JP2005253830A - Medical treatment material and method of manufacturing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medical treatment material and a method of manufacturing the same, capable of not only satisfying clinical requirements on the adhesion of tissues but also reducing the toxicity of the component of a synthetic material itself or its decomposed material when the synthetic material is used, having the biological decomposing/absorption properties, capable of quickly coping with the urgent application by reducing the preparation work whose timing is previously estimated, performed during an operation, without requiring a special device in using the treatment material, and to provide a polysaccharide derivative, or a medical treatment material using the composition and a method of manufacturing the same. <P>SOLUTION: The medical treatment material is a sheet-like material made of a powder layer and a support layer. The powder layer is compressed. Preferably, the particle size of the powder in the powder layer is 0.1-500 μm. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to a sheet-like medical treatment material comprising a powder layer and a support layer, and a method for producing the same.

In a surgical operation or the like, a medical treatment material has an important role in contributing to shortening of the operation time by simplifying a surgical operation. In particular, a medical treatment material used in the body may be placed in order to perform a desired function at an application site. In this case, it is desirable that after healing, it disappears quickly from the application site and is absorbed by the living body. Such medical treatment materials include tissue adhesives, hemostatic materials, anti-adhesion materials, embolization materials, and the like, and bioabsorbable materials that are decomposed and absorbed into the body in a physiological environment are used. The bioabsorbable material varies in the range of several minutes to several years depending on the type of material, and is absorbed into the living body after performing the intended function as each medical treatment material. The materials are selected as follows.

Currently, bioabsorbable materials with clinical experience include bio-derived materials (materials obtained from living organisms such as humans and animals). For example, fibrin, albumin, collagen or gelatin are tissue adhesives, hemostatic agents, etc. Has been used. It is well known that these biological materials are absorbed in the biological metabolic system.

Fibrin glue is one of the most frequently used biological tissue adhesives with many clinical achievements (see Non-Patent Document 1, for example). Fibrin glue is a two-component hemostatic material that utilizes the coagulation reaction of blood. First, fibrinogen is converted into fibrin through the enzymatic action of thrombin. Next, factor XIII activated by thrombin crosslinks fibrin to form a fibrin clot.

Non-Patent Document 1 also describes a technique using gelatin glue (GRF adhesive) as another biological tissue adhesive having clinical experience. GRF adhesives crosslink a mixture of gelatin and resorcinol with formaldehyde and glutaraldehyde. It is characterized by a strong tissue adhesive force, and is used for filling and adhering dissociative space in dissecting aortic aneurysms in addition to using it like fibrin glue.

In recent years, the development of synthetic material-based tissue adhesives that do not use biological materials has been extensively carried out, and several proposals have been made. For example, among 2-cyanoacrylates widely used as instant adhesives, ethyl or isobutyl ester cyanoacrylate-based adhesives can be mentioned (for example, see Non-Patent Document 2). This adhesive is characterized in that it is rapidly polymerized, cured and bonded using moisture as a polymerization initiator, so that the bonding speed is high and the bonding strength is high.

As another example, a method of forming a crosslinked polymer matrix by applying a mixed polymer cross-linking material for two components of a synthetic polymer having different groups capable of reacting with each other to a tissue has been proposed (for example, patents). References 1-3). Specifically, a first component in which a nucleophilic group such as a primary amino group or a thiol group is introduced and an electrophilic group such as a succinimidyl group are introduced at the molecular chain end of a polyethylene glycol having a multi-branched structure. A 2nd component is mixed and a crosslinked gel (hydrogel) is formed (patent document 1). Polyethylene glycol, which is the skeleton of each component, has a weight average molecular weight of 10,000, which is sufficient for the degradation product of the cross-linked product to be excreted by the kidneys, and is designed based on biodegradability and absorption. Yes. However, it is necessary to prepare the above two components in separate solutions for use, and each prepared solution is sprayed from a separate spray port of the applicator and applied to the application part while mixing the two components at the time of use. There is a need to.

By the way, a polysaccharide is known as a material having high biocompatibility, and in particular, a crosslinked product of a polysaccharide having a carboxy group in a molecule such as hyaluronic acid has been proposed (see Patent Documents 4 to 5). In order to form these polysaccharide cross-linked products, carbodiimide, ethoxyacetylene, Woodward reagent, chloroacetonitrile (Patent Document 4), and an intramolecular carboxy group activated by an activator used in peptide chemistry (Patent Document 5) It's being used. In these publications, as a method for crosslinking activated polysaccharides, a method of crosslinking by heating or ultraviolet irradiation (Patent Document 4) and a method of crosslinking with polyamine (Patent Document 5) are disclosed.
In each of the above publications, the use of the crosslinked product has been proposed for use in medicine and surgery in the form of a film, sponge-like, capsule, tablet, DDS carrier or the like.

On the other hand, examples of the synthetic bioabsorbable material include polylactic acid, polyglycolic acid and copolymers thereof, and oxidized cellulose. In general, polylactic acid is used as an absorptive bone fixing material and is gradually hydrolyzed and absorbed into a living body over several months to several years. Polyglycolic acid is used for absorbable sutures, absorbable suture reinforcing materials, and the like, and is absorbed by the living body over 40 to 70 days by hydrolysis. Oxidized cellulose is also used as a hemostatic agent, gradually becomes water-soluble under physiological conditions and disappears from the application site in about 30 days, and the oxidized cellulose itself originally has a low molecular weight. It is excreted.

These synthetic bioabsorbable materials can be designed in accordance with required specifications such as mechanical properties (strength, flexibility, etc.) and absorption period according to the use of each medical treatment material. However, there is little local inflammation due to the synthetic material itself or degradation products in its absorption process, and it disappears quickly from the application site after healing and does not accumulate excessively in the organ tissue. It is necessary to consider the safety to living bodies such as being excreted outside the body.

In addition to the above synthetic materials, research and development of new synthetic materials are being actively conducted. For example, focusing on bioabsorbable hemostatic materials and anti-adhesion materials, many synthetic polymers represented by polysaccharide-based and polyether-based polymers with excellent biocompatibility are applied. Specifically, for example, a soluble wound healing hemostatic cellulose fiber using carboxymethyl cellulose as a hemostatic material (see Patent Document 6), and a bioabsorbable anti-adhesion carboxypolysaccharide / polyether polymer as an adhesion prevention material. A composite (see Patent Document 7) and the like have been proposed.

These medical treatment materials use a synthetic polymer having a relatively high molecular weight (weight average molecular weight of several tens of thousands to several hundreds of thousands) in order to provide the bulk form as a fiber or a film. However, these relatively high molecular weight synthetic polymers can reduce the molecular weight to some extent by hydrolysis or liver metabolism under physiological conditions, but they are originally water-soluble polymers or decomposed to become water-soluble. Even if the polymer can disappear from the site of application after healing of the wound, it degrades to a molecular weight sufficient to be excreted through the kidney (about 70,000 or less, and in some cases about 40,000 or less). The material needs to be designed to be.

A polyether ester obtained by reacting a polyalkylene oxide and a polyvalent carboxylic acid compound is used as a material for a molded article such as a hydrophilic film or sheet (see, for example, Patent Document 8). In addition, the polyether ester exhibits high performance in terms of water resistance, mechanical strength, stability over time, adhesion, etc. without losing the excellent hydrophilicity and water absorption of the polyether ester, and also in the balance between them. An excellent crosslinkable material has been proposed (see Patent Document 9).

Thus, attempts have been made to use non-biologically derived synthetic materials as medical treatment materials, but a powder layer is formed from powders containing these non-biologically-derived materials that function as medical treatment materials. However, no attempt has been made to use this powder layer in combination with a support layer.

US Pat. No. 6,323,278 Special Table 2000-502380 JP-T-2002-541923 US Pat. No. 5,676,964 International Publication No. 00/27886 Japanese Patent No. 3057446 Japanese translation of PCT publication No. 2002-511897 JP-A-9-52950 JP 2003-113240 A Shojiro Matsuda, “Adhesion of biological tissues”, Adhesion, Vol. 44, No. 1, p. 19-27, High Polymer Publications, Japan (January 25, 2000) Shida Kawada et al., “Stanford Type A Dissecting Aortic Aneurysm”, Surgical Practice, Vol. 32, No. 9, p. 1250–1258, Diagnosis and Treatment, Japan (September 1, 1990)

As mentioned above, medical treatment materials used in the body, represented by tissue adhesives and anti-adhesion materials, use synthetic materials not only to meet their clinical requirements but also in terms of safety. Therefore, it is important to reduce the toxicity of the component itself or its degradation product, and to design the material so as to have biodegradability. Furthermore, it is desirable that the number of preparatory operations to be performed in advance during the operation can be reduced, a rapid application can be quickly handled, and no special device is required for the use. An object of the present invention is to provide a sheet-like medical treatment material composed of a powder layer and a support layer and a method for manufacturing the same, as a medical treatment material required as described above. .

It is another object of the present invention to provide a medical treatment material that can maintain a shape in a living body and can quickly disappear from an application site after achieving its purpose and can be discharged out of the living body. That is, the molecular weight is sufficient to maintain the desired mechanical strength, and after maintaining a shape for a certain period in a physiological environment, it can quickly disappear from the application site. An object of the present invention is to provide a medical treatment material that can be safely discharged outside the body without being excessively accumulated in an organ.

Furthermore, in addition to the above characteristics, the period until the medical treatment material is decomposed in a physiological environment can be adjusted within a longer period, and mechanical properties (strength, flexibility, etc.) according to various applications can be adjusted. It aims at providing the medical treatment material which can be obtained.

That is, the present invention provides the following (1) to (12).
(1) A medical treatment material comprising a powder layer and a support layer, wherein the powder layer is compressed.
(2) The medical treatment material according to (1), wherein the powder layer has a particle size of 0.1 to 500 μm.
(3) The medical treatment material according to (1) or (2), wherein a powder amount of the powder layer is 1 to 100 mg / cm ² .
(4) The medical treatment material according to any one of (1) to (3), wherein the powder of the powder layer includes a polymer having an active ester group capable of reacting with an active hydrogen-containing group.
(5) The medical treatment material according to any one of (1) to (4), wherein the powder layer contains an alkalizing agent.
(6) The medical treatment material according to any one of (1) to (5), wherein the support layer is made of a bioabsorbable material.
(7) The bioabsorbable material of the support layer is at least one selected from the group consisting of polyetherester, oxidized cellulose, polyglycolic acid, carboxymethylcellulose, hyaluronic acid, and a composite thereof. (1) The medical treatment material in any one of thru | or (6).
(8) The medical treatment material according to any one of (1) to (7), wherein the support layer is in the form of a film, sponge, woven fabric, nonwoven fabric, or powder compact.
(9) It consists of a powder layer and a support layer, comprising a powder containing a polymer having an active ester group capable of reacting with an active hydrogen-containing group, and a sheet-like bioabsorbable material. A method for producing a sheet-like medical treatment material.
(10) The method according to (9), wherein the compression force during the compression is 1 to 100 MPa.
(11) The medical treatment material according to any one of (1) to (8), which is used for tissue adhesion and / or closure.
(12) A sheet-like medical treatment material comprising a powder layer and a support layer, wherein the powder layer is compressed, and the powder of the powder layer can react with an active hydrogen-containing group A medical treatment material in the form of a sheet, comprising a polymer made of a non-biological material having an active ester group.

The medical treatment material of the present invention has chemical safety by not using a potentially toxic chemical substance as a derivative skeleton. Furthermore, since the medical treatment material of the present invention is a bioabsorbable material, it is not necessary to remove it after application to a living body. The medical treatment material of the present invention can be used for adhesion and / or closure of biological tissue, such as stopping leakage of body fluids such as blood and lymph from sutured or joined tissues or gas in the body. The powder layer of the material is made of a polymer having an active ester group capable of reacting with an active hydrogen-containing group, and adheres to the living body surface by bonding with the active hydrogen-containing group on the living body surface, and the powder layer itself absorbs water. It has an adhesive function by gelling. Further, the support layer of the medical treatment material has a support function of the powder layer and a compression function that enables the powder layer to be pressed against the living body surface. The medical treatment material of the present invention can be used for preventing adhesion of organs and living tissues. This medical treatment material can be used simply and efficiently from its shape.

Hereinafter, the present invention will be described in detail.
The medical treatment material of the present invention is a medical treatment material in the form of a sheet comprising a powder layer and a support layer, and the powder layer is compressed. The powder layer is a layer obtained by compressing powder. The powder particles are fixed as a powder layer by compressing the powder. The powder layer fixed by the weight of the powder itself is preferably compressed to such an extent that it does not peel off from the powder layer and / or the support layer. It has been clarified in the invention of the present application that a powder layer that can be prepared with a high density expresses better performance as a medical treatment material than a sponge that cannot be prepared with a high density. The powder is not particularly limited, but can be a powder having a particle size of substantially 0.1 to 500 μm, preferably a particle size of substantially 0.5 to 250 μm, more preferably a particle size of substantially. 1 to 100 μm. The amount of powder can be substantially in the range of 1-100 mg / cm ² , preferably the amount of powder is substantially 5-80 mg / cm ² , more preferably the amount of powder is substantially 10-50 mg. / Cm ² .

The powder contains at least a polymer having an active ester group capable of reacting with an active hydrogen-containing group. The polymer is not particularly limited but is preferably bioabsorbable. In addition to the polymer, the component contained in the powder is also preferably bioabsorbable. In this specification, bioabsorbability means having local disappearance and extracorporeal discharge. The local disappearance means that it is decomposed within a predetermined number of days in a physiological environment and disappears from the application site. In the present specification, the “predetermined number of days” is 90 days at the maximum, and in some cases 70 days, 50 days, 40 days, or 30 days. No inflammatory reaction is visually observed during or after the disappearance process. The material is degraded by hydrolysis of the material itself and / or phagocytosis (phagocytosis) of phagocytes.

Here, since conditions under physiological environment may not be specified widely, in this specification, as a simple and clear indicator, at least 1% by mass polymer in physiological saline (pH 4-8) at 37 ° C. in vitro. When a sample corresponding to the concentration is added, mixed with a rotor mixer, and visually observed, the sample has a local disappearance when the sample loses its shape within a predetermined number of days and becomes a transparent aqueous solution (hereinafter referred to as “the present invention”). Sometimes referred to as “local disappearance”.) The period during which the shape of the bioabsorbable material of the present invention is maintained in a physiological environment varies depending on the application and is not particularly limited as long as it is within a predetermined number of days. In this specification, a polymer or powder may be referred to as a “bioabsorbable material”.

Further, the term “extravasation” means that after the material has disappeared from the application site, it can be safely discharged out of the living body without being excessively accumulated in organs such as the kidney and liver. In the present specification, when a material is decomposed to a molecular weight of 70,000 or less, and in some cases, 40,000 or less, the sample has extracorporeal excretion (hereinafter may be referred to as “extracorporeal excretion of the present invention”). .)

Although the component contained in a powder other than a polymer or a polymer is not specifically limited, A biological material or a non-biological material can be used. “Biological material” means a material obtained directly from a living body. More specifically, it means that the material is obtained directly from vertebrates. “Non-biological material” means that the material is not directly obtained from a living body. More specifically, it means that the material is not material obtained directly from vertebrates. The non-living material can be a material that is originally synthesized in a living body, chemically synthesized, genetically engineered, or synthesized by an animal other than a vertebrate, such as a fungus. Thus, the polymer can be a synthetic material that naturally exists or does not exist in nature. In this specification, the polymer contained in the powder may be referred to as “biological material”, “non-biological material”, or “synthetic material”.

The polymer has an active ester group that can react with an active hydrogen-containing group, and an active ester group that can react with an active hydrogen-containing group is bonded to the raw material of the polymer. The active ester group introduced into the polymer may be any group that can react with the active hydrogen-containing group to form a covalent bond. Such active ester groups are usually self-owned by the polymer molecule or have a strong electrophilic group attached to the carbonyl carbon of the carboxy group or methylcarboxy group introduced into the polymer compared to normal esters. It is a group. Specifically, when this active ester group is represented by “—COOX”, the electrophilic group forming the alcohol moiety “—OX” is preferably a group introduced from an N-hydroxyamine compound. Since the N-hydroxyamine compound is a relatively inexpensive raw material, it is easy to industrially introduce an active ester group.

Specific examples of the N-hydroxyamine compound for forming “-OX” include N-hydroxysuccinimide, N-hydroxynorbornene-2,3-dicarboxylic acid imide, and 2-hydroxyimino-2-cyanoacetic acid. Typical examples include ethyl ester, 2-hydroxyimino-2-cyanoacetamide, N-hydroxypiperidine and the like.
In this invention, the active ester group which a polymer has may be single 1 type, or 2 or more types may exist. Among such active ester groups, succinimide ester groups are preferred.

In the present invention, the active hydrogen-containing group involved in the reaction with the active ester group is not particularly limited as long as it is a group capable of reacting with the active ester group to form a covalent bond under the reaction conditions specific to the present invention. Also in this invention, it can apply to the thing illustrated as a general active hydrogen containing group. Specific examples include a hydroxyl group, an amino group, and a thiol group. Here, the amino group includes a primary amino group and a secondary amino group. Among these, when the active hydrogen-containing group is a hydroxyl group or a primary amino group, it is preferable because the reactivity with the active ester group is good and the time until crosslinking and gelation is short.

The method of crosslinking (gelling) a polymer having an active ester group capable of reacting with an active hydrogen-containing group is a method in which an active ester group and an active hydrogen-containing group react to form a covalent bond. Is a method in which a polymer prepared to have an active ester group capable of reacting with an active hydrogen-containing group is cross-linked by subjecting the polymer to water, water vapor, a water-containing solvent, etc. in the presence of water under alkaline conditions. Can be mentioned. Therefore, it is actually achieved by subjecting the powder or powder layer containing the polymer to the presence of water such as water, water vapor, a solvent containing water under alkaline conditions. In the present specification, “water” includes any form of water such as water, water vapor, and a solvent containing water.

More specifically, the polymer having an active ester group capable of reacting with an active hydrogen-containing group can be cross-linked by being provided in the presence of water having a pH of 7.5 to 12, preferably pH 9.0 to 10.5. At that time, if the pH of water is lower than 7.5, the self-crosslinking property is low, and a sufficient degree of crosslinking cannot be obtained. On the other hand, application of a material having a pH higher than 12 is not preferable in terms of physiological conditions although the crosslinking reaction proceeds.

“Alkaline conditions” refer to conditions where water having a pH of at least substantially 7.5 or more is present. In a polymer having an active ester group capable of reacting with an active hydrogen-containing group, since the contribution of heat to the crosslinking reaction is not substantially large, the temperature of “alkaline conditions” is not particularly limited. It can be in the range of ° C.

“Contacting water under alkaline conditions” means contacting a polymer having an active ester group capable of reacting with an active hydrogen-containing group with any form of moisture under alkaline conditions to place the polymer in alkaline conditions. Since this polymer is in the form of powder, it is possible to add water that has been adjusted to alkaline conditions in advance, or to add water in a powdered state in which polymer powder and an alkalizing agent described below are mixed. . By these operations, the polymer body is placed in an alkaline environment, and a crosslinking reaction is started. That is, when the polymer comes into contact with moisture under alkaline conditions, the crosslinking reaction starts and proceeds. Accordingly, the pH of the mixture of moisture and polymer under alkaline conditions may be alkaline conditions, but not necessarily alkaline conditions. When the polymer comes into contact with moisture under alkaline conditions, the formation of a cross-link is initiated, and the cross-linking reaction is not substantially initiated by UV (ultraviolet light) or heating, and the formation of the cross-linking is not substantially advanced by UV or heat. Therefore, “contact with water under alkaline conditions” includes adding water using an “alkalizing agent” described later.

The powder used in the present invention can contain an alkalizing agent as long as the characteristics of the present invention are not impaired. The alkalizing agent is mainly a salt (powder) or the like for adjusting the pH of a polymer having an active ester group capable of reacting with an active hydrogen-containing group to 7.5 to 12. Although it does not specifically limit as an alkalinizing agent, Specifically, sodium hydrogencarbonate aqueous solution or powder, phosphate buffer solution (disodium hydrogen phosphate-dihydrogen potassium phosphate), an acetic acid-ammonia buffer solution, etc. Can be mentioned. Among these, sodium bicarbonate can be suitably used from the viewpoint of safety because a 7% aqueous solution (pH 8.3) thereof is used as an intravenous injection solution as a medical pH adjuster.

Therefore, the polymer (A) having an active ester group capable of reacting with the active hydrogen-containing group can be provided as a powder, and further an alkalizing agent (B) can be provided. The alkalizing agent (B) may be supplied without being mixed with the powder, or may be previously mixed with the powder. The timing of mixing is not particularly limited, but is appropriately selected before or during use of the medical treatment material of the present invention. In the combination of the polymer (A) having an active ester group capable of reacting with the active hydrogen-containing group and the alkalizing agent (B), it may contain other substances as necessary. It may be mixed with polymer powder or not.

The polymer having an active ester group is not particularly limited as long as it has an active ester group capable of reacting with an active hydrogen-containing group, but is not limited to polysaccharides, polyethylene oxide (PEO) (Special Table 2000-502380, Special Table 2002-541923). , US5583114) and polyamino acids (Japanese Patent Laid-Open No. 9-296039) or a mixture thereof. Further, the polymer having an active ester group contained in the powder may be one component that functions as a medical treatment material, or two components (two materials) or more may function as a medical treatment material. . Of these, polysaccharides are preferred.

Hereinafter, an embodiment in which the polymer is a polysaccharide will be described in detail as one embodiment of the present invention.
The polysaccharide has at least one active ester group introduced into the polysaccharide side chain and capable of reacting with an active hydrogen-containing group, and is brought into contact with water under an alkaline condition to share the active ester group and the active hydrogen-containing group. It can be a crosslinkable polysaccharide derivative for forming a crosslinked product by bonding.

The polysaccharide has at least one active ester group, which is introduced into the side chain of the polysaccharide and can react with the active hydrogen-containing group. Although the polysaccharide (raw material) into which this active ester group is introduced will be described later, since the polysaccharide molecule inherently has a hydroxyl group, that is, has an active hydrogen-containing group, the polysaccharide in which the active ester group has been introduced into the polysaccharide. The derivative has both an active ester group and an active hydrogen-containing group in one molecular chain, and exhibits self-crosslinking property under reaction conditions.

This self-crosslinking property means that an active ester group and an active hydrogen-containing group react within one molecule or between molecules of a polysaccharide derivative to form a covalent bond. Further, when the active hydrogen-containing group on the surface of the living body is used for the reaction, this crosslinkable polysaccharide derivative exhibits adhesion to the surface of the living body.
In the present specification, “polysaccharide” may be referred to as “crosslinkable polysaccharide derivative” or “active esterified polysaccharide”, and may be simply referred to as “polysaccharide derivative” hereinafter. Therefore, in the present invention, “polysaccharide” includes “polysaccharide molecule”, “crosslinkable polysaccharide derivative”, “active esterified polysaccharide”, and “polysaccharide derivative”. The term “single molecular chain” or “intramolecular” means one molecule in a range connected by a continuous bond through a covalent bond.

The polysaccharide used in the present invention is an active esterified polysaccharide and essentially retains the polysaccharide skeleton. Therefore, in the following, the polysaccharide derivative may be described in parallel with the polysaccharide active esterification method (polysaccharide derivative production method).

In the present invention, the active ester group introduced into the polysaccharide may be any group that can react with the active hydrogen-containing group to form a covalent bond in the presence of water under alkaline conditions. Moreover, in this invention, the active ester group of a polysaccharide derivative may exist individually by 1 type, or 2 or more types may exist. Among such active ester groups, succinimide ester groups are preferred. The polysaccharide derivative used in the present invention has at least one active ester group in the molecule, but usually has two or more in one molecule in order to form a crosslinked matrix. Although it varies depending on the purpose of use, it is preferably 0.1 to 2 mmol / g when expressed in terms of the amount of active ester groups per 1 g of the dry weight.

The polysaccharide in which the active ester group is introduced and which constitutes the main skeleton of the polysaccharide derivative is not particularly limited as long as it has two or more monosaccharide structures in the main skeleton. Such polysaccharides are monosaccharides such as arabinose, ribose, xylose, glucose, mannose, galactose, fructose, sorbose, rhamnose, fucose, ribodeose; disaccharides such as trehalose, sucrose, maltose, cellobiose, gentiobiose, lactose, melibiose; Examples include those formed by covalently bonding polysaccharides of three or more sugars such as raffinose, gentianose, meretitol, and stachyose, and those having a functional group introduced thereto. Such polysaccharides may be naturally occurring or artificially synthesized. The polysaccharide derivative can be a single skeleton or a skeleton of two or more polysaccharides.

There is no restriction | limiting in particular in the weight average molecular weight of the polysaccharide used as the main frame | skeleton of the polysaccharide derivative used in this invention. Preferably, it is a polysaccharide having a weight average molecular weight of 5,000 to 2,500,000 corresponding to a combination of several tens to several thousands of the above-mentioned monosaccharides, disaccharides, or trisaccharides. This is because with such a polysaccharide, it is easy to adjust the hardness of the gel after the polysaccharide derivative is crosslinked, and it is easy to introduce a plurality of active ester groups and active hydrogen-containing groups into one molecular chain. More preferably, it is a polysaccharide having a weight average molecular weight of 10,000 to 1,000,000.

The raw material polysaccharide that forms the main skeleton of the polysaccharide derivative has the above-described constituents and has a carboxylic acid group for forming an active ester group “—COOX” in the active esterification precursor stage (hereinafter referred to as an acid group-containing polysaccharide). (Sometimes called polysaccharides). The carboxylic acid group here refers to a carboxy group and / or a carboxyalkyl group (hereinafter sometimes referred to as a carboxylic acid group), and the carboxyalkyl group refers to a carboxymethyl group, a carboxyethyl group, a carboxypropyl group. , A functional group in which a carboxy group is bonded to an alkyl skeleton, as exemplified by carboxyisopropyl group, carboxybutyl group and the like.

The raw material polysaccharide may be an acid group-containing polysaccharide at the precursor stage of the crosslinkable polysaccharide derivative, may be a natural polysaccharide that self-holds a carboxylic acid group, and is itself a polysaccharide that does not have a carboxylic acid group. It may be a polysaccharide introduced with a carboxy group and / or a carboxyalkyl group. Among such carboxylic acid group-containing polysaccharides, natural polysaccharides having a carboxy group, carboxylated polysaccharides introduced with a carboxy group, carboxymethylated polysaccharides introduced with a carboxymethyl group, and carboxyethylated polysaccharides introduced with a carboxyethyl group are preferred. . More preferred are natural polysaccharides having a carboxy group, carboxylated polysaccharides introduced with a carboxy group, and carboxymethylated polysaccharides introduced with a carboxymethyl group.

Although it does not specifically limit as said natural polysaccharide which self-holds the said carboxylic acid group, Pectin, hyaluronic acid, etc. containing galacturonic acid are mentioned. For example, “GENUE pectin” from CP Kelco (Denmark) can be used for pectin, and “hyaluronic acid FCH” from Kibunsha (Japan) can be used as hyaluronic acid. Pectin is a polysaccharide mainly composed of galacturonic acid. About 75 to 80% or more of pectin is composed of galacturonic acid, and other components are mainly composed of other sugars. Pectin is a polysaccharide formed by binding galacturonic acid and other sugars at the above ratio. Hyaluronic acid is used as an ophthalmic surgical aid, a knee osteoarthritis therapeutic agent, and the like. Hyaluronic acid does not contain galacturonic acid.

The carboxy group and / or carboxyalkyl group of the polysaccharide derivative is preferably “non-salt type” in which the salt is not coordinated, and the polysaccharide derivative finally obtained is preferably not in the salt form. Here, the “salt” includes inorganic salts such as alkali metals and alkaline earth metals, quaternary amines such as tetrabutylammonium (TBA), and halogen salts such as chloromethylpyridylium iodide. “Non-salt type” means that these “salts” are not coordinated, and “not in salt form” means that these salts are not included.

The polysaccharide into which the carboxy group and / or carboxyalkyl group is introduced is not particularly limited, and examples thereof include dextran and pullulan.

The above dextran is used as a plasma substitute. Dextran includes “Dextran T fractions” from Amersham Biosciences (Japan), and pullulan includes “Pullulan PI-20” from Hayashibara (Japan). Pullulan is used as a pharmaceutical additive including oral drugs, and those with low biological contamination such as endotoxin are suitable.
Any polysaccharide that is generally commercially available can be used. In the present invention, the polysaccharide having a proven record in the above medical use is a polysaccharide that can be suitably used in terms of safety.

The carboxylation reaction of a polysaccharide can be carried out without particular limitation using a known oxidation reaction. The type of the carboxylation reaction is not particularly limited, and examples thereof include dinitrogen tetroxide oxidation, fuming sulfuric acid oxidation, phosphoric acid oxidation, nitric acid oxidation, and hydrogen peroxide oxidation, each of which is a commonly known reaction using a reagent. Can be selected and oxidized. Each reaction condition can be appropriately set depending on the amount of carboxy group introduced. For example, by suspending a polysaccharide as a raw material in chloroform or carbon tetrachloride and adding dinitrogen tetroxide, the hydroxyl group of the polysaccharide can be oxidized to prepare a carboxylated polysaccharide (polysaccharide carboxylate). .

In addition, the carboxyalkylation reaction can utilize a known polysaccharide carboxyalkylation reaction, and is not particularly limited. Specifically, in the case of carboxymethylation reaction, monochloroacetic acid is used after alkalizing the polysaccharide. The selected reaction can be selected. The reaction conditions can be appropriately set depending on the amount of carboxymethyl group introduced.

As a method for introducing a carboxylic acid group into a polysaccharide, any of the above-mentioned carboxylation or carboxyalkylation methods can be used, and is not particularly limited. Carboxyalkylation, particularly carboxymethylation, is preferred because it is relatively easy to control. Further, the introduction of the carboxylic acid group is not particularly limited to the introduction into a polysaccharide which does not itself have a carboxylic acid group. A carboxy group and / or a carboxymethyl group may be further introduced into a natural polysaccharide having its own carboxylic acid group, for example, the hyaluronic acid.

In the active esterification of the carboxy group and / or carboxymethyl group of the acid group-containing polysaccharide as described above, the acid group-containing polysaccharide may be used alone or in combination of two or more kinds. May be.

The acid group-containing polysaccharide used for the active esterification is usually 0.1 to 5 mmol / g, preferably 0.4, in terms of the amount of carboxylic acid groups per 1 g of dry weight (assuming the group is one molecule). -3 mmol / g, more preferably 0.6-2 mmol / g. When the ratio of the amount of the carboxylic acid group is less than 0.1 mmol / g, the number of active ester groups derived from the group and serving as a crosslinking point is often insufficient. On the other hand, when the ratio of the amount of carboxylic acid groups is more than 5 mmol / g, the polysaccharide derivative (uncrosslinked) becomes difficult to dissolve in a solvent containing water.

The active esterification method of the acid group-containing polysaccharide (a method for producing a polysaccharide derivative) is not particularly limited. For example, the acid group-containing polysaccharide is combined with an electrophilic group introducing agent in the presence of a dehydration condensing agent. Examples thereof include a method of reaction, a method of using an ester exchange reaction in which an active ester group is introduced into a polysaccharide from a compound having an active ester group. Among these, the former method is preferable, and this method will be mainly described below.

In carrying out the preferred method, the acid group-containing polysaccharide is usually prepared in an aprotic polar solvent solution and subjected to the reaction. More specifically, the method includes a solution preparation step in which a polysaccharide having a carboxy group or a carboxyalkyl group is dissolved in an aprotic polar solvent, and an electrophilic group introducing agent and a dehydrating condensing agent are added to the solution. Examples include a method of performing a reaction step of esterifying a carboxy group or a carboxyalkyl group of a polysaccharide, and a method of performing a purification step and a drying step of the reaction product.

In the solution preparation step, the polysaccharide is added to the solvent and heated to 60 ° C. to 120 ° C., whereby the polysaccharide is dissolved in the aprotic polar solvent.

Therefore, as the acid group-containing polysaccharide to be active esterified by this method, among the polysaccharides exemplified above, those that dissolve in an aprotic polar solvent at a temperature between 60 ° C. and 120 ° C. are preferably used. Specifically, the polysaccharide used in the reaction for introducing the electrophilic group preferably has a carboxy group or a carboxymethyl group in an acid form from the viewpoint of solubility in an aprotic polar solvent. “Acid type” means that the cation group of the carboxy group or carboxymethyl group is a proton. A polysaccharide having an acid-type carboxy group is called an acid-type (raw material) polysaccharide. For example, pectin, which is a polysaccharide having a carboxy group, is called acid-type pectin. Carboxymethyldextran having an acid-type carboxymethyl group is referred to as acid-type carboxymethyl (CM) dextran (acid-type CM dextran). The “acid type” is synonymous with the “non-salt type” in that the counter cation species is a proton and is not in a salt form.

An “aprotic polar solvent” is a polar solvent that does not have a proton capable of forming a hydrogen bond with a nucleophile having an electrically positive functional group. The aprotic polar solvent that can be used in the production method of the present invention is not particularly limited, but dimethyl sulfoxide (DMSO), N, N-dimethylformamide, N-methyl-2-pyrrolidone, N, N-dimethylacetamide, 1, 3-dimethyl-2-imidazolidinone is exemplified. Dimethyl sulfoxide can be suitably used because the solubility of the polysaccharide in the solvent is good.

In the reaction step, an electrophilic group-introducing agent and a dehydrating condensing agent are added to the acid-type polysaccharide solution to cause the carboxy group and / or carboxymethyl group of the polysaccharide to be active esterified. Although the reaction temperature at the time of carrying out active esterification is not specifically limited, Preferably it is 0 to 70 degreeC, More preferably, it is 20 to 40 degreeC. While the reaction time varies depending on the reaction temperature, it is generally 1 to 48 hours, preferably 12 to 24 hours.

The “electrophilic group introduction agent” refers to a reagent that introduces an electrophilic group into a carboxy group or a carboxyalkyl group and converts them into an active ester group. Although it does not specifically limit as an electrophilic group introduction | transduction agent, The active ester derivative compound widely used for peptide synthesis can be utilized, N-hydroxyamine type | system | group active ester derivative compound is mentioned as an example. The N-hydroxyamine-based active ester-derived compound is not particularly limited. For example, N-hydroxysuccinimide, N-hydroxynorbornene-2,3-dicarboxylic imide, 2-hydroxyimino-2-cyanoacetic acid ethyl ester, Examples include 2-hydroxyimino-2-cyanoacetamide, N-hydroxypiperidine and the like. Among these, N-hydroxysuccinimide is more preferable because it has a track record in the field of peptide synthesis and is easily available commercially.

The “dehydration condensing agent” is a condensation of a carboxy group or a carboxyalkyl group with an electrophilic group introducing agent when an electrophilic group introducing agent is used for the carboxy group or carboxyalkyl group to form an active ester group. One water molecule to be generated is extracted, that is, dehydrated, and both are ester-bonded. The dehydrating condensing agent is not particularly limited. For example, 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC / HCl), 1-cyclohexyl- (2-morpholin-4-ethyl) -carbodiimide / meso p- And toluene sulfonate. Among these, 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC · HCl) is more preferable because it has a track record in the peptide synthesis field and is easily available commercially.

In the purification process, after the completion of the reaction process, the unreacted electrophilic group introducing agent, dehydrating condensing agent, and reaction by-products are removed from the reaction solution by means such as ordinary reprecipitation, filtration and / or washing. And polysaccharide derivatives can be obtained.

In the drying step, in order to remove the washing solvent from the polysaccharide derivative obtained in the purification step, it may be dried by a commonly used method.

As described above, the active ester group amount of the polysaccharide derivative is preferably 0.1 to 2 mmol / g in the end. In the above, the active esterification raw material polysaccharide is used so that such a polysaccharide derivative is obtained. The amount of active ester group introduced into the carboxy group can be controlled.

In order to control the introduction amount of the active ester group, the mixing amount of the electrophilic group introduction agent and the dehydration condensing agent can be adjusted in the reaction step. Specifically, the ratio (Z / X) of the number of moles (Zmmol) of the dehydration condensing agent to the number of moles (Xmmol) of all carboxy groups of the polysaccharide is 0.1 <Z / X <50 at the reaction temperature described above. It is preferable that the addition conditions satisfy the conditions. When Z / X is less than 0.1, the reaction efficiency is low because the addition amount of the dehydrating condensing agent is small, making it difficult to achieve the desired active ester group introduction rate. When Z / X is greater than 50, the dehydrating condensing agent This is because, although the amount of added is large, the introduction rate of the active ester group is high, but the obtained polysaccharide derivative is difficult to dissolve in water.

The number of moles (Ymmol) of the electrophilic group-introducing agent relative to the number of moles (Xmmol) of all carboxy groups of the polysaccharide is not particularly limited as long as the reaction amount or more according to the introduction rate of the active ester group is added. It is preferable that the addition conditions satisfy 1 <Y / X <100.

Even after the active ester group is introduced, the polysaccharide derivative usually has the hydroxyl group of the glucopyranose ring in the polysaccharide skeleton molecule, and thus possesses an active hydrogen-containing group, but the active hydrogen-containing group in the molecule is However, the present invention is not limited thereto, and it may further have an active hydrogen-containing group introduced into the molecule as necessary. In this case, the active hydrogen-containing group possessed by the polysaccharide derivative may be one type or two or more types.

In addition to the active ester group and the active hydrogen-containing group, the polysaccharide derivative can widely include functional groups such as known elements and atomic groups as long as the characteristics of the present invention are not impaired. Specific examples of such functional groups include halogen elements such as fluorine, chlorine, bromine and iodine; carboxy groups; carboxyalkyl groups such as carboxymethyl groups, carboxyethyl groups, carboxypropyl groups, and carboxyisopropyl groups; silyl groups; An alkylene silyl group, an alkoxy silyl group, a phosphoric acid group etc. are mentioned. Such functional groups may be used alone or in combination of two or more.

The introduction rate (%) of the active ester group is obtained with respect to the carboxy group-containing molar amount and the carboxymethyl group-containing molar amount (hereinafter referred to as total carboxy group (TC)) of the polysaccharide of the active esterification raw material. The ratio (AE / TC) of the molar amount (AE) of active ester groups in the polysaccharide derivative can be expressed by multiplying by 100.
The active ester group introduction rate can be determined, for example, by the method described in Biochemistry Vol. 14, No. 7 (1975), p1535-1541.
In particular, it may have a carboxy group and / or a carboxymethyl group of the remaining raw material polysaccharide when the active ester group is introduced at an introduction rate of the active ester group of less than 100%.

The “crosslinked structure” means that a covalent bond is formed within one molecular chain and / or between a plurality of molecular chains of the polysaccharide derivative, and as a result, the molecular chain of the polysaccharide derivative has a network-like three-dimensional structure. By this cross-linking, the active ester group and the active hydrogen-containing group can be bonded within one molecular chain, but may be cross-linked by covalent bonding between a plurality of molecules. The polysaccharide derivative that is water-soluble before the cross-linking formation reaction forms a cross-linked structure as the reaction proceeds, the fluidity decreases, and a water-insoluble mass (hydrous gel) is formed to form a cross-linked polysaccharide. In particular, when a property capable of forming a crosslinked structure by covalent bonding within its own molecular chain or between molecular chains without using other crosslinking agents is defined as “self-crosslinking”, a polysaccharide derivative is self-crosslinking. It is a sex polysaccharide.

In addition, the polysaccharide derivative is not only self-crosslinkable due to the involvement of an intramolecular active hydrogen-containing group as described above, but if the polysaccharide derivative is applied to a biological surface, the active hydrogen-containing group and the active ester group on the biological surface It is possible to show adhesion to the surface of a living body by reaction with. Such usage is a preferred embodiment of the polysaccharide derivative. Needless to say, self-crosslinking may occur simultaneously when applied to the surface of a living body.

As described above, the method of crosslinking a polysaccharide derivative is a method in which an active ester group and an active hydrogen-containing group react to form a covalent bond. Specifically, a polysaccharide derivative prepared as a medical treatment material is used. And a method of crosslinking under the presence of water such as water, water vapor, and a solvent containing water under alkaline conditions.

The polysaccharide derivative as described above can be provided as a cross-linking material composed solely of it due to its self-crosslinking property, and further, a cross-linkable material in the form of a composition by combination with other components can be provided. Other components may form a composition in contact with the polysaccharide derivative, depending on the type.

The polysaccharide derivative is provided as a powder. That is, the powdered polysaccharide derivative can be obtained by crushing or pulverizing the polysaccharide derivative obtained by the above-described synthesis reaction, adjusting the particle size as necessary, and adjusting the particle size range. Although there is no particular limitation for reducing the particle size, freeze pulverization, mill pulverization and / or classification may be performed. After pulverization and pulverization, it can be adjusted to an arbitrary particle size distribution by sieving.

In the present invention, a combination of a polysaccharide derivative (A) and a crosslinkable polysaccharide composition (sometimes abbreviated as a polysaccharide composition) containing another polymer (C) is also provided as a powder. Here, “polymer (C)” is different from the “polymer” having an active ester group capable of reacting with the active hydrogen-containing group described above, but an active ester group capable of reacting with the active hydrogen-containing group. You may have. The polymer (C) is used to adjust the hardness and properties of the hydrated gel when the polysaccharide composition is crosslinked. In the polysaccharide composition, the polysaccharide derivative (A) may be used alone or in combination of two or more. Moreover, you may include the said alkalizing agent (B) in this composition.

The polymer (C) is not particularly limited, but it is preferable to use a polymer (C) having two or more primary amino groups, thiol groups, or hydroxyl groups in one molecule. Specific examples of the polymer (C) include polyalkylene glycol derivatives, polypeptides, polysaccharides or derivatives thereof. Although there is no restriction | limiting in particular in content of the polymer (C) in a polysaccharide composition, It is preferable to mix | blend with 5-50 mass% with respect to the whole polysaccharide composition. In addition, the polymer (C) can be used alone or in combination of two or more. The polymer (C) can be any of a biological material, a non-biological material, a synthetic material, or a mixture thereof. The polymer (C) can be a substance that naturally exists in nature or a substance that does not exist in nature. The polymer (C) can be a substance (biological material) obtained directly from a living body, specifically a vertebrate. Further, the polymer (C) can be a substance (non-living material) that cannot be obtained directly from a living body.

Examples of the polyalkylene glycol derivatives include polyethylene glycol (PEG) derivatives, polypropylene glycol derivatives, polybutylene glycol derivatives, polypropylene glycol-polyethylene glycol block copolymer derivatives, and random copolymer derivatives. Examples of the basic polymer skeleton of the polyethylene glycol derivative include ethylene glycol, diglycerol, pentaerythritol, and hexaglycerol. The molecular weight of the polyalkylene glycol derivative is preferably 100 to 50,000. More preferably, it is 1,000 to 20,000.

The polyethylene glycol derivative is not particularly limited. For example, an ethylene glycol type polyethylene glycol derivative having a thiol group at both ends and a weight average molecular weight of 1,000, 2,000, 6,000 or 10,000, Ethylene glycol type polyethylene glycol derivatives having an amino group having a weight average molecular weight of 1,000, 2,000, 6,000 or 10,000, and a weight average molecular weight having a thiol group at three terminals of 5,000 or 10,000 Trimethylolethane type polyethylene glycol derivatives having 3 amino groups at the ends and a weight average molecular weight of 5,000 or 10,000, and 5 weight average molecular weights having thiol groups at the 4 ends. , 00 10,000 or 20,000 diglycerol-type polyethylene glycol derivatives, diglycerol-type polyethylene glycol derivatives having amino groups at four ends, weight-average molecular weights of 5,000, 10,000, or 20,000, four ends Pentaerythritol type polyethylene glycol derivative having a thiol group and a weight average molecular weight of 10,000 or 20,000, and a pentaerythritol type polyethylene glycol derivative having an amino group at the four ends and a weight average molecular weight of 10,000 or 20,000 , A hexaglycerol type polyethylene glycol derivative having a thiol group at eight ends and a weight average molecular weight of 10,000 or 20,000, and a weight average molecular weight having an amino group at eight ends of 10,000 or 2 Include hexaglycerol polyethylene glycol derivative 000.

“Weight-average molecular weight” is one of numerical values representing the average molecular weight of a polymer. Since a polymer is a mixture of molecules having the same basic structural unit and different molecular lengths (chain lengths), it has a molecular weight distribution corresponding to the difference in molecular chain length. Average molecular weight is used to indicate its molecular weight. The average molecular weight includes a weight average molecular weight, a number average molecular weight, and the like. Here, the weight average molecular weight is used. In addition, the value (100%) of the weight average molecular weight in the present invention includes those having an upper limit of 110% and a lower limit of 90%. Polyethylene glycol derivatives can be prepared, for example, according to the method described in Chapter 22 of Poly (ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, edited by J Milton Harris, Plenum Press, NY (1992). Alternatively, it can be chemically modified to contain multiple primary amino groups or thiol groups. Moreover, it can be purchased as a polyethylene glycol derivative (Sunbright HGEO-20TEA, Sunbright PTE-10TSH, etc.) from Nippon Oil & Fats.

Although it does not specifically limit as said polypeptide, Collagen, gelatin, albumin, or polylysine is mentioned. Examples of the polysaccharide include, but are not limited to, pectin, hyaluronic acid, chitin, chitosan, carboxymethyl chitin, carboxymethyl chitosan, chondroitin sulfate, keratin sulfate, kerato sulfate, heparin, or derivatives thereof.

In the powder composed of the polysaccharide composition containing the polysaccharide derivative (A) and the polymer (C), the preferred combination of the polysaccharide derivative (active esterified polysaccharide) (A) and the polymer (C) is as follows: Street. In addition, in these combinations, it can select suitably by referring the below-mentioned Example.

An ethylene glycol type PEG derivative having a thiol group at two ends, an ethylene glycol type PEG derivative having an amino group at two ends, a trimethylolethane type PEG derivative having a thiol group at three ends, and an amino group at three ends A trimethylolethane type PEG derivative having four pentyl erythritol type PEG derivatives having a thiol group at four terminals, a pentaerythritol type PEG derivative having an amino group at four terminals, a hexaglycerol type PEG derivative having a thiol group at eight terminals, At least one polymer selected from the group consisting of hexaglycerol-type PEG derivatives having amino groups at eight terminals, albumin, gelatin, collagen, polylysine, pectin, chitosan, chitin and carboxymethyl (CM) chitin The combination of C) and the active ester pectin.

An ethylene glycol type PEG derivative having a thiol group at two ends, an ethylene glycol type PEG derivative having an amino group at two ends, a trimethylolethane type PEG derivative having a thiol group at three ends, and an amino group at three ends A trimethylolethane type PEG derivative having four pentyl erythritol type PEG derivatives having a thiol group at four terminals, a pentaerythritol type PEG derivative having an amino group at four terminals, a hexaglycerol type PEG derivative having a thiol group at eight terminals, At least one polymer (C) selected from the group consisting of eight glycerol derivatives having amino groups at the ends, albumin, gelatin, collagen, polylysine, pectin, chitosan, chitin and CM chitin and an active ester The combination of the CM dextran.

An ethylene glycol type PEG derivative having a thiol group at two ends, an ethylene glycol type PEG derivative having an amino group at two ends, a trimethylolethane type PEG derivative having a thiol group at three ends, and an amino group at three ends A trimethylolethane type PEG derivative having four pentyl erythritol type PEG derivatives having a thiol group at four terminals, a pentaerythritol type PEG derivative having an amino group at four terminals, a hexaglycerol type PEG derivative having a thiol group at eight terminals, At least one polymer (C) selected from the group consisting of eight glycerol derivatives having amino groups at the ends, albumin, gelatin, collagen, polylysine, pectin, chitosan, chitin and CM chitin and an active ester The combination of the CM pullulan.

An ethylene glycol type PEG derivative having a thiol group at two ends, an ethylene glycol type PEG derivative having an amino group at two ends, a trimethylolethane type PEG derivative having a thiol group at three ends, and an amino group at three ends A trimethylolethane type PEG derivative having four pentyl erythritol type PEG derivatives having a thiol group at four terminals, a pentaerythritol type PEG derivative having an amino group at four terminals, a hexaglycerol type PEG derivative having a thiol group at eight terminals, At least one polymer (C) selected from the group consisting of eight glycerol derivatives having amino groups at the ends, albumin, gelatin, collagen, polylysine, pectin, chitosan, chitin and CM chitin and an active ester The combination of the CM hydroxyethyl starch.

Ethylene glycol type PEG derivative having a thiol group at both ends and a weight average molecular weight of 1,000, 2,000, 6,000 or 10,000, a weight average molecular weight having an amino group at both ends of 1,000, 2, Ethylene glycol type PEG derivative of 000, 6,000 or 10,000, trimethylolethane type PEG derivative having thiol group at three ends and weight average molecular weight of 5,000 or 10,000, and amino group at three ends A trimethylolethane type PEG derivative having a weight average molecular weight of 5,000 or 10,000, a diglycerol type PEG derivative having a weight average molecular weight of 5,000, 10,000 or 20,000 having a thiol group at four terminals, Weight average molecular weight having amino groups at four terminals is 5,000, 10,000 Alternatively, a 20,000 diglycerol-type PEG derivative, a pentaerythritol-type PEG derivative having a thiol group at four ends of 10,000 or 20,000, and a weight-average molecular weight of 10 having an amino group at four ends 1,000 or 20,000 pentaerythritol type PEG derivatives, hexaglycerol type PEG derivatives having a thiol group at 8 terminals and a weight average molecular weight of 10,000 or 20,000 and an amino group at 8 terminals A combination of at least one polymer (C) selected from the group consisting of 10,000 or 20,000 hexaglycerol-type polyethylene glycol derivatives and active esterified pectin.

Ethylene glycol type PEG derivative having a thiol group at both ends and a weight average molecular weight of 1,000, 2,000, 6,000 or 10,000, a weight average molecular weight having an amino group at both ends of 1,000, 2, Ethylene glycol type PEG derivative of 000, 6,000 or 10,000, trimethylolethane type PEG derivative having thiol group at three ends and weight average molecular weight of 5,000 or 10,000, and amino group at three ends A trimethylolethane type PEG derivative having a weight average molecular weight of 5,000 or 10,000, a diglycerol type PEG derivative having a weight average molecular weight of 5,000, 10,000 or 20,000 having a thiol group at four terminals, Weight average molecular weight having amino groups at four terminals is 5,000, 10,000 Alternatively, a 20,000 diglycerol-type PEG derivative, a pentaerythritol-type PEG derivative having a thiol group at four ends of 10,000 or 20,000, and a weight-average molecular weight of 10 having an amino group at four ends 1,000 or 20,000 pentaerythritol type PEG derivatives, hexaglycerol type PEG derivatives having a thiol group at 8 terminals and a weight average molecular weight of 10,000 or 20,000 and an amino group at 8 terminals A combination of at least one polymer (C) selected from the group consisting of 10,000 or 20,000 hexaglycerol-type PEG derivatives and active esterified CM dextran.

Ethylene glycol type PEG derivative having a thiol group at both ends and a weight average molecular weight of 1,000, 2,000, 6,000 or 10,000, a weight average molecular weight having an amino group at both ends of 1,000, 2, Ethylene glycol type PEG derivative of 000, 6,000 or 10,000, trimethylolethane type PEG derivative having thiol group at three ends and weight average molecular weight of 5,000 or 10,000, and amino group at three ends A trimethylolethane type PEG derivative having a weight average molecular weight of 5,000 or 10,000, a diglycerol type PEG derivative having a weight average molecular weight of 5,000, 10,000 or 20,000 having a thiol group at four terminals, Weight average molecular weight having amino groups at four terminals is 5,000, 10,000 Alternatively, a 20,000 diglycerol-type PEG derivative, a pentaerythritol-type PEG derivative having a thiol group at four ends of 10,000 or 20,000, and a weight-average molecular weight of 10 having an amino group at four ends 1,000 or 20,000 pentaerythritol type PEG derivatives, hexaglycerol type PEG derivatives having a thiol group at 8 terminals and a weight average molecular weight of 10,000 or 20,000 and an amino group at 8 terminals A combination of at least one polymer (C) selected from the group consisting of 10,000 or 20,000 hexaglycerol-type PEG derivatives and active esterified pullulan.

Ethylene glycol type PEG derivative having a thiol group at both ends and a weight average molecular weight of 1,000, 2,000, 6,000 or 10,000, a weight average molecular weight having an amino group at both ends of 1,000, 2, Ethylene glycol type PEG derivative of 000, 6,000 or 10,000, trimethylolethane type PEG derivative having thiol group at three ends and weight average molecular weight of 5,000 or 10,000, and amino group at three ends A trimethylolethane type PEG derivative having a weight average molecular weight of 5,000 or 10,000, a diglycerol type PEG derivative having a weight average molecular weight of 5,000, 10,000 or 20,000 having a thiol group at four terminals, Weight average molecular weight having amino groups at four terminals is 5,000, 10,000 Alternatively, a 20,000 diglycerol-type PEG derivative, a pentaerythritol-type PEG derivative having a thiol group at four ends of 10,000 or 20,000, and a weight-average molecular weight of 10 having an amino group at four ends 1,000 or 20,000 pentaerythritol type PEG derivatives, hexaglycerol type PEG derivatives having a thiol group at 8 terminals and a weight average molecular weight of 10,000 or 20,000 and an amino group at 8 terminals A combination of at least one polymer (C) selected from the group consisting of 10,000 or 20,000 hexaglycerol-type PEG derivatives and active esterified CM hydroxyethyl starch.

The mixing ratio (SD / AP) with the polymer (C) (AP) to the polysaccharide derivative (SD) (A) is preferably SD / AP = 20/80 to 98/2 (W / W). When (C) is mixed in an amount of more than 80% by mass, it is difficult to obtain the self-crosslinking property of the polysaccharide derivative (A) due to the inhibition of the polymer (C). This is because it is difficult to adjust the hardness and properties of the water-containing gel obtained.

The powder used in the present invention can further contain widely known additives within a range not impairing the characteristics of the present invention. Additives are not particularly limited, but include curing catalysts, fillers, plasticizers, softeners, stabilizers, dehydrating agents, colorants, anti-sagging agents, thickeners, physical property modifiers, reinforcing agents, thixotropic agents, and aging. Inhibitors, flame retardants, antioxidants, UV absorbers, pigments, solvents, carriers, excipients, preservatives, binders, swelling agents, isotonic agents, solubilizers, preservatives, buffers, diluents, etc. Is mentioned. These additives can be used alone or in combination of two or more. As these additives, those provided as powders as well as the polymer can be used. A powder layer made of a powder containing a polymer, an alkalizing agent or an additive may be formed directly on the support layer, or a powder layer formed at a place other than the support layer may be applied to the support layer. May be.

The medical treatment material of the present invention comprises a support layer in addition to the powder layer described above. The support layer can be provided in the form of a sheet in advance before application of the powder layer. The support layer can be prepared as a sheet or a plate by pressing the material.

The support layer is preferably bioabsorbable. “Bioresorbability” is as described herein. In the present specification, the support layer and components contained therein may be referred to as “bioabsorbable material”.

Although the specific example of a support layer is not specifically limited, A polyether ester (Unexamined-Japanese-Patent No. 9-52950), an oxidized cellulose (Unexamined-Japanese-Patent No. 10-66723), polyglycolic acid (Unexamined-Japanese-Patent No. 2000-157622), Carboxymethyl cellulose (CMC) (Japanese Patent Laid-Open No. 10-77571, Japanese Patent No. 3057446), hyaluronic acid (HA) (US Pat. No. 5,676,964, Japanese Patent Laid-Open No. 2003-252905), polyethylene oxide (PEO) and carboxy Membrane made of methylcellulose (CMC) (Japanese Patent Publication No. 2002-511897), membrane made of hyaluronic acid (HA) and carboxymethylcellulose (CMC) (Patent No. 3425147), made of polyethylene oxide (PEO) and peptide Membrane (Japanese Patent Laid-Open No. 2002-371131) And at least one selected from the group consisting of future composites. The support layer can be in the form of a film, sponge, woven fabric, non-woven fabric, or powder compact. This invention includes using the bioabsorbable material which can be used for the adhesion prevention use as a support layer including the above-mentioned specific example.

Hereinafter, an embodiment in which the support layer is a polyether ester will be described in detail as one embodiment of the present invention.
The polyether ester as the support layer is a polyether ester obtained by reacting a polyalkylene oxide with at least one selected from the group consisting of a polyvalent carboxylic acid, a polyvalent carboxylic acid anhydride, and a polyvalent carboxylate. Can be more.

Although the shape of a support layer is not specifically limited, It is preferable that it is a sheet form or a powder form. When it is finally used as a medical treatment material, it may be in the form of a sheet. The sheet form is a non-porous material such as a film, or a porous material such as a sponge and a compressed body thereof. Among them, the porous material is preferable in that the material and the water in the living body can be sufficiently brought into contact with each other and the desired mechanical strength is not impaired. The porous material is preferably smaller than the density of the non-porous material having the same composition as the porous material. Preferably, it has a predetermined density ratio (porous material / non-porous material) to the non-porous material of the porous material. In the present specification, the “predetermined density ratio” is 0.001 to 0.5.

The polyether ester is a porous material, and is preferably smaller than the density of the non-porous material having the same composition as the porous material. Preferably, the density ratio of the porous material to the non-porous material (porous material / non-porous material) is 0.001 to 0.5. Specifically, for example, an aqueous solution obtained by dissolving a polyether ester in water is spread on a petri dish, and freeze-dried to remove moisture to obtain a density of a sponge-like porous material (mg / mg). The sponge-like porous material having a value obtained by dividing cm3) by the density (mg / cm3) of the non-porous material obtained by extruding the polyether ester into a film is 0.001 to 0.5 Is mentioned. Here, the porous material and the non-porous material are only required to be formed from the same material, and the solvents and the like used in the manufacturing process may be different.
If the ratio of the density is within this range, the material and the water in the living body can be in sufficient contact, and the desired mechanical strength is not impaired. The density ratio is more preferably from 0.01 to 0.03, and particularly preferably from 0.05 to 0.2, in that these properties are more excellent.

The polyether ester has a porous structure and preferably has a density of 1 to 500 mg / cm ³ . Within this range, it has the necessary mechanical strength and is also excellent in handleability. The density is more preferably from 10 to 300 mg / cm ³ , and particularly preferably from 50 to 200 mg / cm ^{3 in} terms of being superior in these characteristics.
Moreover, in the compressed sheet produced by compressing the sponge-like support layer, the material weight per sheet unit area is preferably 0.4 to 200 mg / cm ² regardless of the thickness. Within this range, it has the necessary mechanical strength and is also excellent in handleability. From the viewpoint of excellent these properties, the material weight per the sheet unit area is more preferably ^{4~120mg / cm 2, 20~80mg / cm} 2 is particularly preferred.

When producing a sponge-like support layer, the polyether ester solution used preferably has a polymer concentration of 0.1 to 50% by mass. When the polymer concentration is 0.1% by mass, the density of the obtained sponge-like support layer is about 1 mg / cm ³ , or the material per sheet unit area of the compressed sheet produced by compressing the sponge-like material The weight is about 0.4 mg / cm ² . When the polymer concentration is 50% by mass, the density of the obtained sponge-like material is about 500 mg / cm ³ , or the material weight per sheet unit area of the compressed sheet produced by compressing the sponge-like support layer Is about 200 mg / cm ² . Since a sponge-like support layer having a more preferable density or a compressed sheet having a more preferable material weight per unit area of the sheet can be obtained, the polymer concentration is more preferably 1 to 30% by mass, and particularly preferably 5 to 20% by mass. .

The polyalkylene oxide used as the support layer is not particularly limited, and preferred examples include those obtained from aliphatic cyclic ethers having 2 to 6 carbon atoms or aliphatic glycols having 2 to 6 carbon atoms. Specifically, for example, polyethylene glycol, polypropylene glycol, polytetraethylene glycol, polyepichlorohydrin, and copolymers thereof can be mentioned. Among them, it is easily commercially available and has excellent biocompatibility. Polyethylene glycol is particularly preferred.

The weight average molecular weight of the polyalkylene oxide is preferably 5,000 to 50,000. When the molecular weight is within this range, when the polyether ester is decomposed into polyalkylene oxide in a physiological environment, it can be discharged out of the living body without being excessively accumulated in organs such as kidney and liver. Satisfies local disappearance and extracorporeal discharge. Furthermore, the viscosity when the polyalkylene oxide is melted is also moderate, and the workability during production is good. The weight average molecular weight is more preferably 10,000 to 40,000 in that these properties are superior.
In the present specification, the weight average molecular weight is a value calculated by performing an aqueous measurement using GPC (gel permeation chromatography) and using a polyethylene glycol standard product having a known molecular weight.

The polyvalent carboxylic acid is not particularly limited as long as it is a compound having two or more carboxy groups, but is preferably a tetravalent carboxylic acid capable of obtaining a sufficient crosslinking density when reacted with a crosslinking agent described later to form a crosslinked structure. . Specifically, for example, butane-1,2,3,4-tetracarboxylic acid, pyromellitic acid, biphenyltetracarboxylic acid, p-terphenyl 3,3 ′, 4,4′-tetracarboxylic acid, 3, 3 ′, 4,4′-benzophenonetetracarboxylic acid, 1,2,3,4-cyclopentanetetracarboxylic acid, naphthalene-1,4,5,8-tetracarboxylic acid, 3,4,9,10-perylene Tetracarboxylic acid, 2,3,4,5-tetrahydrofurantetracarboxylic acid, 3,3 ′, 4,4′-diphenylsulfonetetracarboxylic acid, bicyclo [2.2.2] oct-7-ene-2,3 , 5,6-tetracarboxylic acid and the like. These may be used alone or in combination of two or more.

The polyvalent carboxylic acid anhydride is not particularly limited, and may be basically the anhydride of the polyvalent carboxylic acid. Especially, what has two acid anhydride groups in the molecule | numerator from which sufficient crosslinking density is obtained when reacting with the crosslinking agent mentioned later and forming a crosslinked structure is preferable. Specifically, for example, butane-1,2,3,4-tetracarboxylic dianhydride, dianhydropyromellitic acid, biphenyltetracarboxylic dianhydride, p-terphenyl 3,3 ′, 4 , 4′-tetracarboxylic dianhydride, 3,3 ′, 4,4′-benzophenone tetracarboxylic dianhydride, 1,2,3,4-cyclopentanetetracarboxylic dianhydride, naphthalene -1,4,5,8-tetracarboxylic dianhydride, 3,4,9,10-perylenetetracarboxylic dianhydride, 2,3,4,5-tetrahydrofurantetracarboxylic dianhydride 3,3 ′, 4,4′-diphenylsulfonetetracarboxylic dianhydride, bicyclo [2.2.2] oct-7-ene-2,3,5,6-tetracarboxylic dianhydride, etc. Dihydric acid anhydride; maleic anhydride Styrene copolymer, maleic anhydride-vinyl acetate copolymer, maleic anhydride-vinyl chloride copolymer, maleic anhydride-butadiene copolymer, maleic anhydride-methyl vinyl ether copolymer, maleic anhydride-ethylene copolymer A polymer etc. are mentioned. These may be used alone or in combination of two or more. Of these, pyromellitic dianhydride, butane-1,2,3,4-tetracarboxylic dianhydride and 3,3 ′, 4,4′-benzophenone tetracarboxylic dianhydride are the above polyalkylene oxides. It is more preferable because it has a high reactivity with and a high production efficiency of polyetherester.

The polyvalent carboxylate is not particularly limited as long as it is obtained by reacting the polyvalent carboxylic acid with a substance that forms a salt with the carboxylic acid (hereinafter also referred to as “neutralizing agent”). Specific examples include the metal salts or ammonium salts of the above polyvalent carboxylic acids. Examples of the substance that forms a salt with the polyvalent carboxylic acid include metals and amines, and specific examples of the metal include lithium, sodium, potassium, rubidium, cesium, francium, beryllium, magnesium, calcium, and strontium. , Barium, radium, titanium, zirconium, hafnium, vanadium, niobium, chromium, molybdenum, tungsten, manganese, iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, copper, silver, zinc, cadmium, mercury, aluminum, gallium , Indium, thallium, silicon, germanium, tin, lead, antimony, bismuth, scandium, etc., oxides, carboxylates, metal alkoxides, carbonates, hydroxides, hydrides, peroxides, chlorides of these metals Product, sulfuric acid , Sulfites, nitrates, phosphates, carbides, and the like.

Specific examples of the amines include trimethylamine, triethylamine, tripropylamine, ammonia, pyridine, pyrrolidine, pyrrole, dimethylamine, diethylamine, dipropylamine, hexamethylenediamine, 1,4-diazabicyclo [2.2.2]. Octane, hydrazine, N, N-dimethylcyclohexylamine, ethanamine, aniline, toluidine, allylamine, diallylamine, triallylamine, isopropylamine, diisopropylamine, 3,3′-iminobis (propylamine), 2-ethylhexylamine, 3- ( 2-ethylhexyloxy) propylamine, 3-ethoxypropylamine, diisobutylamine, 3- (diethylamino) propylamine, di-2-ethylhexylamine, 3- (dibutyl) Amino) propylamine, tetramethylethylenediamine, tri-n-octylamine, t-butylamine, 2-butylamine, monoethanolamine, diethanolamine, triethanolamine, picoline, vinylpyridine, pipecoline, piperazine, piperidine, pyrazine and the like. .

The polyvalent carboxylate is preferably synthesized by adding the neutralizing agent during and / or after the synthesis of the polyether polyester. By using polyvalent carboxylate in this way, pH adjustment and the mechanical strength of the resulting polyether ester are enhanced.

The addition amount of the neutralizing agent is not particularly limited, but is preferably 0.001 to 10.0 mol, more preferably 0.01 to 1 mol with respect to 1 mol of the polyvalent carboxylic acid or polyvalent carboxylic anhydride. The amount is 6.0 mol, particularly preferably 0.05 to 5.0 mol, and most preferably 0.1 to 4.0 mol. When the addition amount is larger than the above range, the neutralizing agent cannot be uniformly dispersed and dissolved in the polyether ester, so that the mechanical strength of the polyether ester is lowered. Moreover, when there are few this neutralizing agents, reaction time will become long and manufacturing efficiency will fall. When the addition amount of the neutralizing agent is less than the above range, the effect of increasing the pH and the mechanical strength, which are the addition effect of the neutralizing agent, are reduced.
When the neutralizing agent is added, a solvent may be used in order to improve the dispersion of the neutralizing agent. However, the absence of a solvent is preferable because the step of removing the solvent can be omitted, which is efficient.

The blending amount of at least one selected from the group consisting of a polyvalent carboxylic acid, a polyvalent carboxylic acid anhydride, and a polyvalent carboxylate salt is not particularly limited, but is 0.1% with respect to 1.0 mol of the polyalkylene oxide. 1 to 4.0 mol is preferred. If it is the compounding quantity of this range, it will be excellent in the mechanical strength of the molded object using the bioabsorbable material obtained. From the point which is excellent by this characteristic, the said compounding quantity becomes like this. More preferably, it is 0.2-3.0 mol, More preferably, it is 0.3-2.0 mol, Most preferably, it is 0.5-1.5 mol.

The polyether ester used as the support layer is obtained by reacting the polyalkylene oxide with at least one selected from the group consisting of the polyvalent carboxylic acid, polyvalent carboxylic acid anhydride and polyvalent carboxylate. Can be things.
The polyether ester is water soluble. Since the polyether ester is water-soluble, the bioabsorbable material of the present invention retains its shape for a certain period in a physiological environment, and is then decomposed by an action such as hydrolysis and disappears from the application site, resulting in kidney and liver. It can be safely discharged outside the body without being excessively accumulated in organs.
In this specification, “water-soluble” means that a sample corresponding to a polymer concentration of at least 1% by mass in 37 ° C. physiological saline (pH 4 to 8) is mixed with a rotor mixer and visually observed. Sometimes, it means that the sample loses its shape within a predetermined number of days and becomes a transparent aqueous solution.

The solubility of the polyether ester in physiological saline (pH 4 to 8) at 37 ° C. is not particularly limited because it varies depending on the use of the support layer, but generally it is 0.001 to 0.5 g / ml. preferable. When the solubility is within this range, the obtained material can satisfy a range where bioabsorbability and shape retention in a physiological environment are required. The solubility is more preferably from 0.005 to 0.1 g / ml, and particularly preferably from 0.01 to 0.05 g / ml, in that it is more excellent in this characteristic.

The polyether polyester preferably has a weight average molecular weight of 50,000 to 500,000. When the molecular weight is within this range, the resulting support layer is excellent in bioabsorbability and excellent in processability during production.

In addition to the above components, the polyether ester may contain an additive as long as the required biocompatibility is satisfied. Specific examples include fillers, plasticizers, softeners, stabilizers, colorants, physical property modifiers, reinforcing agents, antioxidants, ultraviolet absorbers, pigments and solvents. These additives can be used alone or in combination of two or more.

The polyether ester is produced by a known method (for example, see JP-A-9-52950). Specifically, for example, 10 g of polyethylene glycol having a weight average molecular weight of 25,000 and 0.106 g of pyromellitic dianhydride are charged into a 100 ml flask and reacted at 150 ° C. under normal pressure for 4 hours to obtain the above polyether ester. It is done.

Moreover, the said polyetherester can also use a commercial item. As a commercial item, PX3-EH1000 (EH1000N and EH1000A, Nippon Shokubai Co., Ltd. product) etc. are mentioned suitably, for example.

The support layer may or may not have a cross-linked structure between the polyether ester molecules, but preferably has a cross-linked structure. By having a crosslinked structure, the period until the support layer is decomposed in a physiological environment can be lengthened, and bioabsorbability can be adjusted by changing the crosslinking density. In addition, it is possible to provide a support layer that exhibits high performance in terms of water resistance, mechanical strength, stability over time, adhesiveness, and the like, and is excellent in mutual balance. On the other hand, a support layer that does not have a crosslinked structure has a feature that a period required for bioabsorption is shorter than that having a crosslinked structure. Used for. The crosslinked structure may be formed through a covalent bond between the polyether ester main chains, or may be formed by reacting the carboxy group of the polyether ester with a crosslinking agent. These may be used in combination to form a crosslinked structure.

The support layer having a cross-linked structure formed through a covalent bond between the polyether ester main chains is cross-linked only by the polyether ester by irradiation with ionizing radiation such as ultraviolet rays. When this material is irradiated with ionizing radiation such as ultraviolet rays and the polyether ester contained in the material is cross-linked, hydrogen on the carbon adjacent to the hetero atom is irradiated with ultraviolet rays or the like at the hetero bonds in the polyether ester. Therefore, it is considered that some radicals are generated on the molecular chain, and the radicals on the polymer molecular chain thus formed are bonded to each other to form a crosslinked structure. This cross-linked structure is a cross-link between the polyether esters, and since the radical concentration is low, a gently cross-linked structure with a low cross-linking density is formed.

Photoinitiators, photosensitizers, photocrosslinkers and unsaturated bond-containing compounds that are usually required for curing radiation curable resins, etc. are not particularly required, but crosslinking efficiency is within the range that does not degrade the performance after irradiation. In order to improve the above, these additives or compounds may be used in combination.

Although it does not specifically limit as said ionizing radiation, For example, (alpha) ray, (beta) ray, (gamma) ray, X-ray, an electron beam etc. other than the ultraviolet-ray mentioned above is mentioned. Among these, ultraviolet rays are preferable because they are easy to handle and are widely used industrially.
Although the irradiation time depends on the type of ionizing radiation, for example, in the case of ultraviolet rays, when a high-pressure mercury lamp is used, it is preferably 1 minute to 10 minutes, more preferably 2 minutes to 8 minutes. As a light source to be used, for example, a low pressure mercury lamp, a medium pressure mercury lamp, a high pressure mercury lamp, a xenon lamp, a tungsten lamp, or the like is used.

The support layer made of a bioabsorbable material having a cross-linked structure formed by reacting the carboxy group of the polyether ester with a cross-linking agent is cross-linked by reacting the polyether ester with the cross-linking agent. When crosslinking is performed using a crosslinking agent, it is advantageous in that the crosslinking reaction can be performed reliably and the crosslinking density can be easily adjusted.

Although it does not specifically limit as said crosslinking agent, A general polyfunctional compound can be used. As the polyfunctional compound, those having two or more functional groups capable of reacting with the carboxy group of the polyether ester, or a bivalent or higher metal or metal compound capable of forming a salt with the carboxy group are particularly preferable. It is not limited. The said polyfunctional compound may be used individually by 1 type, and may use 2 or more types together.

Specific examples of the functional group capable of reacting with the carboxy group of the polyether ester include an epoxy group, an aziridine group, an oxazoline group, an amino group, an isocyanate group, a benzoguanamine group, and a melamine group. Of these, an oxazoline group, an isocyanate group, and an epoxy group are preferable. The kind of functional group which the said polyfunctional compound has may be the same, or may differ. For example, a compound having one oxazoline group and one epoxy group can also be used as the polyfunctional compound.

Specific examples of the compound having two or more functional groups capable of reacting with the carboxy group of the polyether ester include, for example, epoxy compounds, melamine compounds, benzoguanamine compounds, isocyanate compounds, oxazoline compounds, amines Examples thereof include compounds, aziridines, silane coupling agents and the like. These may be used alone or in combination of two or more. Among these, oxazoline compounds are preferable in that they react with a carboxy group at a relatively low temperature and there are no by-products associated with the reaction.

The epoxy compounds are not particularly limited. Specifically, for example, sorbitol polyglycidyl ether, sorbitan polyglycidyl ether, polyglycerol polyglycidyl ether, pentaerythritol polyglycidyl ether, diglycerol polyglycidyl ether, triglycidyl tris. (2-hydroxyethyl) isocyanurate, glycerol polyglycidyl ether, trimethylolpropane polyglycidyl ether, resorcin diglycidyl ether, neopentyl glycol diglycidyl ether, 1,6-hexanediol diglycidyl ether, ethylene glycol diglycidyl ether, polyethylene Glycol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene Glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, and the like preferably. These may be used alone or in combination of two or more.

Although it does not specifically limit as said melamine compounds or benzoguanamine compounds, Specifically, a hexamethoxymethylol melamine, its modified material, etc. are mentioned suitably, for example. More specifically, the following Cymel series (C-number) and My Coat series (M-number) manufactured by Cytec Industries, Ltd. may be mentioned. Among the above series, as the complete alkyl type, C-300, C-301, C-303, C-350, C-232, C-235, C-236, C-238, C-266, C-267 , C-285, C-1123, C-1123-10, C-1170, M-506 and the like. Examples of the methylol group include C-370, C-771, C-272, C-1172, M-102 and the like. As the imino group type, C-325, C-327, C-703, C-712, C-254, C-253, C-212, C-1128, M-101, M-106, M-130, M-132, M-508, M-105 etc. are mentioned. Examples of the methylol / imino group type include C-701, C-202, and C-207. These may be used alone or in combination of two or more.

The isocyanate compounds are not particularly limited. Specifically, for example, 1,6-hexamethylene diisocyanate, diphenylmethane diisocyanate, tolylene diisocyanate, 2,2,4-trimethylhexamethylene diisocyanate, p-phenylene diisocyanate, 4,4′-dicyclohexylmethane diisocyanate, 3,3′-dimethylphenyl-4,4′-diisocyanate, dianisidine diisocyanate, m-xylene diisocyanate, tetramethylxylene diisocyanate, isophorone diisocyanate, 1,5-naphthalene diisocyanate, trans Preferred examples include -1,4-cyclohexyl diisocyanate and lysine diisocyanate. These may be used alone or in combination of two or more.

The oxazoline compounds are not particularly limited. Specifically, for example, bisoxazoline, polyvalent oxazoline compound (for example, Epocros WS-700 (manufactured by Nippon Shokubai Co., Ltd.)), polymer having an oxazoline ring (for example, And Epocros WS-500 (manufactured by Nippon Shokubai Co., Ltd.). Among them, a polyvalent oxazoline compound is preferable in that sufficient crosslinkability is expressed and desired bioabsorbability is easily obtained. These may be used alone or in combination of two or more.

Although it does not specifically limit as said amine compounds, Specifically, a triethylenetetramine, ethylenediamine, a 1, 4- diazabicyclo- (2,2,2) -octane etc. are mentioned suitably, for example. These may be used alone or in combination of two or more.

Although it does not specifically limit as said aziridine compounds, Specifically, for example, tris-2,4,6- (1-aziridinyl) -1,3,5-triazine, tris [1- (2-methyl) Preferred examples include -aziridinyl] phosphine oxide, hexa [1- (2-methyl) -aziridinyl] triphosphatriazine and the like. These may be used alone or in combination of two or more.

The metal atom constituting the divalent or higher-valent metal or metal compound capable of forming a salt with the carboxy group of the polyether ester is not particularly limited, and specifically, beryllium, magnesium, calcium, strontium, barium, radium, Scandium, yttrium, titanium, zirconium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, manganese, technetium, rhenium, iron, ruthenium, osmium, copper, rhodium, iridium, nickel, palladium, zinc, cadmium, mercury, aluminum, Examples thereof include silicon, gallium, germanium, tin, lead, thallium, bismuth, antimony, polonium, therium, selenium, lanthanoids, and actinoids. Preferably, beryllium, magnesium, calcium, strontium, zinc, aluminum, iron, and copper are preferable because they easily form a salt with the carboxyl group of the polyether ester.

The divalent or higher-valent metal or metal compound capable of forming a salt with the carboxyl group of the polyether ester is not particularly limited as long as it can react with the carboxyl group. For example, simple metal, oxide, carboxylate, hydroxide, sulfide, phosphate, phosphite, nitrate, nitrite, hydrochloride, sulfate, sulfite, sulfonate, carbonate, carbide Etc.

The content of the cross-linking agent is preferably adjusted so that the ratio (Y / X) of the functional group number Y of the cross-linking agent to the carboxy group number X of the polyether ester is 0.05 to 1.5. . When the ratio is within this range, an appropriate crosslinking density can be obtained, so that mechanical strength can be obtained and bioabsorbability that satisfies a period required for various applications can be obtained. The ratio (Y / X) is more preferably from 0.1 to 1.0, and particularly preferably from 0.2 to 0.5, in that this property is more excellent.

Examples of the method of reacting the crosslinking agent with the polyether ester include general crosslinking methods such as heat treatment and room temperature drying. When performing the heat treatment, the conditions are not particularly limited, but the treatment is preferably performed at 40 to 200 ° C. When the heating temperature is within this range, the crosslinking reaction proceeds rapidly and the polyether ester is not decomposed. More preferably, it is 40-150 degreeC at the point which is excellent by this characteristic.
Moreover, although heat processing time is based also on heating temperature, 0.1 to 8 hours are preferable. When the heat treatment time is within this range, the crosslinking reaction proceeds rapidly and the polyether ester is not decomposed. The heat treatment time of 10 minutes to 5 hours is more preferable because it is superior in this characteristic.

The support layer according to one embodiment of the present invention can be produced by a known method (for example, see JP-A-9-52950 and JP-A-2003-113240). As a method for producing the sponge-like support layer of the present invention, for example, the above polyether ester is dissolved in RO water at room temperature to prepare an aqueous solution having a polymer concentration of about 10% by mass, and 10 g of the aqueous solution is added to a polystyrene dish (50 × 50 × 25 mm), and a method in which the polymer portion remaining after freeze-drying becomes a sponge-like support layer is preferable. In this method, instead of the RO water, a solvent in which a polymer such as an alcohol aqueous solution dissolves and can be removed by reduced pressure or the like may be used.

The material for the powdery support layer can be obtained by crushing or pulverizing the polyether ester obtained by the above-described synthesis reaction, adjusting the particle size if necessary, and adjusting the particle size range. Although there is no particular limitation for reducing the particle size, freeze pulverization, mill pulverization and / or classification may be performed. After pulverization and pulverization, it can be adjusted to an arbitrary particle size distribution by sieving. The average particle size is not particularly limited, but an average particle size of several tens nm to several hundreds μm is preferable. The obtained powdery material can be prepared as a support layer for a medical treatment material by a commonly used method.

In addition, a powdery bioabsorbable material can be obtained by a chemical pulverization method (for example, see JP-A-4-339828) using a principle generally called spinodal decomposition. Specifically, for example, the polyether ester is heated and dissolved and mixed in a solvent, and then the powder deposited by cooling is washed, dried, crushed, classified, and the like to obtain a powder having an average particle diameter of 1 μm to 150 μm. Can be obtained. More specifically, heat and dissolve at 80 to 100 ° C. using a solvent such as xylene, and then slowly cool the solution to room temperature to precipitate a polyether ester and wash the xylene with hexane. By this, powder can be obtained.

The manufacturing method of the support layer of one form is not limited to this, You may bridge | crosslink by heating etc., after mixing a crosslinking agent in a raw material and removing water. Moreover, after removing water, you may bridge | crosslink polyether esters by ultraviolet irradiation.

The support layer according to one embodiment is preferably used after being sterilized by a method such as filtration sterilization or ethylene oxide gas sterilization during or after production. The filter sterilization may be performed, for example, by passing the aqueous polyether ester solution through a commercially available filter sterilization filter when the support layer is produced. The ethylene oxide gas sterilization may be performed, for example, by putting the obtained material into a sealed container and enclosing the ethylene oxide gas, and then leaving it for a predetermined time.

Another form of the support layer is a polyether ester obtained by reacting a polyalkylene oxide with at least one selected from the group consisting of a polyvalent carboxylic acid, a polyvalent carboxylic acid anhydride, and a polyvalent carboxylate. And a radical trapping agent.
The support layer according to another embodiment is basically the same as the support layer according to the first embodiment of the present invention except that the support layer according to another embodiment further includes a radical trap agent. Hereinafter, the radical trapping agent will be described in detail.

As described above, the support layer is preferably used after being sterilized. However, since the physical properties of the bioabsorbable material may be lowered in the sterilization process, the support layer preferably has sterilization resistance that suppresses the decrease in physical properties in the sterilization process.
In particular, the polymer may be decomposed in sterilization treatment using radiation such as γ rays or electron beams. This is believed to occur by the excision of the polymer and by the cleavage of polymer radicals generated during the stabilization process of the excitable molecules, or by reaction of the generated radicals with enzymes. By suppressing the generation of radicals related to such decomposition and oxidation reaction, it is possible to suppress deterioration of physical properties of the material. Examples of the compounding agent (radical trapping agent) that can inactivate radicals include an electron / ion scavenger, an energy transfer agent, a radical scavenger, and an antioxidant.

Examples of the electron / ion scavenger include N, N′-tetramethylphenylenediamine, which inactivate electrons and ions generated in the initial process. Examples of the energy transfer agent include acenaphthene and the like, which inactivate the excited species.
Examples of radical scavengers include mercaptans and octahydrophenanthrenes, which inactivate radicals. Examples of the antioxidant include L-ascorbic acid, isoascorbic acid, tocopherol and the like, and these prevent the oxidation reaction. Among these, L-ascorbic acid, isoascorbic acid, and tocopherol that are highly safe for living bodies are preferable. In particular, L-ascorbic acid is more preferable because it is water-soluble and bioabsorbable.

The content of the radical trapping agent is preferably 0.5 to 10 parts by mass with respect to 100 parts by mass of the polyether ester. When the content is within this range, the function as a radical trapping agent can be sufficiently achieved, the mechanical properties of the support layer are not deteriorated, and the influence on the bioabsorbability of the support layer is small. The content is more preferably from 1 to 5 parts by mass because it is more excellent in this characteristic.

The radical trapping agent may be used by being mixed with the polyether ester or an aqueous solution thereof, or may be mixed in the production of the polyether ester and contained in the polyether ester.
Specifically, for example, 0.02 g of L-ascorbic acid is mixed and used in an aqueous solution in which 1 g of a polyether ester is dissolved in 9 g of RO water.

The support layer according to another embodiment can be subjected to γ-ray sterilization or electron beam sterilization by containing a radical trapping agent.

As described above, the support layer has a molecular weight sufficient to maintain a desired mechanical strength, and after maintaining a shape for a certain period in a physiological environment, the support layer is decomposed by an action such as hydrolysis to be applied quickly. Furthermore, the decomposed support layer can have a molecular weight equal to or lower than that of the above polyalkylene oxide, so that it excessively accumulates in organs such as kidney and liver. And can be safely discharged outside the body. In addition, by changing the crosslink density, it is possible to adjust the period until it is absorbed by the living body, and to obtain mechanical properties (strength, flexibility, etc.) according to various applications. Furthermore, by containing a radical trapping agent, sterilization can be performed with γ rays or electron beams.

The method for producing a medical treatment material comprising a powder layer and a support layer according to the present invention comprises a powder containing a polymer having an active ester group capable of reacting with an active hydrogen-containing group, and a sheet-like bioabsorbable material. Consisting of compressing material. The powder layer and the support layer may be formed separately or simultaneously. At least the powder layer may be compressed so that the polymer powder is substantially 1 to 100 MPa when compressed. The compressive force during compression is preferably substantially 5 to 70 MPa, and more preferably substantially 10 to 50 MPa. The powder to be compressed may be compressed on the support layer or may be compressed at a place not on the support layer.

The medical treatment material comprising the powder layer and the support layer of the present invention can be used after being developed into a desired shape. The “medical treatment material” means a substance that is composed of a safe component having low toxicity harmful to a living body and is acceptable to the living body when used in a living body. The medical treatment material may have absorbability or degradability in a living body. Preferably, it is bioabsorbable and / or biodegradable. For example, it can be used for hemostasis, adhesion, sealing and / or fixation of tissues and organs in surgery. The dosage form of the medical treatment material is not particularly limited, and examples thereof include a sheet shape and a plate shape. In the present specification, a sheet form includes a plate form. The medical treatment material composed of the powder layer and the support layer thus prepared can be crosslinked by being provided in the presence of moisture. At that time, the moisture described in this specification can be used.

The medical treatment material can be provided as a kit containing the aforementioned alkalizing agent in consideration of convenience during use. The medical treatment material comprises a powder layer and a support layer, and the alkalizing agent can be included in the package or package with the medical treatment material or separately in an unmixed state. It may contain other components that can be used as a medical treatment material.

The medical treatment material can be used for tissue adhesion and / or closure. The adhesion and / or closure of tissue means that it can be used as a hemostatic material, an adhesive, an adhesion prevention material, or the like, although not particularly limited thereto. The hemostatic material is used for the purpose of hemostasis at or near the bleeding site of a living body. By attaching a medical treatment material to the target site and covering the bleeding site as necessary, the bleeding stops and exerts a hemostatic effect. The adhesive is used for the purpose of adhering at least one part of a living tissue, organ or organ to another part. A medical treatment material is attached to a target location, and another desired portion is bonded, fixed, allowed to stand, or pressure-bonded, and a predetermined time elapses. At that time, a fixing tool or the like can be used. The anti-adhesive material is used for the purpose of preventing adhesions in or around a living tissue or organ. By attaching a medical treatment material to the target location, fixing, standing or crimping at least one part of a living tissue, organ or organ so as not to adhere to other parts, and allowing a certain period of time to pass, Adhesion is prevented and an anti-adhesion effect can be exhibited.

The medical treatment material of the present invention satisfies clinical requirements. The component itself or its degradation product has low toxicity, and since the polysaccharide is the main skeleton, the material is designed to have biodegradability. In addition, the medical treatment material of the present invention reduces the number of preparatory operations to be performed in advance, can respond quickly to sudden application, and no special device is required for its use, so anyone can use it easily can do. And since a medical treatment material can be provided individually or as a polysaccharide composition, it can be used for a wide variety of uses. From the above characteristics, the medical treatment material of the present invention is suitable as a hemostatic material, an adhesive, an adhesion prevention material and the like.

One form of the medical treatment material of the present invention is a sheet formed of a powder layer and a support layer, the powder layer is compressed, and the powder of the powder layer contains active hydrogen A polymer composed of a non-biological material having an active ester group capable of reacting with the group. Further, one form of the medical treatment material of the present invention is a sheet shape composed of a powder layer and a support layer, the powder layer is compressed, and the powder of the powder layer is activated. Includes polymers made of synthetic materials having active ester groups capable of reacting with hydrogen-containing groups.

The following shows one embodiment of the present invention in which a polymer having an active ester group capable of reacting with an active hydrogen-containing group is specifically used for a powder layer and a bioabsorbable polymer is used for a support layer. The invention is not limited to this.

Example 1
1. Active esterified polysaccharide (polysaccharide derivative) powder as a polymer having an active ester group capable of reacting with an active hydrogen-containing group used in the powder layer used in the powder layer The body was prepared.

1-1. Preparation of Raw Material Polysaccharide As a raw material polysaccharide used as a raw material for the active esterified polysaccharide (polysaccharide derivative), a polysaccharide having an acid-type carboxy group or an acid-type carboxymethyl group, that is, an acid group-containing polysaccharide was prepared.
10 g of dextran (Dextran T-40, Amersham Biosciences, weight average molecular weight 40,000) is added to 125 g of 18 wt% aqueous sodium hydroxide solution (sodium hydroxide, manufactured by Wako Pure Chemical Industries, Ltd.), and at 25 ° C. for 3 hours. Stir. Subsequently, 75 g of 40 wt% monochloroacetic acid aqueous solution (monochloroacetic acid, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at 60 ° C. for 6 hours. The reaction solution was allowed to cool to 25 ° C., adjusted to pH 1.0 using 20% hydrochloric acid, and stirred at 25 ° C. for 2 hours. The reaction solution was dropped into 5 L of a 92.5 vol% aqueous ethanol solution (100% ethanol, manufactured by Wako Pure Chemical Industries, Ltd.) for crystallization, and the precipitate was collected using a suction funnel. The precipitate obtained using 3 L of 92.5 vol% ethanol aqueous solution was washed, finally replaced with ethanol, and then dried under reduced pressure. Thereby, acid type carboxymethyl dextran (acid type CM dextran) was prepared.

The amount of carboxymethyl group in the obtained acid-type CM dextran was quantified. 0.2 g (A (g)) of raw material polysaccharide was weighed and added to a mixed solution of 20 mL of 0.1 mol / L sodium hydroxide aqueous solution and 10 mL of 80 vol% methanol aqueous solution, and stirred at 25 ° C. for 3 hours. To the resulting solution, 3 drops of 1.0% phenolphthalein (W / V) / 90 vol% ethanol aqueous solution as an indicator was added, and acid-base back titration was performed using 0.05 mol / L sulfuric acid. The amount of use of 05 mol / L sulfuric acid (V1 mL) was measured (phenolphthalein, manufactured by Wako Pure Chemical Industries, Ltd.). Moreover, the usage-amount (V0 mL) of 0.05 mol / L sulfuric acid in the blank performed similarly except not adding raw material polysaccharide was measured. According to the following numerical formula (1), the base amount (Bmmol / g) of the carboxy group and the carboxymethyl group of the raw material polysaccharide was calculated. The titers of the 0.1 mol / L aqueous sodium hydroxide solution and 0.05 mol / L sulfuric acid used were 1.00.

B = (V0−V1) × 0.1 ÷ A (1)
A: Mass of raw material polysaccharide (g)
B: Group amount of carboxy group and carboxymethyl group (mmol / g)
The amount of carboxymethyl group of the obtained acid-type CM dextran was 1.2 mmol / g.

1-2. Preparation of Active Esterified Polysaccharide (Polysaccharide Derivative) In the active esterification reaction of the aforementioned raw material polysaccharide, the reaction solvent is DMSO, the electrophilic group introducing agent is N-hydroxysuccinimide (NHS) (manufactured by Wako Pure Chemical Industries, Ltd.), As the dehydrating condensing agent, 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride (EDC) (manufactured by Wako Pure Chemical Industries, Ltd.) was used to prepare an active esterified polysaccharide (polysaccharide derivative).

Acid type CM dextran (carboxymethyl group content 1.2 mmol / g) 5.0 g (carboxymethyl group content 6 mmol / g) was added to DMSO 100 g and dissolved by stirring at 70 ° C. for 2 hours. Thereafter, 7.02 g (60 mmol) of NHS and 11.69 g (60 mmol) of EDC were added, and the mixture was stirred at 25 ° C. for 18 hours. The reaction solution was dropped into 3 L of an ethanol / acetone mixed solution (1/1 V / V) for crystallization, and the precipitate was collected using a suction funnel. The precipitate obtained using 3 L of ethanol / acetone mixed solution (1/1 V / V) was washed and dried under reduced pressure. Thereby, active esterified CM dextran was prepared. The ratio of Z / X and Y / X was Z / X = 10 and Y / X = 10.

The amount of NHS group in the obtained active esterified CM dextran was quantified, and the NHS introduction rate was calculated. The NHS introduction rate is the ratio of the amount of active ester groups of the obtained polysaccharide derivative to the amount of carboxy groups present per unit weight of the raw material polysaccharide as the raw material of the active esterified polysaccharide (polysaccharide derivative) or the amount of carboxymethyl groups. is there.

In order to prepare a calibration curve for N-hydroxysuccinimide (NHS), 0.1, 0.2, 0.5, 1.0, 2.5, 5.0, and 10 mM NHS standard aqueous solutions were prepared. 0.2 mL of 2N sodium hydroxide aqueous solution was added to 1 mL of each NHS standard aqueous solution, and it heated at 60 degreeC and stirred for 10 minutes. After standing to cool, 1.5 mL of 0.85N hydrochloric acid and 0.75 mL of 0.05% FeCl ₃ / 1N hydrochloric acid solution were added, and the absorbance at an absorption wavelength of 500 nm was measured using a spectrophotometer (FeCl ₃ , Wako Pure). Yakuhin Kogyo). The concentration of each NHS aqueous solution was plotted with the X axis and the absorbance as the Y axis, and linear approximation was performed to obtain the following formula (2) for calculating the NHS concentration.

Y = αX + β (2)
X: NHS concentration (mM)
Y: Absorbance at a wavelength of 500 nm α = 0.102 (slope)
β = 0.0138 (intercept)
r = 0.991 (correlation coefficient)
By multiplying X (mM) calculated based on the absorbance by the volume of the measurement solution (3.45 ml), the amount of NHS group (Cmmol) in the sample described later can be obtained.

Next, 0.01 g of the active esterified polysaccharide of Examples 1 to 7 was weighed and added to 1 mL of pure water and stirred at 25 ° C. for 3 hours, and then 0.2 mL of 2N aqueous sodium hydroxide solution was added, The mixture was heated at 60 ° C. and stirred for 10 minutes. After allowing to cool to room temperature, 1.5 mL of 0.85N hydrochloric acid was added. The insoluble matter was removed from the obtained solution containing insoluble matter using a filter cotton, and then 0.75 ml of 0.05% FeCl3 / 1N hydrochloric acid solution was added, and the absorbance at a wavelength of 500 nm was measured. When the absorbance measurement value exceeded the absorbance when the NHS standard solution concentration was 5 mM, it was diluted with pure water (dilution ratio H). The NHS group content (Cmmol) of the active esterified polysaccharide was determined from the absorbance measurement using the formula (2) for calculating the NHS concentration. Subsequently, the NHS introduction rate of the active esterified polysaccharide was calculated from the following mathematical formula (3).

NHS introduction rate (%) = {(C × H) /0.01} / B × 100 (3)
B: Total amount of carboxy groups in raw polysaccharide of active esterified polysaccharide (mmol / g)
C: NHS group content of active esterified polysaccharide (mmol)
The amount of NHS group of the obtained active esterified CM dextran was 1.0 mmol / g. The NHS introduction rate was 83.3%.

1-3. Self-crosslinking property of active esterified polysaccharide (polysaccharide derivative) The above-mentioned active esterified polysaccharide was tested for self-crosslinking property. In a 10 mL clean test tube (Lalvo LT-15100, Terumo), 0.2 g of active esterified polysaccharide was weighed, and 1 mL of pure water was added and mixed. Next, 1 mL (pH 8.3) of 8.3% aqueous sodium hydrogen carbonate solution (W / V) (sodium hydrogen carbonate, manufactured by Wako Pure Chemical Industries, Ltd.) was added as a pH adjuster, and a test tube mixer (MT-31, For about 1 minute at about 2,000 rpm. The state of the contents of the test tube before and after the mixing was visually confirmed. After mixing, the test tube contents are fluid as before mixing “no self-crosslinkability (−)”, and the test tube contents after mixing are in a lump (hydrogel) “Self-crosslinking (+)”. 1-2. The active esterified CM dextran (NHS group content 1.0 mmol / g, NHS introduction rate 83.3%) obtained in 1 was “with self-crosslinkability (+)”.

1-4. Preparation of Powder of Active Esterified Polysaccharide (Polysaccharide Derivative) The above-mentioned active esterified polysaccharide (polysaccharide derivative) was pulverized to prepare powder of active esterified polysaccharide (polysaccharide derivative) to be used for the powder layer.
5 g of active esterified CM dextran (NHS group content 1.0 mmol / g, NHS introduction rate 83.3%) was added by compressed air using a desktop lab jet mill (A-O JET MILL, manufactured by Seishin Enterprise Co., Ltd.). Grinding was performed at a nozzle pressure of 7 kg / cm 2 and a processing speed of 0.3 g / min to prepare 4 g of powder of active esterified CM dextran.
The average particle size of the obtained powder of active esterified CM dextran was 5 μm as measured using a particle size distribution analyzer (LMS-30, manufactured by Seishin Enterprise Co., Ltd.).
The obtained active esterified CM dextran powder was used for the powder layer.

2. Bioabsorbable polymer used for the support layer A sponge was prepared using a polyether ester as the bioabsorbable polymer used for the support layer.
As a polyether ester, 1 g of PX3-EH1000A (acid value 8.4 KOH mg / g, weight average molecular weight 220,000, manufactured by Nippon Shokubai Co., Ltd.) was dissolved in 9 g of RO water at room temperature to prepare a 10% by mass polymer concentration aqueous solution. . To the aqueous solution, 0.136 g of Epocross WS-700 (oxazoline group equivalent 4.54 mmol / g, solid content 25% by mass, manufactured by Nippon Shokubai Co., Ltd.) was added as a crosslinking agent, and the mixture was stirred at room temperature for 1 hour. About 10 g of the obtained aqueous solution was developed on a polystyrene dish (50 × 50 × 25 mm). Next, using a lyophilizer (LYOFLEX04, manufactured by Edwards), lyophilized by evaporating the water by reducing the pressure to 6.7 Pa while cooling to -40 ° C. and evaporating the water, thereby producing a sponge-like material. . The resulting sponge-like material was heat-treated at 50 ° C. for 3 hours. Thereby, a polyether ester sponge (density 100 mg / cm 3) having a crosslinked structure obtained by reacting the carboxy group of the polyether ester with the crosslinking agent was produced. The ratio (Y / X) of the functional group number Y of the cross-linking agent to the carboxy group number X of the polyether ester was 1.0.
As described above, the obtained polyetherester sponge was used for the support layer.

3. Production of a sheet comprising a powder layer and a support layer 1. Active esterified CM dextran powder obtained in 1. A sheet comprising a powder layer and a support layer was produced using the polyetherester sponge obtained in 1.
2. 1. On one piece of polyetherester sponge (50 × 50 × 4 mm) obtained in 1. A mixed composition consisting of 0.4 g of the powder of active esterified CM dextran obtained in 1 above and 0.1 g of powder of disodium hydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd.) having an average particle size of 25 μm was evenly placed. The product was compressed for 1 minute at 40 MPa at 25 ° C. using a press machine (desktop test press, manufactured by Tester Sangyo Co., Ltd.). The shape of the obtained sheet composed of the powder layer and the support layer was 50 × 50 × 0.6 mm, in particular, the thickness of the powder layer was 0.25 mm, and the thickness of the support layer was 0.35 mm. The powder weight per sheet unit area of the powder layer was 20 mg / cm ² , and the powder density was 800 mg / cm ³ . The material weight per sheet unit area of the support layer was 40 mg / cm ² and the powder density was 100 mg / cm ³ .
Thus, a sheet A was produced.

Example 2
In Example 1, 3. In the production of a sheet comprising a powder layer and a support layer, 0.4 g of powder of active esterified CM dextran and a powder of disodium hydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd.) having an average particle size of 25 μm were obtained. A sheet B was prepared in the same manner as in Example 1 except that the mixed formulation consisting of 1 g was changed to 0.5 g of powder of active esterified CM dextran.

Example 3
In Example 1, 2. As a bioabsorbable polymer used in the support layer, a sponge was produced using polyether ester, and a woven fabric made of oxidized cellulose (50 × 50 mm, bioabsorbable hemostatic agent, surge cell, Johnson & Johnson). A sheet C was produced in the same manner as in Example 1 except that the product was changed to that prepared by the company.

Example 4
In Example 1, 2. As a bioabsorbable polymer used in the support layer, a polyether ester was used to produce a sponge, and a non-woven fabric made of polyglycolic acid (50 × 50 mm, absorbent polyglycolic acid felt, neobale, sheet type, Gunze A sheet D was produced in the same manner as in Example 1 except that it was prepared.

Example 5
In Example 1, 2. As a bioabsorbable polymer used in the support layer, a sponge was produced using a polyether ester, and a film made of sodium hyaluronate / carboxymethyl cellulose (50 × 50 mm, synthetic absorbent anti-adhesion material, Sepra film, A sheet E was prepared in the same manner as in Example 1 except that Genzyme) was prepared.

Example 6
In Example 1, 2. As a bioabsorbable polymer used in the support layer, a sponge was produced using a polyether ester. A sponge made of collagen (50 × 50 mm, bioabsorbable hemostatic agent, Instat, Johnson & Johnson Co., Ltd.) A sheet F was produced in the same manner as in Example 1 except that the product was changed to that prepared.

Comparative Example 1
In Example 1, 3. In the production of a sheet composed of a powder layer and a support layer, a press machine (desktop test press, manufactured by Tester Sangyo Co., Ltd.) was used for compression for 1 minute at 40 MPa at 25 ° C. A sheet G was produced in the same manner as in Example 1 except that.

Comparative Example 2
In Example 1, 3. In the production of a sheet comprising a powder layer and a support layer, 0.4 g of powder of active esterified CM dextran and a powder of disodium hydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd.) having an average particle size of 25 μm were obtained. A sheet H was prepared in the same manner as in Example 1 except that the mixed composition consisting of 1 g was changed to 0.5 g of disodium hydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd.) having an average particle diameter of 25 μm. did.

Hemostasis performance evaluation using the rabbit carotid artery model of the prepared sheet was performed. Rabbits (Japanese white, male, manufactured by Nippon Medical Sciences Animal Materials Research Laboratories), xylazine (Seractal 2% injection, Bayer) 5 mg / kg and ketamine (Ketamine (Fuji), manufactured by Fujita Pharmaceutical Co., Ltd.) ) After general anesthesia by intramuscular administration of 35 mg / kg, the neck was incised to expose the left and right carotid arteries. The experiment was started about 10 minutes after 200 IU / kg of heparin solution (1000 IU / mL, manufactured by Novo Nordix, Inc.) was administered from the auricular vein. The blood flow was blocked by avoiding the branch of the carotid artery and sandwiching the central side and the peripheral side with an arterial clamp. The blood vessel wall in the meantime was punctured with a 22G injection needle (outer diameter 0.7 mm, manufactured by Terumo) to produce a puncture hole. The prepared sheet (1 × 1 cm) was placed immediately above the puncture hole, and compression was performed by sandwiching the sheet and artery with a clip. After the compression time of 1 minute, the clip and then the arterial clamp were removed, and then the presence or absence of bleeding from the puncture site was confirmed for 1 minute. “○” indicates that hemostasis was achieved, and “×” indicates that hemostasis was not achieved. The load per contact area of the clip used for compression was 200 g / cm ² .

In the case where the powder layer of the sheet does not contain an alkalizing agent, an aqueous solution in which the alkalizing agent is dissolved in the vicinity of the puncture hole immediately before placing the sheet (1 × 1 cm) prepared immediately above the puncture hole. 1 mL was sprayed. For example, in Example 2, 1 mL of 1M aqueous sodium hydrogenphosphate aqueous solution was sprayed, and then the sheet B was placed immediately above the puncture hole.

The results are as follows.
Example 1-6: ○, Comparative Example 1-2: ×.
From the above, it has become clear that the medical treatment material of the present invention functions effectively.

Claims (12)

A medical treatment material in the form of a sheet comprising a powder layer and a support layer, wherein the powder layer is compressed. The medical treatment material according to claim 1, wherein the powder layer has a particle diameter of 0.1 to 500 μm. Powder quantity of the powder layer is 1 to 100 mg / cm ^2, a medical treatment material according to claim 1 or 2. The medical treatment material according to any one of claims 1 to 3, wherein the powder of the powder layer includes a polymer having an active ester group capable of reacting with an active hydrogen-containing group. The medical treatment material according to any one of claims 1 to 4, wherein the powder layer contains an alkalizing agent. The medical treatment material according to any one of claims 1 to 5, wherein the support layer is made of a bioabsorbable material. The bioabsorbable material of the support layer is at least one selected from the group consisting of polyetheresters, oxidized cellulose, polyglycolic acid, carboxymethylcellulose, hyaluronic acid, and composites thereof. The medical treatment material according to any one of the above. The medical treatment material according to any one of claims 1 to 7, wherein the support layer is in the form of a film, sponge, woven fabric, non-woven fabric, or powder compact. A sheet comprising a powder layer and a support layer, comprising a powder comprising a polymer having an active ester group capable of reacting with an active hydrogen-containing group, and a sheet-like bioabsorbable material. A method for producing a medical treatment material. The manufacturing method according to claim 9, wherein a compression force at the time of compression is 1 to 100 MPa. The medical treatment material according to any one of claims 1 to 8, which is used for adhesion and / or closure of tissue. A sheet-like medical treatment material comprising a powder layer and a support layer, wherein the powder layer is compressed, and the powder of the powder layer is an active ester group capable of reacting with an active hydrogen-containing group A medical treatment material in the form of a sheet, comprising a polymer made of a non-biological material having a surface.