JP2019119769A - Production method of water-insoluble molded body and water-insoluble molded body - Google Patents
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Description
本発明は、水不溶性成形体の製造方法、及び水不溶性成形体に関する。 The present invention relates to a method for producing a water-insoluble molded body, and a water-insoluble molded body.
ヒアルロン酸やアルギン酸等のポリアニオン性多糖類は、適度な粘性、粘着性、保湿性、及び生体適合性を示すことが知られている。このため、これらのポリアニオン性多糖類及びその塩は、医療用材料、食品用材料、及び化粧品用材料等の原材料として幅広く用いられている。 Polyanionic polysaccharides such as hyaluronic acid and alginic acid are known to exhibit appropriate viscosity, adhesiveness, moisture retention and biocompatibility. Therefore, these polyanionic polysaccharides and salts thereof are widely used as raw materials for medical materials, food materials, and cosmetic materials.
なかでもヒアルロン酸は、保水性などの特徴的な物性に優れているとともに、安全性及び生体適合性が高いことから、食品、化粧品、及び医薬品等の様々な用途に利用されている。例えば医療分野では、ヒアルロン酸は関節潤滑剤や癒着防止材の原料などに利用されている。但し、原料となるヒアルロン酸ナトリウムは水溶性が高いため、用途によっては何らかの水不溶化処理を施す必要がある。 Among them, hyaluronic acid is used for various applications such as food, cosmetics and medicines because it is excellent in characteristic physical properties such as water retention and is high in safety and biocompatibility. For example, in the medical field, hyaluronic acid is used as a raw material for joint lubricants and adhesion prevention materials. However, since sodium hyaluronate which is a raw material has high water solubility, it is necessary to perform some water insolubilization treatment depending on the use.
これまで、カルボキシ基を利用した架橋反応によりヒアルロン酸ナトリウムを水不溶化させる方法について種々検討されている。例えば、特許文献１には、カルボジイミドを用いた架橋反応により、ヒアルロン酸やカルボキシメチルセルロース等のポリアニオン性多糖類の非水溶性誘導体を製造する方法が記載されている。また、特許文献２には、粉末状ヒアルロン酸と無水酢酸とを濃硫酸の存在下で反応させてアセチル化することが記載されている。さらに、特許文献３には、アルコールを含む酸性の液を用いてヒアルロン酸ゲルを製造する方法が記載されている。 Until now, various studies have been made on a method of water-solubilizing sodium hyaluronate by a crosslinking reaction using a carboxy group. For example, Patent Document 1 describes a method for producing a water-insoluble derivative of a polyanionic polysaccharide such as hyaluronic acid or carboxymethyl cellulose by a crosslinking reaction using carbodiimide. Patent Document 2 describes that acetylation is caused by reacting powdered hyaluronic acid with acetic anhydride in the presence of concentrated sulfuric acid. Furthermore, Patent Document 3 describes a method for producing a hyaluronic acid gel using an acidic solution containing an alcohol.
しかしながら、特許文献１に記載の方法は化学架橋剤を用いる方法であるため、医薬品等の人体に付与される用途等の安全性を考慮する場合には適用が困難な場合が多い。また、特許文献２には、得られたヒアルロン酸のアセチル化物の水不溶性の程度については一切記載されていない。さらに、特許文献３に記載の方法で得られるヒアルロン酸ゲルは多量の水分を含むため、持ち上げることも難しい。このため、成形体の形状を維持したまま不溶化することは困難である。 However, since the method described in Patent Document 1 is a method using a chemical crosslinking agent, its application is often difficult when considering the safety of applications such as pharmaceuticals applied to the human body. In addition, Patent Document 2 does not describe at all the degree of water insolubility of the obtained acetylated product of hyaluronic acid. Furthermore, since the hyaluronic acid gel obtained by the method described in Patent Document 3 contains a large amount of water, it is also difficult to lift it. For this reason, it is difficult to insolubilize while maintaining the shape of the molded body.
一方、化学架橋剤を用いることなく、ポリアニオン性多糖類本来の特性が保持された水不溶性成形体を簡便に製造すべく、ヒアルロン酸等の水溶性塩からなる原料成形体を酸無水物で処理して水不溶化する方法が提案されている（特許文献４）。 On the other hand, in order to easily produce a water-insoluble molded article in which the inherent properties of polyanionic polysaccharides are maintained without using a chemical crosslinking agent, a raw material molded article comprising a water-soluble salt such as hyaluronic acid is treated with an acid anhydride A method of water insolubilization is proposed (Patent Document 4).
特許文献４で提案された方法によれば、実質的に取り扱い可能な水不溶性成形体を比較的簡便に製造することが可能であった。しかしながら、得られる水不溶性成形体の水による膨潤率を低く抑えることは困難であった。水による膨潤率が比較的高い水不溶性成形体は、強度や形状保持日数など、要求される物性が用途によっては不十分となる場合がある。このため、ポリアニオン性多糖類本来の特性が保持された、膨潤率の低い水不溶性成形体を簡便に製造する方法が要望されていた。 According to the method proposed in Patent Document 4, it has been possible to relatively easily produce a water-insoluble molded article that can be substantially handled. However, it has been difficult to suppress the water swelling rate of the resulting water-insoluble molded product to a low level. Water-insoluble molded articles having a relatively high swelling ratio by water may have insufficient required physical properties such as strength and shape retention days depending on the application. For this reason, there has been a demand for a method of easily producing a water-insoluble molded article with a low swelling ratio, in which the original properties of polyanionic polysaccharides are maintained.
本発明は、このような従来技術の有する問題点に鑑みてなされたものであり、その課題とするところは、原料であるポリアニオン性多糖類本来の特性が保持されているとともに、安全性が高く、医療用材料、食品用材料、及び化粧品用材料等として有用な、水による膨潤率が低い水不溶性成形体を簡便に製造する方法を提供することにある。また、本発明の課題とするところは、原料であるポリアニオン性多糖類本来の特性が保持されているとともに、安全性が高く、医療用材料、食品用材料、及び化粧品用材料等として有用な、水による膨潤率が低い水不溶性成形体を提供することにある。 The present invention has been made in view of the problems of the prior art as described above, and the problems to be solved by the present invention are that the original characteristics of the polyanionic polysaccharide as the raw material are maintained, and the safety is high. It is an object of the present invention to provide a method for easily producing a water-insoluble molded article having a low swelling ratio with water, which is useful as a medical material, a food material, a cosmetic material and the like. In addition, the object of the present invention is that the original characteristics of the polyanionic polysaccharide which is the raw material are maintained, the safety is high, and useful as a medical material, a food material, a cosmetic material, etc. An object of the present invention is to provide a water-insoluble molded article having a low rate of swelling by water.
すなわち、本発明によれば、以下に示す水不溶性成形体の製造方法が提供される。
［１］ポリアニオン性多糖類の水溶性塩からなる原料成形体を、前記原料成形体の形状を維持したまま水不溶して水不溶性成形体を得る水不溶性成形体の製造方法であって、前記原料成形体を、酸無水物をそれぞれ含有する第１の処理液及び第２の処理液に順次接触させて複数回水不溶化処理し、膨潤率１６０％以下の水不溶性成形体を得る工程を有し、前記第１の処理液に比して前記第２の処理液の疎水性が高い水不溶性成形体の製造方法。
［２］前記原料成形体の形状が、膜状、塊状、繊維状、棒状、管状、粉末状、粒子状、又はスポンジ状である前記［１］に記載の水不溶性成形体の製造方法。
［３］前記ポリアニオン性多糖類が、ヒアルロン酸、カルボキシアルキルセルロース、アルギン酸、及びカラギーナンからなる群より選択される少なくとも一種である前記［１］又は［２］に記載の水不溶性成形体の製造方法。
［４］前記酸無水物が、無水酢酸及び無水プロピオン酸の少なくともいずれかである前記［１］〜［３］のいずれかに記載の水不溶性成形体の製造方法。
［５］前記第１の処理液及び前記第２の処理液が、水及び水溶性有機溶媒の少なくともいずれかの媒体をさらに含有する前記［１］〜［４］のいずれかに記載の水不溶性成形体の製造方法。
［６］前記水溶性有機溶媒が、メタノール、エタノール、プロパノール、ジメチルスルホキシド、アセトニトリル、及びテトラヒドロフランからなる群より選択される少なくとも一種である前記［５］に記載の水不溶性成形体の製造方法。
［７］前記第１の処理液に比して、前記第２の処理液の前記水の含有量が少ない前記［５］又は［６］に記載の水不溶性成形体の製造方法。
［８］前記第１の処理液に比して、前記第２の処理液の前記酸無水物の含有量が多い前記［１］〜［７］のいずれかに記載の水不溶性成形体の製造方法。
［９］前記原料成形体を前記第１の処理液及び第２の処理液のそれぞれとともに袋状容器内に封入し、加熱して水不溶化処理する前記［１］〜［８］のいずれかに記載の水不溶性成形体の製造方法。
［１０］前記原料成形体１００質量部に対する、前記第１の処理液及び第２の処理液のそれぞれの量が、５〜５０質量部である前記［９］に記載の水不溶性成形体の製造方法。
That is, according to the present invention, the following method for producing a water-insoluble molded article is provided.
[1] A method for producing a water-insoluble molded article, wherein a raw material molded body comprising a water-soluble salt of a polyanionic polysaccharide is water-insoluble while maintaining the shape of the raw material molded body to obtain a water-insoluble molded body, The raw material compact is sequentially brought into contact with the first treatment liquid and the second treatment liquid each containing an acid anhydride and subjected to a plurality of times of water insolubilization treatment to obtain a water insoluble compact having a swelling ratio of 160% or less And a method of producing a water-insoluble molded article in which the hydrophobicity of the second treatment liquid is higher than that of the first treatment liquid.
[2] The method for producing a water-insoluble molded article according to the above [1], wherein the shape of the raw material molded body is in the form of a film, a block, a fiber, a rod, a tube, a powder, a particle or a sponge.
[3] The method for producing a water-insoluble molded article according to the above [1] or [2], wherein the polyanionic polysaccharide is at least one selected from the group consisting of hyaluronic acid, carboxyalkyl cellulose, alginic acid, and carrageenan .
[4] The method for producing a water-insoluble molded article according to any one of the above [1] to [3], wherein the acid anhydride is at least one of acetic anhydride and propionic anhydride.
[5] The water insoluble matter according to any one of the above [1] to [4], wherein the first treatment liquid and the second treatment liquid further contain a medium of at least one of water and a water-soluble organic solvent. Method for producing a molded body.
[6] The method for producing a water-insoluble molded article according to the above [5], wherein the water-soluble organic solvent is at least one selected from the group consisting of methanol, ethanol, propanol, dimethylsulfoxide, acetonitrile and tetrahydrofuran.
[7] The method for producing a water-insoluble molded article according to the above [5] or [6], wherein the water content of the second treatment liquid is smaller than that of the first treatment liquid.
[8] The production of the water-insoluble molded article according to any one of the above [1] to [7], wherein the content of the acid anhydride of the second treatment liquid is higher than that of the first treatment liquid. Method.
[9] In any one of the above [1] to [8], the raw material compact is sealed in a bag-like container together with each of the first treatment liquid and the second treatment liquid, and is heated for water insolubilization treatment. The manufacturing method of the water-insoluble molded object as described.
[10] The production of a water-insoluble molded article according to the above [9], wherein the amount of each of the first treatment liquid and the second treatment liquid is 5 to 50 parts by mass with respect to 100 parts by mass of the raw material molded body. Method.
また、本発明によれば、以下に示す水不溶性成形体が提供される。
［１１］前記［１］〜［１０］のいずれかに記載の製造方法によって製造された、膨潤率１６０％以下の水不溶性成形体。
Further, according to the present invention, the following water-insoluble molded article is provided.
[11] A water-insoluble molded article having a swelling ratio of 160% or less produced by the production method according to any one of the above [1] to [10].
本発明によれば、原料であるポリアニオン性多糖類本来の特性が保持されているとともに、安全性が高く、医療用材料、食品用材料、及び化粧品用材料等として有用な、水による膨潤率が低い水不溶性成形体を簡便に製造する方法を提供することができる。また、本発明によれば、原料であるポリアニオン性多糖類本来の特性が保持されているとともに、安全性が高く、医療用材料、食品用材料、及び化粧品用材料等として有用な、水による膨潤率が低い水不溶性成形体を提供することができる。 According to the present invention, while maintaining the original characteristics of polyanionic polysaccharide which is the raw material, it is highly safe and has a swelling ratio with water which is useful as a medical material, food material, cosmetic material, etc. It is possible to provide a method of easily producing a low water-insoluble shaped article. Further, according to the present invention, the swelling property by water is maintained as well as the original characteristics of the polyanionic polysaccharide which is a raw material, is highly safe, and is useful as a medical material, a food material, a cosmetic material, etc. It is possible to provide a water-insoluble molded article with a low rate.
以下、本発明の実施の形態について説明するが、本発明は以下の実施の形態に限定されるものではない。 Hereinafter, although the embodiment of the present invention is described, the present invention is not limited to the following embodiment.
＜水不溶性成形体及びその製造方法＞
本発明の水不溶性成形体の製造方法（以下、単に「（本発明の）製造方法」とも記す）は、ポリアニオン性多糖類の水溶性塩からなる原料成形体を、原料成形体の形状を維持したまま水不溶して水不溶性成形体を得る方法であり、原料成形体を、酸無水物をそれぞれ含有する第１の処理液及び第２の処理液に順次接触させて複数回水不溶化処理し、膨潤率１６０％以下の水不溶性成形体を得る工程（水不溶化工程）を有する。そして、第１の処理液に比して第２の処理液の疎水性が高いことを要する。以下、本発明の水不溶性成形体及びその製造方法の詳細について説明する。
<Water-Insoluble Molded Article and Method for Producing the Same>
The method for producing a water-insoluble molded article of the present invention (hereinafter simply referred to as “the production process according to the present invention”) maintains the shape of the raw material molded body from the raw material molded body consisting of a water-soluble salt of polyanionic polysaccharide This is a method of obtaining a water-insoluble molding by water-insoluble molding as it is, and the raw material molding is sequentially contacted with a first treatment liquid and a second treatment liquid containing acid anhydride respectively to carry out a plurality of water-insolubilization treatments And a step of obtaining a water-insoluble molded article having a swelling ratio of 160% or less (water insolubilization step). And, it is required that the hydrophobicity of the second processing liquid is higher than that of the first processing liquid. Hereinafter, the details of the water-insoluble molded article of the present invention and the method for producing the same will be described.
原料成形体は、ポリアニオン性多糖類の水溶性塩を用いて形成される。ポリアニオン性多糖類は、カルボキシ基やスルホン酸基等の負電荷を帯びた１以上のアニオン性基をその分子構造中に有する多糖類である。また、ポリアニオン性多糖類の水溶性塩は、ポリアニオン性多糖類中のアニオン性基の少なくとも一部が塩を形成したものである。なお、ポリアニオン性多糖類中のアニオン性基は、多糖類の分子中に導入されたものであってもよい。 The raw material compact is formed using a water-soluble salt of polyanionic polysaccharide. The polyanionic polysaccharide is a polysaccharide having one or more negatively charged anionic groups such as a carboxy group and a sulfonic acid group in its molecular structure. Moreover, the water-soluble salt of polyanionic polysaccharide is a salt in which at least a part of the anionic group in the polyanionic polysaccharide is formed. The anionic group in the polyanionic polysaccharide may be one introduced in the molecule of the polysaccharide.
ポリアニオン性多糖類の具体例としては、カルボキシメチルセルロースやカルボキシエチルセルロース等のカルボキシアルキルセルロース、カルボキシメチルでんぷん、カルボキシメチルアミロース、コンドロイチン硫酸（コンドロイチン−４−硫酸及びコンドロイチン−６−硫酸を含む）、ヒアルロン酸、ヘパリン、ヘパリン硫酸、ヘパラン硫酸、アルギン酸、ペクチン、カラギーナン、デルマタン硫酸、及びデルマタン−６−硫酸等を挙げることができる。これらのポリアニオン性多糖類は、一種単独で又は二種以上を組み合わせて用いることができる。 Specific examples of polyanionic polysaccharides include carboxyalkylcelluloses such as carboxymethylcellulose and carboxyethylcellulose, carboxymethyl starch, carboxymethyl amylose, chondroitin sulfate (including chondroitin-4-sulfate and chondroitin-6-sulfate), hyaluronic acid, Heparin, heparin sulfate, heparan sulfate, alginic acid, pectin, carrageenan, dermatan sulfate, dermatan 6-sulfate and the like can be mentioned. These polyanionic polysaccharides can be used alone or in combination of two or more.
ポリアニオン性多糖類の水溶性塩としては、無機塩、アンモニウム塩、及び有機アミン塩等を挙げることができる。無機塩の具体例としては、ナトリウム、カリウム等のアルカリ金属塩；カルシウム塩等のアルカリ土類金属塩；亜鉛、鉄等の金属塩等を挙げることができる。 As water-soluble salts of polyanionic polysaccharides, inorganic salts, ammonium salts, organic amine salts and the like can be mentioned. Specific examples of the inorganic salt include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium salt; and metal salts such as zinc and iron.
原料成形体は、例えば、ポリアニオン性多糖類の水溶性塩を水に溶解させて得た水溶液を所望の形状に成形した後、乾燥等させることによって得ることができる。原料成形体の形状としては、例えば、膜状、塊状、繊維状、棒状、管状、粉末状、粒子状、及びスポンジ状等を挙げることができる。これらの形状の原料成形体を水不溶化させることによって、膜状、塊状、繊維状、棒状、管状、粉末状、粒子状、及びスポンジ状等の用途に応じた形状の水不溶性成形体を得ることができる。なお、必要に応じて、得られた水不溶性成形体をさらに成形して所望の形状に加工してもよい。 The raw material molded product can be obtained, for example, by forming an aqueous solution obtained by dissolving a water-soluble salt of a polyanionic polysaccharide in water into a desired shape, and then drying or the like. Examples of the shape of the raw material molded body include a film, a block, a fiber, a rod, a tube, a powder, a particle, and a sponge. By making the raw material compacts of these shapes into water-insoluble, it is possible to obtain water-insoluble compacts of shapes such as films, lumps, fibers, rods, tubes, powders, particles, and sponges according to the application. Can. In addition, you may shape | mold the obtained water-insoluble molded object further, and process it into a desired shape as needed.
例えば、ポリアニオン性多糖類の水溶性塩の水溶液を適当な容器に流し入れた後、乾燥又は凍結乾燥することによって、膜状（シート状）又は塊状（ブロック状、スポンジ状）の原料成形体を得ることができる。また、ポリアニオン性多糖類の水溶性塩の水溶液をノズルから貧溶媒中に押し出すことによって、繊維状の原料成形体を得ることができる。ポリアニオン性多糖類の水溶性塩の水溶液を適当な管に充填した後、乾燥又は凍結乾燥することによって、棒状の原料成形体を得ることができる。また、乾燥したポリアニオン性多糖類を粉砕して粉体化することによって、粉末状又は粒子状の原料成形体を得ることができる。このように、本発明の水不溶性成形体の製造方法によれば、ポリアニオン性多糖類の水溶性塩を所望とする形状に成形した後に水不溶化処理するため、用途に応じた形状の水不溶化物（水不溶性成形体）を得ることができる。 For example, an aqueous solution of a water-soluble salt of a polyanionic polysaccharide is poured into a suitable container and then dried or freeze-dried to obtain a film-like (sheet-like) or massive (block-like, sponge-like) raw material compact. be able to. Moreover, a fibrous raw material compact can be obtained by extruding an aqueous solution of a water-soluble salt of polyanionic polysaccharide from a nozzle into a poor solvent. A rod-like raw material compact can be obtained by filling an aqueous solution of a water-soluble salt of a polyanionic polysaccharide in a suitable tube and drying or lyophilizing it. Also, by pulverizing and drying the dried polyanionic polysaccharide, a powdery or particulate raw material compact can be obtained. As described above, according to the method for producing a water-insoluble molded article of the present invention, a water-insoluble salt of a polyanionic polysaccharide is formed into a desired shape and then subjected to a water-insolubilization treatment. (Water-insoluble molded body) can be obtained.
原料成形体を処理するために用いる第１の処理液及び第２の処理液は、酸無水物をそれぞれ含有する。酸無水物の具体例としては、無水酢酸、無水プロピオン酸、無水コハク酸、無水酪酸、無水フタル酸、及び無水マレイン酸等を挙げることができる。なかでも、無水酢酸及び無水プロピオン酸が好ましい。これらの酸無水物は、一種単独で又は二種以上を組み合わせて用いることができる。 The first treatment liquid and the second treatment liquid used to treat the raw material compact each contain an acid anhydride. Specific examples of the acid anhydride include acetic anhydride, propionic anhydride, succinic anhydride, butyric anhydride, phthalic anhydride, and maleic anhydride and the like. Among these, acetic anhydride and propionic anhydride are preferable. These acid anhydrides can be used alone or in combination of two or more.
第１の処理液及び第２の処理液（以下、纏めて、単に「処理液」とも記す）は、それぞれ、水及び水溶性有機溶媒の少なくともいずれかの媒体をさらに含むとともに、この媒体中に酸無水物が溶解又は分散していることが好ましい。このような媒体中に酸無水物が溶解又は分散した処理液を使用することで、原料成形体を十分かつ速やかに水不溶化させて水不溶性成形体を得ることができる。 The first treatment solution and the second treatment solution (hereinafter collectively referred to simply as “treatment solution”) each further contain at least one medium of water and a water-soluble organic solvent, and in this medium It is preferable that the acid anhydride be dissolved or dispersed. By using the treatment liquid in which the acid anhydride is dissolved or dispersed in such a medium, the raw material molded body can be sufficiently and rapidly made water-insoluble to obtain a water-insoluble molded body.
水溶性有機溶媒の具体例としては、メタノール、エタノール、プロパノール、ジメチルスルホキシド（ＤＭＳＯ）、アセトニトリル、及びテトラヒドロフラン等を挙げることができる。なかでも、メタノール、エタノール、及びジメチルスルホキシドが好ましい。これらの水溶性有機溶媒は、一種単独で又は二種以上を組み合わせて用いることができる。 Specific examples of the water-soluble organic solvent include methanol, ethanol, propanol, dimethylsulfoxide (DMSO), acetonitrile, and tetrahydrofuran. Among them, methanol, ethanol and dimethyl sulfoxide are preferable. These water-soluble organic solvents can be used alone or in combination of two or more.
水不溶化工程では、第１の処理液及び第２の処理液に原料成形体を順次接触させ、複数回（ｎ回）かけて原料成形体を水不溶化処理する。そして、少なくとも２回目の処理には、初回（１回目）の処理に用いる第１の処理液よりも疎水性の高い第２の処理液を用いる。これにより、水による膨潤率が低い、具体的には１６０％以下である水不溶性成形体を製造することができる。水不溶化処理する回数（ｎ回）の上限については特に限定されないが、多すぎると水不溶化処理に要する時間がかかりすぎるため、例えば２０回以下、好ましくは１５回以下、さらに好ましくは１１回以下とすればよい。処理液の疎水性は、例えば、処理液中の酸無水物、水溶性有機溶媒、及び水の各濃度を適宜設定することで制御することができる。具体的には、酸無水物や水溶性有機溶剤の濃度を高めることで、処理液の疎水性を上昇させることができる。一方、水の濃度を高めることで、処理液の疎水性を低下させることができる。 In the water insolubilization step, the raw material compact is sequentially brought into contact with the first treatment liquid and the second treatment liquid, and the raw material compact is subjected to a plurality of (n times) water insolubilization treatments. Then, for at least the second treatment, a second treatment liquid that is more hydrophobic than the first treatment liquid used for the first (first) treatment is used. This makes it possible to produce a water-insoluble molded article having a low degree of swelling with water, specifically 160% or less. The upper limit of the number of times of water insolubilization treatment (n times) is not particularly limited, but if it is too much, it takes too much time for the water insolubilization treatment to take, for example, 20 times or less, preferably 15 times or less, more preferably 11 times or less do it. The hydrophobicity of the treatment liquid can be controlled, for example, by appropriately setting the concentrations of the acid anhydride, the water-soluble organic solvent, and water in the treatment liquid. Specifically, the hydrophobicity of the treatment liquid can be increased by increasing the concentration of the acid anhydride or the water-soluble organic solvent. On the other hand, by increasing the concentration of water, the hydrophobicity of the treatment liquid can be reduced.
第１の処理液中の酸無水物の濃度は、通常、０．１〜５０体積％であり、５〜３０体積％であることが好ましい。第１の処理液中の酸無水物の濃度が０．１体積％未満であると、得られる水不溶性成形体の水不溶化の程度が不十分になる、或いは水不溶化に長時間を要する傾向にある。一方、第１の処理液中の酸無水物の濃度が５０体積％を超えると、効果が頭打ちになる傾向にある。 The concentration of the acid anhydride in the first treatment liquid is usually 0.1 to 50% by volume, preferably 5 to 30% by volume. If the concentration of the acid anhydride in the first treatment liquid is less than 0.1% by volume, the degree of water insolubilization of the obtained water-insoluble molded article tends to be insufficient, or the water insolubilization tends to take a long time. is there. On the other hand, when the concentration of the acid anhydride in the first treatment liquid exceeds 50% by volume, the effect tends to plateau.
ポリアニオン性多糖類は親水性が高いため、原料成形体をより十分かつ速やかに水不溶化させる観点から、第１の処理液が媒体として水を含有することが好ましい。第１の処理液中の水の含有量は、原料成形体が溶解又は膨潤しない程度とすることが好ましい。具体的には、第１の処理液中の水の含有量は、０．０１〜５０体積％であることが好ましく、５〜２０体積％であることがさらに好ましい。第１の処理液中の水の含有量が０．０１体積％未満であると、メタノール以外の溶媒では不溶化が不十分となる場合がある。一方、第１の処理液中の水の含有量が５０体積％超であると、得られる水不溶性成形体の形状維持が困難となる場合がある。 Since the polyanionic polysaccharide has high hydrophilicity, it is preferable that the first treatment liquid contains water as a medium from the viewpoint of water-solubilizing the raw material molded body sufficiently and rapidly. The content of water in the first treatment liquid is preferably such that the raw material compact does not dissolve or swell. Specifically, the content of water in the first treatment liquid is preferably 0.01 to 50% by volume, and more preferably 5 to 20% by volume. When the content of water in the first treatment liquid is less than 0.01% by volume, insolubilization may be insufficient in solvents other than methanol. On the other hand, when the content of water in the first treatment liquid is more than 50% by volume, it may be difficult to maintain the shape of the obtained water-insoluble formed article.
前述の通り、第２の処理液の疎水性は、第１の処理液の疎水性よりも高く設定する必要がある。このため、例えば、第２の処理液中の酸無水物の濃度を、第１の処理液中の酸無水物の濃度よりも高くする。第２の処理液中の酸無水物の濃度は、通常、２０〜９９体積％であり、５０〜８０体積％であることが好ましい。第１の処理液中の酸無水物の濃度が２０体積％未満であると、得られる水不溶性成形体の水不溶化の進行程度が不十分になる、或いは膨潤度を十分に低下させることが困難になる場合がある。一方、第２の処理液中の酸無水物の濃度が８０体積％を超えると、効果が頭打ちになる傾向にある。 As described above, the hydrophobicity of the second treatment liquid needs to be set higher than the hydrophobicity of the first treatment liquid. Therefore, for example, the concentration of the acid anhydride in the second treatment liquid is set higher than the concentration of the acid anhydride in the first treatment liquid. The concentration of the acid anhydride in the second treatment liquid is usually 20 to 99% by volume, preferably 50 to 80% by volume. If the concentration of the acid anhydride in the first treatment liquid is less than 20% by volume, the progress of water insolubilization of the obtained water-insoluble molded article becomes insufficient, or it is difficult to sufficiently reduce the degree of swelling May be On the other hand, when the concentration of the acid anhydride in the second treatment liquid exceeds 80% by volume, the effect tends to plateau.
第１の処理液で処理した後の原料成形体は、水不溶化の進行に伴い、親水性が低下している。このため、原料成形体との親和性を高める観点から、第１の処理液よりも水の濃度が低い第２の処理液を用いることが好ましい。具体的には、第２の処理液中の水の濃度は、０．０１〜３０体積％であることが好ましく、１〜２０体積％であることがさらに好ましい。第２の処理液中の水の含有量が０．０１体積％未満であると、無水酢酸の開裂が起こりにくく、反応（処理）速度が不十分となる場合がある。一方、第２の処理液中の水の濃度が３０体積％超であると、原料成形体と第２の処理液との親和性が低く、反応（処理）速度が不十分となる場合がある。 The raw material compact after being treated with the first treatment liquid has a reduced hydrophilicity as the water insolubilization progresses. For this reason, it is preferable to use a second treatment liquid having a lower concentration of water than the first treatment liquid from the viewpoint of enhancing the affinity to the raw material compact. Specifically, the concentration of water in the second treatment liquid is preferably 0.01 to 30% by volume, and more preferably 1 to 20% by volume. When the content of water in the second treatment liquid is less than 0.01% by volume, cleavage of acetic anhydride is unlikely to occur, and the reaction (treatment) rate may be insufficient. On the other hand, if the concentration of water in the second treatment liquid is more than 30% by volume, the affinity between the raw material compact and the second treatment liquid may be low, and the reaction (treatment) speed may be insufficient. .
水不溶化工程では、第１の処理液及び第２の処理液に原料成形体を順次接触させて、原料成形体を水不溶化処理する。原料成形体を処理液に接触させることによって、その形状を維持したまま原料成形体を水不溶化することができ、対応する形状の水不溶性成形体を得ることができる。原料成形体を処理液に接触させる方法は特に限定されないが、原料成形体の全体に処理液が接触するとともに、原料成形体の内部にまで処理液が浸透するように処理することが好ましい。具体的な処理方法としては、原料成形体を処理液中に浸漬する、原料成形体に処理液を塗布又は吹き付ける（噴霧する）等の方法を挙げることができる。 In the water insolubilization step, the raw material compact is sequentially brought into contact with the first treatment liquid and the second treatment liquid to perform water insolubilization treatment of the raw material compact. By bringing the raw material compact into contact with the treatment liquid, it is possible to make the raw material compact water-insoluble while maintaining its shape, and it is possible to obtain a water-insoluble compact of the corresponding shape. The method for bringing the raw material compact into contact with the treatment liquid is not particularly limited, but it is preferable to treat the treatment liquid so that the treatment liquid penetrates the inside of the raw material compact while contacting the entire raw material compact. Specific examples of the treatment method include a method of immersing the raw material compact in the treatment liquid, and a method of coating or spraying (spraying) the treatment liquid on the raw material compact.
なかでも、原料成形体を第１の処理液及び第２の処理液のそれぞれとともに袋状容器内に封入し、加熱して水不溶化処理することが好ましい。原料成形体を処理液とともに袋状容器内に封入した状態で処理することで、処理液の揮散を抑制することができ、処理に要する時間を短縮することができるとともに、使用する処理液の量を減ずることができる。また、加熱して処理することで、処理時間をさらに短縮することができる。 Among them, it is preferable to enclose the raw material compact together with each of the first treatment liquid and the second treatment liquid in a bag-like container and heat it to perform water insolubilization treatment. By treating the raw material compact together with the treatment liquid in a bag-like container, the volatilization of the treatment liquid can be suppressed, and the time required for treatment can be shortened, and the amount of treatment liquid used Can be reduced. Moreover, processing time can be further shortened by heating and processing.
処理液の量は、原料成形体が十分に水不溶化する最低限の量とすればよい。具体的には、原料成形体１００質量部に対する、第１の処理液及び第２の処理液のそれぞれの量は、５〜５０質量部とすることが好ましい。処理液の量が多すぎると、製造費や廃液処理費が増大し、コスト面で不利になる場合がある。原料成形体及び処理液を封入した袋状容器をヒートプレスや熱ローラーなどで挟むとともに、加熱することで、処理液の揮散を抑制しながら原料成形体を水不溶化処理することができる。 The amount of the treatment liquid may be set to a minimum amount that allows the raw material compact to be sufficiently water-insoluble. Specifically, the amount of each of the first treatment liquid and the second treatment liquid is preferably 5 to 50 parts by mass with respect to 100 parts by mass of the raw material compact. If the amount of the processing solution is too large, the production cost and the waste liquid processing cost may increase, which may be disadvantageous in cost. The raw material molded body can be subjected to water insolubilization treatment while suppressing volatilization of the treatment liquid by holding the raw material molded body and the bag-like container in which the treatment liquid is sealed with a heat press, a heat roller or the like and heating.
水不溶化処理の際には、原料成形体を処理液に接触させた状態で加熱することが好ましい。加熱温度は、処理液の沸点を大きく超えない温度であればよい。ポリアニオン性多糖類の分解変性や、処理液及び副生成物等の揮散を抑制する観点からは、０〜９０℃で水不溶化処理することが好ましく、２０〜８０℃に加熱して水不溶化処理することがさらに好ましい。また、５０〜７５℃に加熱して水不溶化処理することが、反応（処理）速度が向上するために好ましい。加熱時間は、得ようとする水不溶性成形体の膨潤度に応じて適宜設定すればよい。具体的には、１〜６０分とすることが好ましく、１〜３０分とすることがさらに好ましく、３〜１０分とすることが特に好ましい。加熱時間を長くしすぎると、エネルギー面で無駄が生ずる場合がある。 In the case of the water insolubilization treatment, it is preferable to heat the raw material compact while being in contact with the treatment liquid. The heating temperature may be a temperature that does not significantly exceed the boiling point of the treatment liquid. From the viewpoint of suppressing degradation and modification of polyanionic polysaccharides and volatilization of the treatment solution and by-products, it is preferable to perform water insolubilization treatment at 0 to 90 ° C., and heat at 20 to 80 ° C. to perform water insolubilization treatment Is more preferred. Moreover, it is preferable to heat to 50-75 degreeC and to carry out a water insolubilization process in order to improve reaction (process) speed | rate. The heating time may be appropriately set in accordance with the degree of swelling of the water-insoluble molded article to be obtained. Specifically, it is preferably 1 to 60 minutes, more preferably 1 to 30 minutes, and particularly preferably 3 to 10 minutes. If the heating time is too long, energy may be wasted.
水不溶化工程の終了後、必要に応じて水や水溶性有機溶媒等を用いて洗浄すれば、膨潤率１６０％以下である本発明の水不溶性成形体を得ることができる。なお、第２の処理液による処理の回数を増加させたり、第１の処理液に比してより疎水性の高い第２の処理液を用いたりすることで、得られる水不溶性成形体の膨潤率を１６０％以下に制御することができる。本発明の水不溶性成形体の膨潤率の下限については特に限定されないが、１１０％程度とすることができる。本明細書における「膨潤率」とは、「水分保持前（膨潤前）の水不溶性成形体の質量」に対する、「水分保持後（膨潤後）の水不溶性成形体の質量」の割合（質量％）を意味する。 After completion of the water insolubilization step, if necessary, washing with water, a water-soluble organic solvent or the like can be performed to obtain a water-insoluble molded article of the present invention having a swelling ratio of 160% or less. In addition, swelling of the water-insoluble molded article obtained by increasing the frequency | count of the process by a 2nd process liquid, or using a 2nd process liquid with higher hydrophobicity compared with a 1st process liquid. The rate can be controlled to 160% or less. The lower limit of the swelling ratio of the water-insoluble molded article of the present invention is not particularly limited, but can be about 110%. The term "swelling ratio" as used herein means the ratio (% by mass) of "mass of water-insoluble molded article after holding water (after swelling)" to "mass of water-insoluble molded body before holding water (before swelling)". Means).
なお、本明細書における「水不溶性」とは、水に容易に溶解しない性質を意味する。より具体的には、ポリアニオン性多糖類からなる本発明の水不溶性成形体は、水により膨潤状態とした後に乾燥する操作を２回繰り返して得た乾燥体の質量が、この操作前の乾燥質量の８０％以上である。 In the present specification, "water insoluble" means a property which is not easily dissolved in water. More specifically, in the water-insoluble molded article of the present invention comprising a polyanionic polysaccharide, the mass of the dried substance obtained by repeating the procedure of drying after being swollen with water twice is the dry mass before this operation. 80% or more of
ポリアニオン性多糖類のナトリウム塩を用いて形成した原料成形体を、無水酢酸のアルコール溶液で処理した場合に想定される反応を以下に示す。なお、想定した反応が水不溶化の一つの要因とはなりうるが、他の水不溶化要因との組み合わせ、あるいは全く別の要因により水不溶化している可能性もある。すなわち、本発明は想定される以下の反応によって何ら限定されるものではない。 The reaction assumed when the raw material compact formed with the sodium salt of polyanionic polysaccharide is treated with an alcohol solution of acetic anhydride is shown below. In addition, although the reaction assumed may be one factor of water insolubilization, it may be water insolubilization due to a combination with other water insolubilization factors or completely another factor. That is, the present invention is not limited at all by the following reactions which are supposed.
反応式（１）中、Ｒ1はポリアニオン性多糖類の主鎖を示し、Ｒ2はアルコールの主鎖を示す。無水酢酸はアルコール存在下で開裂する際に、ポリアニオン性多糖類のナトリウムを奪い、カルボキシ基がナトリウム塩型から酸型となる。この点については、水不溶性成形体中のＮａ含量の測定、又は水不溶性成形体のアルカリ溶液による滴定によって確認することができる。 In the reaction formula (1), R 1 represents the main chain of polyanionic polysaccharide, and R 2 represents the main chain of alcohol. When acetic anhydride is cleaved in the presence of alcohol, it removes sodium of the polyanionic polysaccharide and the carboxy group changes from sodium salt form to acid form. This point can be confirmed by measurement of the Na content in the water-insoluble shaped body or titration of the water-insoluble shaped body with an alkaline solution.
反応系に水が存在する場合には、上記反応式（１）で示される反応の他に、下記式（２）で示される反応が同時に進行し、カルボキシ基がナトリウム塩型から酸型となると予想される。 When water is present in the reaction system, in addition to the reaction represented by the above reaction formula (1), when the reaction represented by the following formula (2) simultaneously proceeds and the carboxy group changes from a sodium salt type to an acid type is expected.
原料成形体を第１の処理液で処理して得られたものは、分子中のすべてのアニオン性基が酸型には変換されていないと推測される。第２の処理液で引き続き処理することで、残存する分子中のアニオン性基がさらに酸型へと変換され、水不溶化が進行すると考えられる。 What is obtained by processing the raw material compact with the first treatment liquid is presumed that all anionic groups in the molecule are not converted to the acid form. Continued treatment with the second treatment solution is considered to further convert the anionic group in the remaining molecule into an acid form and promote water insolubilization.
ポリアニオン性多糖類の水溶性塩を用いて形成した原料成形体を塩酸等の無機酸や酢酸等の有機酸に浸漬しても、十分に水不溶化した成形体を得ることは極めて困難である。また、処理液中の酸無水物を、この酸無水物に対応する酸に置き換えても水不溶性成形体を得ることはできない。このことから、ポリアニオン性多糖類のアニオン基が酸型に変化する以外の要因も加わり、水不溶性成形体が得られると予想される。ここで、多糖類等の高分子化合物は分子量の異なる様々な分子鎖の混合物であることを考慮すると、ポリアニオン性多糖類の水溶性塩からなる原料成形体を水不溶化処理して製造される本発明の水不溶性成形体は複雑な、反応機構によって得られるものであり、しかも、その反応機構は上述の通り必ずしも明らかではない。このため、本発明の水不溶性成形体を、その構造等で直接特定することはおよそ実際的であるとは言えない。 Even if the raw material compact formed using the water-soluble salt of polyanionic polysaccharide is immersed in an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, it is extremely difficult to obtain a sufficiently water-insoluble compact. In addition, even if the acid anhydride in the treatment liquid is replaced with the acid corresponding to this acid anhydride, it is not possible to obtain a water-insoluble shaped article. From this, it is expected that a water-insoluble shaped article can be obtained by adding factors other than the conversion of the anionic group of the polyanionic polysaccharide to the acid form. Here, considering that a high molecular compound such as a polysaccharide is a mixture of various molecular chains having different molecular weights, it is manufactured by subjecting a raw material molded product made of a water-soluble salt of polyanionic polysaccharide to water insolubilization treatment. The water-insoluble molded article of the invention is obtained by a complicated reaction mechanism, and the reaction mechanism is not necessarily clear as described above. For this reason, it can not be said that specifying the water-insoluble molded article of the present invention directly by its structure etc. is practically practical.
本発明の製造方法では化学的架橋剤を用いる必要がないため、得られる水不溶性成形体を構成する分子中に化学的架橋剤に由来する官能基等の構造が取り込まれることがない。このため、上記の製造方法によって製造される水不溶性成形体は、原料であるポリアニオン性多糖類本来の特性が保持されているとともに、安全性が高い。したがって、本発明の水不溶性成形体は、癒着防止材等の医療用材料の他、食品用材料や化粧品用材料として好適である。 In the production method of the present invention, since it is not necessary to use a chemical crosslinking agent, a structure such as a functional group derived from the chemical crosslinking agent is not incorporated into the molecules constituting the resulting water-insoluble molded article. For this reason, the water-insoluble molded article produced by the above-mentioned production method has high safety while maintaining the original properties of the polyanionic polysaccharide which is the raw material. Therefore, the water-insoluble molded article of the present invention is suitable as a food material or a cosmetic material as well as a medical material such as an adhesion prevention material.
以下、本発明を実施例に基づいて具体的に説明するが、本発明はこれらの実施例に限定されるものではない。なお、実施例、比較例中の「部」及び「％」は、特に断らない限り質量基準である。 EXAMPLES Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited to these examples. In the examples and comparative examples, "parts" and "%" are based on mass unless otherwise specified.
＜ヒアルロン酸ナトリウム膜の製造＞
ヒアルロン酸ナトリウム（分子量（公称値）：８０万、キッコーマンバイオケミファ社製）１．０ｇ及び水９９．０ｇを混合し、ビーカー中で撹拌して均一な水溶液を得た。得られた水溶液をステンレス製バットに流し入れ、３０℃で乾燥してヒアルロン酸ナトリウム膜を得た。
<Production of sodium hyaluronate membrane>
Sodium hyaluronate (molecular weight (nominal value): 800,000, manufactured by Kikkoman Biochemifa) 1.0 g and water 99.0 g were mixed and stirred in a beaker to obtain a uniform aqueous solution. The obtained aqueous solution was poured into a stainless steel vat and dried at 30 ° C. to obtain a sodium hyaluronate membrane.
＜処理液の調製＞
無水酢酸及び７５体積％エタノール水溶液を混合して、以下に示す組成の第１の処理液、及び第２の処理液を調製した。
・「第１の処理液」無水酢酸：７５体積％エタノール水溶液＝２０：８０（体積比）
・「第２の処理液」無水酢酸：７５体積％エタノール水溶液＝５０：５０（体積比）
<Preparation of treatment solution>
Acetic anhydride and a 75% by volume aqueous ethanol solution were mixed to prepare a first treatment solution and a second treatment solution having the compositions shown below.
・ "First treatment liquid" Acetic anhydride: 75% by volume ethanol aqueous solution = 20: 80 (volume ratio)
Second treatment liquid: acetic anhydride: 75% by volume aqueous ethanol solution = 50: 50 (volume ratio)
＜水不溶性膜の製造＞
（実施例１）
ヒアルロン酸ナトリウム膜を第１の処理液１００ｍＬに浸漬し、５０℃で１時間放置して水不溶化処理した後、エタノール、７５体積％エタノール水溶液、及び水の順に洗浄した。次いで、第２の処理液１００ｍＬに浸漬し、５０℃で１時間放置して水不溶化処理した後、エタノール、７５体積％エタノール水溶液、及び水の順に洗浄した。この第２の処理液による水不溶化処理を合計４回実施して、水不溶性膜を得た。
<Production of water insoluble membrane>
Example 1
The sodium hyaluronate membrane was immersed in 100 mL of the first treatment solution, allowed to stand at 50 ° C. for 1 hour for water insolubilization treatment, and then washed sequentially with ethanol, 75% by volume ethanol aqueous solution, and water. Next, the substrate was immersed in 100 mL of a second treatment liquid, left to stand at 50 ° C. for 1 hour for water insolubilization treatment, and then washed sequentially with ethanol, a 75% by volume aqueous ethanol solution, and water. The water insolubilization treatment with the second treatment liquid was performed a total of four times to obtain a water insoluble film.
（実施例２〜３、比較例１〜６）
第１の処理液による処理回数、及び第２の処理液による処理回数を表１に示す通りとしたこと以外は、前述の実施例１と同様にして水不溶性膜を得た。
(Examples 2 to 3, Comparative Examples 1 to 6)
A water-insoluble film was obtained in the same manner as in Example 1 except that the number of times of treatment with the first treatment liquid and the number of times of treatment with the second treatment liquid were as shown in Table 1.
（実施例４）
ヒアルロン酸ナトリウム膜を３ｃｍ×３ｃｍの正方形に切り出した後、市販のポリエチレン製チャック付き袋（商品名「ユニパックＣ−４」、７０ｍｍ×１００ｍｍ、日本生産社製）に入れた。さらに、第１の処理液１ｍＬを入れ、チャックを閉めて封入した。加熱プレス面を５０℃に設定した卓上ヒートプレス機（商品名「ＶＤ−１０型」、ＲＯＭＡＮＯＦＦ社製）でチャック付き袋を挟み、５分間加熱して水不溶化処理した。チャック付き袋から取り出した内容物をエタノール、７５体積％エタノール水溶液、及び水の順に洗浄した。次いで、第２の処理液１ｍＬを使用して同様の水不溶化処理（５０℃、５分間）を合計１０回実施して、水不溶化膜を得た。
(Example 4)
The sodium hyaluronate film was cut into a square of 3 cm × 3 cm and then placed in a commercially available polyethylene zippered bag (trade name “Unipak C-4”, 70 mm × 100 mm, manufactured by Japan Production Co., Ltd.). Furthermore, 1 mL of the first treatment solution was added, and the chuck was closed and sealed. The bag with a chuck was sandwiched by a table-top heat press (trade name "VD-10 type", manufactured by ROMANOFF) whose heating press surface was set at 50 ° C., and heated for 5 minutes to perform water insolubilization treatment. The contents removed from the zippered bag were washed sequentially with ethanol, 75% by volume aqueous ethanol and water. Next, the same water insolubilization treatment (50 ° C., 5 minutes) was performed a total of 10 times using 1 mL of the second treatment liquid to obtain a water insolubilized film.
＜評価＞
（膨潤率の測定）
乾燥状態の水不溶性膜の質量を測定し「膨潤前質量」とした。次に、水不溶性膜を十分な水に浸漬し、室温で１時間静置した。十分膨潤した水不溶性膜の表面に付着した余分な水分を紙タオル等で除去し、質量を測定して「膨潤後質量」とした。「膨潤率」とは、「膨潤前質量」に対する「膨潤後質量」の割合（質量％）を意味する。測定結果を表１に示す。
<Evaluation>
(Measurement of swelling rate)
The mass of the water-insoluble film in the dry state was measured and defined as "pre-swelling mass". Next, the water-insoluble membrane was immersed in sufficient water and allowed to stand at room temperature for 1 hour. Excess water adhering to the surface of the fully swollen water-insoluble film was removed with a paper towel or the like, and the mass was measured to obtain “mass after swelling”. The “swelling ratio” means the ratio (% by mass) of “mass after swelling” to “weight before swelling”. The measurement results are shown in Table 1.
（長期溶解性試験）
実施例１〜４で製造した水不溶性膜を２ｃｍ×２ｃｍのサイズに切断し、直径３．５ｃｍ、深さ１．５ｃｍの容器に入れ、ＰＢＳ緩衝液（ｐＨ６．８）５ｍＬを加えた。この容器を３７℃に調整した振盪機に入れ、１０〜２０ｒｐｍで振盪した。その結果、９ヶ月以上経過しても膜の原形が保持されていることが判明した。また、比較例１〜６で製造した水不溶性膜を上記と同様に試験した。その結果、比較例１、２、及び５で製造した水不溶性膜はいずれも２ヶ月以内に溶解し、比較例３、４、及び６で製造した水不溶性膜はいずれも４ヶ月以内に溶解した。
(Long-term solubility test)
The water-insoluble membrane prepared in Examples 1 to 4 was cut into a size of 2 cm × 2 cm, placed in a vessel 3.5 cm in diameter and 1.5 cm in depth, and 5 mL of PBS buffer (pH 6.8) was added. The container was placed in a shaker adjusted to 37 ° C. and shaken at 10 to 20 rpm. As a result, it was found that the original shape of the membrane was maintained even after 9 months or more. In addition, the water-insoluble films produced in Comparative Examples 1 to 6 were tested in the same manner as described above. As a result, the water-insoluble films produced in Comparative Examples 1, 2 and 5 were all dissolved within 2 months, and the water-insoluble films produced in Comparative Examples 3, 4 and 6 were all dissolved within 4 months. .
＜水不溶性スポンジ状成形体の製造＞
（実施例５）
ヒアルロン酸ナトリウム（分子量（公称値）：８０万、キッコーマンバイオケミファ社製）３．０ｇ及び水９７．０ｇを混合し、ビーカー中で撹拌して均一な水溶液を得た。得られた水溶液を１５ｃｍ×１０ｃｍのポリエチレンテレフタレート製トレイに液厚が１ｃｍとなるように分注した。このトレイを真空凍結乾燥機（商品名「ＲＬＩＩ−１０３」、共和真空技術社製）の乾燥棚に入れ、−４０℃で予備凍結した。凍結後に真空乾燥してスポンジ状成形体を得た。得られたスポンジ状成形体を前述の実施例３と同様の方法で水不溶化処理して、水不溶性スポンジ状成形体を得た。得られた水不溶性スポンジ状成形体について、前述の「長期溶解性試験」を行ったところ、９ヶ月以上経過しても成形体（スポンジ）の原形が保持されていた。
<Production of Water-Insoluble Sponge-Like Molded Body>
(Example 5)
Sodium hyaluronate (molecular weight (nominal value): 800,000, manufactured by Kikkoman Biochemifa) 3.0 g and water 97.0 g were mixed and stirred in a beaker to obtain a uniform aqueous solution. The obtained aqueous solution was dispensed to a 15 cm × 10 cm polyethylene terephthalate tray so that the solution thickness was 1 cm. The tray was placed in the drying shelf of a vacuum freeze drier (trade name "RLII-103", manufactured by Kyowa Vacuum Technology Co., Ltd.) and pre-frozen at -40 ° C. After freezing, it was vacuum dried to obtain a sponge-like molded body. The obtained sponge-like molded product was subjected to water insolubilization treatment by the same method as in Example 3 described above to obtain a water-insoluble sponge-like molded product. The above-mentioned "long-term solubility test" was carried out on the obtained water-insoluble sponge-like molded product, and the original shape of the molded product (sponge) was maintained even after 9 months or more.
（化粧材への応用）
実施例５で製造した水不溶性スポンジ状成形体を繭型に切り出した後、市販の化粧水を含浸させた。繭型のスポンジ状成形体は、化粧水に溶解することはなかった。また、肌への貼り付き性が高いため、目元貼付用の化粧材として使用することができた。
(Application to cosmetic materials)
After the water-insoluble sponge-like molded article produced in Example 5 was cut into a bowl shape, a commercially available lotion was impregnated. The cocoon-shaped sponge-like molded body did not dissolve in the lotion. In addition, because of the high adhesion to the skin, it could be used as a cosmetic material for eye patching.
（動物実験）
１２ｃｍ×９ｃｍのサイズに切り出した実施例３で製造した水不溶性膜を、１０体積％グリセリン水溶液に浸漬した後、風乾して滅菌用袋に封入した。２５ｋＧｙの放射線を照射して滅菌用袋ごと滅菌して癒着防止膜を得た。成犬（ビーグル犬、雌、１．５歳、体重約１０ｋｇ）を全身麻酔処置後に開腹し、腹側壁表皮を３ｃｍ角に剥離した。剥離部分を覆うように癒着防止膜を配置して閉腹した。２週間後、同犬を全身麻酔処置後に開腹したところ、癒着は発生していなかった。また、犬の体内に配置（埋植）した癒着防止膜は、埋植後２週間で消失していた。これは、生体内のナトリウムイオン等によって癒着防止膜を構成するヒアルロン酸のカルボキシ基が徐々に中和され、可溶性のヒアルロン酸塩と変化して溶解し、生体内に吸収されたものと推測される。これに対して、癒着防止膜を配置することなく閉腹した犬については、剥離部分と腸に癒着が生じていることが観察された。
(Animal experimentation)
The water-insoluble film produced in Example 3 cut into a size of 12 cm × 9 cm was immersed in a 10% by volume aqueous solution of glycerin, air-dried and sealed in a bag for sterilization. The whole of the sterilization bag was sterilized by irradiation with 25 kGy of radiation to obtain an adhesion preventive film. An adult dog (beagle dog, female, 1.5 years old, weight about 10 kg) was opened after general anesthesia treatment, and the ventral side wall epidermis was peeled into 3 cm square. An anti-adhesion membrane was placed to cover the exfoliated part and closed. Two weeks later, when the same dog was opened after general anesthesia treatment, adhesions did not occur. In addition, the adhesion prevention membrane placed (implanted) in the dog's body disappeared 2 weeks after implantation. It is speculated that the carboxy groups of hyaluronic acid that make up the adhesion-preventing film are gradually neutralized by the sodium ion etc. in the living body, changed into soluble hyaluronate, dissolved, and absorbed in the living body. Ru. On the other hand, it was observed that adhesion occurred between the exfoliated part and the intestine in the case of a dog closed without placing the adhesion preventing film.
本発明の水不溶性成形体は、医療用材料、食品用材料、及び化粧品用材料等として有用である。 The water-insoluble molded article of the present invention is useful as a medical material, a food material, a cosmetic material and the like.
Claims (11)
前記原料成形体を、酸無水物をそれぞれ含有する第１の処理液及び第２の処理液に順次接触させて複数回水不溶化処理し、膨潤率１６０％以下の水不溶性成形体を得る工程を有し、
前記第１の処理液に比して前記第２の処理液の疎水性が高い水不溶性成形体の製造方法。 A process for producing a water-insoluble molded article, comprising obtaining a water-insoluble molded article, wherein the raw material molded article comprising a water-soluble salt of a polyanionic polysaccharide is insoluble in water while maintaining the shape of the raw material molded article,
A step of obtaining a water-insoluble molded product having a swelling ratio of 160% or less by sequentially bringing the raw material molded product into contact with a first treatment liquid and a second treatment liquid each containing an acid anhydride and carrying out a plurality of water insolubilization treatments; Have
The manufacturing method of the water-insoluble molded object whose hydrophobicity of a said 2nd process liquid is high compared with a said 1st process liquid.
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