JPS6320301A - chitosan microparticles - Google Patents
chitosan microparticlesInfo
- Publication number
- JPS6320301A JPS6320301A JP16208786A JP16208786A JPS6320301A JP S6320301 A JPS6320301 A JP S6320301A JP 16208786 A JP16208786 A JP 16208786A JP 16208786 A JP16208786 A JP 16208786A JP S6320301 A JPS6320301 A JP S6320301A
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- Japan
- Prior art keywords
- chitosan
- microparticles
- acid
- average particle
- aqueous solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明はキトサン微小粒体に関し、更に詳しくは、医療
品担体、注射薬材料、クロマトグラフィー用吸着材、バ
イオリアクタ担体等として有用な高純度キトサン微小粒
体に関する。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to chitosan microparticles, and more specifically, to chitosan particles with high purity useful as carriers for medical products, materials for injections, adsorbents for chromatography, carriers for bioreactors, etc. Regarding chitosan microparticles.
（従来の技術）
従来、キチンを脱アセチル化して得られるキトサンは公
知であり、そのユニークな性質からして各種の吸着材、
医療品担体、医療材料としての研究が行なわれている。(Prior art) Chitosan, which is obtained by deacetylating chitin, has been known, and due to its unique properties, it has been used as a variety of adsorbents,
Research is being conducted on its use as a carrier for medical products and as a medical material.
例えば、各種担体として利用する場合には、キトサンを
粒状化する技術が重要であり、このような粒状化技術と
しては、キトサンが酸の水溶液に可溶であり、且つキト
サンの酸水溶液は、その中にアルカリを添加することに
よって再びキトサンを析出させるという性質を利用して
、キトサンの酸水溶液を調製し、これをアルカリにより
中和して粒状化する技術が最も多く提案されている。For example, when using chitosan as a variety of carriers, a technique for granulating chitosan is important. The most commonly proposed technique is to prepare an acid aqueous solution of chitosan, neutralize it with an alkali, and granulate it, taking advantage of the property that chitosan is re-precipitated by adding an alkali therein.
これらの粒状化方法によれば、平均粒径が数ｍｍから数
１００μｍ程度の粒状キトサンが提供される。According to these granulation methods, granular chitosan having an average particle size of about several mm to several 100 μm is provided.
（発明が解決しようとしている問題点）上記の公知の方
法は、いずれも水性媒体中において、キトサンの凝固を
行うものであり、比較的平均粒径の大なる粒状キトサン
は得られるものの、例えば、数１０μｍ程度のキトサン
微小粒体を得るのは非常に困難であり、更に数μｍ程度
のキトサン微小粒体を得ることはできない。これは、キ
トサンの粒状化を水性媒体中で行う結果、キトサン粒子
が微小であるとそれらが水性媒体中で凝集を生じ易いこ
と、および、このような微小な状態で凝集を生じること
なく乾燥するのは極めて困難なためである。(Problems to be Solved by the Invention) The above-mentioned known methods all involve coagulating chitosan in an aqueous medium, and although granular chitosan with a relatively large average particle size can be obtained, for example, It is very difficult to obtain chitosan microparticles with a size of about several tens of micrometers, and furthermore, it is impossible to obtain chitosan microparticles with a size of about several micrometers. This is because chitosan is granulated in an aqueous medium, and if the chitosan particles are small, they tend to aggregate in the aqueous medium, and it is difficult to dry them in such a small state without causing aggregation. This is because it is extremely difficult.
また、従来方法の場合には、キトサンの粒状化に際して
は、キトサンの酸水溶液からキトサンを析出させるため
のアルカリ等の凝固剤、析出したキトサン粒子を安定に
分散させるための界面活性剤等の懸濁化剤等が必要であ
るため、これらの各袖補助剤が、得られるキトサン粒体
中に混入し、不純物を含んだキトサン粒体となるという
問題がある。この問題は、キトサン粒体を医療分野で使
用しようとする時には非常に重要であり、従来方法によ
るキトサン粒体は殆ど医療分野では利用することができ
なかった。In addition, in the case of the conventional method, when granulating chitosan, a coagulant such as alkali is used to precipitate chitosan from an acid aqueous solution of chitosan, and a surfactant is used to stably disperse the precipitated chitosan particles. Since a clouding agent and the like are required, there is a problem that each of these sleeve auxiliary agents is mixed into the obtained chitosan granules, resulting in chitosan granules containing impurities. This problem is very important when trying to use chitosan granules in the medical field, and chitosan granules produced by conventional methods could hardly be used in the medical field.
また、最近では、キトサンが免疫活性効果があること、
また生理活性物の徐放性担体としての利用可能性等が報
告されているが、このような用途においては、キトサン
の平均粒径はμｍオーダーであること、および不純物を
含有しないことが要求されるため、従来技術によるキト
サン粒体は殆ど利用可能性が見い出し得ないものであっ
た。In addition, recently, chitosan has been shown to have an immunostimulating effect.
In addition, it has been reported that chitosan can be used as a sustained release carrier for physiologically active substances, but for such uses, chitosan is required to have an average particle size on the μm order and to be free of impurities. Therefore, chitosan granules according to the prior art could hardly be used.
従ワて、その平均粒径が１０μｍ以下であるキトサン微
小粒体の提供が強く要望されている。Therefore, it is strongly desired to provide chitosan microparticles having an average particle size of 10 μm or less.
（問題点を解決するための手段）
本発明者は上記の如き従来技術の問題点を解決し、上記
の要望に応えるべく鋭意研究の結果、本発明を完成した
。(Means for Solving the Problems) The present inventor has completed the present invention as a result of intensive research to solve the problems of the prior art as described above and to meet the above demands.
すなわち、本発明は、平均粒径が１０μｍ以下であるこ
とを特徴とするキトサン微小粒体である。That is, the present invention is a chitosan microparticle characterized by having an average particle size of 10 μm or less.
次に本発明を更に詳細に説明する。本発明者は従来から
キトサンの粒状化について鋭意研究のところ、キトサン
を酸の水溶液に適当な濃度で溶解し、従来技術の如く、
凝固浴中に加えて凝固させるのではなく、得られた水溶
液を加熱空気中に噴石して乾燥する、すなわちスプレー
ドライ方式で乾燥する時は、何らの凝固剤や懸濁化剤等
を使用することなく１０μｍ以下のキトサン微小粒体が
極めて容易に得られることを知見したものである。しか
も、このようにして得られる１０μｍ以下のキトサン微
小粒体は、その形状が殆ど角のない球状であり、しかも
、凝固剤や懸濁化剤等を使用しないため、得られるキト
サン微小粒体は非常に高純度であり、吸着材等の一般的
用途は勿論、特に医療分野における担体材料等として非
常に通しているものであった。Next, the present invention will be explained in more detail. The present inventor has been conducting extensive research on the granulation of chitosan, and has discovered that chitosan is dissolved in an aqueous acid solution at an appropriate concentration, and as in the prior art,
When drying the resulting aqueous solution by spray-drying, in which the resulting aqueous solution is dried by volcanic stones in heated air rather than being added to a coagulation bath and coagulated, no coagulant or suspending agent is used. It was discovered that chitosan microparticles of 10 μm or less can be obtained extremely easily without any problems. Moreover, the chitosan microparticles with a size of 10 μm or less obtained in this way are spherical with almost no corners, and since no coagulant or suspending agent is used, the chitosan microparticles obtained in this way are It has extremely high purity and has been used not only for general purposes such as adsorbents, but also as a carrier material particularly in the medical field.
以上の如き本発明のキトサン微小粒体は次の如くして提
供される。The chitosan microparticles of the present invention as described above are provided as follows.
本発明において使用するキトサンとは、カニやエビの甲
殻類の外皮中に存在するキチンを脱アセチル化して得ら
れるものであり、それ自体としては周知の材料であり、
種々の塩アセチル化度、種々の分子量のものが市場から
入手できるし、また容易に製造し得るものである。本発
明において使用するキトサンは、これらの公知のキトサ
ン中で、酸の水溶液に溶解できるものはいずれの脱アセ
チル化度でもいずれの分子量のものでも使用できる。The chitosan used in the present invention is obtained by deacetylating chitin present in the outer skin of crustaceans such as crabs and shrimp, and is a well-known material in itself.
Salts with various degrees of acetylation and various molecular weights are commercially available and can be easily produced. The chitosan used in the present invention may have any degree of deacetylation and any molecular weight among these known chitosan as long as it can be dissolved in an aqueous acid solution.
キトサンを溶解するための酸の水溶液は、酢酸、乳酸等
の存機酸および塩酸等の無機酸のいずれの水溶液でもよ
い。The aqueous acid solution for dissolving chitosan may be any of organic acids such as acetic acid and lactic acid, and inorganic acids such as hydrochloric acid.
酸の水溶液の酸濃度は、溶解するキトサンの濃度にもよ
るが、一般的には０．１〜１０重量％程度の濃度が好ま
しく、またキトサンの濃度はいずれの濃度でもよいが、
一般的には０．０５〜２０重量％、好ましくは０．１〜
１０重量％程度である。濃度が上記範囲未満であると経
済性が劣り、また上記濃度を越えると、キトサン水溶液
の粘度が高くなり、取扱不便であるとともに、得られる
キトサン微小粒体の平均粒径が１０μｍを越えることが
あるので好ましくない。このようなキトサンの濃度や噴
霧する際の送液速度等を調製することによって、サブミ
クロンのものから１０μｍに近い種々のキトサン微小粒
体を提供することができる。The acid concentration of the aqueous acid solution depends on the concentration of chitosan to be dissolved, but is generally preferably about 0.1 to 10% by weight, and the concentration of chitosan may be any concentration.
Generally 0.05 to 20% by weight, preferably 0.1 to 20% by weight
It is about 10% by weight. If the concentration is less than the above range, the economic efficiency will be poor, and if it exceeds the above concentration, the viscosity of the chitosan aqueous solution will increase, making it inconvenient to handle, and the average particle size of the obtained chitosan microparticles may exceed 10 μm. I don't like it because it is. By adjusting the concentration of chitosan, the liquid feeding speed during spraying, etc., it is possible to provide various chitosan microparticles ranging from submicron to nearly 10 μm.
上記のキトサンの水溶液はキトサンの溶解によってｐＨ
は７に近くなるが、更に無害な塩基性物質を加えてｐＨ
を更に７に近づけることによって、−層容易にキトサン
微小粒体を得ることができる。またキトサンが凝固しな
い程度にアルコール等の有機溶剤を添加してもよい。更
に、キトサン水溶液中には予め有用な薬剤、例えば、酵
素、生理活性物質等を適当量添加させておくこともでき
る。The above chitosan aqueous solution has a pH of
becomes close to 7, but by adding a harmless basic substance, the pH
By making the value even closer to 7, chitosan microparticles can be easily obtained. Further, an organic solvent such as alcohol may be added to an extent that chitosan does not coagulate. Furthermore, an appropriate amount of useful drugs such as enzymes, physiologically active substances, etc. may be added in advance to the aqueous chitosan solution.
本発明で使用する噴霧乾燥方法自体は公知の方法であり
、いずわの公知の噴石乾燥装置も有用である。The spray drying method used in the present invention itself is a known method, and any known cinder drying device is also useful.
このような噴霧乾燥機中で上記の如きキトサンの酸水溶
液を１００〜１８０℃程度の熱風中に噴霧することによ
り、溶液は微細な液滴のまま水分が蒸発し、本発明のキ
トサン微小粒体が得られる。このようにして得られた本
発明のキトサン微小粒体は、角の殆ど無い球状体であり
、その平均粒径は１０μｍ以下である。得られたキトサ
ン微小粒体には若干酸が残っていることもあるので、更
に水洗したり、中和および水洗して残っている酸を十分
に除去してもよく、少量の酸が残留しても問題のない用
途ではそのままでもよい。By spraying the chitosan acid aqueous solution as described above into hot air at about 100 to 180°C in such a spray dryer, water evaporates from the solution while leaving fine droplets, and the chitosan microparticles of the present invention are formed. is obtained. The chitosan microparticles of the present invention thus obtained are spherical bodies with almost no corners, and the average particle size is 10 μm or less. Since some acid may remain in the obtained chitosan microparticles, the remaining acid may be sufficiently removed by further washing with water or by neutralizing and washing with water, so that a small amount of acid remains. For applications where there is no problem, it may be left as is.
また得られたキトサン微小粒体は、用途によってはポリ
イソシアネート、ポリエポキシ化合物、グルタルアルデ
ヒド等の架橋剤によって架橋処理を行い、その耐水性等
を高めてもよい。Further, the obtained chitosan microparticles may be crosslinked with a crosslinking agent such as polyisocyanate, polyepoxy compound, glutaraldehyde, etc. to improve their water resistance etc., depending on the purpose.
（作用・結果）
以上の如き本発明のキトサン微小粒体はその平均粒径が
１０μｍ以下であり、且つ粒度分布の狭い球状の微粒子
であり、従来公知の平均粒径の大きなキトサン粒子と同
様にゲルクロマトグラフィー、イオン交換クロマトグラ
フィー等の交換材、透析材、イオン交換体、バイオリア
クタの担体等として有用であることは勿論、平均粒径が
１０μｍ以下であり、且つ高純度であることから、従来
では使用できなかった医療分野での用途、例えば、生理
活性物質の担体や静脈注射剤の材料等として有用である
。(Action/Result) The chitosan microparticles of the present invention as described above are spherical microparticles with an average particle size of 10 μm or less and a narrow particle size distribution, and are similar to conventionally known chitosan particles with a large average particle size. Not only is it useful as an exchange material for gel chromatography, ion exchange chromatography, etc., dialysis material, ion exchanger, carrier for bioreactors, etc., but also because it has an average particle size of 10 μm or less and high purity. It is useful for applications in the medical field that could not be used conventionally, such as as a carrier for physiologically active substances and as a material for intravenous injections.
次に実施例を挙げて本発明を更に具体的に説明する。な
お、文中、部または％とあるのは特に断りのない限り重
量基準である。Next, the present invention will be explained in more detail with reference to Examples. In addition, parts and percentages in the text are based on weight unless otherwise specified.
実施例１
１％の酢酸水溶液中に脱アセチル化度６３％のキトサン
（分子量約２３万）を０．１％の濃度に溶解してキトサ
ンの酸水溶液を調製し、これを入口温度１３０℃、噴霧
空気圧１ ｋｇｆ／ｃ ｒｆおよび送液ｉｉ５．５−６
ｒｎＪＺ／ｍ１ｎ−で噴霧乾燥して、本発明のキトサン
微小粒体を得た。このキトサン微小粒体の１００個を任
意に取り出し、顕微鏡下で観察したところ殆どが真球状
であり、平均粒径は２μｍであった。このキトサン微小
粒体は各種吸着材や静脈注射剤の材料として有用である
。Example 1 Chitosan with a degree of deacetylation of 63% (molecular weight approximately 230,000) was dissolved in a 1% acetic acid aqueous solution to a concentration of 0.1% to prepare an acid aqueous solution of chitosan, and this was heated at an inlet temperature of 130°C. Atomizing air pressure 1 kgf/c rf and liquid delivery II5.5-6
The chitosan microparticles of the present invention were obtained by spray drying with rnJZ/m1n-. When 100 of these chitosan microparticles were arbitrarily taken out and observed under a microscope, most of them were perfectly spherical, with an average particle size of 2 μm. These chitosan microparticles are useful as materials for various adsorbents and intravenous injections.
実施例２〜６
実施例１におけるキトサン、酸および噴霧乾燥条件を下
記第１表の如く変えたことを除いて、他は実施例１と同
様にして本発明のキトサン微小粒体を得た。こわらのキ
トサン微小粒体はいずれも各種吸着材や静脈注射剤の材
料として有用である。Examples 2 to 6 Chitosan microparticles of the present invention were obtained in the same manner as in Example 1, except that the chitosan, acid, and spray drying conditions in Example 1 were changed as shown in Table 1 below. All of Kowara's chitosan microparticles are useful as materials for various adsorbents and intravenous injections.
第１−′− 火へ例ス キトサン：脱アセチル化度９８％ 分子量１５万 溶液濃度１％ 酸： １％乳酸 噴霧乾燥：入口温度１３０℃ 噴霧空気圧１にｇｆ／ｃｒｎ’ 送液速度５．５〜６ｍｌ１／ｍｉｎ。1st-′- example to fire Chitosan: degree of deacetylation 98% Molecular weight 150,000 Solution concentration 1% Acid: 1% lactic acid Spray drying: Inlet temperature 130℃ Atomizing air pressure 1 to gf/crn' Liquid feeding rate: 5.5 to 6 ml/min.
キトサン微小粒体の平均粒径：８μｍ Ｘ属廻ｌ キトサン：脱アセチル化度８０％ 分子量４０万 溶液濃度０．１％ 酸： ０．２％塩酸 噴霧乾ｌｉ：入ロ温度１００℃ 噴霧空気圧Ｉ Ｋｇｆ／ｃ ｍ’ 送液速度４〜５ｍ見／ｗｉｎ。Average particle size of chitosan microparticles: 8μm X Chitosan: degree of deacetylation 80% Molecular weight 400,000 Solution concentration 0.1% Acid: 0.2% hydrochloric acid Spray drying Li: Inlet temperature 100℃ Spray air pressure I Kgf/c m’ Liquid feeding speed 4-5m/win.
キトサン微小粒体の平均粒径：３μｍ 叉菰胴Ａ キトサン：脱アセチル化度５０％ 分子量２０万 溶液濃度０．１％ 酸： ０．５％酢酸 噴霧乾燥：入口温度１２０℃ 噴霧空気圧１にｇｆ／ｃｒｎ２ 送液速度４〜５ｍｌ／ｗｉｎ。Average particle size of chitosan microparticles: 3μm Crossbody A Chitosan: degree of deacetylation 50% Molecular weight 200,000 Solution concentration 0.1% Acid: 0.5% acetic acid Spray drying: Inlet temperature 120℃ Spray air pressure 1 to gf/crn2 Liquid feeding rate 4-5ml/win.
キトサン微小粒体の平均粒径；２μｍ ＸＡ廻二 キトサン：脱アセチル化度８５％ 分子量２０万 溶液濃度０．５％ ＰＩＲ： ０．７％クエン酸 噴霧乾燥；入口温度１１０℃ 噴霧空気圧１．２にｇｆ／ｃｍ’ 送液速度２〜３ｍｆ／ｗｉｎ。Average particle size of chitosan microparticles: 2 μm XA Meiji Chitosan: degree of deacetylation 85% Molecular weight 200,000 Solution concentration 0.5% PIR: 0.7% citric acid Spray drying; inlet temperature 110℃ Atomizing air pressure 1.2 gf/cm’ Liquid feeding rate 2-3 mf/win.
キトサン微小粒体の平均粒径ニアμｍ 失施珂１ キトサン：脱アセチル化度８５％ 分子量３万 溶液濃度０．５％ ｅＩＲ： ０．５％酢酸 噴霧乾燥：入口温度１１０℃ 噴霧空気圧１にｇｆ／ｃゴ 送液速度５〜６ ｍ ｌ ／ ｍｉｎ。Average particle size of chitosan microparticles near μm Lost practice 1 Chitosan: degree of deacetylation 85% Molecular weight 30,000 Solution concentration 0.5% eIR: 0.5% acetic acid Spray drying: Inlet temperature 110℃ GF/C go to spray air pressure 1 Liquid feeding rate 5-6 ml/min.
キトサン微小粒体の平均粒径ニアμｍ 特許出願人 大口鯖化工業株式会社 Ｎ −でAverage particle size of chitosan microparticles near μm Patent applicant: Oguchi Sabaka Kogyo Co., Ltd. N - in
Claims (1)
ン微小粒体。Chitosan microparticles characterized by an average particle size of 10 μm or less.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16208786A JPS6320301A (en) | 1986-07-11 | 1986-07-11 | chitosan microparticles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16208786A JPS6320301A (en) | 1986-07-11 | 1986-07-11 | chitosan microparticles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS6320301A true JPS6320301A (en) | 1988-01-28 |
Family
ID=15747834
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16208786A Pending JPS6320301A (en) | 1986-07-11 | 1986-07-11 | chitosan microparticles |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6320301A (en) |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5010181A (en) * | 1988-03-28 | 1991-04-23 | Coughlin Robert W | Partially treated shellfish waste for removal of heavy metals from aqueous solution |
| JP2006233113A (en) * | 2005-02-28 | 2006-09-07 | Yaizu Suisankagaku Industry Co Ltd | Fine particle chitosan and method for producing the same |
| US8394414B2 (en) * | 1995-05-15 | 2013-03-12 | Mannkind Corporation | Method for drug delivery to the pulmonary system |
| US8933023B2 (en) | 2004-03-12 | 2015-01-13 | Biodel Inc. | Rapid acting injectable insulin compositions |
| US9060927B2 (en) | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
| US9610351B2 (en) | 2011-10-24 | 2017-04-04 | Mannkind Corporation | Methods and compositions for treating pain |
| US9630930B2 (en) | 2009-06-12 | 2017-04-25 | Mannkind Corporation | Diketopiperazine microparticles with defined specific surface areas |
| US9717689B2 (en) | 2005-09-14 | 2017-08-01 | Mannkind Corporation | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
| US9796688B2 (en) | 2004-08-20 | 2017-10-24 | Mannkind Corporation | Catalysis of diketopiperazine synthesis |
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| JPS6262827A (en) * | 1985-09-12 | 1987-03-19 | Fuji Boseki Kk | Method for producing ultrafine spherical chitosan |
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