JP2003062057A - Minute particles of biopolymer for homeostasis and adhesion prevention - Google Patents
Minute particles of biopolymer for homeostasis and adhesion preventionInfo
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- JP2003062057A JP2003062057A JP2001259212A JP2001259212A JP2003062057A JP 2003062057 A JP2003062057 A JP 2003062057A JP 2001259212 A JP2001259212 A JP 2001259212A JP 2001259212 A JP2001259212 A JP 2001259212A JP 2003062057 A JP2003062057 A JP 2003062057A
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- fine particles
- biopolymer
- adhesion
- gas
- particle size
- Prior art date
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- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、止血・癒着防止性
のバイオポリマーの微細粒子に係り、詳細にはガスによ
り流動し、ガス噴射剤と共に、あるいはエアゾール製剤
として手術部位、創傷部位等の出血部位に噴霧し、止血
・癒着防止をし得るバイオポリマーの微細粒子に関す
る。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to fine particles of biopolymer having hemostatic / adhesion-preventing properties, and in particular, it flows with gas and is accompanied by a gas propellant, or as an aerosol preparation, bleeding at a surgical site, a wound site, etc. The present invention relates to fine particles of biopolymer that can be sprayed onto a site to prevent hemostasis and adhesion.
【０００２】[0002]
【従来の技術】従来から、酸化セルロース、カルボキシ
メチルセルロース、ヒアルロン酸、コラーゲン等の生体
適合性を有するバイオポリマーが、種々の目的に応じて
使用されてきている。これらのバイオポリマーは、止血
作用あるいは癒着防止作用を有するため、外科的手術時
の手術部位、あるいは創傷部位に適用され、止血、癒着
防止、ケロイド防止、創傷治癒、傷口の接着またはシー
リングのために用いられてきている。Biocompatible biopolymers such as oxidized cellulose, carboxymethyl cellulose, hyaluronic acid, and collagen have been conventionally used for various purposes. Since these biopolymers have hemostatic or adhesion preventing effects, they are applied to the surgical site or the wound site during surgical operation, and are used for hemostasis, adhesion prevention, keloid prevention, wound healing, wound adhesion or sealing. Has been used.
【０００３】しかしながら、これらのバイオポリマーの
適用形態は、それぞれの使用目的に応じて異なってお
り、繊維シート状物、フィルム状物、顆粒状物あるいは
ゲル状物として開発されてきているものである。したが
ってその適用も、それぞれの使用目的に応じて制限があ
り、広く一般的に止血・癒着防止には適用し得るもので
はなかった。However, the application form of these biopolymers differs depending on the purpose of use, and has been developed as a fibrous sheet, film, granule or gel. . Therefore, its application is also limited depending on the intended use, and it is not generally applicable to hemostasis / adhesion prevention.
【０００４】特に、これらのバイオポリマーの適用目的
部位は、その大きさ、形状、適用位置などが千差万別で
あり、極めて変化に富んだものとなっている。したがっ
て、バイオポリマーを目的位置に適切に貼り付けたり、
留置させたりすることは困難なものであり、特に体腔内
や経内視鏡手術を行った後の術部の止血、癒着防止のた
めにこれらのバイオポリマーを適用することは、ほとん
ど不可能なものであるといえる。In particular, the application target sites of these biopolymers vary greatly in size, shape, application position, etc., and are extremely varied. Therefore, properly attach the biopolymer to the target position,
It is difficult to indwell it, and it is almost impossible to apply these biopolymers to prevent hemostasis and adhesion of the surgical site, especially after performing endoscopic surgery in the body cavity. It can be said that it is a thing.
【０００５】そこで本発明者は、これらのバイオポリマ
ーを適用部位の大きさ、形状、位置に関係なく、的確に
付着、留置し得る技術を開発するべく検討を行い、その
結果バイオポリマーをガスの噴射力で流動し得る極めて
微細な微粒子とし、この微粒子をガス噴射剤と共に体腔
内や経内視鏡手術を行った後の術部へ噴霧させること、
あるいはエアゾール製剤の形態で噴射させ得るものとす
れば、極めて簡便に目的とする適用を行い得る点に着目
した。しかしながら、これまでバイオポリマーについて
は、ガスで流動し得る微細粒子としての検討はほとんど
なされておらず、また、微細粒子としてどの程度の粒度
分布の微細粒子であることが必要かの検討は、一切なさ
れていない。Therefore, the present inventor conducted studies to develop a technique capable of accurately attaching and detaining these biopolymers irrespective of the size, shape and position of the application site, and as a result, the biopolymers of gas To make extremely fine particles that can flow by injection force, and to spray these particles together with a gas propellant to the operating site after performing endoscopic surgery in a body cavity,
Alternatively, attention was paid to the fact that the intended application could be carried out very easily if it could be injected in the form of an aerosol formulation. However, biopolymers have so far not been studied as fine particles that can flow in a gas, and no consideration has been made as to what degree of fine particles the fine particles need to have. Not done.
【０００６】[0006]
【発明が解決しようとする課題】したがって、本発明は
上記の現状に鑑み、これらのバイオポリマーを適用部位
の大きさ、形状、その位置に関係なく適用することがで
き、その結果、目的とする止血、癒着防止、ケロイド防
止、創傷治癒、接着またはシーリング等を簡便に行い得
るバイオポリマーの微細粒子を提供することを課題とす
る。Therefore, in view of the above situation, the present invention can apply these biopolymers irrespective of the size, shape and position of the application site, and as a result, it is an object. It is an object of the present invention to provide biopolymer fine particles that can easily perform hemostasis, adhesion prevention, keloid prevention, wound healing, adhesion or sealing, and the like.
【０００７】[0007]
【課題を解決するための手段】かかる課題を解決するた
めの請求項１に記載の本発明は、粒度分布においてその
ほぼ８０％が粒子径１００μｍまでの範囲内にあり、か
つ平均粒子径が５０μｍ以下であるガスにより流動可能
な噴霧用の止血・癒着防止性のバイオポリマーの微細粒
子である。According to the present invention as set forth in claim 1 for solving the above-mentioned problems, almost 80% of the particle size distribution is within the range up to 100 μm and the average particle size is 50 μm. The following are fine particles of a hemopolymer / adhesion-preventing biopolymer for spraying, which can be flowed by the following gases.
【０００８】本発明にいうバイオポリマーとは、いわゆ
る生体適合性を有するポリマーをいい、特に止血・癒着
防止性を有する生体適合性のポリマーである。そのよう
なバイオポリマーとしてはカルボキシメチルセルロー
ス、カルボキシエチルセルロース、酸化セルロース、キ
チン、キトサン、ヒアルロン酸、デンプン、グリコーゲ
ン、アルギネート、ペクチン、デキストラン、コンドロ
イチン硫酸、ゼラチン、コラーゲン等を例示することが
でき、これらのバイオポリマーは一種または二種以上の
ものを使用することができる。The biopolymer referred to in the present invention refers to a polymer having so-called biocompatibility, particularly a biocompatible polymer having hemostatic / adhesion preventing properties. Examples of such biopolymers include carboxymethyl cellulose, carboxyethyl cellulose, oxidized cellulose, chitin, chitosan, hyaluronic acid, starch, glycogen, alginate, pectin, dextran, chondroitin sulfate, gelatin, collagen, and the like. As the polymer, one kind or two or more kinds can be used.
【０００９】したがって請求項２に記載の本発明は、バ
イオポリマーがカルボキシメチルセルロース、カルボキ
シエチルセルロース、酸化セルロース、キチン、キトサ
ン、ヒアルロン酸、デンプン、グリコーゲン、アルギネ
ート、ペクチン、デキストラン、コンドロイチン硫酸、
ゼラチン、コラーゲンから選択される一種または二種以
上である請求項１に記載の噴霧用の止血・癒着防止性の
バイオポリマーの微細粒子である。Therefore, in the present invention according to claim 2, the biopolymer is carboxymethyl cellulose, carboxyethyl cellulose, oxidized cellulose, chitin, chitosan, hyaluronic acid, starch, glycogen, alginate, pectin, dextran, chondroitin sulfate,
The microparticles of a spraying hemostatic / adhesion-preventing biopolymer according to claim 1, wherein the fine particles are one or more selected from gelatin and collagen.
【００１０】これらのバイオポリマーのなかでも、カル
ボキシメチルセルロース、カルボキシエチルセルロー
ス、酸化セルロース等のセルロース系バイオポリマーが
好ましく、特にカルボキシメチルセルロース、酸化セル
ロースが好ましい。Among these biopolymers, cellulosic biopolymers such as carboxymethyl cellulose, carboxyethyl cellulose and oxidized cellulose are preferable, and carboxymethyl cellulose and oxidized cellulose are particularly preferable.
【００１１】これらのバイオポリマーは、その特異的な
粒度分布ならびに粒子径により、ガスにより流動するこ
とができ、ガス噴射力により適用部位に噴霧することが
でき、またエアゾール製剤として噴霧することができ
る。Due to their specific particle size distribution and particle size, these biopolymers can be flowed by gas, can be sprayed on the application site by the gas injection force, and can be sprayed as an aerosol formulation. .
【００１２】したがって請求項３に記載の本発明は、ガ
スにより流動し、ガス噴射剤と共に噴霧されることを特
徴とする請求項１または２に記載の止血・癒着防止性の
バイオポリマー微細粒子であり、また請求項４に記載の
本発明は、エアゾール製剤の形態にある請求項１または
２に記載の止血・癒着防止性のバイオポリマーの微細粒
子である。Therefore, the present invention according to claim 3 is a biopolymer fine particle with hemostatic / adhesion-preventing properties according to claim 1 or 2, characterized in that it is fluidized by a gas and is sprayed together with a gas propellant. The present invention according to claim 4 provides the hemostatic / adhesion-preventing biopolymer fine particles according to claim 1 or 2, which are in the form of an aerosol preparation.
【００１３】本発明により提供される、ガスにより流動
し、ガス噴射剤と共に噴霧される止血・癒着防止性のバ
イオポリマーの微細粒子は、細いチューブの中をガスの
流れによって運ぶことが可能であることより、狭くて深
い目的部位まで、確実にバイオポリマーの微細粒子を付
着し得る利点を有するものであり、目的部位の大きさ、
形状に影響されることなく、所望量のバイオポリマーを
適切に適用し得る特徴を有するものである。The microparticles of the hemostatic / adhesion-preventing biopolymer provided by the present invention which are fluidized by a gas and sprayed with a gas propellant can be carried by a gas flow in a thin tube. Therefore, it has the advantage that fine particles of the biopolymer can be reliably attached to a narrow and deep target site, and the size of the target site,
It has a characteristic that a desired amount of biopolymer can be appropriately applied without being affected by the shape.
【００１４】特に外科手術における可燃性ガスを使用す
ることができない手術室では、例えば炭酸ガス、窒素ガ
ス等の不燃性ガスと共に、バイオポリマーを定量混合チ
ャンバー等により流動化させた後、細いチューブを用い
て目的部位まで運び、噴霧することにより、的確にその
適用部位に付着させ、滞留させることができるものであ
り、近年の経内視鏡手術処置による低侵襲手術において
は特に有用である特徴を有するものである。Particularly in an operating room where a flammable gas cannot be used in a surgical operation, a thin tube is fluidized with a non-combustible gas such as carbon dioxide gas or nitrogen gas by fluidizing a biopolymer in a quantitative mixing chamber or the like. By using it to carry it to the target site and spraying it, it can be accurately attached to the application site and retained, which is particularly useful in recent minimally invasive surgery by endoscopic surgery. I have.
【００１５】また一方、切り傷、擦り傷、火傷、採皮
傷、褥瘡等の外傷に対する適用にあっては、本発明のバ
イオポリマーの微細粒子は、エアゾール製剤として一定
の距離より噴霧し、適用部位に付着させ、留置させるこ
とができる。このような適用は病院内においても手術に
よることなく、また病院の外来もしくは病院外でも、簡
便な止血・癒着防止を確保し得る特徴を有する。On the other hand, in the case of application to cuts, abrasions, burns, skin scars, pressure ulcers, and other external wounds, the fine particles of the biopolymer of the present invention are sprayed as an aerosol formulation from a certain distance and applied to the application site. It can be attached and left in place. Such an application has a characteristic that it is possible to ensure simple hemostasis / adhesion prevention even in an outpatient clinic or outside a hospital without surgery.
【００１６】ところで多糖類系のバイオポリマーは、生
体由来成分と共に水溶液中で混合することにより、両者
はお互いに結合して新たな物性や効果を有するマトリッ
クスを形成することが知られている。したがって、本発
明のバイオポリマーの微細粒子を生体由来成分の微細粒
子と共に個別もしくは混合して目的部位に噴霧すれば、
両成分はその部位の水分に溶解して、その部位でマトリ
ックスを形成することとなる。形成されたマトリックス
は、単独で噴霧した場合の各成分に比較して、より粘度
の高い安定した性状のゲルとなり、目的部位の体組織に
対し、体外で結合させ形成させたゲルより、強固に密着
させることができ、より有効な治療効果を挙げることが
できる。By the way, it is known that a polysaccharide-based biopolymer is mixed with an ingredient derived from a living body in an aqueous solution so that the both bind to each other to form a matrix having new physical properties and effects. Therefore, if the fine particles of the biopolymer of the present invention are individually or mixed together with the fine particles of the biogenic component and sprayed on the target site,
Both components will be dissolved in the water | moisture content of the site | part, and will form a matrix in the site | part. The formed matrix becomes a gel with higher viscosity and stability than each component when sprayed alone, and is stronger than the gel formed by binding outside the body tissue to the target site body tissue. They can be brought into close contact with each other and more effective therapeutic effects can be achieved.
【００１７】したがって、請求項５に記載の本発明は、
生体由来成分の微細粒子と混合もしくは個別に噴霧し、
目的部位で結合してマトリックスを形成し得る、請求項
１または２に記載の噴霧用の止血・癒着防止性のバイオ
ポリマーの微細粒子でもあり、さらに、請求項６に記載
の本発明は、別の態様として、請求項１または２に記載
の噴霧用の止血・癒着防止性のバイオポリマーの微細粒
子と混合もしくは個別に噴霧し、目的部位で結合してマ
トリックスを形成し得る生体由来成分の微細粒子でもあ
る。そのような生体由来成分としては、アミノ酸、ペプ
チド、蛋白、ゼラチン、コラーゲンから選択されるもの
である。Therefore, the present invention according to claim 5 is
Mixing or spraying with fine particles of biological origin,
A fine particle of a hemostatic / adhesion-preventing biopolymer for spraying according to claim 1 or 2, which is capable of binding at a target site to form a matrix. Further, the present invention according to claim 6 is different. As an aspect of the present invention, a fine particle of a bio-derived component capable of forming a matrix by being mixed or separately sprayed with fine particles of the hemostatic / adhesion-preventing biopolymer for spraying according to claim 1 or 2. It is also a particle. Such living body-derived components are selected from amino acids, peptides, proteins, gelatin and collagen.
【００１８】[0018]
【発明の実施の形態】以下に、本発明が提供するバイオ
ポリマーの微細粒子の実際を説明することにより、本発
明をより詳細に説明する。BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below by explaining the actual fine particles of biopolymer provided by the present invention.
【００１９】本発明の基本的な態様は、ガスにより流動
することができ、ガス噴射剤と共に体腔内や経内視鏡手
術を行った後の術部へ噴霧させること、あるいはエアゾ
ール製剤の形態で噴射させることができ得るバイオポリ
マーの微粒子である。このようなバイオポリマーとして
は、いわゆる生体適合性を有する、止血、癒着防止、ケ
ロイド防止、創傷治癒、傷口の接着、シーリング等の作
用を有するポリマーである限り特に限定されるものでは
ない。具体的にはカルボキシメチルセルロース、カルボ
キシエチルセルロース、酸化セルロース、アガロース、
キチン、キトサン、ヒアルロン酸、デンプン、グリコー
ゲン、アルギネート、ペクチン、デキストラン、コンド
ロイチン硫酸、ゼラチン、コラーゲン等を挙げることが
でき、これらのバイオポリマーは一種または二種以上の
ものを使用することができる。The basic aspect of the present invention is that it is capable of flowing by gas and is sprayed together with a gas propellant into the body cavity or the surgical site after transendoscopic surgery, or in the form of an aerosol preparation. It is a fine particle of biopolymer that can be jetted. Such a biopolymer is not particularly limited as long as it is a polymer having so-called biocompatibility and effects such as hemostasis, adhesion prevention, keloid prevention, wound healing, wound adhesion, and sealing. Specifically, carboxymethyl cellulose, carboxyethyl cellulose, oxidized cellulose, agarose,
Examples thereof include chitin, chitosan, hyaluronic acid, starch, glycogen, alginate, pectin, dextran, chondroitin sulfate, gelatin and collagen, and these biopolymers may be used alone or in combination of two or more.
【００２０】そのなかでも、カルボキシメチルセルロー
ス、カルボキシエチルセルロース、酸化セルロース等の
セルロース系バイオポリマーが好ましく、特にカルボキ
シメチルセルロース、酸化セルロースが好ましい。これ
らのセルロースは、いわゆる止血性セルロースとして繊
維状、シート状、ガーゼ状、フィルム状等のものは存在
してはいるが、かかる形状のものでは、体腔内や経内視
鏡手術により深部での手術部位には、ほとんど適用する
ことができないものであった。Of these, cellulosic biopolymers such as carboxymethyl cellulose, carboxyethyl cellulose and oxidized cellulose are preferable, and carboxymethyl cellulose and oxidized cellulose are particularly preferable. These celluloses include fibrous, sheet-shaped, gauze-shaped, film-shaped, etc. as so-called hemostatic cellulose, but in such a shape, it can be used in a body cavity or at a deep part due to endoscopic surgery. It was hardly applicable to the surgical site.
【００２１】しかしながら驚くべきことに、粒度分布に
おいてそのほぼ８０％が粒子径１００μｍまでの範囲内
にあり、かつ平均粒子径が５０μｍ以下である微細粒子
とした場合には、ガスで流動し得る微細粒子となり、か
かる微細粒子は、ガス噴射剤と共に体腔内や経内視鏡手
術を行った後の術部へ噴霧させ得ること、あるいはエア
ゾール製剤の形態で噴射させ得ることが可能となったの
である。However, surprisingly, when 80% of the particle size distribution is within the range of up to 100 μm and the average particle size is 50 μm or less, fine particles that can flow with gas are obtained. As a result, such fine particles can be sprayed together with a gas propellant into the body cavity or the surgical site after transendoscopic surgery, or can be sprayed in the form of an aerosol preparation. .
【００２２】本発明者の検討の結果、粒度分布として１
００μｍを越えるものを多く含む場合には、ガスによる
ある程度の流動性はあるものの、ガス噴射あるいはエア
ゾール噴射を行うにはノズルからの噴射に支障をきた
し、適用部位への均一な噴霧が行うことが困難なもので
あった。したがって、本発明が提供するバイオポリマー
の微細粒子としては、その粒度分布においてそのほぼ８
０％が粒子径１００μｍまでの範囲内にあり、かつ平均
粒子径が５０μｍ以下である場合に、目的とする適用が
でき得ることが判明した。As a result of the study by the present inventors, the particle size distribution is 1
When a large amount of particles exceeding 00 μm is contained, there is some fluidity due to the gas, but when performing gas injection or aerosol injection, the injection from the nozzle is hindered, and uniform spraying to the application site may occur. It was difficult. Therefore, the biopolymer fine particles provided by the present invention have a particle size distribution of about 8%.
It was found that the intended application can be achieved when 0% is in the range up to 100 μm and the average particle size is 50 μm or less.
【００２３】このような微細粒子は、例えば、繊維状の
止血性セルロース、例えばカルボキシメチルセルロース
を、適当な粉砕機を用いて粉砕し、適宜分級化を行い、
所望の粒度分布および粒子径を有する微細粒子としての
止血性セルロースを得ることが可能である。しかしなが
ら、バイオポリマーは熱に弱く、また結晶構造自体が柔
らかいため、単純な機械的粉砕では発熱を伴い、所望の
微細粒子化は困難であることより、特別な冷却機構を持
つ特殊な高速粉砕機を使用するのがよい。例えば商品名
としてクリーンミル、アトマイザー、ジェットミル、ブ
レードミル等の名前で販売、使用されている粉砕機等
に、特別な冷却機構を有する粉砕機を挙げることができ
る。For such fine particles, for example, fibrous hemostatic cellulose, for example, carboxymethyl cellulose, is pulverized by using an appropriate pulverizer and appropriately classified,
It is possible to obtain hemostatic cellulose as fine particles with a desired particle size distribution and particle size. However, since the biopolymer is vulnerable to heat and the crystal structure itself is soft, heat is generated by simple mechanical crushing, and it is difficult to make the desired fine particles, so a special high-speed crusher with a special cooling mechanism is used. Is better to use. For example, crushers that are sold and used under the trade names of clean mill, atomizer, jet mill, blade mill and the like include crushers having a special cooling mechanism.
【００２４】かくして粉砕、分級化された本発明のバイ
オポリマーの微細粒子は、粒度分布においてそのほぼ８
０％が粒子径１００μｍまでの範囲内にあり、かつ平均
粒子径が５０μｍ以下であることより、微細粒子として
ガスにより良好に流動でき、ガス噴射剤と共に体腔内や
経内視鏡手術を行った後の術部へ噴霧適用、あるいはエ
アゾール製剤の形態で噴射適用することが可能となった
のである。The fine particles of the biopolymer of the present invention thus pulverized and classified have a particle size distribution of about 8%.
Since 0% is in the range up to 100 μm in particle size and the average particle size is 50 μm or less, fine particles can be satisfactorily flown by gas, and a gas propellant was used to perform intracorporeal or transendoscopic surgery. It became possible to apply it by spraying or spraying it in the form of an aerosol formulation to the operation site later.
【００２５】ガス噴射による体腔内や経内視鏡手術を行
った後の術部へ噴霧適用にあっては、本発明のバイオポ
リマーの微細粒子としては、その平均粒子径が５０μｍ
以下の程度のものであればよい。実際のへ噴霧適用にあ
っては、例えば炭酸ガス、窒素ガス等の不燃性ガスとバ
イオポリマーの微細粒子を定量混合チャンバーで流動化
させた後、プローブチューブ等の細いチューブを用い
て、目的の術部に噴霧させることができる。この場合に
おいて、本発明のバイオポリマーの微細粒子は、二種以
上を混合し、体腔内や経内視鏡手術を行った後の術部へ
噴霧適用することもできる。When the biopolymer of the present invention is applied to the inside of a body cavity by gas injection or a surgical application after transendoscopic surgery, the average particle diameter of the biopolymer fine particles is 50 μm.
It may be of the following degree. In the actual spray application, for example, after incombustible gas such as carbon dioxide gas or nitrogen gas and the fine particles of biopolymer are fluidized in the quantitative mixing chamber, a thin tube such as a probe tube is used to Can be sprayed onto the surgical site. In this case, two or more kinds of fine particles of the biopolymer of the present invention can be mixed and spray-applied to a body cavity or an operation site after transendoscopic surgery.
【００２６】一方エアゾール製剤として噴射適用する場
合にあっては、本発明のバイオポリマーの微細粒子は、
平均粒子径として２０μｍ程度のものが好適に使用され
る。そのような微細粒子としては、例えば、その粒度分
布が約３μｍ〜約１００μｍの範囲内にあり、そのほぼ
８０％が１０μｍ〜３０μｍの粒子径を有するものがあ
げられる。On the other hand, in the case of spray application as an aerosol preparation, the fine particles of the biopolymer of the present invention are:
An average particle size of about 20 μm is preferably used. Examples of such fine particles include those having a particle size distribution in the range of about 3 μm to about 100 μm, and almost 80% of them have a particle size of 10 μm to 30 μm.
【００２７】当該エアゾール製剤として噴射適用するに
は、いわゆる粉末エアゾール製剤として、適宜噴射剤と
共に切り傷、擦り傷、火傷、採皮傷、褥瘡等の外傷に適
用することができる。このような噴射剤としては、粉末
エアゾール製剤の噴射剤として使用されているものであ
れば、特に限定されず、例えば、液化石油ガス（ＬＰ
Ｇ）、ジメチルエーテル（ＤＭＥ）、炭酸ガス、窒素ガ
ス等を挙げることができる。For spray application as the aerosol preparation, so-called powder aerosol preparation can be appropriately applied together with a propellant to external wounds such as cuts, abrasions, burns, skin scratches and pressure ulcers. Such propellant is not particularly limited as long as it is used as a propellant of powder aerosol formulation, and for example, liquefied petroleum gas (LP
G), dimethyl ether (DME), carbon dioxide gas, nitrogen gas and the like can be mentioned.
【００２８】本発明のバイオポリマーの微細粒子を粉末
エアゾール製剤として適用するにあたっては、例えば、
７０〜９９％のエタノールに懸濁させた状態で噴射させ
ることができる。懸濁にあたっては、バイオポリマーの
微細粒子単独でも、また適宜界面活性剤を併用して懸濁
させることもできる。そのような界面活性剤としては、
従来から粉末エアゾール製剤に使用されているものであ
れば特に限定されるものでなく、ミリスチン酸イソプロ
ピル、ミリスチン酸オクチル、パルミチン酸イソプロピ
ル等を挙げることができる。In applying the fine particles of the biopolymer of the present invention as a powder aerosol preparation, for example,
It can be jetted in a state of being suspended in 70 to 99% ethanol. For the suspension, the fine particles of the biopolymer can be used alone or in combination with an appropriate surfactant. As such a surfactant,
There is no particular limitation as long as it has been conventionally used in powder aerosol formulations, and examples thereof include isopropyl myristate, octyl myristate, and isopropyl palmitate.
【００２９】この場合の粉末エアゾール製剤の形態にお
いて、本発明のバイオポリマーの微細粒子をエタノー
ル、好ましくは７０〜９９％のエタノールに懸濁させ、
噴射剤と共に切り傷、擦り傷に適用することは、適用部
位のエタノールによる消毒をも兼ねるものであり、特に
好ましいものといえる。In the form of a powder aerosol formulation in this case, the fine particles of the biopolymer of the invention are suspended in ethanol, preferably 70-99% ethanol,
It is particularly preferable to apply it to cuts and abrasions together with the propellant, since it also serves to disinfect the application site with ethanol.
【００３０】本発明が提供するバイオポリマーの微細粒
子は、上記したガス噴射剤と共に体腔内や経内視鏡手術
を行った後の術部へ噴霧適用、あるいはエアゾール製剤
の形態で噴射適用するにより、出血部位の形状、大きさ
に応じ、柔軟にその損傷部位をバイオポリマーの層で覆
うことができ、そのバイオポリマーの有する止血、癒着
防止、ケロイド防止、創傷治癒、接着またはシーリング
作用により、目的とする効果を挙げることができる。The fine particles of the biopolymer provided by the present invention can be spray-applied to the surgical site after performing endoscopic surgery in the body cavity together with the above-mentioned gas propellant, or by spraying in the form of an aerosol preparation. Depending on the shape and size of the bleeding site, the damaged site can be flexibly covered with a biopolymer layer, and the purpose of the biopolymer is to achieve hemostasis, adhesion prevention, keloid prevention, wound healing, adhesion or sealing. The effect can be obtained.
【００３１】また、本発明のバイオポリマーの微細粒
子、特に多糖類系のバイオポリマーの微細粒子は、個別
もしくは混合して体腔内の目的部位に噴霧することによ
り、両成分をその部位の水分に溶解させ、その部位でマ
トリックスを形成させることができる。体腔内の目的部
位で形成されたマトリックスは、単独で噴霧した場合の
各成分に比較して、より粘度の高い安定した性状のゲル
であり、体組織に対して強固に密着することから、より
有効な治療効果が期待できるのである。Further, the fine particles of the biopolymer of the present invention, particularly the fine particles of the polysaccharide-based biopolymer, are sprayed individually or in admixture to a target site in the body cavity, so that both components are dissolved in water of the site. It can dissolve and form a matrix at that site. The matrix formed at the target site in the body cavity is a gel with a stable and highly viscous property compared to each component when sprayed alone, and because it firmly adheres to the body tissue, An effective therapeutic effect can be expected.
【００３２】そのような生体由来成分としては、アミノ
酸、ペプチド、蛋白、ゼラチン、コラーゲン等を挙げる
ことができ、この微細粒子は、好ましくは、バイオポリ
マーの微細粒子と同様にガスで流動し得る微細粒子であ
り、より好ましくは、粒度分布においてそのほぼ８０％
が粒子径１００μｍまでの範囲内にあり、かつ平均粒子
径が５０μｍ以下であるガスにより流動可能微細粒子で
ある。なお、かかる生体由来成分の微細粒子は、バイオ
ポリマーと微細粒子と同様の処理により得ることができ
る。Examples of such bio-derived components include amino acids, peptides, proteins, gelatin, collagen and the like. The fine particles are preferably fine particles that can flow in a gas like the fine particles of biopolymer. Particles, more preferably approximately 80% of the particle size distribution
Is a fine particle that is flowable by a gas having a particle diameter of up to 100 μm and an average particle diameter of 50 μm or less. The fine particles of the biogenic component can be obtained by the same treatment as the biopolymer and the fine particles.
【００３３】[0033]
【実施例】以下に本発明を実施例により、より詳細に説
明するが、本発明はこれらの実施例に何ら限定されるも
のではないことに留意すべきである。EXAMPLES The present invention will be described below in more detail with reference to examples, but it should be noted that the present invention is not limited to these examples.
【００３４】実施例１：バイオポリマーとしてカルボキ
シメチルセルロース（ＣＭＣ）を選び、その微細粒子化
を検討した。市販のＣＭＣの粉末をブレードミルＢＭ−
１５（鉄製）型粉砕機により粉砕を行い、バグフィルタ
ーにて分級回収を行い、本発明のＣＭＣの微細粒子を得
た。得られた微細粒子の粒度分布を図１として示す。Example 1 Carboxymethyl cellulose (CMC) was selected as a biopolymer, and its microparticulation was investigated. Commercially available CMC powder is put into blade mill BM-
Crushing was performed with a No. 15 (iron) type crusher, and classification and collection were performed with a bag filter to obtain fine particles of CMC of the present invention. The particle size distribution of the obtained fine particles is shown in FIG.
【００３５】図中の結果から判明するように、本発明の
ＣＭＣの微細粒子は、その粒度分布が約３μｍ〜約１０
０μｍの範囲にあり、その約８０％が１０μｍ〜３０μ
ｍの粒子径を有し、２０μｍ付近を中心とする正規分布
的に構成された微細粒子であることが理解される。As can be seen from the results in the figure, the fine particles of CMC of the present invention have a particle size distribution of about 3 μm to about 10.
0 μm range, about 80% of which is 10 μm to 30 μm
It is understood that the fine particles have a particle diameter of m and are normally distributed around 20 μm.
【００３６】実施例２：バイオポリマーとしてセルロー
ス系の止血繊維：Ｓ−１００を選び、その微細粒子化を
検討した。止血繊維Ｓ−１００を実施例１と同様にブレ
ードミルＢＭ−１５（鉄製）型粉砕機により粉砕を行
い、バグフィルターにて分級回収を行い、本発明のＳ−
１００の微細粒子を得た。得られた微細粒子の粒度分布
を図２として示す。図中の結果から判明するように、得
られた本発明のセルロース系止血剤であるＳ−１００の
微細粒子は、その粒度分布が約３μｍ〜約１００μｍの
範囲にあり、その約８０％が１０μｍ〜３０μｍの粒子
径を有し、１８μｍ付近を中心とするほぼ正規分布的に
構成された微細粒子であることが理解される。Example 2 Cellulosic hemostatic fiber: S-100 was selected as a biopolymer, and its microparticulation was examined. The hemostatic fiber S-100 was pulverized by a blade mill BM-15 (made of iron) type pulverizer in the same manner as in Example 1, and classified and collected by a bag filter to obtain S-of the present invention.
100 fine particles were obtained. The particle size distribution of the obtained fine particles is shown in FIG. As is clear from the results in the figure, the fine particles of the obtained cellulosic hemostatic agent S-100 of the present invention have a particle size distribution in the range of about 3 μm to about 100 μm, and about 80% of them are 10 μm. It is understood that the fine particles have a particle diameter of ˜30 μm and are formed in a substantially normal distribution centered around 18 μm.
【００３７】実施例３
バイオポリマーとしてデキストランを選び、その微細粒
子化を検討した。市販のデキストランの粉末を実施例１
と同様にしてブレードミルＢＭ−１５（鉄製）型粉砕機
により粉砕を行い、バグフィルターにて分級回収を行
い、本発明のデキストランの微細粒子を得た。得られた
微細粒子の粒度分布は約５μｍ〜約１００μｍの範囲に
あり、その約８０％が１０μｍ〜３０μｍの粒子径を有
し、２０μｍ付近を中心とする正規分布的に構成された
微細粒子であった。なお、コラーゲンも同様に微細粒子
化がされた。Example 3 Dextran was selected as a biopolymer, and its formation into fine particles was examined. Commercially available dextran powder was used in Example 1.
In the same manner as the above, pulverization was performed with a blade mill BM-15 (made of iron) type pulverizer, and classification and collection were performed with a bag filter to obtain fine particles of dextran of the present invention. The particle size distribution of the obtained fine particles is in the range of about 5 μm to about 100 μm, about 80% of which have a particle diameter of 10 μm to 30 μm, and are fine particles that are normally distributed around 20 μm. there were. The collagen was also made into fine particles.
【００３８】実施例４：ガスジェットによる本発明の微
細粒子の噴霧適用
実施例１で得られたＣＭＣの微細粒子を用いて、ガスジ
ェットによる噴霧適用を検討した。図３に模式的に示す
ガスジェット噴霧装置により、実施例１で得られたＣＭ
Ｃの微細粒子を定量混合器で窒素ガスと共に混合し、プ
ローブチューブよりガスジェットによりＣＭＣの微細粒
子を噴霧させた。その結果、極めて良好にプローブチュ
ーブの先端よりＣＭＣの微細粒子が噴霧され、目的とす
る箇所に、ＣＭＣを付着、滞留させることができた。Example 4 Application of Spraying Fine Particles of the Invention by Gas Jet Using the fine particles of CMC obtained in Example 1, spray application by gas jet was investigated. The CM obtained in Example 1 by the gas jet spraying device schematically shown in FIG.
Fine particles of C were mixed with nitrogen gas in a quantitative mixer, and fine particles of CMC were sprayed from a probe tube by a gas jet. As a result, the fine particles of CMC were extremely well sprayed from the tip of the probe tube, and the CMC could be attached and retained at the intended location.
【００３９】実施例５：粉末エアゾール製剤
実施例１で得られたＣＭＣの微細粒子を用いて、粉末エ
アゾール製剤を調製した。粉末相として実施例１で得ら
れたＣＭＣの微細粒子４．５ｇ、アルコール相として９
９％エタノール０．５ｇおよび噴射剤としてＬＰＧ
（０．１５ＭＰａ）４５ｇを用い、Φ３５ｍｍ×１２０
ｍｍのスプレー容器内に充填し、粉末エアゾール製剤を
調製した。Example 5: Powder aerosol formulation Using the fine particles of CMC obtained in Example 1, a powder aerosol formulation was prepared. 4.5 g of the fine particles of CMC obtained in Example 1 as a powder phase and 9 as an alcohol phase
0.5 g of 9% ethanol and LPG as propellant
(0.15 MPa) 45 g, Φ35 mm × 120
A powder aerosol formulation was prepared by filling into a mm spray container.
【００４０】実施例６：粉末エアゾール製剤
実施例１で得られたＣＭＣの微細粒子を用いて、粉末エ
アゾール製剤を調製した。粉末相として実施例１で得ら
れたＣＭＣの微細粒子４．５ｇ、アルコール相として７
０％エタノール２０．５ｇおよび噴射剤としてＤＭＥ２
５ｇを用い、Φ３５ｍｍ×１２０ｍｍのスプレー容器内
に充填し、粉末エアゾール製剤を調製した。Example 6 Powder Aerosol Formulation The fine CMC particles obtained in Example 1 were used to prepare a powder aerosol formulation. 4.5 g of CMC fine particles obtained in Example 1 as a powder phase and 7 as an alcohol phase
20.5 g of 0% ethanol and DME2 as propellant
5 g was used and filled in a Φ35 mm × 120 mm spray container to prepare a powder aerosol formulation.
【００４１】実施例５で得られた粉末エアゾール製剤
を、実際の損傷部位（擦り傷による出血部位）に適用し
た結果、損傷部位を覆う血液をＬＰＧの噴射ガス圧によ
り除去し、直接出血点をＣＭＣの層でカバーすることが
でき、合わせて、９９％エタノールにより消毒効果も認
められた。損傷部位を覆ったＣＭＣ層は、血液により膨
潤し、ゲル状となって傷口を覆い、その結果、血餅が形
成され、良好な止血効果が認められた。なお、治癒過程
で傷口の癒着は認められなかった。The powder aerosol preparation obtained in Example 5 was applied to the actual damaged site (bleeding site due to abrasion). As a result, the blood covering the damaged site was removed by the gas pressure of LPG, and the direct bleeding site was detected by CMC. In addition, 99% ethanol also showed a disinfecting effect. The CMC layer covering the damaged site swelled with blood to form a gel and covered the wound, resulting in the formation of a blood clot and a good hemostatic effect. No adhesion of the wound was observed during the healing process.
【００４２】実施例６：ガスジェットによるバイオポリ
マーの微細粒子と、生体由来成分の微細粒子との同時噴
霧によるマトリックスゲルの生成
実施例１と同様の手段により、酸化セルロースおよびゼ
ラチンの微細粒子を調製した。両者を同重量部用い、図
３に模式的に示すガスジェット噴霧装置により、定量混
合器中で窒素ガスと共に両者を混合し、プローブチュー
ブよりガスジェットにより、水分を含んだ黒い布上に噴
霧し、マトリックスの形成を観測した。その結果、両成
分を混合して噴霧した場合には、各成分を単独で噴霧し
たときより、粘度の高い安定した、強い性状のマトリッ
クスゲルの膜が布の表面に生成することが確認された。Example 6 Production of Matrix Gel by Simultaneous Spraying of Fine Particles of Biopolymer and Fine Particles of Biological Component by Gas Jet By the same procedure as in Example 1, fine particles of oxidized cellulose and gelatin are prepared. did. Using the same parts by weight, both were mixed with nitrogen gas in a quantitative mixer by a gas jet spraying device schematically shown in Fig. 3, and sprayed on a black cloth containing water by a gas jet from a probe tube. , Matrix formation was observed. As a result, it was confirmed that when both components were mixed and sprayed, a matrix gel film with high viscosity, stability, and strong properties was formed on the surface of the fabric, as compared with spraying each component alone. .
【００４３】[0043]
【発明の効果】以上記載のように、本発明は生体適合性
のある、止血・癒着防止性のバイオポリマーの微細粒子
を提供するものであり、特にガスにより流動可能な極め
て微細なバイオポリマーの微細粒子である。かかるバイ
オポリマーの微細粒子は、特に粒度分布において、その
ほぼ８０％が粒子径１００μｍまでの範囲内にあり、か
つ平均粒子径が５０μｍ以下のものである。INDUSTRIAL APPLICABILITY As described above, the present invention provides biocompatible fine particles of a hemostatic / adhesion-preventing biopolymer, and in particular, an extremely fine biopolymer capable of flowing by gas. It is a fine particle. In particular, in the particle size distribution, about 80% of the fine particles of the biopolymer have a particle size of up to 100 μm and an average particle size of 50 μm or less.
【００４４】したがって、このような特異的形態を有す
る止血・癒着防止性のバイオポリマーの微細粒子である
ことより、ガス噴射剤と共に体腔内や経内視鏡手術を行
った後の術部へ噴霧させること、あるいはエアゾール製
剤の形態で噴射させることができるものであり、その結
果、（１）出血部位の形状、大きさに柔軟に対応でき、
損傷部位を自在にカバーし得ること、（２）創傷表面を
覆う血液をガス圧で吹き飛ばし、出血点に直接止血作用
を有するバイオポリマーを適用させることができるこ
と、（３）ガス圧で表面を圧迫できるので、圧迫作用に
よる止血効果も期待できること、（４）噴霧する箇所を
ガスの膨張により冷却するので、冷却による止血作用の
増強が図れること、（５）噴霧用チューブにより体腔内
（鼻腔、膣腔等）への適用もY方位に行い得ること、
（６）経内視鏡手術装置を組み合わせることにより、体
腔内深部での術部の止血、癒着防止が的確に行い得るこ
と、等の利点を有するものである。Therefore, since it is a fine particle of a biopolymer having a hemostatic / adhesion-preventing property having such a specific morphology, it is sprayed into a body cavity together with a gas propellant or to a surgical site after transendoscopic surgery. Or, it can be sprayed in the form of an aerosol formulation, and as a result, (1) it can flexibly respond to the shape and size of the bleeding site,
Being able to freely cover the damaged area, (2) being able to blow away the blood covering the wound surface with gas pressure and applying a biopolymer having a hemostatic action directly to the bleeding point, (3) pressing the surface with gas pressure Therefore, it is possible to expect a hemostatic effect due to the compression effect. (4) Since the sprayed area is cooled by expanding the gas, it is possible to enhance the hemostatic effect by cooling. (5) Inside the body cavity (nasal cavity, vagina) with a spray tube. Can also be applied to the Y direction,
(6) By combining a transendoscopic surgery device, it has advantages such as hemostasis and adhesion prevention of a surgical site deep inside a body cavity.
【００４５】特に、これまで止血・癒着防止性のバイオ
ポリマーとして、繊維シート状物、フィルム状物、顆粒
状物あるいはゲル状物は存在したが、その適用も、それ
ぞれの使用目的に応じて制限があり、広く一般的に止血
・癒着防止には適用し得るものではなかった。これに対
して本発明のバイオポリマーの微細粒子は、特にガスに
よる流動性を確保したことより、適用目的部位の大き
さ、形状、適用位置などに関係なく、適用し得るもので
あり、その医療上の効果ならびに価値は、多大なものと
いえる。In particular, fibrous sheet-like materials, film-like materials, granule-like materials or gel-like materials have heretofore existed as biopolymers having anti-hemostasis / adhesion properties, but their application is also limited according to their intended use. However, it was not generally applicable to hemostasis and adhesion prevention. On the other hand, the fine particles of the biopolymer of the present invention can be applied irrespective of the size, shape, and application position of the application target site by securing the fluidity due to the gas. The above effect and value can be said to be enormous.
【００４６】さらに、体腔内深部まで適用し得ることよ
り、本発明のバイオポリマーの微細粒子と親和性を有す
る生理活性ペプチド、タンパク、アミノ酸等を、同様に
微細粉砕し、ノズルから混合噴射すると、目的部位でバ
イオポリマーの微細粒子が水分で溶解し、イオン結合あ
るいはアフィニティー結合等により新たにマトリックス
を形成し、単独では得られない、優れた治療効果が可能
となる利点を有している。Further, since the bioactive peptide, protein, amino acid, etc. having affinity for the fine particles of the biopolymer of the present invention can be applied to deep inside the body cavity, finely pulverized in the same manner and mixed and jetted from a nozzle, The biopolymer fine particles are dissolved in water at a target site, and a new matrix is formed by ionic bond or affinity bond, which has an advantage that an excellent therapeutic effect which cannot be obtained by itself can be obtained.
【図１】実施例１で得られた本発明の、ＣＭＣの微細粒
子の粒度分布ならびに粒度累積分布を示す図である。FIG. 1 is a diagram showing a particle size distribution and a particle size cumulative distribution of fine particles of CMC of the present invention obtained in Example 1.
【図２】実施例２で得られた本発明の、セルロース系の
止血繊維：Ｓ−１００の微細粒子の粒度分布ならびに粒
度累積分布を示す図である。FIG. 2 is a diagram showing a particle size distribution and a particle size cumulative distribution of fine particles of a cellulosic hemostatic fiber: S-100 of the present invention obtained in Example 2.
【図３】実施例４における、ガスジェットによる本発明
の微細粒子の噴霧適用について使用するガスジェット噴
霧装置を模式的に示す図である。FIG. 3 is a diagram schematically showing a gas jet spraying device used for spraying fine particles of the present invention by a gas jet in Example 4.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 31/721 Ａ６１Ｋ 31/722 31/722 31/728 31/728 31/729 31/729 31/732 31/732 31/734 31/734 31/737 31/737 47/42 38/17 Ａ６１Ｐ 7/04 47/42 41/00 Ａ６１Ｐ 7/04 Ａ６１Ｌ 15/01 41/00 Ａ６１Ｋ 37/12 Ｆターム(参考） 4C076 AA24 BB31 CC18 DD37E EE41L EE42L EE43L FF15 FF29 4C081 AA04 BA11 BB04 CD011 CD021 CD031 CD041 CD071 CD081 CD091 CD121 CD151 DA15 4C084 AA02 BA44 MA01 MA05 MA13 NA10 ZA531 ZA532 ZA891 ZA892 4C086 AA01 EA20 EA23 EA25 EA26 MA01 MA02 MA04 MA05 MA13 MA63 NA10 ZA53 ZA89 ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 7 Identification code FI theme code (reference) A61K 31/721 A61K 31/722 31/722 31/728 31/728 31/729 31/729 31/732 31 / 732 31/734 31/734 31/737 31/737 47/42 38/17 A61P 7/04 47/42 41/00 A61P 7/04 A61L 15/01 41/00 A61K 37/12 F term (reference) 4C076 AA24 BB31 CC18 DD37E EE41L EE42L EE43L FF15 FF29 4C081 AA04 BA11 BB04 CD011 CD021 CD031 CD041 CD071 CD081 CD091 CD121 CD151 DA15 4C08 MA25 AEA EA86EA25AEA EA086A89A02 ZA086A53 ZA5320 ZA531 ZA531
Claims (7)
径１００μｍまでの範囲内にあり、かつ平均粒子径が５
０μｍ以下であるガスにより流動可能な噴霧用の止血・
癒着防止性のバイオポリマーの微細粒子。1. In the particle size distribution, almost 80% of the particles have a particle size within a range of up to 100 μm and an average particle size of 5
Hemostasis for spraying that can be flowed by gas that is 0 μm or less
Fine particles of anti-adhesion biopolymer.
シエチルセルロース、酸化セルロース、アガロース、キ
チン、キトサン、ヒアルロン酸、デンプン、グリコーゲ
ン、アルギネート、ペクチン、デキストラン、コンドロ
イチン硫酸、ゼラチン、コラーゲンから選択される一種
または二種以上のものである請求項１に記載の噴霧用の
止血・癒着防止性のバイオポリマーの微細粒子。2. One or more selected from carboxymethyl cellulose, carboxyethyl cellulose, oxidized cellulose, agarose, chitin, chitosan, hyaluronic acid, starch, glycogen, alginate, pectin, dextran, chondroitin sulfate, gelatin and collagen. The fine particles of a hemopolymer / adhesion-preventing biopolymer for spraying according to claim 1.
たは２に記載の噴霧用の止血・癒着防止性のバイオポリ
マーの微細粒子。3. Fine particles of a hemopolymer / adhesion-preventing biopolymer for spraying according to claim 1, which is sprayed with a non-combustible gas.
たは２に記載の噴霧用の止血・癒着防止性のバイオポリ
マーの微細粒子。4. Fine particles of a hemopolymer / adhesion preventive biopolymer for spraying according to claim 1 or 2, which is in the form of an aerosol formulation.
個別に噴霧し、目的部位で結合してマトリックスを形成
し得る、請求項１または２に記載の噴霧用の止血・癒着
防止性のバイオポリマーの微細粒子。5. The hemostatic / adhesion-preventing biopolymer for spraying according to claim 1, which can be mixed or sprayed with fine particles of a bio-derived component and can be bonded at a target site to form a matrix. Fine particles.
・癒着防止性のバイオポリマーの微細粒子と混合もしく
は個別に噴霧し、目的部位で結合してマトリックスを形
成し得る生体由来成分の微細粒子。6. A bio-derived component capable of forming a matrix by being mixed or separately sprayed with fine particles of the hemostatic / adhesion-preventing biopolymer according to claim 1 or 2 and being bonded at a target site. Fine particles.
コラーゲンから選択されるものである請求項６記載の生
体由来成分の微細粒子。7. Amino acids, peptides, proteins, gelatin,
The fine particles of a bio-derived component according to claim 6, which are selected from collagen.
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| JP2001259212A JP3805654B2 (en) | 2001-08-29 | 2001-08-29 | Fine particles of biopolymers that prevent hemostasis and adhesion |
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| Publication Number | Publication Date |
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| JP3805654B2 JP3805654B2 (en) | 2006-08-02 |
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