane, the water resistance of the membrane is lowered, and the chitosan is hydrolyzed with time, and the membrane is colored and the physical properties are lowered during storage, whereby the degradation proceeds. Therefore, once the chitosan membrane is manufactured, it is necessary to remove the acid from the membrane. For example, increasing the drying temperature of the produced chitosan film or keeping the drying time long to lower the acid content in the film. However, it is difficult to completely remove the acid from the chitosan film, and the fact is that it remains a little. Furthermore, since chitosan alone has a low film forming property, the film forming property was imparted by adding a plasticizer or the like when a conventional chitosan film was formed.
これに対し、特許文献２には、キトサン酸性水溶液に、所定量のグリセリン脂肪酸エステルを含有することを特徴とするキトサンコーティング溶液を用いることにより、耐水性が高く、酸の残存量が少ないキトサン膜を得ることが記載されている。また特許文献２には、キトサン膜の可塑性を向上させるため、該キトサンコーティング溶液に、さらに多価アルコール等の可塑剤を添加することが記載されている。しかし、キトサン酸性水溶液にグリセリン脂肪酸エステルを添加すると、膜の乾燥速度が遅くなるためコーティング膜形成に長時間を必要としたり、得られた膜の強度が弱くなるという問題があった。また、グリセリン脂肪酸エステルを添加すると、コーティング溶液に泡が発生して膜製造の際にコーティング溶液の送液速度を一定にすることが困難になるため、均一な膜の製造がより難しくなる。 On the other hand, Patent Document 2 discloses a chitosan film having high water resistance and low residual amount of acid by using a chitosan coating solution characterized by containing a predetermined amount of glycerin fatty acid ester in an acidic aqueous solution of chitosan. Is described. Patent Document 2 describes that a plasticizer such as a polyhydric alcohol is further added to the chitosan coating solution in order to improve the plasticity of the chitosan film. However, when glycerin fatty acid ester is added to an acidic aqueous chitosan solution, the drying speed of the film is slowed down, so that it takes a long time to form a coating film, and the strength of the obtained film is reduced. In addition, when glycerin fatty acid ester is added, bubbles are generated in the coating solution, and it becomes difficult to make the coating solution feeding rate constant during the production of the membrane, which makes it more difficult to produce a uniform membrane.
したがって、より造膜性がよく、可塑性や強度に優れ、且つ酸の残存率の低いキトサン膜が所望されている。 Therefore, a chitosan film having better film forming properties, excellent plasticity and strength, and a low acid residual ratio is desired.
本発明は、造膜性がよく、耐水性や、可塑性、強度に優れ、且つ酸の残存率の低いキトサン膜、特に、食品、医薬品及び動物飼料分野で経口組成物のコーティングに使用することができるキトサン膜を提供することを課題とする。 The present invention has a good film-forming property, is excellent in water resistance, plasticity and strength, and has a low acid residue rate, and can be used for coating an oral composition, particularly in the fields of food, medicine and animal feed It is an object to provide a chitosan film that can be produced.
上記課題を解決するため、本発明者らは鋭意検討した結果、キトサン含有酸性水溶液に所定量の多価アルコールと水溶性セルロースとを配合することにより、造膜性が向上し、酸の残存率が低く、且つ耐水性、弾力性及び強度に優れたキトサン膜を得ることができることを見出した。 In order to solve the above-mentioned problems, the present inventors have intensively studied. It has been found that a chitosan film having a low water resistance and excellent in water resistance, elasticity and strength can be obtained.
すなわち、本発明は、キトサン１００質量部に対し、多価アルコール０．５〜１５０質量部と、水溶性セルロース０．３〜１５０質量部とを含有する酸性溶液であることを特徴とする、キトサン含有組成物を提供する。
また本発明は、上記キトサン含有組成物を用いることを特徴とする、キトサン膜の製造方法を提供する。
また本発明は、上記キトサン膜で被覆されていることを特徴とする、キトサンコーティング組成物を提供する。
また本発明は、上記キトサンコーティング組成物を含有する食品、医薬品又は飼料を提供する。
That is, the present invention is an acidic solution containing 0.5 to 150 parts by mass of a polyhydric alcohol and 0.3 to 150 parts by mass of water-soluble cellulose with respect to 100 parts by mass of chitosan. A containing composition is provided.
Moreover, this invention provides the manufacturing method of a chitosan film | membrane characterized by using the said chitosan containing composition.
The present invention also provides a chitosan coating composition characterized by being coated with the chitosan film.
Moreover, this invention provides the foodstuff, pharmaceutical, or feed containing the said chitosan coating composition.
本発明のキトサン含有組成物によれば、造膜性がよく、乾燥後の酸の残存率が低く、且つ耐水性、弾力性及び強度に優れたキトサン膜を得ることができる。本発明のキトサン含有組成物から製造されたキトサン膜は、食品、医薬品及び動物飼料分野における経口組成物用のキトサンコーティングとして有用である。さらに、当該キトサンコーティングを施した組成物に、さらに耐酸性被膜を施すことにより、胃と小腸を通過し大腸で崩壊する大腸ＤＤＳ製剤を得ることができる。 According to the chitosan-containing composition of the present invention, it is possible to obtain a chitosan film having good film-forming properties, low residual ratio of acid after drying, and excellent water resistance, elasticity and strength. The chitosan film produced from the chitosan-containing composition of the present invention is useful as a chitosan coating for oral compositions in the food, pharmaceutical and animal feed fields. Furthermore, a colorectal DDS preparation that passes through the stomach and small intestine and disintegrates in the large intestine can be obtained by further applying an acid-resistant film to the chitosan-coated composition.
本発明のキトサン含有組成物に用いるキトサンは、その分子量や脱アセチル化度に特に制限はなく、目的に応じて適宜選択することができる。酸性液への溶解性やコーティング適正を考慮すると、脱アセチル化度が６０％以上のものが好ましい。本発明のキトサン含有組成物におけるキトサンの含有量は、該組成物の全質量中、０．０５〜１２質量％、好ましくは１〜５質量％であり得る。 The chitosan used in the chitosan-containing composition of the present invention is not particularly limited in its molecular weight and degree of deacetylation, and can be appropriately selected according to the purpose. In consideration of solubility in acidic liquid and coating suitability, those having a degree of deacetylation of 60% or more are preferable. The chitosan content in the chitosan-containing composition of the present invention may be 0.05 to 12 mass%, preferably 1 to 5 mass%, based on the total mass of the composition.
本発明のキトサン含有組成物に用いる多価アルコールとしては、２〜６価の多価アルコールが挙げられるが、キトサンとの相溶性やキトサン膜の可塑性の点からは、グリセリン、ソルビトール及びマンニトールが好ましく、グリセリンがより好ましい。本発明のキトサン含有組成物において、上記の多価アルコールは、１種でまたは２種以上組み合わせて用いることができる。本発明のキトサン含有組成物における上記多価アルコールの含有量は、キトサン１００質量部に対して０．５〜１５０質量部、好ましくは５〜１２０質量部であり得る。多価アルコールの含有量が上記の量よりも多いかまたは少ない場合、該組成物から調製したキトサン膜が軟らかくなりすぎるかまたは硬くなりすぎ、いずれの場合も、キトサン膜が崩壊しやすくなる。 Examples of the polyhydric alcohol used in the chitosan-containing composition of the present invention include divalent to hexavalent polyhydric alcohols, and glycerin, sorbitol, and mannitol are preferable from the viewpoint of compatibility with chitosan and plasticity of the chitosan film. Glycerin is more preferable. In the chitosan-containing composition of the present invention, the polyhydric alcohols can be used alone or in combination of two or more. Content of the said polyhydric alcohol in the chitosan containing composition of this invention is 0.5-150 mass parts with respect to 100 mass parts of chitosan, Preferably it may be 5-120 mass parts. When the content of the polyhydric alcohol is larger or smaller than the above-mentioned amount, the chitosan film prepared from the composition becomes too soft or too hard, and in any case, the chitosan film tends to collapse.
本発明のキトサン含有組成物に用いる水溶性セルロ−スとしては、アルキルセルロース（例えば、メチルセルロース、エチルセルロース等）、ヒドロキシアルキルセルロース（例えば、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等）、ヒドロキシアルキルアルキルセルロース（例えば、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシエチルエチルセルロース等）等が挙げられる。このうち、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）が好ましい。本発明のキトサン含有組成物において、上記水溶性セルロ−スは、１種でまたは２種以上組み合わせて用いることができる。本発明のキトサン含有組成物における上記水溶性セルロ−スの含有量は、キトサン１００質量部に対して０．３〜１５０質量部、好ましくは５〜１００質量部であり得る。水溶性セルロ−スの含有量が上記の量よりも多いかまたは少ない場合、該組成物から調製したキトサン膜が軟らかくなりすぎるかまたは硬くなりすぎ、いずれの場合も、キトサン膜が崩壊しやすくなる。 Examples of the water-soluble cellulose used in the chitosan-containing composition of the present invention include alkyl cellulose (eg, methyl cellulose, ethyl cellulose, etc.), hydroxyalkyl cellulose (eg, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), hydroxyalkyl alkyl cellulose (eg, Hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, etc.). Of these, hydroxypropylmethylcellulose (HPMC) is preferred. In the chitosan-containing composition of the present invention, the water-soluble cellulose can be used alone or in combination of two or more. Content of the said water-soluble cellulose in the chitosan containing composition of this invention is 0.3-150 mass parts with respect to 100 mass parts of chitosan, Preferably it may be 5-100 mass parts. When the content of water-soluble cellulose is larger or smaller than the above amount, the chitosan film prepared from the composition becomes too soft or too hard, and in any case, the chitosan film tends to collapse. .
本発明のキトサン含有組成物には、乾燥する際の酸の揮発性を高めるため、エタノールを添加してもよい。エタノールは通常の食品や医薬品の製造に用いられるものを用いることができる。本発明のキトサン含有組成物におけるエタノールの含有量は、組成物の全質量中、３〜８０質量％、好ましくは５〜４０質量％であり得る。エタノールの含有量が３質量％未満であると乾燥効率が低く、他方、８０質量％を超えると、コストの面で高くなるとともに該組成物中の成分が溶解しにくくなるため好ましくない。本発明のキトサン含有組成物は、澄明な液であることが望ましい。 Ethanol may be added to the chitosan-containing composition of the present invention in order to increase the volatility of the acid during drying. Ethanol that can be used for the production of ordinary foods and pharmaceuticals can be used. The content of ethanol in the chitosan-containing composition of the present invention can be 3 to 80% by mass, preferably 5 to 40% by mass, based on the total mass of the composition. If the ethanol content is less than 3% by mass, the drying efficiency is low. On the other hand, if it exceeds 80% by mass, the cost increases and the components in the composition become difficult to dissolve, which is not preferable. The chitosan-containing composition of the present invention is desirably a clear liquid.
本発明のキトサン含有組成物に配合できるその他の成分としては、例えば、造膜性基材、フィラー、可塑剤等が挙げられるが、さらに他の成分も目的に応じて適宜選択することができ、本発明の効果を損なわない限り特に制限はない。 Other components that can be blended in the chitosan-containing composition of the present invention include, for example, a film-forming substrate, a filler, a plasticizer, and the like, and other components can be appropriately selected depending on the purpose. There is no particular limitation as long as the effects of the present invention are not impaired.
本発明のキトサン含有組成物に造膜性を有する基材を添加すると、キトサン膜を製造するのにさらに有利であり、また被膜の形成もより容易となる。造膜性を有する基材としては、プルラン、アラビアガム、カラギーナン、アルギン酸、微粒酸化ケイ素、微結晶セルロース、塩化カルシウム、炭酸カルシウム、塩化カリウム、燐酸カルシウム、ヘミロース、寒天、ゼラチン、キサンタンガム、カゼイン、乳蛋白質、オリゴ糖、デキストリン、カルメロースナトリウム（ＣＭＣナトリウム）、アルファー化デンプン、加工デンプン、ポリエチレングリコール、ポリビニルピロリドン（ＰＶＰ）、ならびにコーンファイバー、デンプン、グアーガム及びペクチン等の水溶性多糖類が挙げられる。これらのうち、造膜性と乳化力を併せ持つ基材、例えばアラビアガム、プルラン、ヘミロースなどがより好ましい。本発明のキトサン含有組成物における造膜性基材の含有量は、該組成物のキトサン質量に対し、０．１〜１００質量％であり得る。 When a base material having film-forming properties is added to the chitosan-containing composition of the present invention, it is further advantageous for producing a chitosan film, and the formation of a film becomes easier. Base materials having film-forming properties include pullulan, gum arabic, carrageenan, alginic acid, fine silicon oxide, microcrystalline cellulose, calcium chloride, calcium carbonate, potassium chloride, calcium phosphate, hemirose, agar, gelatin, xanthan gum, casein, milk Examples include proteins, oligosaccharides, dextrin, carmellose sodium (CMC sodium), pregelatinized starch, modified starch, polyethylene glycol, polyvinylpyrrolidone (PVP), and water-soluble polysaccharides such as corn fiber, starch, guar gum and pectin. Of these, base materials having both film-forming properties and emulsifying power, such as gum arabic, pullulan, hemirose, and the like are more preferable. Content of the film-forming base material in the chitosan containing composition of this invention may be 0.1-100 mass% with respect to the chitosan mass of this composition.
フィラーとしては、特に制限はないが、例えば、タルク、二酸化珪素、微結晶セルロース、還元麦芽糖、ベントナイト、炭素数１０以上の有機酸の金属塩などが挙げられる。本発明のキトサン含有組成物におけるフィラーの含有量は、該組成物のキトサン１００質量部に対して０．０１〜６０質量部であり得る。 The filler is not particularly limited, and examples thereof include talc, silicon dioxide, microcrystalline cellulose, reduced maltose, bentonite, and a metal salt of an organic acid having 10 or more carbon atoms. Content of the filler in the chitosan containing composition of this invention may be 0.01-60 mass parts with respect to 100 mass parts of chitosan of this composition.
可塑剤としては、特に制限はないが、例えば、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、有機酸モノグリセリド、ジグリセリン、ジエチレングリコール、プロピレングリコール、トリエチレングリコール、ポリエチレングリコール、レシチン、ソルビタン脂肪酸エステル、中鎖脂肪酸トリグリセライド、ショ糖エステル等が挙げられる。これらの中でも、食品や医薬品分野で用いるプロピレングリコール、ポリグリセリン脂肪酸エステル、グリセリン脂肪酸エステル、有機酸モノグリセリド、ポリエチレングリコール、中鎖脂肪酸トリグリセライド、ショ糖エステル、植物油脂などが好ましい。本発明のキトサン含有組成物における可塑剤の含有量は、該組成物のキトサン１００質量部に対して０．０５〜８０質量部であり得る。 The plasticizer is not particularly limited. For example, glycerin fatty acid ester, polyglycerin fatty acid ester, organic acid monoglyceride, diglycerin, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, lecithin, sorbitan fatty acid ester, medium chain fatty acid. Triglycerides, sucrose esters and the like can be mentioned. Among these, propylene glycol, polyglycerin fatty acid ester, glycerin fatty acid ester, organic acid monoglyceride, polyethylene glycol, medium chain fatty acid triglyceride, sucrose ester, vegetable oil and the like, etc. used in the food and pharmaceutical fields are preferable. Content of the plasticizer in the chitosan containing composition of this invention may be 0.05-80 mass parts with respect to 100 mass parts of chitosan of this composition.
本発明のキトサン含有組成物は、上記キトサン、多価アルコール及び水溶性セルロース、ならびに必要に応じて上記エタノールやその他の成分を、酸性水溶液に溶解させることによって調製することができる。上記酸性水溶液に共存させる酸としては、無機酸及び有機酸が挙げられるが、無機酸はキトサンとの相互作用が強いため、有機酸が好ましい。有機酸としては、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、常圧において十分な揮発性を有する点で、ギ酸、酢酸、乳酸、スルファミン酸、プロピオン酸、トリクロロ酢酸が好ましい。これらの中でも、安価であり、取り扱い易く、且つキトサン含有層に残留しても人体への影響が少ない点で、酢酸がより好ましい。 The chitosan-containing composition of the present invention can be prepared by dissolving the chitosan, polyhydric alcohol and water-soluble cellulose, and if necessary, the ethanol and other components in an acidic aqueous solution. Examples of the acid to be coexisted in the acidic aqueous solution include inorganic acids and organic acids, but organic acids are preferred because inorganic acids have a strong interaction with chitosan. The organic acid is not particularly limited and may be appropriately selected depending on the intended purpose. Formic acid, acetic acid, lactic acid, sulfamic acid, propionic acid, and trichloroacetic acid are preferable from the viewpoint of sufficient volatility at normal pressure. . Among these, acetic acid is more preferable because it is inexpensive, easy to handle, and has little influence on the human body even if it remains in the chitosan-containing layer.
上記酸性水溶液のｐＨは、３．５〜６．５の範囲であればよい。ｐＨが３．５未満であると、キトサン膜からの酸の除去が効率良く行えず、耐水性の高いキトサン膜を得ることが困難となることがある。他方、ｐＨが６．５より高くなると、水溶液へのキトサンの溶解性が低下する。 The pH of the acidic aqueous solution may be in the range of 3.5 to 6.5. If the pH is less than 3.5, acid removal from the chitosan film cannot be performed efficiently, and it may be difficult to obtain a chitosan film with high water resistance. On the other hand, when the pH is higher than 6.5, the solubility of chitosan in the aqueous solution decreases.
本発明のキトサン含有組成物を調製する手順としては、最終的に上記キトサン、多価アルコール及び水溶性セルロース、ならびに必要に応じて、上記エタノールやその他の成分が溶解した酸性水溶液が得られるのであれば、特に限定されない。例えば、キトサンと多価アルコールを溶解させた酸性溶液に、別途調製した水溶性セルロースを溶解させた水溶液を添加した後、必要に応じてさらにエタノールを添加することによって、本発明のキトサン含有組成物を調製することができる。当該組成物の調製には攪拌機などを用いてもよいが、攪拌は比較的低速で行うことが望ましい。溶液を過度に攪拌すると、キトサンの分子量が低下することによりキトサン膜が形成されにくくなる場合がある。 As a procedure for preparing the chitosan-containing composition of the present invention, an acidic aqueous solution in which the chitosan, polyhydric alcohol and water-soluble cellulose, and, if necessary, the ethanol and other components are dissolved can be finally obtained. There is no particular limitation. For example, the chitosan-containing composition of the present invention is added by adding an aqueous solution in which separately prepared water-soluble cellulose is dissolved in an acidic solution in which chitosan and polyhydric alcohol are dissolved, and then adding ethanol as necessary. Can be prepared. A stirrer or the like may be used for the preparation of the composition, but the stirring is desirably performed at a relatively low speed. When the solution is excessively stirred, a chitosan film may not be formed easily due to a decrease in the molecular weight of chitosan.
本発明のキトサン含有組成物は、ｐＨ３．５〜６．５、より好適にはｐＨ５．０〜５．９の範囲の溶液であることが好ましい。ｐＨが低くなるほど、キトサン膜からの酸の除去が効率良く行えず、耐水性の高いキトサン膜を得ることがより困難となる。他方、ｐＨが高いほど、該組成物中でのキトサンの溶解性が低下する。 The chitosan-containing composition of the present invention is preferably a solution having a pH in the range of 3.5 to 6.5, more preferably in the range of pH 5.0 to 5.9. The lower the pH, the more efficiently the acid can be removed from the chitosan film, making it more difficult to obtain a chitosan film with high water resistance. On the other hand, the higher the pH, the lower the solubility of chitosan in the composition.
本発明のキトサン含有組成物の粘度は、室温状態で５〜８００ｍＰａ・ｓが好ましい。粘度が上記範囲より小さいかまたは大きい場合、当該組成物からキトサン膜を形成しにくくなる。本明細書におけるキトサン含有組成物の粘度とは、Ｃ型粘度計（例えば、TOKIMEC INC製）によって測定された値である。 The viscosity of the chitosan-containing composition of the present invention is preferably 5 to 800 mPa · s at room temperature. When the viscosity is smaller or larger than the above range, it becomes difficult to form a chitosan film from the composition. The viscosity of the chitosan-containing composition in the present specification is a value measured by a C-type viscometer (for example, manufactured by TOKIMEC INC).
本発明のキトサン含有組成物を用いてキトサン膜を製造することができる。キトサン膜は、塗布、噴霧、浸漬等の手段によって、固体基材表面に本発明のキトサン含有組成物を付着させ、次いで付着させた該組成物を乾燥させることによって製造することができる。または、カプセルの被膜形成時にその基材であるゼラチン、セルロースやデンプンなどと一緒に本発明のキトサン含有組成物を配合して通常の方法で被膜形成を行い、カプセルを成型してもよい。その場合は、必要に応じてカラギーナン、アルギン酸、ペクチン、グアーガム、アラビアガム及び大豆多糖類等のゲル化剤や増粘安定剤などをカプセル基材にさらに添加してもよい。 A chitosan film can be produced using the chitosan-containing composition of the present invention. The chitosan film can be produced by attaching the chitosan-containing composition of the present invention to the surface of a solid substrate by means such as coating, spraying, or dipping, and then drying the attached composition. Alternatively, the capsule may be molded by forming the film by a conventional method by blending the chitosan-containing composition of the present invention together with gelatin, cellulose, starch or the like as the base material when forming the film of the capsule. In that case, a gelling agent such as carrageenan, alginic acid, pectin, guar gum, gum arabic, and soybean polysaccharide, a thickening stabilizer, and the like may be further added to the capsule base as necessary.
より好ましくは、通常使用されるコーティング装置、例えば、通気式コーティング装置（例えば、パウレックコーター：株式会社パウレック社製）、流動層造粒コーティング装置（例えば、フローコーター、フロイント産業株式会社製）、遠心転動造粒コーティング装置（例えば、ＣＦグラニュレーター、グラニュレックス、フロイント産業株式会社製）、複合型造粒コーティング装置（例えば、スパイラフロー、フロイント産業株式会社製）、糖衣フィルムコーティング装置（例えば、ハイコーター、アクアコーター：フロイント産業株式会社製）などを用いて、固体基材を流動させながら、乾燥空気を給気及び排気させつつ、スプレーなどを用いて当該固体基材の表面に本発明のキトサン含有組成物を噴霧するととともに、噴霧した該組成物を乾燥させて酸を除去することによって、キトサン膜を製造することができる。 More preferably, a normally used coating apparatus, for example, a breathable coating apparatus (for example, Powrec coater: manufactured by Powrec Co., Ltd.), a fluidized bed granulation coating apparatus (for example, flow coater, manufactured by Freund Sangyo Co., Ltd.), Centrifugal rolling granulation coating device (for example, CF granulator, Granurex, manufactured by Freund Sangyo Co., Ltd.), composite granulation coating device (for example, Spiraflow, manufactured by Freund Sangyo Co., Ltd.), sugar coating film coating device (for example, Using a high coater, aqua coater (Freund Sangyo Co., Ltd.) and the like, while supplying the solid air to the surface of the solid substrate using a spray or the like while supplying and exhausting dry air. The chitosan-containing composition is sprayed and the sprayed set Things a by removing the dried acid can be prepared chitosan films.
上記給気の温度としては、特に制限はないが、４５〜９０℃が好ましい。給気温度が４５℃未満であると、酸が十分に除去されないため、キトサン膜に耐水性が十分に付与されない。他方、９０℃を超えると、キトサン膜に着色、変形などの外観上の問題が生じるため好ましくない。また、水系のコーティングで給気温度が９０℃を超えることは、コーティング装置にかかる負担も大きくなるため好ましくない。上記排気の温度としては、３０〜８５℃であればよい。 The temperature of the air supply is not particularly limited, but is preferably 45 to 90 ° C. When the supply air temperature is less than 45 ° C., the acid is not sufficiently removed, so that the water resistance is not sufficiently imparted to the chitosan film. On the other hand, when the temperature exceeds 90 ° C., the chitosan film is not preferable because appearance problems such as coloring and deformation occur. In addition, it is not preferable that the supply air temperature exceeds 90 ° C. due to the aqueous coating because the burden on the coating apparatus increases. The exhaust temperature may be 30 to 85 ° C.
本発明のキトサン含有組成物から製造されたキトサン膜は、食品、医薬品及び動物飼料分野に適用できる。すなわち、本発明のキトサン含有組成物から製造されたキトサン膜で医薬成分、機能性成分等の各種有効成分を被覆することにより、キトサンコーティング組成物を得ることができる。さらに、当該キトサンコーティング組成物を含有する食品、飼料、医薬品、サプリメント等を製造することもできる。当該キトサンコーティング組成物は、好ましくは経口で投与または摂取される組成物である。 The chitosan film produced from the chitosan-containing composition of the present invention can be applied to the food, pharmaceutical and animal feed fields. That is, a chitosan coating composition can be obtained by coating various active ingredients such as pharmaceutical ingredients and functional ingredients with a chitosan membrane produced from the chitosan-containing composition of the present invention. Furthermore, foods, feeds, pharmaceuticals, supplements and the like containing the chitosan coating composition can also be produced. The chitosan coating composition is preferably a composition that is administered or ingested orally.
本発明のキトサンコーティング組成物の剤形としては、カプセル、錠剤、丸剤、顆粒などが挙げられるが、特に制限されない。 Examples of the dosage form of the chitosan coating composition of the present invention include capsules, tablets, pills, granules and the like, but are not particularly limited.
本発明のキトサンコーティング組成物をカプセルとする場合は、本発明のキトサン含有組成物から得られたキトサン膜をハードカプセル状に成型して、キトサン含有カプセルを製造し、これに上記固形物や液体を充填してもよい。例えば、キトサン含有カプセルは、本発明のキトサン含有組成物に金属製のピンを浸し、引き上げ、形状を確保した後、乾燥させることによって製造することができる。必要に応じて、該組成物に、さらに水、着色剤（例えば、酸化チタン、ベンガラ、青色２号、黄色５号等）、不透明化剤（例えば、酸化チタン等）、香料などを配合することもできる。ハードカプセルのサイズとしては、００号、０号、１号、２号、３号、４号、５号などがあるが、本発明ではいずれのサイズのハードカプセルも使用することができる。 When the chitosan coating composition of the present invention is used as a capsule, a chitosan film obtained from the chitosan-containing composition of the present invention is molded into a hard capsule to produce a chitosan-containing capsule, and the solid or liquid is added to the capsule. It may be filled. For example, a chitosan-containing capsule can be produced by immersing a metal pin in the chitosan-containing composition of the present invention, pulling it up, securing the shape, and drying it. If necessary, the composition may further contain water, a colorant (for example, titanium oxide, bengara, blue No. 2, yellow No. 5, etc.), an opacifying agent (for example, titanium oxide, etc.), a fragrance, and the like. You can also. As the size of the hard capsule, there are 00, 0, 1, 2, 3, 4, 4, 5, etc., but any size of hard capsule can be used in the present invention.
あるいは、通常のハードカプセル、ソフトカプセル、シームレスカプセルを、本発明のキトサン含有組成物から得られたキトサン膜で被覆してもよい。または、カプセルの被膜形成時にその基材であるゼラチン、セルロースやデンプンなどと一緒に本発明のキトサン含有組成物を配合して通常の方法で被膜形成を行い、カプセルを成型してもよい。その場合は、必要に応じてカラギーナン、アルギン酸、ペクチン、グアーガム、アラビアガム及び大豆多糖類等のゲル化剤や増粘安定剤などをカプセル基材にさらに添加してもよい。本発明のキトサン含有組成物で被覆されるハードカプセルとしては、植物由来のセルロースを変性させたセルロース誘導体や、ゼラチン由来の原料を用いて製造されたものが好ましい。当該ハードカプセルはまた、カプセルに内容物を充填した後、そのカプセルのボディ部とキャップ部との嵌合部に、バンドシールによりシールを行ってもよい。これにより、コーティングの際に嵌合部から本発明のキトサン含有組成物がカプセル内部に侵入することが防止され、また嵌合部が平滑化されることにより、薄く均等な厚さのキトサン被膜を形成することができる。 Or you may coat | cover a normal hard capsule, a soft capsule, and a seamless capsule with the chitosan film | membrane obtained from the chitosan containing composition of this invention. Alternatively, the capsule may be molded by forming the film by a conventional method by blending the chitosan-containing composition of the present invention together with gelatin, cellulose, starch or the like as the base material when forming the film of the capsule. In that case, a gelling agent such as carrageenan, alginic acid, pectin, guar gum, gum arabic, and soybean polysaccharide, a thickening stabilizer, and the like may be further added to the capsule base as necessary. As the hard capsule to be coated with the chitosan-containing composition of the present invention, a cellulose derivative obtained by modifying a plant-derived cellulose or a gelatin-derived raw material is preferable. In the hard capsule, after the capsule is filled with the contents, the fitting portion between the body portion and the cap portion of the capsule may be sealed with a band seal. This prevents the chitosan-containing composition of the present invention from entering the capsule from the fitting part during coating, and the fitting part is smoothed to form a thin and uniform thickness chitosan film. Can be formed.
本発明のキトサンコーティング組成物を錠剤や丸剤、顆粒とする場合は、通常の方法で得られた錠剤や丸剤、顆粒を、本発明のキトサン含有組成物から製造されたキトサン膜で被覆すればよい。当該錠剤や丸剤は、その用途及び使用目的を考慮して、多層錠、有核錠などの通常の形態にすることができる。また当該錠剤、丸剤または顆粒は、目的とする医薬成分や機能性成分に、必要に応じて、結合剤、滑沢剤、崩壊剤、賦形剤等の、錠剤、丸剤または顆粒の製造に通常用いられる添加剤を配合して、製造することができる。製造後の当該錠剤、丸剤または顆粒を、本発明のキトサン含有組成物から得られたキトサン膜で被覆すればよい。 When the chitosan coating composition of the present invention is used as a tablet, pill or granule, the tablet, pill or granule obtained by the usual method is coated with a chitosan film produced from the chitosan-containing composition of the present invention. That's fine. The tablets and pills can be made into ordinary forms such as multilayer tablets and dry-coated tablets in consideration of their uses and intended purposes. In addition, the tablets, pills, or granules can be produced into tablets, pills, or granules, such as binders, lubricants, disintegrants, excipients, etc., if necessary, in addition to the intended pharmaceutical ingredients and functional ingredients. Can be produced by blending with additives usually used. What is necessary is just to coat | cover the said tablet, pill, or granule after manufacture with the chitosan film | membrane obtained from the chitosan containing composition of this invention.
あるいは、直径７ｍｍ以下の小さな錠剤、丸剤または顆粒を本発明のキトサン含有組成物から製造されたキトサン膜で被覆し、その被覆された錠剤、丸剤または顆粒を、通常のカプセルに充填してもよい。 Alternatively, a small tablet, pill or granule having a diameter of 7 mm or less is coated with a chitosan film produced from the chitosan-containing composition of the present invention, and the coated tablet, pill or granule is filled into a normal capsule. Also good.
本発明のキトサンコーティング組成物における、本発明のキトサン含有組成物から製造されたキトサン膜の質量比は、該キトサンコーティング組成物の形状、大きさ、質量などに応じて適宜選択することができる。例えば、本発明のキトサンコーティング組成物が錠剤、カプセルまたは顆粒である場合は、それらの全質量に対して、キトサン膜の質量は０．３〜８．０質量％、好ましくは０．５〜４．０質量％、より好ましくは０．７〜３．０質量％である。上記質量が０．３質量％未満であると、キトサン膜が薄くなり、被膜としての機能を十分に果たさない。他方、上記質量が８．０質量％を超えると、キトサン膜形成に時間がかかり、組成物に相当量の熱が負荷されてしまうため、好ましくない。 The mass ratio of the chitosan film produced from the chitosan-containing composition of the present invention in the chitosan coating composition of the present invention can be appropriately selected according to the shape, size, mass, etc. of the chitosan coating composition. For example, when the chitosan coating composition of the present invention is a tablet, capsule or granule, the mass of the chitosan film is 0.3 to 8.0% by mass, preferably 0.5 to 4%, based on the total mass thereof. It is 0.0 mass%, More preferably, it is 0.7-3.0 mass%. When the mass is less than 0.3% by mass, the chitosan film becomes thin and does not sufficiently function as a film. On the other hand, if the mass exceeds 8.0 mass%, it takes time to form a chitosan film, and a considerable amount of heat is applied to the composition, which is not preferable.
本発明のキトサンコーティング組成物は、本発明のキトサン含有組成物から製造されたキトサン被膜のさらにその上に耐酸性被膜を施すことにより、大腸で崩壊する大腸ＤＤＳ製剤として製造することができる。当該大腸ＤＤＳ製剤は、耐酸性被膜によりキトサン被膜が崩壊することなく胃を通過することができ、その後小腸で耐酸性被膜が溶解されるとキトサン被膜を露出し、次いで露出したキトサン被膜が大腸で分解されると、崩壊して内部の有効成分を放出し、大腸に当該有効成分を送達することができる。 The chitosan coating composition of the present invention can be produced as a large intestine DDS preparation that disintegrates in the large intestine by further applying an acid-resistant film on the chitosan film produced from the chitosan-containing composition of the present invention. The colorectal DDS preparation can pass through the stomach without the chitosan coating being disintegrated by the acid-resistant coating, and then the chitosan coating is exposed when the acid-resistant coating is dissolved in the small intestine, and then the exposed chitosan coating is formed in the large intestine. When broken down, it can disintegrate to release the active ingredient inside and deliver it to the large intestine.
上記耐酸性被膜としては、胃で溶解せず、小腸から大腸で溶解する腸溶性基材から形成された被膜が好ましい。当該腸溶性基材としては、トウモロコシ蛋白ツエイン（ゼイン）、カルボキシメチルエチルセルロース（ＣＭＥＣ）、メタクリル酸コポリマー、ヒプロメロースフタル酸エステル（ＨＰＭＣＰ）、エチルセルロース、精製セラック、白色セラック、セラック、水性セラック等のセラック類などが挙げられる。これらの中でも、メタクリル酸コポリマー、ＣＭＥＣ、ＨＰＭＣＰ及び、セラック類が、カプセル内部への水の浸入を防止する働きに優れている点で好ましい。 The acid-resistant coating is preferably a coating formed from an enteric base material that does not dissolve in the stomach but dissolves from the small intestine to the large intestine. Examples of the enteric base material include corn protein zein (zein), carboxymethyl ethyl cellulose (CMEC), methacrylic acid copolymer, hypromellose phthalate (HPMCP), ethyl cellulose, purified shellac, white shellac, shellac, and aqueous shellac. Examples include shellacs. Among these, methacrylic acid copolymers, CMEC, HPMCP, and shellacs are preferable in that they are excellent in preventing water from entering the capsule.
本発明のキトサンコーティング組成物に含有させる有効成分としては、組成物の用途に応じて、あらゆる医薬成分及び機能性成分が挙げられ、特に制限されない。例えば、本発明のキトサンコーティング組成物が大腸ＤＤＳ製剤である場合の有効成分としては、ビフィズス菌や乳酸菌、納豆菌等の大腸有用菌が挙げられる。 The active ingredient to be contained in the chitosan coating composition of the present invention includes all pharmaceutical ingredients and functional ingredients, and is not particularly limited, depending on the use of the composition. For example, useful ingredients when the chitosan coating composition of the present invention is a colon DDS preparation include useful colon bacteria such as bifidobacteria, lactic acid bacteria, and natto bacteria.
ビフィズス菌は、人に対して有用な作用をもたらすものである限り特に制限はなく、目的に応じて適宜選択することができる。例えば、ビフィドバクテリウム ロンガム(Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｌｏｎｇｕｍ)、ビフィドバクテリウム ビフィダム(Ｂ．ｂｉｆｉｄｕｍ)、ビフィドバクテリウム ブレーベ(Ｂ．ｂｒｅｖｅ)、ビフィドバクテリウム アドレセンティス(Ｂ．ａｄｏｌｅｓｃｅｎｔｉｓ)、ビフィドバクテリウム インファンティス(Ｂ．ｉｎｆａｎｔｉｓ)、ビフィドバクテリウム アニマリス(Ｂ．ａｎｉｍａｌｉｓ)、ビフィドバクテリウム シュードロンガム(Ｂ．ｐｓｅｕｄｏｌｏｎｇｕｍ)などのビフィドバクテリウム属菌が挙げられる。これらの中でも、ビフィドバクテリウム ロンガム（Ｂ．ｌｏｎｇｕｍ）、ビフィドバクテリウム ビフィダム（Ｂ．ｂｉｆｉｄｕｍ）、ビフィドバクテリウム ブレーベ（Ｂ．ｂｒｅｖｅ）が好適に用いられる。上記ビフィズス菌は、いずれか１種を単独で使用してもよく、２種以上を適宜併用してもよい。 The Bifidobacterium is not particularly limited as long as it has a useful effect on humans, and can be appropriately selected according to the purpose. For example, Bifidobacterium longum, Bifidobacterium Bifidum, B. bleve, B. adolescentis, Bifidobacterium Examples include Bifidobacterium, such as B. infantis, B. animaris, and B. pseudolongum. Among these, Bifidobacterium longum (B. longum), Bifidobacterium bifidum (B. bifidum), and Bifidobacterium breve (B. breve) are preferably used. Any one of these bifidobacteria may be used alone, or two or more thereof may be used in combination as appropriate.
乳酸菌も、人に対して有用な作用をもたらすものである限り特に制限はなく、目的に応じて適宜選択することができる。好適な例としては、ラクトバチルス属やストレプトコッカス属の菌、例えば、ラクトバチルス ガッセリ（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｇａｓｓｅｒｉ）、ラクトバチルス アシドフィルス（Ｌ．ａｃｉｄｏｐｈｉｌｕｓ）、ラクトバチルス ラムノーサ（Ｌ．ｒｈａｍｎｏｓｕｓ）、および乳酸菌ＲＩＥ株等の植物乳酸菌などが挙げられる。上記乳酸菌は、いずれか１種を単独で使用してもよく、２種以上を適宜併用してもよい。 Lactic acid bacteria are not particularly limited as long as they have a useful effect on humans, and can be appropriately selected according to the purpose. Preferable examples include bacteria of the genus Lactobacillus and Streptococcus, such as Lactobacillus gasseri, L. acidophilus, Lactobacillus rhamnosus, and Lactobacillus RIE strains. Examples include lactic acid bacteria. Any one of these lactic acid bacteria may be used alone, or two or more thereof may be used in combination as appropriate.
納豆菌もまた、人に対して有用な作用をもたらすものである限り特に制限はなく、目的に応じて適宜選択することができる。納豆菌の好適な例としては、市販の納豆に由来する納豆菌、ならびに市販の納豆菌、例えば高橋菌（高橋祐蔵研究所製、山形）、成瀬菌（株式会社成瀬醗酵化学研究所製、東京）、宮城野菌（有限会社宮城野納豆製造所製、仙台）、朝日菌（株式会社朝日工業製、東京）、日東菌（株式会社日東薬品工業製、京都）、目黒菌（株式会社目黒研究所製、大阪）などが挙げられる。上記納豆菌は、いずれか１種を単独で使用してもよく、またはいずれか２種以上を併用してもよい。 The natto bacteria are not particularly limited as long as they have a useful effect on humans, and can be appropriately selected according to the purpose. Suitable examples of Bacillus natto include Bacillus natto derived from commercially available natto, as well as commercially available Bacillus natto, such as Takahashi bacteria (manufactured by Yuzo Takahashi Laboratory, Yamagata), Naruse bacteria (manufactured by Naruse Fermentation Chemistry Laboratories, Inc., Tokyo, Japan) ), Miyagino fungus (manufactured by Miyagino Natto Factory, Sendai), Asahi fungus (Asahi Kogyo Co., Ltd., Tokyo), Nitto fungus (manufactured by Nitto Yakuhin Kogyo Co., Ltd., Kyoto), Meguro fungus (manufactured by Meguro Research Co., Ltd.) , Osaka). Any one of these Bacillus natto may be used alone, or any two or more thereof may be used in combination.
上記ビフィズス菌や乳酸菌、納豆菌等の大腸有用菌に加えて、これらの菌に有用なオリゴ糖や、水溶性食物繊維、水不溶性食物繊維などの腸内環境の改善に役立つ成分を本発明のキトサンコーティング組成物にさらに含有させてもよい。オリゴ糖としては、乳糖、ラフィノース、ラクチュロース、スタキオース、フラクトオリゴ糖、大豆オリゴ糖、イソマルトオリゴ糖、ガラクトオリゴ糖、乳果オリゴ糖などが好ましい。 In addition to the above-mentioned useful bacteria of the large intestine such as bifidobacteria, lactic acid bacteria, and natto, oligosaccharides useful for these bacteria, ingredients useful for improving the intestinal environment such as water-soluble dietary fiber and water-insoluble dietary fiber are used in the present invention. It may be further contained in the chitosan coating composition. As the oligosaccharide, lactose, raffinose, lactulose, stachyose, fructooligosaccharide, soybean oligosaccharide, isomaltoligosaccharide, galactooligosaccharide, dairy oligosaccharide and the like are preferable.
さらに、本発明のキトサンコーティング組成物が大腸ＤＤＳ製剤である場合の有効成分としては、上記大腸有用菌以外にも、小腸で失活しやすい有効成分や、小腸で吸収されやすく大腸に到達しにくい有効成分を挙げることができる。そのような有効成分としては、例えば、ビタミンＣ、ビタミンＢ１、Ｂ２、Ｂ６、Ｂ１２、ナイアシン（ニコチン酸）、葉酸等の水溶性ビタミン、大腸で放出されることを目的とした薬理成分、及びそれらの組み合わせを挙げることができる。当該有効成分は、それら自体を単独もしくは組み合わせて、または上記大腸有用菌とともに、本発明のキトサンコーティング組成物に適用することができる。 Furthermore, as an active ingredient when the chitosan coating composition of the present invention is a large intestine DDS preparation, in addition to the above-mentioned useful bacteria for the large intestine, active ingredients that are easily inactivated in the small intestine, easily absorbed in the small intestine, and difficult to reach the large intestine An active ingredient can be mentioned. Examples of such active ingredients include vitamin C, vitamins B1, B2, B6, B12, water-soluble vitamins such as niacin (nicotinic acid) and folic acid, pharmacological ingredients intended to be released in the large intestine, and the like Can be mentioned. The active ingredients can be applied to the chitosan coating composition of the present invention by themselves or in combination, or together with the above-mentioned useful bacteria for the large intestine.
本発明のキトサンコーティング組成物は、他の医薬製剤や機能性製剤と一緒に投与または摂取されてもよい。あるいは、他の医薬成分や機能性成分と一緒に、食品、飼料、医薬品、サプリメント等に含有されてもよい。 The chitosan coating composition of the present invention may be administered or ingested together with other pharmaceutical preparations and functional preparations. Or you may contain in a foodstuff, feed, a pharmaceutical, a supplement, etc. with other pharmaceutical ingredients and functional ingredients.
以下、実施例を挙げて、本発明をさらに詳細に説明するが、本発明はこれらの実施例にのみ限定されるものではない。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not limited only to these Examples.
＜キトサン含有組成物の調製＞
（実施例１）
精製水に酢酸を加えｐＨを約４とした酸性水に、脱アセチル化度が８０モル％以上であるキトサン（フローナックＣ：日本水産株式会社製）を溶解した。ここにグリセリン（花王株式会社製）をキトサン１００質量部に対して２５質量部の量で添加し、キトサン溶解液を得た。別に、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ：信越化学工業株式会社製）をキトサン１００質量部に対して２５質量部の量で熱水に分散させ、その後冷却して溶解液を得た。得られた溶解液をキトサン溶解液と混合し、キトサン含有酸性水溶液を得た。次いで、得られたキトサン含有酸性水溶液にエタノールを液全体質量の２０質量％となる量で加え、さらにキトサンの最終濃度が２．５質量％になるように精製水で調整して、キトサン含有組成物を調製した。
<Preparation of chitosan-containing composition>
Example 1
Chitosan having a degree of deacetylation of 80 mol% or more (Flownac C: manufactured by Nihon Suisan Co., Ltd.) was dissolved in acid water having a pH of about 4 by adding acetic acid to purified water. Glycerin (manufactured by Kao Corporation) was added thereto in an amount of 25 parts by mass with respect to 100 parts by mass of chitosan to obtain a chitosan solution. Separately, hydroxypropyl methylcellulose (HPMC: manufactured by Shin-Etsu Chemical Co., Ltd.) was dispersed in hot water in an amount of 25 parts by mass with respect to 100 parts by mass of chitosan, and then cooled to obtain a solution. The obtained solution was mixed with the chitosan solution to obtain an acidic aqueous solution containing chitosan. Next, ethanol is added to the obtained chitosan-containing acidic aqueous solution in an amount that makes 20% by mass of the total liquid mass, and the chitosan-containing composition is adjusted with purified water so that the final concentration of chitosan becomes 2.5% by mass. A product was prepared.
（実施例２）
グリセリンの添加量をキトサン１００質量部に対して１００質量部とした以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Example 2)
A chitosan-containing composition was prepared in the same procedure as in Example 1 except that the amount of glycerin added was 100 parts by mass with respect to 100 parts by mass of chitosan.
（実施例３）
ヒドロキシプロピルメチルセルロースの添加量をキトサン１００質量部に対して１００質量部とした以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Example 3)
A chitosan-containing composition was prepared in the same procedure as in Example 1 except that the amount of hydroxypropylmethylcellulose added was 100 parts by mass with respect to 100 parts by mass of chitosan.
（実施例４）
実施例１と同じ手順で、但しエタノールを添加せずにキトサン含有組成物を調製した。
Example 4
A chitosan-containing composition was prepared in the same procedure as Example 1, but without adding ethanol.
（実施例５）
ヒドロキシプロピルメチルセルロースとともに、ポリグリセリン脂肪酸エステル（デカグリセリンモノオレエート：理研ビタミン株式会社製）をキトサン１００質量部に対して３質量部の量で熱水に溶解させた以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Example 5)
The same as Example 1 except that polyglycerin fatty acid ester (decaglycerin monooleate: manufactured by Riken Vitamin Co., Ltd.) was dissolved in hot water in an amount of 3 parts by mass with respect to 100 parts by mass of chitosan together with hydroxypropylmethylcellulose. According to the procedure, a chitosan-containing composition was prepared.
（実施例６）
精製水に酢酸を加えｐＨを約４とした酸性水に、脱アセチル化度が８０モル％以上であるキトサン（フローナックＣ：日本水産株式会社製）を溶解した。ここにグリセリン（花王株式会社製）をキトサン１００質量部に対して５０質量部の量で添加し、キトサン溶解液を得た。別に、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ：信越化学工業株式会社製）をキトサン１００質量部に対して５０質量部の量で熱水に分散させた。また、ショ糖ステアリン酸エステル（Ｓ−５７０：三菱化学フーズ株式会社製）を冷水にキトサン１００質量部に対して５０質量部の量で分散させ、この分散液をヒドロキシプロピルメチルセルロース熱水分散液に混ぜ、溶解液を調製した。得られた溶解液をキトサン溶解液と混合し、キトサン含有酸性水溶液を得た。次いで、得られたキトサン含有酸性水溶液にエタノールを液全体質量の２０質量％となる量で加え、さらにキトサン濃度が２．５質量％になるように精製水で調整して、キトサン含有組成物を調製した。
(Example 6)
Chitosan having a degree of deacetylation of 80 mol% or more (Flownac C: manufactured by Nihon Suisan Co., Ltd.) was dissolved in acid water having a pH of about 4 by adding acetic acid to purified water. Here, glycerin (made by Kao Corporation) was added in an amount of 50 parts by mass with respect to 100 parts by mass of chitosan to obtain a chitosan solution. Separately, hydroxypropyl methylcellulose (HPMC: manufactured by Shin-Etsu Chemical Co., Ltd.) was dispersed in hot water in an amount of 50 parts by mass with respect to 100 parts by mass of chitosan. In addition, sucrose stearate ester (S-570: manufactured by Mitsubishi Chemical Foods Co., Ltd.) is dispersed in cold water in an amount of 50 parts by mass with respect to 100 parts by mass of chitosan, and this dispersion is dispersed in a hydroxypropylmethylcellulose hot water dispersion. Mix to prepare a solution. The obtained solution was mixed with the chitosan solution to obtain an acidic aqueous solution containing chitosan. Next, ethanol is added to the obtained chitosan-containing acidic aqueous solution in an amount that makes 20% by mass of the total liquid mass, and the chitosan-containing composition is further adjusted with purified water so that the chitosan concentration becomes 2.5% by mass. Prepared.
（実施例７）
ヒドロキシプロピルメチルセルロースとともに、有機酸モノグリセライド（クエン酸モノグリセライド：理研ビタミン株式会社製）をキトサン１００質量部に対して３質量部の量で熱水に溶解させた以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Example 7)
Along with hydroxypropylmethylcellulose, except that organic acid monoglyceride (citric acid monoglyceride: manufactured by Riken Vitamin Co., Ltd.) was dissolved in hot water in an amount of 3 parts by mass with respect to 100 parts by mass of chitosan, the same procedure as in Example 1, A chitosan-containing composition was prepared.
（実施例８）
実施例１と同じ手順で、エタノールを液全体質量の４０質量％となる量で加え、さらにキトサンの最終濃度が２．５質量％になるように精製水で調整して、キトサン含有組成物を調製した。
(Example 8)
In the same procedure as in Example 1, ethanol was added in an amount to be 40% by mass of the total mass of the liquid, and further adjusted with purified water so that the final concentration of chitosan was 2.5% by mass, to obtain a chitosan-containing composition. Prepared.
（実施例９）
実施例１と同じ手順で、エタノールを液全体質量の６０質量％となる量で加え、さらにキトサンの最終濃度が２．５質量％になるように精製水で調整して、キトサン含有組成物を調製した。
Example 9
In the same procedure as in Example 1, ethanol was added in an amount that would be 60% by mass of the total mass of the liquid, and the final concentration of chitosan was adjusted to 2.5% by mass with purified water to obtain a chitosan-containing composition. Prepared.
（実施例１０）
多価アルコールのグリセリンをソルビトール（三菱商事フードテック株式会社製）とした以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Example 10)
A chitosan-containing composition was prepared in the same procedure as in Example 1 except that glycerin of polyhydric alcohol was sorbitol (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.).
（実施例１１）
ヒドロキシプロピルメチルセルロースとともに、中鎖脂肪酸トリグリセライド（ココナードMT：花王株式会社製）をキトサン１００質量部に対して３質量部の量で熱水に溶解させた以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Example 11)
In the same procedure as in Example 1, except that hydroxypropylmethylcellulose and medium chain fatty acid triglyceride (Coconard MT: manufactured by Kao Corporation) were dissolved in hot water in an amount of 3 parts by mass with respect to 100 parts by mass of chitosan. A containing composition was prepared.
（実施例１２）
ヒドロキシプロピルメチルセルロースとともに、小麦胚芽油（日清ファルマ株式会社製）をキトサン１００質量部に対して２質量部の量で熱水に溶解させた以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Example 12)
A chitosan-containing composition was prepared in the same manner as in Example 1 except that wheat germ oil (manufactured by Nisshin Pharma Co., Ltd.) and hydroxypropylmethylcellulose were dissolved in hot water in an amount of 2 parts by mass with respect to 100 parts by mass of chitosan. A product was prepared.
（実施例１３）
ヒドロキシプロピルメチルセルロースとともに、グリセリン脂肪酸エステル（グリセリルモノオレエート：日光ケミカルズ製）をキトサン１００質量部に対して３質量部の量で熱水に溶解させた以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Example 13)
Chitosan was prepared in the same procedure as in Example 1 except that glycerin fatty acid ester (glyceryl monooleate: manufactured by Nikko Chemicals) was dissolved in hot water in an amount of 3 parts by mass with respect to 100 parts by mass of chitosan together with hydroxypropylmethylcellulose. A containing composition was prepared.
（比較例１）
キトサン溶解液にヒドロキシプロピルメチルセルロース溶解液を添加しなかったこと以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Comparative Example 1)
A chitosan-containing composition was prepared in the same procedure as in Example 1 except that the hydroxypropylmethylcellulose solution was not added to the chitosan solution.
（比較例２）
実施例１と同じ手順でキトサン溶解液を得た。ポリグリセリン脂肪酸エステル（デカグリセリンモノオレエート：理研ビタミン株式会社製）をキトサン１００質量部に対して２５質量部の量で熱水に溶解し、冷却して溶解液を得、これをキトサン溶解液と混合して、キトサン含有酸性水溶液を得た。次いで、得られたキトサン含有酸性水溶液にエタノールを液全体質量の２０質量％となる量で加え、キトサン濃度が２．５質量％になるように精製水で調整して、キトサン含有組成物を調製した。
(Comparative Example 2)
A chitosan solution was obtained in the same procedure as in Example 1. Polyglycerin fatty acid ester (decaglycerin monooleate: manufactured by Riken Vitamin Co., Ltd.) is dissolved in hot water in an amount of 25 parts by mass with respect to 100 parts by mass of chitosan, cooled to obtain a solution, and this is obtained as a chitosan solution. To obtain an acidic aqueous solution containing chitosan. Next, ethanol is added to the obtained chitosan-containing acidic aqueous solution in an amount that makes 20% by mass of the total liquid mass, and the chitosan-containing composition is prepared by adjusting with purified water so that the chitosan concentration becomes 2.5% by mass. did.
（比較例３）
グリセリンを添加しなかったこと以外は、実施例１と同じ手順で、キトサン含有組成物を調製した。
(Comparative Example 3)
A chitosan-containing composition was prepared in the same procedure as in Example 1 except that glycerin was not added.
実施例１〜１３及び比較例１〜３で調製したキトサン含有組成物の組成を、下記表１に示す。 The compositions of the chitosan-containing compositions prepared in Examples 1 to 13 and Comparative Examples 1 to 3 are shown in Table 1 below.
＜試験例１ キャスティングフィルム作製＞
実施例１〜５、１０及び比較例１〜３の各キトサン含有組成物をトレーに流し入れ、５０℃で１８時間乾燥させてキャスティングフィルムを作製した。当該フィルムの乾燥速度、残存酢酸量、耐水性、及び弾力性を測定した。乾燥速度は、乾燥工程中に経時的にキャスティングフィルムの状態及び臭いを調べることにより判定した。得られたキャスティングフィルムの一部を酸に溶解し、フィルムの残存酢酸量を、Ｉｎｅｒｔｓｉｌ ＯＤＳ−４のカラムを用いたＨＰＬＣにて、別に準備した酢酸の標準溶液に対するピーク面積比として求めた。耐水性は、日本薬局方崩壊試験法に基づき、１０ｍｍ角のフィルムが精製水中で９０分以上崩壊しないか否かで評価した。弾力性は、キャスティングフィルムを手で折り曲げて判断した。
<Test Example 1 Casting Film Production>
The chitosan-containing compositions of Examples 1 to 5, 10 and Comparative Examples 1 to 3 were poured into trays and dried at 50 ° C. for 18 hours to prepare casting films. The drying rate, residual acetic acid amount, water resistance, and elasticity of the film were measured. The drying rate was determined by examining the state and odor of the casting film over time during the drying process. A part of the obtained casting film was dissolved in an acid, and the amount of residual acetic acid of the film was determined as a peak area ratio with respect to a standard solution of acetic acid prepared separately by HPLC using an Inertsil ODS-4 column. The water resistance was evaluated based on whether or not a 10 mm square film was disintegrated for 90 minutes or more in purified water based on the Japanese Pharmacopoeia Disintegration Test Method. The elasticity was judged by bending the casting film by hand.
結果を表２に示す。グリセリン又はソルビトールとヒドロキシプロピルメチルセルロース（ＨＰＭＣ）とを含有するキトサン含有組成物から製造されたキトサンフィルムは、乾燥が速く、酸の残存量が少なく、且つ耐水性と弾力性も良好であった。 The results are shown in Table 2. A chitosan film produced from a chitosan-containing composition containing glycerin or sorbitol and hydroxypropylmethylcellulose (HPMC) was fast-drying, had a small amount of residual acid, and had good water resistance and elasticity.
＜試験例２ 大腸ＤＤＳ製剤試験−１＞
（キトサンコーティングカプセルの製造）
澱粉を充填した３号ハードカプセルを準備し、緘口部にバンドシールを施した。当該カプセルに、実施例１、５、１０及び比較例１、３の各キトサン含有組成物を用いてキトサンコーティングを施した。コーティングは、フィルムコーティング装置ハイコーターミニ型パン（フロイント産業株式会社製）を用いて、乾燥温度を一定（７５℃）にして行った。キトサン膜で被覆した後のカプセルの表面に、カルナウバロウを微量塗布した。
カプセル質量に対するキトサンコーティングの質量は、約１．３質量％であった。必要量のコーティングを施すのに要した時間をコーティング時間として測定した。
得られた各カプセルの一部を酸に溶解し、残存酢酸量を、Ｉｎｅｒｔｓｉｌ ＯＤＳ−４のカラムを用いたＨＰＬＣにて、別に準備した酢酸の標準溶液に対するピーク面積比として求めた。またカプセルの膜強度を、加圧式測定器（ミネベア株式会社製 荷重測定器）でカプセルが割れる圧力として測定した。
<Test Example 2 Colon DDS Formulation Test-1>
(Manufacture of chitosan coated capsules)
A No. 3 hard capsule filled with starch was prepared, and a band seal was applied to the mouth. The capsules were subjected to chitosan coating using the chitosan-containing compositions of Examples 1, 5, 10 and Comparative Examples 1, 3. The coating was performed at a constant drying temperature (75 ° C.) using a film coater high coater mini-type pan (Freund Sangyo Co., Ltd.). A small amount of carnauba wax was applied to the surface of the capsule after coating with the chitosan film.
The mass of the chitosan coating relative to the capsule mass was about 1.3% by mass. The time required to apply the required amount of coating was measured as the coating time.
A part of each of the obtained capsules was dissolved in acid, and the amount of residual acetic acid was determined as a peak area ratio with respect to a standard solution of acetic acid prepared separately by HPLC using an Inertsil ODS-4 column. The membrane strength of the capsules was measured as a pressure at which the capsules were broken with a pressurization type measuring device (load measuring device manufactured by Minebea Co., Ltd.).
（崩壊試験）
上記で得られた各キトサンコーティングカプセルの大腸崩壊性を調べた。崩壊試験は、各カプセルを６個ずつ用い、日本薬局方の崩壊試験装置を用いて行った。
最初にカプセルを補助盤無しの条件で、精製水中で９０分間上下運動を行った後、カプセルの崩壊性を下記評価基準に従って３段階で判定した。
−評価基準−（精製水中での崩壊性）
◎：６個すべてが形状を維持し、膨潤や崩壊などの変形が認められなかった。（適合）
○：６個中２個以内で若干膨潤・崩壊などの変形が認められる。（適合）
×：６個中３個以上で内容物が溶出された。（不適）
精製水中での崩壊試験で適合の評価が出たカプセルを、続いて、大腸想定液であるｐＨ３．５の酢酸緩衝液（Ｍｉｃｈａｅｌｉｓの緩衝液）中に入れ、６０分間上下運動を行った後、カプセルの崩壊の有無を観察した。
(Disintegration test)
Each of the chitosan-coated capsules obtained above was examined for colon disintegration. The disintegration test was performed using 6 capsules each and using a disintegration test apparatus of Japanese Pharmacopoeia.
First, the capsule was moved up and down in purified water for 90 minutes under the condition without an auxiliary board, and then the disintegration property of the capsule was determined in three stages according to the following evaluation criteria.
-Evaluation criteria-(disintegration in purified water)
A: All six pieces maintained their shapes, and no deformation such as swelling or collapse was observed. (Conformity)
○: Some deformation such as swelling / disintegration is observed within 2 out of 6 pieces. (Conformity)
X: The content was eluted in 3 or more of 6 pieces. (Unsuitable)
Capsules that were evaluated for suitability in a disintegration test in purified water were subsequently placed in a pH 3.5 acetic acid buffer solution (Michaelis buffer solution), which is an assumed large intestine solution, and moved up and down for 60 minutes. The presence or absence of capsule disintegration was observed.
結果を表３に示す。グリセリン又はソルビトールとヒドロキシプロピルメチルセルロース（ＨＰＭＣ）を含有するキトサン含有組成物から製造されたキトサンコーティングカプセルは、酸の残存量が少なく、また耐水性及び強度が高く、良好な大腸崩壊性を示した。 The results are shown in Table 3. Chitosan-coated capsules produced from a chitosan-containing composition containing glycerin or sorbitol and hydroxypropylmethylcellulose (HPMC) showed low residual amount of acid, high water resistance and strength, and good colonic disintegration.
＜試験例３ 大腸ＤＤＳ製剤試験−２＞
澱粉を充填した３号ハードカプセルを準備し、緘口部にバンドシールを施した。当該カプセルに、実施例１、５及び比較例１、３の各キトサン含有組成物を用いてキトサンコーティング約１．３質量％を施した後、耐酸性被膜であるシェラック約１．２質量％コーティングを施した後、カプセルの表面に、カルナウバロウを微量塗布した。
得られた各カプセルの一部を酸に溶解し、残存酢酸量を、Ｉｎｅｒｔｓｉｌ ＯＤＳ−４のカラムを用いたＨＰＬＣにて、別に準備した酢酸の標準溶液に対するピーク面積比として求めた。またカプセルの膜強度を、加圧式測定器（ミネベア株式会社製 荷重測定器）でカプセルが割れる圧力として測定した。
<Test Example 3 Colon DDS Formulation Test-2>
A No. 3 hard capsule filled with starch was prepared, and a band seal was applied to the mouth. The capsule was subjected to about 1.3% by mass of chitosan coating using the chitosan-containing compositions of Examples 1 and 5 and Comparative Examples 1 and 3, followed by coating of about 1.2% by mass of shellac, which is an acid-resistant film. Then, a small amount of carnauba wax was applied to the capsule surface.
A part of each of the obtained capsules was dissolved in acid, and the amount of residual acetic acid was determined as a peak area ratio with respect to a standard solution of acetic acid prepared separately by HPLC using an Inertsil ODS-4 column. The membrane strength of the capsules was measured as a pressure at which the capsules were broken with a pressurization type measuring device (load measuring device manufactured by Minebea Co., Ltd.).
（崩壊試験）
上記で得られた各キトサンコーティングカプセルの大腸崩壊性を調べた。崩壊試験は、各カプセルを６個ずつ用い、日本薬局方の崩壊試験装置を用いて行った。
カプセルを補助盤無しの条件で、胃想定液（ｐＨ１．２）中で６０分間上下運動させ、続けて小腸想定液（ｐＨ６．８）中で１２０分間上下運動させた。各溶液中でのカプセルの崩壊性を下記評価基準に従って３段階で判定した。小腸想定液での崩壊試験で適合の評価が出たカプセルを、大腸想定液（ｐＨ３．５）中で１２０分間上下運動させ、カプセルの崩壊の有無を観察した。
−評価基準−（液中での崩壊性）
◎：６個すべてが形状を維持し、膨潤や崩壊などの変形が認められなかった。（適合）
○：６個中２個以内で若干膨潤・崩壊などの変形が認められる。（適合）
×：６個中３個以上で内容物が溶出された。（不適）
(Disintegration test)
Each of the chitosan-coated capsules obtained above was examined for colon disintegration. The disintegration test was performed using 6 capsules each and using a disintegration test apparatus of Japanese Pharmacopoeia.
The capsule was moved up and down in the assumed stomach solution (pH 1.2) for 60 minutes under the condition without an auxiliary board, and then moved up and down in the assumed small intestine solution (pH 6.8) for 120 minutes. The disintegration properties of the capsules in each solution were determined in three stages according to the following evaluation criteria. Capsules that were evaluated for conformity in the disintegration test with the assumed small intestine solution were moved up and down in the assumed large intestine solution (pH 3.5) for 120 minutes, and the presence or absence of capsule disintegration was observed.
-Evaluation criteria-(disintegration in liquid)
A: All six pieces maintained their shapes, and no deformation such as swelling or collapse was observed. (Conformity)
○: Some deformation such as swelling / disintegration is observed within 2 out of 6 pieces. (Conformity)
X: The content was eluted in 3 or more of 6 pieces. (Unsuitable)
結果を表４に示す。グリセリン及びヒドロキシプロピルメチルセルロース（ＨＰＭＣ）を含有するキトサン含有組成物から製造されたキトサンコーティングカプセルは、酸の残存量が少なく、また耐酸性及び強度が高く、良好な大腸崩壊性を示した。 The results are shown in Table 4. Chitosan-coated capsules produced from a chitosan-containing composition containing glycerin and hydroxypropylmethylcellulose (HPMC) showed low acid residue, high acid resistance and strength, and good colonic disintegration.
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| JP2017515879A (en) * | 2014-05-19 | 2017-06-15 | ティロッツ・ファルマ・アクチエンゲゼルシャフトＴｉｌｌｏｔｔｓ Ｐｈａｒｍａ Ａｇ | Controlled release coating capsules |
| JP2021501676A (en) * | 2017-11-03 | 2021-01-21 | ディーエスエム アイピー アセッツ ビー．ブイ．Ｄｓｍ Ｉｐ Ａｓｓｅｔｓ Ｂ．Ｖ． | New delivery system |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2017515879A (en) * | 2014-05-19 | 2017-06-15 | ティロッツ・ファルマ・アクチエンゲゼルシャフトＴｉｌｌｏｔｔｓ Ｐｈａｒｍａ Ａｇ | Controlled release coating capsules |
| US11160762B2 (en) | 2014-05-19 | 2021-11-02 | Tillotts Pharma Ag | Modified release coated capsules |
| KR101730556B1 (en) | 2015-05-27 | 2017-04-26 | 하이트진로 주식회사 | Method for preparing complex coating capsule containing fruit juice |
| JP2022097602A (en) * | 2016-11-29 | 2022-06-30 | 三生医薬株式会社 | Film coating composition, and solid preparations |
| JP2021501676A (en) * | 2017-11-03 | 2021-01-21 | ディーエスエム アイピー アセッツ ビー．ブイ．Ｄｓｍ Ｉｐ Ａｓｓｅｔｓ Ｂ．Ｖ． | New delivery system |
| JP7331322B2 (en) | 2017-11-03 | 2023-08-23 | ディーエスエム アイピー アセッツ ビー．ブイ． | novel delivery system |
| CN115110105A (en) * | 2022-07-28 | 2022-09-27 | 广东海洋大学 | Method for simply preparing chitosan oligosaccharide from shrimp shells |
| CN115110105B (en) * | 2022-07-28 | 2023-11-21 | 广东海洋大学 | Simple preparation method of chitosan oligosaccharide from shrimp shells |
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| JP6062802B2 (en) | 2017-01-18 |
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