JP2005247967A - Polyelectrolyte complex and its preparation process - Google Patents
Polyelectrolyte complex and its preparation process Download PDFInfo
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本発明は、キトサンとカルボキシメチルセルロース（ＣＭＣ）とが結合してゲル状となった高分子電解質複合体とその製造方法に関する。 The present invention relates to a polymer electrolyte composite in which chitosan and carboxymethyl cellulose (CMC) are bonded to form a gel and a method for producing the same.
キチン、キチンの脱アセチル化物であるキトサンおよびカルボキシメチルセルロースは直鎖状の多糖類であり、生体適合性を有するため、医薬、食品或いは農業の分野において注目されている。 Chitin, chitosan and carboxymethylcellulose, which are deacetylated products of chitin, are linear polysaccharides and have biocompatibility, and thus are attracting attention in the fields of medicine, food or agriculture.
例えば、特許文献１にはナノ微粒子に生物活性剤を包含せしめ、このナノ微粒子を生物系の組織または細胞に結合させて、生理活性物質の持続放出性を強化する内容が開示されている。
また特許文献２には、ＤＮＡなどの生物学的材料を標的細胞に送達するための
組成物、即ち、ＤＤＳ（ドラッグデリバリーシステム）の媒体として、カルボキシメチルセルロース、キチンまたはキトサンと多価脂肪族アルコールまたはその誘導体を基にしたものが提案されている。
また特許文献３には、一般式がＭ−Ｓ−Ｌ−Ｚ（Ｍは磁性核粒子、Ｓはカルボキシメチルセルロースやキチンなどの生体適合性基質、Ｌはリンカー基、Ｚは核酸やタンパク質等）で表される磁性ナノ粒子が提案されている。
For example, Patent Document 1 discloses contents in which a bioactive agent is included in a nanoparticle, and the nanoparticle is bound to a biological tissue or cell to enhance the sustained release of a physiologically active substance.
Patent Document 2 discloses a composition for delivering a biological material such as DNA to target cells, that is, as a DDS (drug delivery system) medium, carboxymethylcellulose, chitin or chitosan and a polyhydric aliphatic alcohol or Those based on the derivatives have been proposed.
In Patent Document 3, the general formula is M-S-L-Z (M is a magnetic core particle, S is a biocompatible substrate such as carboxymethylcellulose and chitin, L is a linker group, Z is a nucleic acid, a protein, and the like). Magnetic nanoparticles represented have been proposed.
ところで、キトサンは水には溶解しないが酢酸などの弱酸には溶解する。そしてキトサンが弱酸に溶解すると、キトサンのアミノ基が水素イオンを受け取ってキトサン分子は正に帯電する。
一方、カルボキシメチルセルロースは水に溶解する。そしてカルボキシメチルセルロースが水に溶解すると、カルボキシメチルセルロースのカルボキシメチル基から水素イオンが離脱し、カルボキシメチルセルロース分子は負に帯電する。
By the way, chitosan does not dissolve in water, but dissolves in weak acids such as acetic acid. When chitosan is dissolved in a weak acid, the amino group of chitosan receives hydrogen ions and the chitosan molecule is positively charged.
On the other hand, carboxymethylcellulose is soluble in water. And when carboxymethylcellulose melt | dissolves in water, a hydrogen ion will detach | leave from the carboxymethyl group of carboxymethylcellulose, and a carboxymethylcellulose molecule will be negatively charged.
上記正に帯電したキトサン分子を含む溶液と負に帯電したカルボキシメチルセルロース分子を含む溶液とを混合すると、互いの正負の官能基（アミノ基とカルボキシメチル基）が反応してキトサン分子とカルボキシメチルセルロース分子が絡み合い、これら分子は共に高分子であるため絡み合った高分子鎖が溶液全体に広がりゲルとなる。 When the above solution containing the positively charged chitosan molecule and the solution containing the negatively charged carboxymethylcellulose molecule are mixed, the positive and negative functional groups (amino group and carboxymethyl group) react with each other to cause the chitosan molecule and the carboxymethylcellulose molecule. Since these molecules are both polymers, the entangled polymer chains spread throughout the solution and become a gel.
上記のゲル中には荷電を持った物質を保持することが可能と考えられ、例えば生理活性物質などを保持せしめれば、ＤＤＳの媒体として極めて有効である。しかしながら、人体に存在しない物質が人体に入ると、肝臓や腎臓などの働き（異物認識機構）によって体外に排除される。この異物認識機構による異物の認識にも特異性がある。つまり、異物のサイズ（直径）が３００ｎｍ以下、特に数１０ｎｍ〜２００ｎｍ程度のサイズの異物は認識されにくいと考えられている。 It is considered possible to retain a charged substance in the gel. For example, if a physiologically active substance is retained, it is extremely effective as a medium for DDS. However, when a substance that does not exist in the human body enters the human body, it is excluded from the body by the action of the liver and kidney (foreign substance recognition mechanism). The foreign object recognition by this foreign object recognition mechanism is also unique. That is, it is considered that a foreign matter having a size (diameter) of 300 nm or less, particularly a size of several tens of nm to 200 nm, is hardly recognized.
そこで、上記のサイズの媒体を生体適合性に優れた材料で作製すれば、ＤＤＳの媒体などに極めて有効であるが、従来の技術ではサイズのコントロールが極めて困難である。
例えば、キトサンの分子量は通常１０万〜１００万程度であり、カルボキシメチルセルロースの分子量は通常１万〜１０万程度であるので、これらが絡まってできる高分子電解質複合体のサイズも大きなものになってしまう。
Therefore, if the medium having the above size is made of a material excellent in biocompatibility, it is extremely effective for a medium of DDS and the like, but it is extremely difficult to control the size with the conventional technique.
For example, the molecular weight of chitosan is usually about 100,000 to 1,000,000, and the molecular weight of carboxymethylcellulose is usually about 10,000 to 100,000. Therefore, the size of the polymer electrolyte complex formed by entanglement thereof becomes large. End up.
本発明は任意の大きさにコントロールされた高分子電解質複合体を提供することを目的とする。この高分子電解質複合体の構造は低分子化され且つ正に帯電したキトサンと、低分子化され且つ負に帯電したカルボキシメチルセルロースが、結合してゲル状となっている。 An object of the present invention is to provide a polyelectrolyte complex controlled to an arbitrary size. The structure of this polyelectrolyte complex is a low molecular weight and positively charged chitosan and a low molecular weight and negatively charged carboxymethyl cellulose bonded to form a gel.
上記の高分子電解質複合体は、その粒径が３００ｎｍ以下、例えば数１０ｎｍに揃えることが可能で、しかも直鎖状の多糖類が絡まって構成されているため、内部に荷電を持った物質を保持させることができる。 The above-mentioned polyelectrolyte complex can have a particle size of 300 nm or less, for example several tens of nm, and is composed of entangled linear polysaccharides. Can be retained.
高分子電解質複合体に内包する荷電物質としてはイオン性官能基（結合点になるので多い方が好ましい）を有する物質、例えば、ＤＮＡ、ＲＮＡ、Texas Red、トリプトファン、WSNSG、FITC−卵白アルブミン、サケカルシトニン、トリプシンインヒビターなどが挙げられる。 As a charged substance included in the polyelectrolyte complex, a substance having an ionic functional group (which is preferably a bonding point is preferable), such as DNA, RNA, Texas Red, tryptophan, WSNSG, FITC-ovalbumin, salmon Examples include calcitonin and trypsin inhibitor.
また、本発明に係る高分子電解質複合体の製造方法は以下の工程からなる。
・ キトサンを弱酸に溶解しキトサン分子を正に帯電させる工程。
・ 正に帯電したキトサン分子をキトサン分解酵素によって切断して低分子化する工程。
・ カルボキシメチルセルロースを水に溶解しカルボキシメチルセルロース分子を負に帯電させる工程。
・ 負に帯電したカルボキシメチルセルロース分子をカルボキシメチルセルロース分解酵素によって切断して低分子化する工程。
前記工程2)で得られた低分子化したキトサン溶液と、前記工程4)で得られた低分子化したカルボキシメチルセルロース溶液とを混合し、互いの正負の官能基を反応させてゲル状に結合する工程。
Moreover, the manufacturing method of the polymer electrolyte composite based on this invention consists of the following processes.
-A process in which chitosan is dissolved in a weak acid to charge the chitosan molecule positively.
A process of reducing positively charged chitosan molecules by cutting them with chitosan degrading enzymes.
A step of dissolving carboxymethylcellulose in water to negatively charge carboxymethylcellulose molecules.
A process of cutting negatively charged carboxymethylcellulose molecules by carboxymethylcellulose degrading enzyme to lower the molecular weight.
The low molecular weight chitosan solution obtained in the step 2) and the low molecular weight carboxymethylcellulose solution obtained in the step 4) are mixed, and the positive and negative functional groups of each other are reacted to form a gel. Process.
尚、上記の製造方法では、キトサン分子を正に帯電させキトサン分子を低分子化した後、カルボキシメチルセルロース分子を負に帯電させカルボキシメチルセルロース分子しているが、これらの工程の前後を逆にしてもよい。
In the above production method, the chitosan molecule is positively charged and the chitosan molecule is reduced in molecular weight, and then the carboxymethylcellulose molecule is negatively charged to form the carboxymethylcellulose molecule. Good.
また、高分子電解質複合体内に内包する荷電物質が負電荷を有する物質である場合には、低分子化されたキトサン溶液に前記被内包物の溶液を添加した後、低分子化されたカルボキシメチルセルロース溶液を添加する。一方、正電荷を有する物質を高分子電解質複合体内に内包せしめる場合には、低分子化されたカルボキシメチルセルロース溶液に被内包物の溶液を添加した後、低分子化されたキトサン溶液を添加する。 In addition, when the charged substance included in the polymer electrolyte complex is a substance having a negative charge, the carboxymethyl cellulose reduced in molecular weight after adding the solution of the inclusion to the reduced molecular chitosan solution. Add the solution. On the other hand, when a positively charged substance is encapsulated in the polyelectrolyte complex, the encapsulated solution is added to the low molecular weight carboxymethylcellulose solution, and then the low molecular weight chitosan solution is added.
本発明に係る高分子電解質複合体は、肝臓や脾臓などの異物認識機構によって検知されにくいサイズの粒子を、低ｐＨ（ｐＨ３.０〜５.６）、高塩濃度（ＮａＣＩ:１Ｍ）或いは低温（０℃）でも形成することができ、しかも安定に存在する。 The polyelectrolyte complex according to the present invention allows particles having a size difficult to be detected by a foreign body recognition mechanism such as the liver and spleen to have a low pH (pH 3.0 to 5.6), a high salt concentration (NaCI: 1M), or a low temperature. It can be formed even at (0 ° C.) and exists stably.
また、本発明に係る高分子電解質複合体は、荷電を持った物質、例えば活性ペプチドやタンパク質、ＤＮＡなどを保持することができる。これらを電解質複合体に取り込むことで、異物認識機構を逃れて体内に長時間滞留させることができ、また経口投与した際にはプロテアーゼなどが入り込めなくなって分解を抑制することができる。 The polyelectrolyte complex according to the present invention can hold a charged substance, such as an active peptide, protein, or DNA. By incorporating them into the electrolyte complex, they can escape the foreign substance recognition mechanism and stay in the body for a long time, and when orally administered, proteases and the like cannot enter and can suppress degradation.
以下に本発明の実施の形態を添付図面に基づいて説明する。本発明に係る高分子電解質複合体は酵素処理されたキトサン溶液と酵素処理されたカルボキシメチルセルロース溶液を混合することで得られ、図１にキトサンの酵素処理法の手順を示し、図２にカルボキシメチルセルロースの酵素処理法の手順を示す。 Embodiments of the present invention will be described below with reference to the accompanying drawings. The polyelectrolyte complex according to the present invention is obtained by mixing an enzyme-treated chitosan solution and an enzyme-treated carboxymethylcellulose solution. FIG. 1 shows the procedure of chitosan enzyme treatment, and FIG. 2 shows carboxymethylcellulose. The procedure of the enzyme treatment method is shown.
先ず、キトサンを用意する。キトサンはキチンからアセチル基を外して抽出精製したものであり、キチンのアセチル基に代わってアミノ基が結合している。それぞれの構造式を以下に示す。 First, prepare chitosan. Chitosan is obtained by removing and purifying chitin from the acetyl group, and has an amino group bonded in place of the acetyl group of chitin. Each structural formula is shown below.
上記のキトサン０.５ｇに酢酸１ｍｌと純水９０ｍｌを加え、更に４Ｍ−ＮａＯＨを用いてｐＨ５.６に調整し、この後、純水を加えて１００ｍｌにして、キトサンの０.５％溶液を得る。
キトサンは水には不溶であるが酸には溶解する。キトサンを酢酸などの弱酸に溶解せしめると、以下の構造式に示すようにアミノ基が水素イオンを受け取りキトサン分子は正に帯電する。
To 0.5 g of the above chitosan, add 1 ml of acetic acid and 90 ml of pure water, adjust to pH 5.6 using 4M NaOH, and then add pure water to 100 ml to obtain a 0.5% solution of chitosan. obtain.
Chitosan is insoluble in water but soluble in acid. When chitosan is dissolved in a weak acid such as acetic acid, the amino group receives hydrogen ions and the chitosan molecule is positively charged as shown in the following structural formula.
次いで、上記０.５％キトサン溶液を４５℃に加温し、キトサン分解酵素であるキトサナーゼを用いて分解（低分子化）する。 Next, the 0.5% chitosan solution is heated to 45 ° C. and decomposed (lower molecular weight) using chitosanase which is a chitosan degrading enzyme.
一方、カルボキシメチルセルロース（ＣＭＣ）を用意する。カルボキシメチルセルロース（ＣＭＣ）の構造式を以下に示す。 On the other hand, carboxymethylcellulose (CMC) is prepared. The structural formula of carboxymethylcellulose (CMC) is shown below.
上記のカルボキシメチルセルロース（ＣＭＣ）０.５ｇに純水９０ｍｌを加え、２Ｍ−ＨCｌを用いてｐＨ５.６に調整し、この後、純水を加えて１００ｍｌにして、カルボキシメチルセルロース（ＣＭＣ）の０.５％溶液を得る。
カルボキシメチルセルロース（ＣＭＣ）を水に溶かすと、以下の構造式に示すように、カルボキシメチル基が電離して負に帯電する。
90 ml of pure water is added to 0.5 g of the above carboxymethyl cellulose (CMC), adjusted to pH 5.6 using 2M HCl, and then made up to 100 ml with pure water to give a carboxymethyl cellulose (CMC) of 0.5. A 5% solution is obtained.
When carboxymethylcellulose (CMC) is dissolved in water, the carboxymethyl group is ionized and negatively charged as shown in the following structural formula.
次いで、上記０.５％カルボキシメチルセルロース溶液を４５℃に加温し、多糖分解酵素であるセルラーゼを用いて分解（低分子化）する。 Next, the 0.5% carboxymethylcellulose solution is heated to 45 ° C. and decomposed (lower molecular weight) using cellulase which is a polysaccharide degrading enzyme.
このようにしてキトサンの部分分解物とカルボキシメチルセルロースの部分分解物が得られたら、図３に示すように、これらを混合する。すると、キトサンの部分分解物のアミノ基とカルボキシメチルセルロースのカルボキシル基がイオン相互作用で結合しゲルが形成される。キトサンの部分分解物及びカルボキシメチルセルロースの部分分解物は短く切断されているのでこれらが絡まって形成されるゲルの粒子径も小さくなる。 When a partially decomposed product of chitosan and a partially decomposed product of carboxymethylcellulose are obtained in this way, they are mixed as shown in FIG. Then, the amino group of the partially decomposed product of chitosan and the carboxyl group of carboxymethyl cellulose are bonded by ionic interaction to form a gel. Since the partially decomposed product of chitosan and the partially decomposed product of carboxymethyl cellulose are cut short, the particle diameter of the gel formed by entanglement thereof becomes small.
形成されるゲルの粒子径は、キトサンの部分分解物及びカルボキシメチルセルロースの部分分解物の分子量によってコントロールすることができる。また各分解物の分子量は酵素による分解の度合いによって定まる。また、キトサンとカルボキシメチルセルロースとの混合比を変えることでサイズをコントロールすることもできる。したがって、酵素による反応時間や混合比などによって得られるゲルの粒子径をコントロールすることができる。 The particle diameter of the gel formed can be controlled by the molecular weight of the partially decomposed product of chitosan and the partially decomposed product of carboxymethyl cellulose. The molecular weight of each degradation product is determined by the degree of degradation by the enzyme. The size can also be controlled by changing the mixing ratio of chitosan and carboxymethylcellulose. Therefore, the particle diameter of the gel obtained can be controlled by the reaction time and mixing ratio of the enzyme.
図４は、上記によって得られた高分子電解質複合体の経過日数と粒子径との関係を示すグラフであり、条件はｐＨ５.６，２５℃で、粒子径は動的光散乱法で測定した。このグラフから、１週間経過しても粒径は殆ど変化せず、本発明によって得られたゲル粒子の安定性が高いことがわかる。 FIG. 4 is a graph showing the relationship between the number of days elapsed and the particle size of the polymer electrolyte composite obtained as described above. The conditions were pH 5.6 and 25 ° C., and the particle size was measured by a dynamic light scattering method. . From this graph, it can be seen that the particle size hardly changes even after one week, and the stability of the gel particles obtained by the present invention is high.
また、以下の（表１）は高分子電解質複合体粒子の分散している溶液の条件を変化させた時の粒子径について試験した結果を示すものである。尚、粒径の経時変化についても測定したが、前記同様、極めて安定していた。 The following (Table 1) shows the results of testing the particle diameter when the conditions of the solution in which the polymer electrolyte composite particles are dispersed are changed. In addition, although the change with time of the particle diameter was also measured, it was extremely stable as described above.
この（表）から本発明に係る高分子電解質複合体粒子は、低ｐＨ、高塩濃度あるいは低温条件においても安定していることが分かる。 From this (table), it can be seen that the polymer electrolyte composite particles according to the present invention are stable even under low pH, high salt concentration or low temperature conditions.
図５は高分子電解質複合体に荷電物質としてTexas Redを内包せしめる手順を示した図、図６はTexas Redの内包率を示すグラフである。
Texas Redを内包せしめるには、前記で得られた低分子化されたキトサン溶液（キトサン部分水解物）にTexas Redの１０ｍM溶液を加え、この後、前記で得られた低分子化されたカルボキシメチルセルロース溶液（CMC部分水解物）を添加する。
FIG. 5 is a diagram showing a procedure for encapsulating Texas Red as a charged substance in a polyelectrolyte complex, and FIG. 6 is a graph showing the encapsulation rate of Texas Red.
To enclose Texas Red, a 10 mM solution of Texas Red was added to the low molecular weight chitosan solution (chitosan partial hydrolyzate) obtained above, and then the low molecular weight carboxymethyl cellulose obtained above was added. Add the solution (CMC partial hydrolyzate).
図６はTexas Redの内包率を示すグラフであり、内包率は、前記で得られた
Texas Redを内包するナノ粒子をＰＢＳに懸濁せしめ、３７℃で２，４，８，２４時間経過した後、ＨＰＬＣ分析（カラム；ＣＭ cellulose、検出；蛍光550/603ｎｍ）によって得た。このグラフから本願の高分子電解質複合体はTexas Redを高効率に且つ安定して長時間内包することができることが分かる。
FIG. 6 is a graph showing the inclusion rate of Texas Red, and the inclusion rate was obtained as described above.
Nanoparticles containing Texas Red were suspended in PBS, and after 2, 4, 8, and 24 hours at 37 ° C., they were obtained by HPLC analysis (column; CM cellulose, detection; fluorescence 550/603 nm). From this graph, it can be seen that the polymer electrolyte composite of the present application can encapsulate Texas Red with high efficiency and stability for a long time.
図７は高分子電解質複合体に負の荷電を有する物質（以下、代表して酸性物質とする）を内包せしめる手順を示した図であり、酸性物質を高分子電解質複合体内に内包せしめる場合には、低分子化されたキトサン溶液（キトサン部分水解物）に酸性物質溶液を加え、この後、低分子されたカルボキシメチルセルロース溶液（ＣＭＣ部分水解物）を添加してナノ粒子を得る。 FIG. 7 is a diagram showing a procedure for encapsulating a negatively charged substance (hereinafter referred to as an acidic substance) in the polymer electrolyte complex. In the case where an acidic substance is encapsulated in the polymer electrolyte complex, FIG. Add an acidic substance solution to a low molecular weight chitosan solution (chitosan partial hydrolyzate), and then add a low molecular weight carboxymethylcellulose solution (CMC partial hydrolyzate) to obtain nanoparticles.
各種酸性物質を内包物としたナノ粒子を上記の工程で作製し、得られたナノ粒子をゲルろ過しまたはイオン交換カラムに供し、カプセル・非カプセルを分離・定量して内包率を測定した結果を以下の（表２）に示す。この（表２）から酸性物質であるTexas RedとFITC−卵白アルブミンの内包率は高いことが分かる。 Result of producing nanoparticles with inclusions of various acidic substances in the above process, subjecting the obtained nanoparticles to gel filtration or ion exchange column, separating and quantifying capsules and non-capsules and measuring the encapsulation rate Is shown in the following (Table 2). From this (Table 2), it can be seen that the inclusion rate of the acidic substances Texas Red and FITC-ovalbumin is high.
図８は高分子電解質複合体に正の荷電を有する物質（以下、代表して塩基性物質とする）を内包せしめる手順を示した図であり、塩基物質を高分子電解質複合体内に内包せしめる場合には、低分子されたカルボキシメチルセルロース溶液（ＣＭＣ部分水解物）に塩基性物質溶液を加え、この後、低分子化されたキトサン溶液（キトサン部分水解物）を添加してナノ粒子を得る。 FIG. 8 is a diagram showing a procedure for encapsulating a positively charged substance (hereinafter referred to as a basic substance) in the polyelectrolyte complex, where the basic substance is encapsulated in the polyelectrolyte complex. For example, a basic substance solution is added to a low molecular weight carboxymethylcellulose solution (CMC partial hydrolyzate), and then a low molecular weight chitosan solution (chitosan partial hydrolyzate) is added to obtain nanoparticles.
前記同様、塩基性物質としてサケカルシトニンとトリプシンインヒビターを選定した場合の内包率を測定した結果を以下の（表３）に示す。この（表３）から、塩基性物質については、先ず、低分子化されたカルボキシメチルセルロース溶液に加えることで内包率が高くなることが分かる。 As described above, the results of measuring the encapsulation rate when salmon calcitonin and trypsin inhibitor are selected as basic substances are shown in the following (Table 3). From this (Table 3), it is understood that the inclusion rate of the basic substance is increased by first adding it to the carboxymethylcellulose solution having a reduced molecular weight.
Claims (5)
1) キトサンを弱酸に溶解しキトサン分子を正に帯電させる工程。
・ 正に帯電したキトサン分子をキトサン分解酵素によって切断して低分子化する工程。
・ カルボキシメチルセルロースを水に溶解しカルボキシメチルセルロース分子を負に帯電させる工程。
・ 負に帯電したカルボキシメチルセルロース分子をカルボキシメチルセルロース分解酵素によって切断して低分子化する工程。
・ 前記工程2)で得られた低分子化したキトサン溶液と、前記工程4)で得られた低分子化したカルボキシメチルセルロース溶液とを混合し、互いの正負の官能基を反応させてゲル状に結合する工程。 A method for producing a polymer electrolyte composite comprising the following steps.
1) A process in which chitosan is dissolved in a weak acid to charge the chitosan molecule positively.
A process of reducing positively charged chitosan molecules by cutting them with chitosan degrading enzymes.
A step of dissolving carboxymethyl cellulose in water to negatively charge carboxymethyl cellulose molecules.
-A process of cutting negatively charged carboxymethylcellulose molecules by carboxymethylcellulose degrading enzyme to reduce the molecular weight.
-The low molecular weight chitosan solution obtained in the step 2) and the low molecular weight carboxymethyl cellulose solution obtained in the step 4) are mixed and reacted with each other's positive and negative functional groups to form a gel. The process of combining.
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