JP2022010417A - Powder spray device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a powder spray device capable of continuously delivering powder having low bulk density and low fluidity, especially, powder having hygroscopic property, by compressed air or a compression gas, especially, a powder spray device for precisely applying a medical adhesive formed of powder mixture formed of powder of an aldehyde α-glucan and powder of partially carboxylated poly-L-lysine during therapy.

SOLUTION: A powder spray device 10 comprises: an application air flow pipe 4 for flowing compressed air for applying; a funnel member 1 for supplying mixture adhesive power into the application air flow pipe; a vibration motor 2 for vibrating the funnel member; a bypass air flow pipe 8 for flowing the compressed air in application and standby-time; and an on off mechanism 6 for mutually switching the application state and the standby state.

SELECTED DRAWING: Figure 1

COPYRIGHT: (C)2022,JPO&INPIT

Description

The present invention relates to a medical adhesive used for leakage occlusion, adhesion, filling, adhesion prevention, hemostasis, etc. of living tissue at the time of surgery or the like. In particular, it is composed of a powder containing the first reaction component (powder-like reaction agent) and a powder containing the second reaction component (powder-like reaction agent), and the first reaction component and the second reaction in the presence of water. It relates to a substance that is decomposed, fluidized and excreted after a certain period of time after the components are reacted with each other and cured into a gel.

As adhesives for medical use, especially for surgery, (1) cyanoacrylate adhesives and (2) fibrin glues (fibrin glues) have been mainly used. However, cyanoacrylate adhesives have problems such as the solidified material is poorly flexible and hard, which may hinder wound healing, and because it is difficult to decompose in the living body, it is easily encapsulated and becomes a foreign substance. rice field. On the other hand, since the fibrin glue has a considerably low adhesive strength, the generated fibrin mass may be peeled off from the tissue. Furthermore, since it is a blood product, there is a problem that virus infection is a concern.

In recent years, (3) aldehyded dextran-polymer chitosan (Patent Document 1). (4) Micell-forming terminal aldehyde polymer-polymer polyallylamine, (5) aldehyded starch-collagen, (6) gelatin-succinimidated poly-L-glutamic acid, (7) gelatin-dicarboxylic acid anhydride, (8) ) Urethane prepolymers and the like have been studied, but each contains problems (see the column of background technology of Patent Document 2).

Therefore, after conducting various searches and studies, the research group of the applicant company used a carboxylic acid anhydride such as a succinic anhydride to remove a relatively low molecular weight ε-poly-L-lysine into a side chain. An attempt was made to use partially carboxylated-poly-L-lysine, which partially blocked the amino group, in place of the above-mentioned high molecular weight chitosan or the like. As a result, medical adhesives and medical adhesives that can rapidly disintegrate after the design disintegration time has elapsed while sufficiently satisfying the general characteristics required for medical adhesives, and can adjust and control the design disintegration time relatively freely. A water-containing gel resin for medical use has been developed (Patent Documents 2 to 3).

On the other hand, as a result of various studies, this research group is able to continuously and evenly deliver various powders such as powders with low bulk density and low fluidity by compressed air or pressurized gas. A body spray device was developed (Patent Document 4). This powder spray device is particularly used by a practitioner such as a surgeon to accurately apply a predetermined area and a predetermined amount of a medical adhesive developed by this research group to an affected area or the like. It is a thing.

International release WO2003 / 035122 (Compatible with AESCULAP AG & CO KG (DE), US2005 / 0002893 A-1 and EP1438079 B1) International release WO / 2006/080523 "Self-degradable medical two-reactant type adhesive and medical resin" International release WO / 2008/066182 "Self-degradable powder-liquid and powder-powder two-reactant type medical adhesives" Japanese Patent Laid-Open No. 2016-63919 "Medical powder spray device"

The medical two-component reactant type adhesive developed earlier by this research group has (1) high adhesion to a water-containing adherend called a living body, and (2) relatively on the surface of a living tissue under normal temperature and pressure. Rapid solidification reactivity, (3) flexibility to the extent that it adheres to the adherend such as skin, blood vessels or organs until the wound is healed, and does not interfere with the physical movement of the adherend. It has excellent performance and characteristics that satisfy all of them.

The inventors of the present invention have made diligent efforts to ensure stable performance by using a two-component reactant type adhesive for medical use in an actual medical field or the like. As a result, the residual amino group ratio of the partially carboxylated-poly-L-lysine was set to a higher specific range when compared with the level specifically tested before, and the above powder spraying device was used. It has been found that particularly excellent adhesiveness and its reliability can be obtained by setting the coating amount to be applied in a specific lower range.

The two-component reactive adhesive for medical use of the present invention comprises a first reactant consisting of a powder of aldehyded glucan having a weight average molecular weight of 1,000 to 200,000 and poly-L- having a weight average molecular weight of 1,000 to 20,000. Aldehyde group with a second reactant consisting of partially carboxylated poly-L-lysine powder obtained by reacting lysine with succinic acid anhydride or periodic acid anhydride so that the residual amino group ratio is 70 to 93%. It consists of a mixed powder mixed so that the molar ratio of / amino groups is 0.9 to 2.0, and the aldehyded glucan oxidizes dextran or dextrin with periodic acid or periodate to anhydrous glucose. -The aldehyde group of 0.2 to 0.5 is introduced per unit, and the aldehyded glucan powder and the poly-L-lysine powder are both porous bodies having a random shape. The mixed powder has an average particle size of 10 to 150 μm, a water content of 2.0% or less, and a single application amount using a powder spray device is 20 to 50 mg / cm ² .

Preferably, the residual amino group ratio in the partially carboxylated poly-L-lysine is 87 to 93%. When this is the case, particularly high adhesive strength and its reliability can be obtained.

In the medical two-component reactive adhesive of the present invention, the hydrogel collapses by changing the amount of aldehyde groups introduced in the aldehyded glucan in the range of 0.2 to 0.4 per anhydrous glucose unit. The period until this is done can be adjusted and set in the range of 2 to 3 days to 4 weeks or more.

The powder spray device used in the preferred embodiment of the medical two-component reactive adhesive is a funnel member to which a powder container can be attached to the upper part or is provided integrally with the powder container, and a funnel member. A three-way joint to which the first opening is connected to the outlet portion at the lower end, an airflow supply pipe connected to the second opening of the three-way joint, and a delivery pipe connected to the third opening of the three-way joint. In a powder spray device including a housing for accommodating these members, a vibration motor is further provided, and the funnel member is integrally provided with a pocket portion on the outer surface of the funnel main body portion, and the funnel member vibrates in the pocket portion. The motor is pushed in and fixed, and the funnel member and the three-way joint are characterized in that the funnel member and the three-way joint are attached to the housing so as to be able to swing and swing due to the clearance between the members.

The powder spray device of the present invention includes a bypass air flow pipe (8) that branches from the air flow supply pipe (41) and is connected so as to join the delivery pipe (42) in the powder spray device as described above. A standby state (off state) in which the compressed gas is sent only through the bypass airflow pipe (8), and the compressed gas is applied by the airflow supply pipe (41), the inside of the three-way joint (3), and the delivery pipe (42). It is characterized by comprising an on / off mechanism (6) for switching between a coating state (on state) that passes through a flow path for the gas and also passes through a bypass air flow pipe (8).

The funnel member and the three-way joint are held in the housing so as to be swingable back and forth, left and right, and up and down by a large clearance (play). Further, for example, the swinging motion is possibly held around the pocket portion. That is, the funnel member and the three-way joint are held in the housing with sufficient clearance (play) so that they can swing in each direction and swing in the axial direction. In addition, it has a mounting structure that limits the movable range so that it will not come off. In one preferred embodiment, the clearance-based vertical swingable dimensional range is 0.5-8 mm, preferably 1-5 mm, particularly 2-4 mm, with clearance in the horizontal direction (on the central axis of the funnel body). The dimensional range that can be swung in the vertical direction) is 0.5 to 5 mm, preferably 0.5 to 4 mm, and particularly 2 to 3 mm. Also, in a preferred embodiment, the funnel member is held from the housing in the vicinity of the upper end and the lower end of the funnel body. The maximum swing motion occurs when the vicinity of the upper end and the vicinity of the lower end of the funnel main body move in opposite directions to the limit of the above-mentioned horizontal swingable range. In a preferred embodiment, the swingable retention and limitation of the range of motion between the housing and the funnel member in the vicinity of the upper end of the funnel body is the abutting of the flanges and the flange and the cylindrical portion. It is done by butt. Specifically, the movable range can be limited so that the flange provided on one of the funnel member and the housing is abutted against the upper and lower flanges and the cylindrical portion provided on the other side. Also, in a preferred embodiment, swingable retention and limitation of the range of motion between the housing and the funnel member and the three-way joint in the vicinity of the lower end of the funnel body is defined by the wall surface or rib of the housing and the three sides. It is done by abutment between the joint or the lower end of the funnel body. Specifically, the lower end of the funnel body or part of the three-way joint is movably inserted horizontally into the circular or other shaped opening provided in the bottom wall of the housing or the horizontal plate rib. It is feasible with. In a preferred embodiment, the flange protrudes outward or inward in the radial direction in a plate shape to form an edge at the tip. However, it may have a cross-sectional shape other than a plate shape, or it may be a stepped portion provided in a part of a cylindrical wall or a bent portion having a U-shaped cross section. For example, a rectangular or laterally U-shaped radial protrusion having a cross section close to a square may be held with a large clearance in a recess provided in a part of the cylindrical wall.

In a vibration motor, a ballast (weight) such as a fan-shaped metal piece is typically attached to a central shaft so as to be biased to one side, and vibration is generated by the rotation of the ballast. The vibration motor is preferably a flat type. That is, the diameter is larger than the dimension in the direction of the rotation axis. The vibration motor is more preferably a coin type. That is, it is a disk shape having a diameter of 25 mm or less, for example, a diameter of 5 to 20 mm. The thickness is, for example, 20-60% of the diameter. The rotation speed (rotation / minute) of the vibration motor is, for example, 1000 to 20,000 rpm (frequency of about 20 to 300 Hz), particularly 2000 to 10,000 rpm (frequency of about 30 to 200 Hz). The pocket for accommodating the vibration motor is set to have corresponding dimensions equal to or slightly smaller than the vibration motor so that the vibration motor is pushed in and fixed. The pockets are preferably arranged such that the axis of rotation of the drive motor faces the inside of the funnel body, in particular the extension of the axis of rotation intersects or nearly intersects the central axis of the funnel body. .. Further, in a preferred embodiment, the opening of the pocket portion faces the circumferential direction of the funnel main body portion, and preferably, the vibration motor is prevented from coming off and further fixed to the opening portion or the inner surface of the pocket portion. , Provide a hook protrusion, attach adhesive tape, or use an adhesive at least. The hooking protrusion can be provided, for example, as an arcuate protrusion protruding from the inner surface of the pocket portion or as a claw portion of the opening edge. Further, as the adhesive tape, for example, a single-sided adhesive type can be attached so as to cover the opening, and a double-sided adhesive type can be sandwiched between the inner surface of the pocket portion and the vibration motor. can. The adhesive can be applied, for example, to the inner surface of the pocket portion before pushing the vibration motor. The adhesive to be applied or used for the adhesive tape is, for example, a modified acrylic resin or a modified silicone resin, and when used for the adhesive tape, for example, one that passes one of JIS Z 1541 can be used. If such a strong adhesive or adhesive tape is used, it is possible to easily and surely prevent the vibration motor from coming off.

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In a preferred embodiment, the funnel member is integrally provided with at least a funnel body and a pocket by resin molding. The resin molding can be performed by injection molding, extrusion molding, or the like, and a polyethylene resin, a polypropylene resin, a polymethylpentene resin, and a polyolefin resin containing a copolymer resin thereof are preferably used.

In the medical two-component reactive adhesive of the present invention, the powder of the first reactant and the powder of the second reactant can be previously stored in a bottle as a mixed adhesive powder, and can be stored in a wet biological part. It can be applied by the above powder spray device or the like.

Generally, for medical purposes, medical adhesives need to ensure storage stability for at least one year. It is desirable that the storage stability can be guaranteed for at least 12 months, preferably at least 18 months, more preferably at least 24 months, and even more preferably at least 30 months.

The aldehyded glucan forming the first reactant is particularly one obtained by oxidizing α-glucan to introduce an aldehyde group, and has a weight average molecular weight in the range of 1,000 to 200,000. The α-glucan is a sugar chain in which glucose is dehydrated and condensed and bonded by an α bond, and the molecular weight of the sugar residue (anhydrous glucose unit) in the glucan is 162.14. The α-glucan used in the present invention includes dextran, dextrin, and pullulan, and these can be mixed and used. Starch and amylose can also be used if they are decomposed appropriately. High molecular weight pullulan products can also be appropriately decomposed and used. Further, in some cases, even a glucan composed of an α-glucan unit and a β-glucan unit can be used in the same manner as the α-glucan as long as it can be dissolved or uniformly dispersed in water. The aldehyde group can be introduced by a general periodic acid oxidation method, and is preferably 0.1 to 1.0 in order to impart appropriate self-degradability per anhydrous glucose unit. An aldehyde group, more preferably 0.2 to 0.9, and even more preferably 0.2 to 0.6 aldehyde groups are introduced. In order to enhance the storage stability of the first reactant, the degree of aldehyde formation should be relatively low, for example 0.2-0.4 aldehyde groups per anhydrous glucose unit are introduced. By using the mixed adhesive powder, curing can be achieved in a sufficiently short time even if the amount of aldehyde groups introduced is 0.2 to 0.4 per anhydrous glucose unit.

Among the aldehyded α-glucans, aldehyded dextran and aldehyded dextrin are particularly preferable because of the stability of the adhesive performance and the like. The dextran used to obtain the aldehyded dextran has a weight average molecular weight of preferably 2000 to 200,000, more preferably 2000 to 100,000. The weight average molecular weight of dextrin is, for example, 1,000 to 10,000. The optimum molecular weight of the aldehyded α-glucan differs depending on the specific use, and the period until liquefaction by autolysis can be adjusted by selecting a specific molecular weight or molecular weight distribution. If the molecular weight of the aldehyded α-glucan is excessively large, liquefaction due to autolysis is excessively delayed. Also, if the molecular weight of the aldehyded α-glucan is too small, the time to maintain the gelled state becomes too short.

As the powder of aldehyded glucan (first reactant), one obtained by mechanically pulverizing after introducing an aldehyde group by oxidation with periodic acid and then drying can be used as it is. In some cases, it can be made into a powder by spray-drying at a relatively low temperature under reduced pressure or while blowing an inert gas such as nitrogen.

The partially carboxylated poly-L-lysine forming the second reactant is formed by a chain of L-lysines and has a weight average molecular weight of 1000 to 20,000, preferably 1000 to 10,000, and more preferably 1500 to 8000. .. Further, preferably, it does not substantially contain a high molecular weight fraction having a molecular weight of 30,000 or more. In particular, it is ε-poly-L-lysine produced using a microorganism or an enzyme and having a molecular weight of 1000 to 20,000, particularly 1000 to 6000.

An acid or an acid salt as a pH adjuster is added to the second reactant or the first reactant, if necessary. Preferably a monovalent or polyvalent carboxylic acid or an anhydride thereof is added. In this way, when the first and second reactants are mixed, the pH is in the range of 5.0 to 8.0, preferably in the range of 5.5 to 7.5. The value of, more preferably in the range of 6.5 to 7.5.

Ε-Poly-L-lysine as an amino group-containing polymer used in the second reactant is mechanically pulverized from a 10 wt% neutral polylysine aqueous solution through drying in exactly the same manner as in the case of aldehyded dextran. The obtained product can be used as it is as a polylysine treated with succinic anhydride. In a preferred embodiment of this neutral polylysine aqueous solution, 0.5 g of succinic anhydride and 14.5 ml of distilled water are added to 10 ml of a 25 wt% ε-polylysine aqueous solution (molecular weight 4,000, Chisso Co., Ltd., free amine). It was prepared by the above.

The powder of aldehyded glucan as the first reactant and the powder of partially carboxylated poly-L-lysine as the second reactant can be used as long as they are in a form having excellent dispersibility and solubility. .. The form of the powder is preferably a porous body having a random shape, and therefore, a powder that is mechanically pulverized after drying the aqueous solution is preferable. When such a powder is obtained, it is preferable not only to have excellent sprayability but also to block leaks, particularly to block air leaks. It is considered that the cured resin becomes tougher as a result of taking a moderately non-uniform solution structure at the time of reaction curing and performing a moderately non-uniform reaction in the micro order. The average particle size of the powder gradually becomes a more preferable range as it progresses from (1) to (4) in the following range. (1) 10 to 150 μm, (2) 15 to 120 μm, (3) 20 to 100 μm, (4) 20 to 80 μm. That is, it is most preferably 20 to 80 μm. Here, the average particle size is set to two axes of each particle by an image analysis program (for example, the image analysis type particle size distribution measurement software "MacView" of Mountech Co., Ltd. can be used) from the image obtained by the stereoscopic microscope. It is obtained by obtaining the average diameter (simple average x of the major axis length and the minor axis length) and then taking the length ^average (Σx2 / Σx). The aspect ratio (major axis length / minor axis length) of the powder is, for example, 1.3 to 3.0, particularly 1.5 to 2.0.

By mixing the powders of the first reactant and the second reactant so as to have a predetermined reaction molar ratio to prepare a mixed adhesive powder, not only the spraying becomes easy but also the leakage pressure is improved, particularly. It is preferable because it can improve the blockage of air leakage. In the case of a mixed adhesive powder, even if it is stored in a bottle or a syringe and vibrated, the mixing ratio of the powders of the first and second reactants does not change locally due to the classification action. .. When stored as a mixed adhesive powder in a sample bottle or the like with a stopper, the water content is 5.0% or less, preferably 2.0% or less, and even more preferably around 1.0%, for example, 0. Hold at 5-1.5%. The same applies when the powder containing only the first reactant is stored.

The molar ratio of the aldehyde group / amino group in the state where the first reactant and the second reactant are mixed is preferably 0.9 to 2.5, more preferably 0.9 to 2.0. Within this range, it is preferable to keep the adhesive strength high. In addition, the amount of residual aldehyde group or amino group can be reduced, which is significant in further reducing the toxicity.

The first reactant and the second reactant can be easily sterilized by radiation sterilization such as gamma ray and electron beam in the state of the mixed adhesive powder. It is preferable to put it in a sample bottle or the like and sterilize it by irradiating it with radiation of 10 to 50 kGy, more preferably 20 to 30 kGy in a sealed state. A closed container such as a sample bottle can be filled with the mixed adhesive powder so that, for example, 60% or more, particularly 80% or more of the volume of the closed container is filled even after sterility. The water content of the mixed adhesive powder at this time can be, for example, 0.5 to 2.0%, particularly 0.5 to 1.0%. When the sterilization operation is performed under such conditions, the fluidity of the mixed adhesive powder can be improved to the extent necessary for application by the powder spray device. This is a completely unexpected effect. It is presumed that the reason for this is that the water contained in the mixed adhesive powder is heated during radiation sterilization, so that the protrusions of the powder are slightly rounded.

The first reactant and the second reactant can be applied by spraying in the state of a mixed adhesive powder by ejecting them together with compressed air by the above powder spraying device. Further, it is preferable to repeat the coating operation by spraying or the like, that is, to perform the coating operation twice or more, for example, 2 to 4 times in order to realize the uniformity of coating, and further adjust the spraying speed of the powder spraying device. By doing so, it is possible to spray quantitatively at an arbitrary spray rate, so that a uniform and thin layer can be formed in a predetermined time. During and after such repeated application, physiological saline, distilled water, or the like is added to the application site by spraying, dropping, or the like. For example, it can be sprayed, sprayed or dropped by attaching a spraying adapter or an injection needle having a very small diameter to the tip of a small syringe, or sprayed with a finger-push type spray bottle for lotion. If there is not much water in the area to be adhered or the affected area, physiological saline or the like can be dropped or sprayed before the first application of the mixed adhesive powder.

The amount of spray coating by one coating operation by the above powder spray device is 20 to 50 mg / cm ² , and more preferably 25 to 50 mg / cm ² . According to the concrete experimental results, it was as follows. When the coating amount was less than 25 mg / cm ² , unevenness was likely to occur on the coated surface, and a portion not completely covered by the mixed adhesive powder was likely to occur. In addition, when the physiological saline solution was dropped, gel formation was partially insufficient in some cases. On the other hand, at a coating amount of 25 to 50 mg / cm ² , the entire coated surface was white and uniformly covered with the mixed adhesive powder. When the coating amount exceeded 50 mg / cm ² , the entire coated surface was covered with the mixed adhesive powder in white, but unevenness was generated in some places. In particular, there was a case where the mixed adhesive powder remained partially even when the physiological saline solution was sufficiently dropped.

When applying thickly so that the coating amount per unit area exceeds 50 mg / cm ² , the coating operation by the above powder spraying device should be repeated instead of applying all at once. That is, it is preferable to produce a layered gel by repeatedly applying the gel twice or more. As a result of various animal evaluations, in order to close a relatively severe air leak location such as an experimental air leak model using a rabbit lung, a coating amount of 100 mg / cm ² or more, for example, 150 to 200 mg / cm ² , is used. It was known that a coating amount may be required.

When water is added to the mixed adhesive powder by the above coating, a shift bond is formed between the aldehyde group of the aldehyded glucan and the amino group of the amino group-containing polymer, and this becomes a cross-linking point to form a network structure. Hydrogel with

The water-containing gel-like cured adhesive produced by such a curing reaction preferably has an adhesive strength of 20 gf / cm ² or more, and more preferably 50 gf / cm ² or more. If it is less than 20 gf / cm ² , not only the original purpose of adhering the living tissue cannot be achieved, but also the flexible movement accompanied by the expansion and contraction of the living tissue may not be tolerated. The adhesive strength here is a value measured by a peeling test using a tensile tester.

The water-containing gel-like cured adhesive produced by such a curing reaction preferably has a pressure-resistant adhesive strength of 100 mmHg or more, and more preferably 150 mmHg or more. If it is less than 100 mmHg, it may not be able to withstand the flexible movement accompanied by the expansion and contraction of the living tissue. The pressure-resistant adhesive strength here is a value measured by a method of applying pressure to the closed needle hole.

The hydrogel-like cured adhesive layer or the hydrogel-like resin produced by such a curing reaction changes to a liquid state (flowable sol state) by autolysis after a predetermined decomposition period. This liquefaction time can be easily adjusted, in particular by adjusting the amount of aldehyde groups introduced per anhydrous glucose unit. In order to shorten the decomposition time, it is preferable that the degree of aldehyde formation is relatively low, and for example, 0.2 to 0.4 aldehyde groups are introduced. In order to adjust the decomposition time within the range of 1 to 2 weeks, introduction of 0.26 to 0.3 aldehyde groups is preferable, and to achieve autolysis in a short period of 2 to 3 days, anhydrous. The introduction of 0.2-0.25 aldehyde groups per glucose unit is even more preferred.

The hydrogel-like cured adhesive layer or hydrogel-like resin produced by such a curing reaction changes to a liquid state (fluidable sol state) by self-decomposition after a liquefaction time based on the design. That is, even if it is in a water-containing state, it naturally decomposes and is converted into a liquid state without undergoing enzymatic decomposition in the living body. Therefore, in the living body, it is possible to promptly absorb or excrete the substance after a certain predetermined period of time so that it disappears. The disassembly time based on the design can be arbitrarily set within the range of several hours to 4 months, usually 1 day to 1 month, and particularly 2 days to 2 weeks.

In order for the water-containing gel-like cured adhesive produced by such a curing reaction to achieve good adhesive performance and self-decomposition, the reactive amino remaining in the partially carboxylated poly-L-lysine is provided. It also depends on how much the group accounts for the number of moles of the original amino group before partial carboxylation. The proportion of residual amino groups needs to be 60-95%, preferably 70-93%, more preferably 87-93%.

Although the mechanism of self-decomposition is not clear, the aldehyde group of the aldehyded α-glucan binds to the amino group to form a Schiff base, and then the adjacent α-glucoside bond is cleaved by the Amadori rearrangement of the Schiff base. It is speculated that this made it easier to reduce the molecular weight.

The medical adhesives and resins of the present invention are bioadhesives, tissue fillers, hemostatic agents, vascular embolizers, aneurysm sealants, sealants, anti-adhesion materials, and carriers for drug delivery systems (DDS). It is used for various purposes.

The medical two-component reactant type adhesive of the present invention exhibits excellent performance in adhesive strength, curability by gelation, coatability by a powder spray device, and the like. In addition, the degree of autolysis and flexibility suitable for living tissue can be arbitrarily adjusted.

It is a right side view of the powder spray device (powder spray gun) of one embodiment in a state where the right housing part is removed. It is a partial cross-sectional view (1) along the airflow path which shows the main part of the powder spraying apparatus of FIG. Indicates the standby state. It is a partial cross-sectional view (2) along the airflow path which shows the main part of the powder spraying apparatus of FIG. Shows the state at the time of spray application. It is a partial cross-sectional perspective view (FIG. 2 of Patent Document 4) which shows the powder supply part of the powder spray apparatus of FIG. It is a perspective view of the funnel member included in the powder spray apparatus of FIG. 1 (FIG. 4 of Patent Document 4). It is a graph which shows the relationship between the spraying time and the spraying amount when the spraying speed is relatively high. It is a graph which shows the relationship between the spraying time and the spraying amount when the spraying speed is relatively low. It is a set of images showing the relationship between the coating amount by one coating operation and the state of the coating surface. It is a graph which shows the relationship between the residual amino group ratio and the adhesive strength. It is a graph which shows the relationship between the residual amino group ratio and the decomposition rate. It is a schematic diagram which shows the apparatus for an in vitro needle hole occlusion test. It is a micrograph of the powder of aldehyded dextran as a first reactant. FIG. 3 is a photomicrograph of a powder of succinic anhydride-treated polylysine as a second reactant. It is a micrograph of a mixed adhesive powder (Ridex) powder.

In the powder spray device (powder spray gun) 10 of the embodiment shown in FIGS. 1 to 5, (i) a funnel (roof) to which the powder container 7 can be attached to the upper part or is provided integrally with the powder container 7. ) Member 1, (ii) First three-way joint 3 to which the first opening 31 is connected to the discharge port 11B at the lower end of the funnel member 1, and second and third openings 32 of the first three-way joint 3. , 33, the airflow supply pipe 41 and the delivery pipe 42, respectively, the housing 5 for accommodating these members, (iii) the vibration motor 2 attached to the funnel member 1, and (iv) branching from the airflow supply pipe 41. Then, the bypass airflow pipe 8 connected so as to join the delivery pipe 42 without passing through the first three-way joint 3, and (v) the compressed gas is inside the airflow supply pipe 41 and the first three-way joint 3. In addition to being sent through the coating flow path 4A passing through the delivery pipe 42, the coating state (on state) sent through the bypass airflow pipe 8 and the compressed gas are sent only through the bypass airflow pipe 8. An on / off mechanism 6 for switching between a standby state (off state) is provided, and the funnel member (1) and the first three-way joint (3) swing with respect to the housing (5). It is mounted so that it can move and swing.

As described above, by providing the bypass airflow pipe 8 and the on / off mechanism 6, it is possible to smoothly deliver powder having low bulk density and fluidity and high hygroscopicity, and to realize uniform coating. In particular, as will be described later, the on / off mechanism 6 keeps the compressed gas flowing through the bypass airflow pipe 8 not only during standby but also during application, so that the powder of the medical adhesive of the present application can be used. It makes it possible to uniformly apply a predetermined amount of powder having low bulk density and fluidity and high hygroscopicity.

Further, in the illustrated embodiment, the connection portion between the bypass airflow pipe 8 and the delivery pipe 42 is formed by the second three-way joint 81, and the connection portion between the bypass airflow pipe 8 and the airflow supply pipe 41 is a third. It is formed by a three-way joint 82. The second three-way joint 81 is provided with a dogleg-shaped bent portion 91 in a region upstream of the branch portion 83 to which the bypass airflow pipe 8 is connected, in which the direction of the airflow is diagonally upward. It is switched from the direction toward the direction to the direction toward the diagonally downward direction. By providing such a bent portion 91, the speed of feeding out the adhesive powder can be further made uniform.

The powder spray device (powder spray gun) 10 of the embodiment shown in FIGS. 1 to 5 is the same as the powder spray device of Patent Document 4 except for the structure related to the bypass air flow tube 8 and the on / off mechanism 6. be. In a specific embodiment, the second three-way joint 81 and the third three-way joint 82 are relatively rigid members made of the same material as the material of the first three-way joint 3 described later. On the other hand, the coating airflow pipe 4 (including the airflow supply pipe 41 and the delivery pipe 42) and the bypass airflow pipe 8 have inner diameters excluding the regions of the three-way joints 3, 81 to 82 and the region inside the on / off mechanism 6. And a flexible tube of uniform outer diameter and made of the same material. In the illustrated embodiment, the angle at which the main body portion 81A of the second three-way joint 81 bends (turns in the direction) at the bent portion 81C is 100 to 130 °. Further, the angle at which the branch portion 81B is connected to the main body portion 81A of the second three-way joint 81 on the downstream side of the bent portion 81C is also the same. On the other hand, the third three-way joint 82 has a T-shape, and the angle formed by the main body portion 82A extending linearly and the branch portion 82B to which the upstream end portion of the bypass airflow pipe 8 is connected is 30 to 60 °. Is.

In the illustrated embodiment, the on / off mechanism 6 includes a trigger lever 61, a valve housing member 62, and a coil spring 63. The trigger lever 61 includes a finger rest portion 61C and a rod-shaped portion 61D extending from the finger rest portion 61C, and the tip portion of the coil spring 63 is locked to the tip portion 61B of the rod-shaped portion 61D. That is, the trigger lever 61 can be pushed against the force of the coil spring 63 by putting an index finger or the like on the finger rest portion 61C. Then, when the pulling is stopped, the coil spring 63 returns to the initial position. The coil spring 63 is housed in a tubular portion formed by a plate-shaped rib 52 in the housing 5. On the other hand, the rod-shaped portion 61D of the trigger lever 61 is slidably inserted into the tubular main body portion 62C of the valve housing member 62. On the other hand, in the valve housing member 62, a first ventilation pipe portion 62A inserted in the middle of the airflow supply pipe 41 and a second ventilation pipe portion 62A inserted in the middle of the bypass airflow pipe 8 so as to intersect the main body portion 62C. A ventilation pipe portion 62B is provided. That is, the upstream portion 41A of the airflow supply pipe 41 is connected to the lower part of the first ventilation pipe portion 62A, and the downstream portion 41B of the airflow supply pipe 41 is connected to the upper part of the first ventilation pipe portion 62A. There is. Further, the upstream portion 8A of the bypass airflow pipe 8 is connected to the lower part of the second ventilation pipe portion 62B, and the downstream portion 8B of the bypass airflow pipe 8 is connected to the upper part of the second ventilation pipe portion 62B. There is.

The rod-shaped portion 61D of the trigger lever 61 is provided with a first valve hole 61A on the tip side and a second valve hole 61B on the root side (the side of the finger rest portion 61C). The first valve hole 61A has a dimension L1 along the axial direction of the rod-shaped portion 61D that is substantially the same as or slightly larger than the inner diameter D1 of the airflow supply pipe 41 and the delivery pipe 42, and the airflow is sent. When viewed from the direction in which it is formed, it is, for example, circular. On the other hand, the dimension L2 of the second valve hole 64 along the axial direction of the rod-shaped portion 61D is the stroke of the trigger lever 61 (moving distance at the time of pushing down and returning) to the inner diameter D2 of the bypass airflow pipe 8. It is almost the same as or slightly larger than the dimension to which L3 is added.

As shown in FIG. 2, in the initial position before the trigger lever 61 is pulled in, the first valve hole 61A of the trigger lever 61 is located between the first ventilation pipe portion 62A and the second ventilation pipe portion 62B. However, it does not contribute to the supply of compressed air. The flow path in the first ventilation pipe portion 62A is closed. On the other hand, at this initial position, the tip of the second valve hole 62B coincides with the flow path in the second ventilation pipe portion 62B. In this way, at the initial position, the compressed air is sent only to the flow path of the bypass airflow pipe 8.

Next, as shown in FIG. 3, when the trigger lever 61 is pulled to the limit where it can be pulled in, the valve hole 61A coincides with the flow path in the first ventilation pipe portion 62A of the valve housing member 62, so that the airflow supply pipe Compressed air is sent through 41. At this coating position, the root end of the second valve hole 64 coincides with the flow path in the second ventilation pipe portion 62B. In this way, at the initial position, the compressed air is sent not only to the coating flow path 65 passing through the inside of the first three-way joint 3 but also to the bypass airflow pipe 8. On the other hand, at the time when the trigger lever 61 starts to be pulled, the switch projection 61E provided at the tip of the rod-shaped portion 61D swings the hinge lever 21A of the switch element 21 to push the button 21B. Then, the electric power from the battery 22 (button battery in the specific example) in the battery box 55 is supplied to the vibration motor 2 through the power wiring 23 to vibrate. In this way, the powder can be smoothly delivered by starting the vibration before supplying the compressed air.

The upstream portion 41A of the airflow supply pipe 41 is connected to the root portion 41C of the airflow supply pipe 41 via the straight tubular main body portion 82A of the third three-way joint 82, and the root portion 41C has a disk-shaped removal. It is connected to the discharge port of the fungus filter unit 47 (for example, a HEPA filter made of glass fiber filter paper). A compressed air supply pipe 43 is connected to the introduction port of the sterilization filter unit 47. The upstream portion 8A of the bypass airflow pipe 8 is connected to the branch portion 82B of the third three-way joint 82. The compressed air supply pipe 43 is a flexible tube made of polyethylene or the like, and is connected to the compressed air pipe in the wall surface through, for example, a wall surface connection port 46 provided on the wall surface of the treatment room and a pressure regulator 49 attached to the wall surface connection port 46. Will be done. The housing 5 is composed of a left housing portion 5A and a right housing portion (not shown), which are manufactured separately and form a funnel member 1, a three-way joint 3, and an air flow pipe 4 for coating, which forms an air flow path during coating. (Including the airflow supply pipe 41 and the delivery pipe 42), the bypass airflow pipe 8, the nozzle 45, the trigger lever 61, etc. are sandwiched and assembled to each other by the claws 53 for assembly between the left and right sides.

The nozzle 45 is a thin tube extending in a straight line made of a rigid resin or metal, and in the illustrated example, a nozzle tip tube portion 44 made of silicone rubber or the like is attached to the tip thereof. The nozzle 45 is removable and can be attached to the main body of the powder spray device 10 at the time of use, and nozzles having different lengths can be used depending on the specific usage situation. For endoscopic surgery, one with a length of 15-40 cm, eg 30 cm, and an outer diameter of 3-7 mm, eg about 5 mm, can be used.

The tip of the nozzle 45 is exposed to a high humidity environment in order to be used as an adhesive for living tissue or as a sealant. However, since the powder spray device (powder spray gun) 10 of the present embodiment has a structure in which compressed air is sent out through the bypass air flow tube 8 even during standby, the eyes in the powder delivery path including the inside of the nozzle 45. The occurrence of clogging is prevented.

In particular, the powder spray device 10 of the present embodiment has a structure in which compressed air is constantly sent out through the bypass airflow pipe 8 during application and standby. However, the flow rate of the compressed air at the time of coating is larger in the flow path 65 for coating than in the bypass airflow pipe 8. Preferably, the flow rate through the bypass airflow pipe 8 at the time of coating is 20 to 70%, or 30 to 60%, for example, 40 to 60% of the flow rate through the flow path 65 for coating. In the illustrated specific example, the inner diameter of the flexible pipe forming the bypass airflow pipe 8 and the inner diameter of the flexible pipe 4 forming the airflow supply pipe 41 and the delivery pipe 42 are the same. However, it is probable that the flow rate of the flow path passing through the bypass airflow pipe 8 was smaller than that of the flow path 65 for coating due to reasons such as bending in the third three-way joint 82. Since the compressed air also flows through the bypass airflow pipe 8 during coating, the amount of the mixed adhesive powder delivered is reduced as compared with the case where it is not. However, when the experiment was conducted under the condition that about 0.1 to 0.2 g was sprayed per second, the decrease in the spray amount was only about 30% as compared with the case where the bypass airflow pipe 8 was blocked at the time of application. On the other hand, when the bypass airflow pipe 8 was closed during coating, when the trigger lever 61 was stopped and the flow path 65 for coating was closed, the mixed adhesive powder was continuously sent out from the nozzle for a short time. However, in the powder spray device 10 of the present embodiment, the delivery of powder stopped at the moment when the pulling of the trigger lever 61 was stopped. It is considered that this is because the pressure in the second three-way joint 81 becomes higher than the pressure in the delivery pipe 42 due to the pressure from the bypass airflow pipe 8. As described above, the powder spraying apparatus 10 of the present embodiment makes it possible to apply a predetermined amount of powder having low bulk density and low fluidity and high hygroscopicity. In particular, at the time of surgery, it is possible to easily realize a predetermined amount of application for a predetermined time only by pulling the trigger lever 61 with one hand.

Except for the portion described above, the powder spray device (powder spray gun) 10 of the present embodiment is the same as that described in Patent Document 4. The common structure will be briefly described below.

The powder spray device 10 in the embodiment shown in the drawing is a pistol type powder spray gun, and the powder in the vial 7 attached upside down at the upper end portion using the compressed air from the compressed air pipe 46. Is sprayed from the nozzle 45 at the front end. The volume of the vial 7 is, for example, 3 to 50 mL, 7 mL in one specific example, and the inner diameter of the bottle mouth 71 is, for example, 3 to 25 mm, 6 mm in one specific example. Except for the vial 7, the nozzle 45 and the compressed air supply pipe 43, almost the entire body is housed in the housing 5. The rear portion of the housing 5 is a handle portion 54, in which the battery box 55 is housed. An on / off mechanism 6 for supplying and shutting off compressed air is provided in the upper part of the handle portion 54, and airflow is supplied only while the trigger lever 61 corresponding to the trigger of the pistol is being pulled in. Further, when the trigger lever 61 is lightly pulled, the vibration motor 2 starts operating through the switch element 21A. The vibration motor 2 is fixed and stored in the pocket portion 12 of the funnel member 1 to which the vial 7 is attached so as not to be displaced, and the funnel member 1 and the three-way joint 3 connected to the lower end thereof are housings. By being held with play from 5, it is possible to swing and swing. Therefore, when the vibration motor 2 operates, the funnel member 1, the vials 7 attached above and below the funnel member 1, and the three-way joint 3 are integrated to vibrate the housing 5. The three-way joint 3 includes a portion forming a straight airflow pipe 36 and a socket portion 34 connected to the lower end of the funnel member 1. The airflow pipe 36 is a coating airflow from the on / off mechanism 6 to the nozzle 45. It is inserted in the middle of the pipe 4 (between the downstream part of the airflow supply pipe 41 and the delivery pipe 42). In this way, the powder dispersed in the air flow at the center of the three-way joint 3 is sent out from the nozzle 45. Urethane rubber having excellent followability to vibration can be used for the downstream portion 41B and the delivery pipe 42 of the airflow supply pipe 41, but a silicone pipe or a PVC pipe (particularly a non-phthalic acid-based soft vinyl chloride resin) can be used. A tube) may be used. The upstream portion 41A of the airflow supply pipe 41 and the bypass supply pipe 8 can also be formed of the same or similar flexible tubes. Further, in a specific example, the vibration motor 2 is used for the manner mode of a mobile phone, has a diameter of 10 mm, a thickness of 3.3 to 3.5 mm, and a drive current of 50 to 70 mA at 3 V. be.

The funnel member 1 includes a funnel main body 11 having a tapered shape as a whole, a pocket portion 12 protruding outward from the outer surface thereof, and a mounting portion 13 extending from the outer surface of the upper end portion 11D of the funnel main body 11. The mounting portion 13 makes it possible to firmly fix the vial 7 so as not to come off due to vibration, and the mounting opening 51 at the upper end of the housing 5 allows the funnel member 1 to have a relatively large amount of play. This is to keep it in place. In the illustrated specific example, the mounting portion 13 of the funnel member 1 has a flange portion 14 extending from a position slightly below the upper end of the funnel main body portion 11 and a cylindrical portion extending slightly from the inside to the upper side from the outer peripheral end of the flange portion 14. It consists of 15. The bottle mouth portion 71 of the vial 7 is inserted and fixed in the circular ring-shaped groove 17 formed by the upper end portion 11D of the funnel main body portion 11, the flange portion 14, and the cylindrical portion 15. Further, in order to prevent the vial 7 from coming out, a plurality of hooking protrusions 16 are provided on the inner peripheral surface of the cylindrical portion 15.

On the other hand, the mounting opening 51 at the upper end of the housing 5 includes a cylindrical portion 51C protruding upward from the upper end of the housing 5, and upper and lower inward flanges 51A and 51B extending from the upper and lower ends. The range of movement of the funnel member 1 is limited by abutting the flange portion 14 of the funnel member 1 against the upper and lower inward flanges 51A and 51B in the vertical direction. On the other hand, the limitation of the movable range in the horizontal direction is that the flange portion 14 is abutted against the cylindrical portion 51C of the mounting opening 51, and the cylindrical portion 15 of the funnel member 1 is abutted against the upward inward flange 51A. Is done by. In the illustrated example, the movable range can also be limited by the lower inward flange 51B being abutted against the stepped portion 18 on the lower surface of the flange portion 14. In one specific example, the movable range of the funnel member 1 is 3 mm in the vertical direction and 2 mm in the horizontal direction at the upper end portion and the lower end portion.

The funnel member 1 is integrally formed by injection molding of polypropylene resin. At this time, the mold surface corresponding to the inner surface of the funnel main body 11 is mirror-processed. In this way, the JIS surface roughness Ra of the inner surface of the funnel main body 11 was set to about 10 (nm). In the illustrated example, the taper angle (angle with respect to the central axis 11C) of the inner surface of the funnel main body 11 is about 10 degrees.

The pocket portion 12 of the funnel member 1 is provided so that the coin-shaped vibration motor 2 can be pushed in exactly. Here, the rotating shaft 2A of the vibration motor 2 is arranged and stored so that its extension line intersects the central shaft 11C of the funnel main body 11. Further, in the illustrated example, the position of this intersection coincides with the equal division point of the height direction dimension of the funnel main body 11. The pocket portion 12 forms an opening 12A that opens unilaterally in the circumferential direction of the funnel main body 11, and the vibration motor 2 is pushed through the opening 12A. After this pushing, for example, the terminal portion 2B protruding from the opening 12A by protruding from the peripheral surface of the vibration motor 2 is attached to the outer surface of the funnel main body 11 or the outer surface of the pocket 12 with a strong adhesive tape. Can be fixed. For example, a single-sided adhesive tape can be attached so as to cover the terminal portion 2B. In this way, the adhesive tape can be used to further prevent the vibration motor 2 from being displaced and coming off. On the other hand, a strong double-sided adhesive tape can be arranged between the vibration motor 2 and the inner surface of the pocket portion 12. For example, the portion of the pocket portion 12 far from the opening 12A, that is, the pocket bottom portion 12B can be provided in a semicircular shape when viewed from the direction of the rotation shaft 2A of the vibration motor 2, and when the vibration motor 2 is pushed in, the portion is provided in a semicircular shape. A strong double-sided adhesive tape can be sandwiched between the peripheral wall surface of the pocket bottom 12B and the peripheral surface of the coin-shaped vibration motor 2.

In the illustrated example, the lower end 11A of the funnel main body 11 is pushed into the socket portion 34 that branches upward from the central portion of the three-way joint 3 until the lower end of the pocket portion 12 substantially touches the upper end of the socket portion 34. It is firmly connected. On the other hand, the lower end discharge port 11B of the funnel main body 11 is connected to the first opening 31 provided at the bottom of the socket portion 34 so that the inner peripheral surfaces are continuous with each other. In particular, the first opening 31 is provided so as to form an opening in the pipe wall of the airflow pipe 36 in the three-way joint 3. Therefore, the lower end discharge port 11B of the funnel main body 11 extends to a position substantially in contact with the airflow pipe line 36. On the other hand, in the illustrated example, a bay entry portion 35 is provided on the pipe wall of the airflow pipe 36 at the bottom surface of the confluence portion 37, that is, at a portion facing the first opening 31.

As shown in FIGS. 1 to 3, the outer surface of the three-way joint 3 is abutted against the plate-shaped rib 52 protruding from the inner surface of the housing 5, so that the holding and movable range of the three-way joint 3 and the lower portion of the funnel member 1 are restricted. Will be done. In the illustrated example, the upper end of the socket portion 34 of the three-way joint 3 is located in the opening 52A of the horizontal plate-shaped rib and can be abutted against the edge of the opening 52A. Further, the protrusion at the lower end of the three-way joint 3 is located in the opening 52B of the other horizontal plate-shaped rib, and can be abutted against the edge of the opening 52B. In the initial position, the lower end of the three-way joint 3 is placed and supported on the peripheral portion of the opening 52B of the horizontal plate-shaped rib.

The medical two-component reactive adhesive in one embodiment will be described below.

1. 1. Preparation of powdered aldehyded dextran (first reactant; AD) 400 g of dextran (Meito Sangyo Co., Ltd., "Dextran 70") having a molecular weight of 70,000 was dissolved in 1600 ml of ion-exchanged water, and 50 g of the dextran was dissolved. Sodium peroxide (molecular weight 213.89) was dissolved in 800 ml of ion-exchanged water and then added, and the reaction was carried out in a water bath at 50 ° C. with stirring for 3 hours. Then, the solution after the reaction was dialyzed, filtered through a 0.45 μm filter, and dried. Further, a pulverization treatment was carried out using a small crusher (Wonder Crush Mill D3V-10, Osaka Chemical Co., Ltd.) to obtain a powdery aldehyded dextran (2.5 / 20). In addition, (2.5 / 20) shows the charge ratio of (sodium periodate / dextran 70) constituting aldehyded dextran. In the obtained aldehyded dextran, the amount of aldehyde group introduced per amount of sugar residue (mol) was 0.28. The amount of aldehyde group introduced was measured by the redox titration method. Specifically, 20 ml of a 0.05 mol / l iodine aqueous solution, 10 ml of a 10 mg / ml aldehyded dextran aqueous solution and 20 ml of a 1 mol / l sodium hydroxide aqueous solution were placed in a 100 ml Meyer flask and stirred at 25 ° C. for 15 minutes. Then, 15 ml of a 6 v / v% sulfuric acid aqueous solution was added, and titration was performed with a 0.1 mol / l sodium thiosulfate aqueous solution. The end point was when the reaction system became colorless and transparent, and the indicator was an aqueous starch solution.

When the particle size of the powder was evaluated using a stereomicroscope, the average particle size was 90 μm as shown in the photograph of FIG. Furthermore, as a result of observing the surface texture with an electron microscope, it was formed as a porous body. The average aspect ratio (ratio of the major axis to the minor axis) was about 1.6.

2. 2. Preparation of succinic anhydride-treated polylysine (second reactant; SAPL) Add 10 g of succinic anhydride (Nacalai Tesque) to 400 g of a 25 wt% ε-polylysine aqueous solution (molecular weight 4,000, Chisso Co., Ltd.) and react at 50 ° C. for 1 hour. I let you. The solution after the reaction was filtered through a 0.45 μm filter and then dried. Further, a crushing treatment was carried out using a small crusher (Wonder Crush Mill D3V-10, Osaka Chemical Co., Ltd.) to obtain a powdery succinic anhydride-treated polylysine.

For the obtained succinic anhydride-treated polylysine, the residual ratio of free amino groups (side chains and terminal amino groups not involved in the formation of peptide bonds) was determined to be 89.5%. For this measurement, after dissolving in water, a ninhydrin solution and a pH 5.5 acetic acid / sodium acetate buffer were added, heated in a boiling water bath for 3 minutes, and then rapidly cooled to prepare a sample solution. Then, the test was carried out by the Japanese Pharmacopoeia ultraviolet-visible absorbance measurement method, the absorbance at a wavelength of 570 nm was measured, and the amino group content in the sample solution was determined.

The obtained powdery succinic anhydride-treated polylysine was evaluated using a stereomicroscope in the same manner as in the case of the above-mentioned aldehyded dextran. It was a porous body of. The average particle size was 80 μm. The average aspect ratio was about 1.7.

3. 3. Mixed Adhesive Powder The mixed adhesive powder (average particle size 80 μm), which is a mixture of the above powdered aldehyded dextran and powdered anhydrous succinic acid-treated polylysine at a weight ratio of 4/1, contains aldehyde groups and amino groups. The molar ratio of is almost 1. FIG. 14 shows the obtained mixed adhesive powder. The bulk density of the mixed adhesive powder was 420 mg / ^cm3 . The mixed adhesive powder is filled in a 7 mL glass vial with an aluminum cap in an amount of 3 g each, and then sealed and stored to have a water content of 1.0% or less, particularly 0.5 to 1. It was kept at 0%. In the present application, this mixed adhesive powder is also referred to as "Ridex (registered trademark)" as appropriate. Unless otherwise specified, the above reaction charge ratio and mixing ratio were used. That is, a water-succinic acid-treated polylysine obtained by reacting 100 g of ε-polylysine with 10 g of succinic anhydride was used, and the charging ratio of sodium periodate / dextran 70 when oxidizing dextran was set to 2.5 / 20. A mixed adhesive powder (“Rydex powder 2.5 / 20”) in which dextran (AD) and succinic anhydride-treated polylysine (SAPL) were mixed at a weight ratio of 4/1 was used.

4. Application of mixed adhesive powder The above mixed adhesive powder was applied using the powder spray device (powder spray gun) 10 shown in FIGS. 1 to 5. At this time, the nozzle 45 was connected to the powder spray device main body 10A, the compressed air supply pipe 43 (air supply tube) was attached to the disinfection filter 47 on the root side, and the pressure regulator 49 was connected. Further, the vial bottle 7 filled with the mixed adhesive powder in which the first reactant and the second reactant were mixed in advance was turned upside down and connected to the powder spraying apparatus main body 10A. The pressure-adjusted compressed air passes through the disinfection filter 47 and is supplied to the measuring unit (inside the first three-way joint 3) connected to the vial bottle 7. In this measuring section, the mixed adhesive powder is further mixed by compressed air. Then, it is sent out through the nozzle 45. Using such a powder spray device 10, the mixed adhesive powder was applied by directly spraying it onto a portion wet with body fluid, blood, or the like. Next, use a "mist adapter" (Maeda Sangyo Co., Ltd .: spray nozzle) on the tip of the syringe that sucked in the saline solution, and spray the saline solution evenly until the mixed adhesive powder gels uniformly and transparently. It was allowed to stand for 2 minutes.

The pressure of the compressed air at the wall connection port was 4 atm (about 400 kPa). The spray rate can be adjusted by adjusting the pressure supplied to the compressed air supply pipe 43 by the pressure regulator 49. As a result of repeating the spraying experiment, it was considered that 0.1 to 0.8 g (100 to 800 mg) per second was the most suitable for uniformly applying a predetermined amount.

5. Spraying speed In FIGS. 6 to 7, the spraying speed is adjusted in two stages of 0.25 g / sec (FIG. 6) and 0.75 g / sec (FIG. 7), and the spraying time and the total spraying amount (spraying) are adjusted. The results of investigating the relationship with the cumulative spray amount from the start) are shown in FIGS. 5 to 6, respectively. In FIGS. 6 to 7, the square (large upright square) is the case where the maximum drive current of the vibration motor 2 is 70 mA, and the diamond shape (the small square tilted 45 degrees) is the minimum 50 mA. Show the case. As a result, it was confirmed that the spraying state is stable regardless of the level of the spraying speed as long as the drive current of the vibration motor 2 is increased, and the spraying can be performed quantitatively within a predetermined time.

6. Application amount in one application operation and sealant performance test using a rabbit lung experimental air leak model After excision at the maximum part of the posterior lobe of the left lung of a Japanese white male rabbit, decrumped and inspiratory pressure up to 30 cmH ₂ O It was raised and a physiological saline solution was dropped on the cut surface of the lung to confirm that there was air leakage. When the number of air leak locations was less than 4, a disposable injection needle 18G was punctured in the direction perpendicular to the cut surface, and an air leak model was prepared so that the total number of air leak locations was 4 or more. It was confirmed that there was air leakage in the same way as above.

Next, using the powder spray device (powder spray gun) 10 shown in FIGS. 1 to 5, the coating amount (amount of powder adhesive per area of the planned bonding area) to be applied by one coating operation is determined. It was changed and applied to a circular area having a diameter of 30 mm including the above-mentioned four or more air leak points. This circular region corresponds to the above-mentioned air leakage model and is a region wet with body fluid. Immediately after applying the mixed adhesive powder, an amount of physiological saline solution that was just inhaled by the mixed adhesive powder was dropped evenly. FIG. 8 shows a series of photographs embedded in a table, and these series of photographs are shown for each application amount on the application surface immediately after such application and 2 minutes after the dropping of physiological saline (2 minutes after the application). The state of the coated surface after gelation) is shown respectively. As shown in FIG. 8, when the coating amount was less than 25 mg / cm ² , the coated surface was uneven, and there was a portion that was not completely covered with the mixed adhesive powder. And even after spraying physiological saline and letting it stand for 2 minutes, there seemed to be a part where the formation of hydrogel was insufficient. At a coating amount of 25 to 50 mg / cm ² , the entire coated surface was considered to be white and uniformly covered with the mixed adhesive powder, and the gel formed was also considered to be very uniform. However, when the coating amount exceeded 50 mg / cm ² , the entire coated surface was covered with the mixed adhesive powder in white, but wavy irregularities were observed in some places. Then, after dropping the physiological saline solution, a portion where gelation did not proceed sufficiently and remained as the mixed adhesive powder was observed.

On the other hand, FIG. 8 shows the results of measuring the maximum pressure (burst value) that can prevent air leakage when sealing is performed at each coating amount per area in the needle hole closing test. For this measurement, a ventilator was attached to the posterior lobe of the left lung of the rabbit that formed the asava model. Then, after 2 minutes or 5 minutes, a load of about 90 mmHg (about 27 cmH ₂ O) is applied as an initial pressure, and after confirming that there is no leakage from the needle hole, a load is applied at a speed of 150 ml / hr to make the needle hole. The pressure-resistant adhesive strength (mmHg) at the time of leakage was determined. As a result, as shown in FIG. 7, it was the highest when the amount of one spray was 45 mg / cm ² , and even at 25 mg / cm ² , it was a high value to some extent. On the other hand, when the amount of one spray was 11 mg / cm ² and 77 mg / cm ² , it was significantly lower.

From these results, it was known that when applying a large amount exceeding 50 mg / cm ² , the application operation by spraying should be repeated instead of applying all at once. That is, it was known that a layered gel should be produced by repeating the coating operation twice or more. In addition, in animal evaluation, a relatively severe air leak such as a rabbit lung experimental air leak model may require a coating amount of 100 mg / cm ² or more. Therefore, the coating amount per unit area after the completion of the coating operation is based on 50 to 100 mg / cm ² , and is appropriately increased to, for example, 150 mg / cm ² .

7. Adhesive performance and resolution based on the residual amino group ratio of succinic anhydride-treated polylysine The same preparation as in "2. Preparation of succinic anhydride-treated polylysine (second reactant)" was made, but 25% by weight of ε-polylysine aqueous solution (molecular weight). 4,000, Chisso Co., Ltd.) By adding 6 to 14 g (5 levels of 6 g, 8 g, 10 g, 12 g, 14 g) of succinic anhydride (Nakalitesk) to 400 g, the reaction was carried out to obtain 5 levels of residual amino group ratio. A powdery succinic anhydride-treated polylysine was obtained. As a result, succinic anhydride-treated polylysine having a residual amino group ratio of 75.8 to 89.5% was obtained. Similarly, by adding succinic anhydride (Nacalai Tesque) to 400 g of a 25 wt% ε-polylysine aqueous solution (molecular weight 4,000, Chisso Co., Ltd.) in the range of 60 g or less, the residual amino group ratio was further significantly changed. A powdery succinic anhydride-treated polylysine was obtained. The residual amino group ratio was quantified as follows. First, the powdered succinic anhydride-treated polylysine was dried and dissolved in water. Then, a ninhydrin solution and a pH 5.5 acetic acid / sodium acetate buffer were added, heated in a boiling water bath for 3 minutes, and then rapidly cooled to prepare a sample solution. Then, the test was carried out by the Japanese Pharmacopoeia ultraviolet-visible absorbance measurement method, the absorbance at a wavelength of 570 nm was measured, and the amino group content in the sample solution was determined.

The above powdered aldehyded dextran and 5 levels of powdered succinic anhydride-treated polylysine were mixed at a weight ratio of 4/1. The mixed adhesive powder was filled into 7 mL vials in 3 g increments using a filling machine.

<Adhesive strength by in vitro peeling test>
Place a stainless steel jig with an inner diameter of 15 mm on a collagen casing wiped with ethanol, put 50 mg of Rydex's mixed adhesive powder in it, spread it with a microspartel to a uniform thickness, and then add 150 μl of physiology. A saline solution was added and gelled. Then, two minutes later, the stainless steel jig was lifted at a speed of 10 mm / min by a tensile tester (Tencilon universal tester RTC-1210A, Orientec Co., Ltd.), and the load load at the time of peeling from the collagen casing was used as the adhesive strength. .. The results are shown in Table 1, FIG. 9, and Table 2.

As shown in Table 1 and FIG. 9, when the residual amino group ratio was about 90%, the adhesive strength was considered to be the largest. However, even if the residual amino group ratio was changed in the range of 70 to 86%, no significant difference was observed in the adhesive strength. When the residual amino group ratio was set to a value of less than 70% or more than about 90%, a good water-containing gel was not formed and a measurable adhesive force could not be obtained.

<In vitro gel decomposition test>
Cut the dialysis membrane (dialysis membrane 36/32, model number: UC36-32-500, Adia Co., Ltd.) into a rectangle of about 5 cm, wash with tap water to remove water, and then wipe one side of the dialysis membrane with ethanol. .. This is called a collagen casing wiped with ethanol. A stainless steel jig with an inner diameter of 15 mm is placed on this collagen casing, 40 mg of Rydex's mixed adhesive powder is placed therein, spread with a microspartel to a uniform thickness, and then 120 μl of physiological saline solution is used. Was added and gelled. Immerse the gelled Rydex in a closed container containing 50 ml of physiological saline and install it in an ultra-compact constant temperature shaking incubator Bio-Shaker (model V-BR-36, TIETECH Co., Ltd.) set at 37 ° C. It was shaken at 100 rpm. After 6 hours and 22 hours, the disappearance rate of the gelled Rydex was visually confirmed. The results are shown in Table 1, FIG. 9, and Table 2.

Degradation of Lydex containing succinic anhydride-treated polylysine having different residual amino group ratios disappeared by about 50% after 6 hours and by about 90% after 22 hours. It was confirmed that the resolution was almost the same even when changed in the range of 70 to about 90%. However, outside this range, the formation of the hydrogel was insufficient as described above.

8. Adhesion performance and resolution depending on the amount of aldehyde group introduced The same preparation as in "Preparation of powdered aldehyded dextran (first reactant)" was made, but the amount of sodium periodate to be added to 400 g of dextran and reacted was 60 g ( The charge ratio was changed to 3.0 / 20) and 80 g (charge ratio 4.0 / 20). In this way, 0.30 and 0.39 aldehyde groups were introduced per anhydrous glucose unit, respectively. In the same manner as above, aldehyded dextran and powdered succinic anhydride-treated polylysine were mixed at a weight ratio of 4/1 to obtain a mixed adhesive powder.

When an in vitro gel decomposition test was conducted in the same manner as in "7." above, as shown in Table 3, when the amount of aldehyde group introduced was 0.27 ("Ridex powder 2.5 / 20"), 2 to 2 to It disappeared in 3 days, and the aldehyde group introduction amount of 0.30 (“Ridex powder 3.0 / 20”) disappeared in 7 to 11 days. It is presumed that the amount of 0.39 aldehyde groups introduced (“Ridex powder 4.0 / 20”) does not change significantly when the Ridex powder (3.0/20) disappears, and it takes more than 4 weeks. rice field. As is known from this result, by reducing the amount of sodium periodate compounded, the amount of aldehyde group introduced can be reduced, so that the cross-linking due to the shiff bond with the succinic anhydride-treated polylysine is reduced, and the gel disappears. It can be accelerated and the decomposition time of the gel can be adjusted arbitrarily.

Even if the amount of aldehyde group introduced was changed, no significant difference was observed in the adhesive strength measured in the same manner as in "6." and the pressure resistance measurement value by the needle hole closing test.

FIG. 11 shows a schematic view of the device used for the needle hole occlusion test. First, a stainless steel jig having an inner diameter of 15 mm was placed on a collagen casing wiped with ethanol, and a hole was made in the center using an 18 G needle. Then, 50 mg of the mixed adhesive powder of Rydex was put in the needle hole portion, spread with a spatula so as to have a uniform thickness, and then 150 μl of physiological saline was added to gel. Then, after 2 minutes or 5 minutes, a load of about 90 mmHg is applied as an initial pressure, and after confirming that there is no leakage from the needle hole, a load is applied at a speed of 150 ml / hr, and the pressure resistance when leaking from the needle hole is applied. The adhesive strength (mmHg) was determined.

9. Effect of gel thickness on gel disappearance time A 7-week-old male rat's abdominal skin was incised 2-3 cm along the midline from the vicinity of the sternal xiphoid process to expose the liver and made of stainless steel on the surface of the medial right lobe. A jig (inner diameter 15 mm) is placed, and the above-mentioned "Ridex powder 2.5 / 20" or Ridex powder "Ridex powder 4/20" is uniformly sprayed on the inside thereof, and then a physiological saline solution is sprayed to gel. I made it. The liver was returned to its original position, the incision was sutured, and the surgical field was cleaned. The coating amount of the Rydex powder was 38 mg, 76 mg, and 114 mg, and the coating thickness was 0.5 mm, 1 mm, and 1.5 mm, respectively. The coating thickness was calculated from the jig area and the bulk density of the Rydex powder (420 mg / cm ³ ).

After 2 weeks, 4 weeks, 6 weeks, and 8 weeks after thoracotomy, the liver was removed and the state of decomposition was observed by macroscopic examination. The results are shown in Table 4.

In the case of Rydex powder (2.5 / 20), a very small amount of gel remained in the medium-thickness (1 mm) coating group 2 weeks after application, and gel residue was observed in the thin (0.5 mm) coating group. No gel remained even in the thick (1.5 mm) coating group at 4 and 6 weeks after application, so it was confirmed that the gel disappeared rapidly. On the other hand, in the Rydex powder (4.0 / 20), gel residue was observed in the intermediate coating group even at 8 weeks after application, and very slight gel residue was observed in the thin coating group. From the above, it was known that the influence of the gel thickness on the decomposition period was not large.

10. Occlusion test for the entire lung parenchymal cut surface (Example 1)
The posterior lobe of the left lung of a Japanese white male rabbit was cut at its maximum to form a parenchyma of the lung. Then, "Ridex powder 2.5 / 20" was sprayed on the lung parenchyma cut surface using the above powder spray device, and then a physiological saline solution was sprayed to gel. Subsequently, the inspiratory pressure of the ventilator connected to the posterior lobe of the left lung of the rabbit was gradually increased from 20 cmH ₂ O to 50 cm H ₂ O, and the presence or absence of air leakage was confirmed. When air leakage was observed under certain intake pressure conditions, no further pressurization was performed, and the intake pressure was defined as the intake pressure at which air leakage occurred. The results are shown in Table 5.

(Example 2)
"Ridex powder 4.0 / 20" was sprayed on the lung parenchyma cut surface using the above powder spray device, and then a physiological saline solution was sprayed to gel. Subsequently, the same operation as described above was performed, and the presence or absence of air leakage was confirmed. The results are shown in Table 5.

(Comparative Example 1)
For fibrin glue, a mixture of A and B was applied to the entire cut surface of the lung parenchyma. Subsequently, the same operation as described above was performed, and the presence or absence of air leakage was confirmed. The results are shown in Table 5.

(Comparative Example 2)
Regarding the combined use of the fibrin glue and the PGA sheet-shaped suture reinforcing material, the fibrin glue A solution was applied to the entire cut surface, and then the PGA sheet-shaped suture reinforcing material cut into about 5 mm square was attached to the air leak portion. Next, a mixed solution of fibrin glue solution A and solution B was applied to the entire cut surface, and the mixture was blended with a sheet-shaped suture reinforcing material made of PGA and left for about 2 minutes. Subsequently, the same operation as described above was performed, and the presence or absence of air leakage was confirmed. The results are shown in Table 5.

As a result of confirming the sealant performance, no air leakage was observed even in the intake pressure of 50 _cmH2O in only one case of Example 1 (Rydex powder (2.5 / 20)). Air leakage was observed in all other cases, and the intake pressure at which air leakage occurred was 30 to 40 cmH ₂ O (mean value: 40 cmH ₂ O) in Example 1 (Ridex powder (2.5 / 20)), respectively. 2 (Ridex powder (4.0 / 20)) 30-40 cmH ₂ O (mean value: 36 cmH ₂ O), Comparative Example 1 (fibrin glue) 20-40 cmH ₂ O (mean value: 30 cmH ₂ O), In Comparative Example 2 (combined use of PGA sheet-like suture reinforcing material and fibrin glue), the temperature was 30 to 50 cmH ₂ O (mean value: 38 cmH ₂ O). As a result of performing a Kruskal-Wallis test for the inspiratory pressure at which air leakage occurred, Examples 1, Example 2 and Comparative Example 2 were almost the same. The Rydex powders of Examples 1 and 2 showed a sealant performance equal to or higher than that of the PGA sheet-shaped suture reinforcing material and fibrin glue used in Comparative Example 2.

11. Change in adhesive strength depending on mixing ratio By changing the mixing ratio of aldehyded dextran (AD) and succinic acid-treated polylysine (SAPL), the molar ratio of aldehyde group to amino group changes from 5/1 to 5/5. Then, the adhesive strength was measured by a peeling test by the same method as in "7." above. The results are shown in Table 6 below. As is clear from Table 6 below, it was confirmed that the adhesive strength was also the highest when the reaction molar ratio was 1/1. Moreover, even if the reaction molar ratio deviated slightly, the decrease in adhesive strength was not so large.

<Table 6>
AD / SAPL adhesive strength (gf)
5/1 58.88
5/2 81.20
5/3 100.15
5/4 102.70
5/5 110.12

The medical adhesive of the present invention is suitable as a bioadhesive, a tissue filler, a hemostatic agent, a vascular embolizer, an aneurysm sealant, a sealant, an anti-adhesion material, and a carrier for a drug delivery system (DDS). Can be used. Further, the powder spraying apparatus of the present invention makes it possible to uniformly apply a predetermined amount of the medical adhesive of the present invention or other powder having a low bulk density and low fluidity and high hygroscopicity. ..

1 ... Funnel member; 10 ... Powder spray gun;
10A ... Spray gun body;
11 ... Funnel body; 11A ... Lower end; 11B ... Lower end outlet;
11C ... Central axis of funnel body; 11D ... Upper end of funnel body;
12 ... Pocket part; 12A ... Opening; 12B ... Pocket bottom;
13 ... Mounting part; 14 ... Flange part; 15 ... Cylindrical part;
16 ... Hanging protrusion; 17 ... Ring-shaped groove; 18 ... Step portion;
2 ... Vibration motor; 2A ... Vibration motor rotation shaft; 21 ... Switch element;
21A ... hinge lever; 21B ... button; 22 ... battery;
3 ... 1st three-way joint; 31 ... Powder receiving opening; 32 ... Airflow receiving opening;
33 ... Airflow delivery opening; 34 ... Socket part; 35 ... Bay entrance part;
36 ... Airflow pipeline; 36A ... Upstream; 36B ... Downstream;
37 ... Confluence; 38A, 38B ... Central axes of upstream and downstream;
4 ... Airflow pipe for coating; 4A ... Channel for coating; 41 ... Airflow supply pipe;
42 ... delivery pipe; 41A ... upstream part; 41B ... downstream part; 41C ... root part;
43 ... Compressed air supply pipe; 44 ... Nozzle tip pipe; 45 ... Nozzle;
46 ... Wall connection port; 47 ... Sterilization filter; 49 ... Pressure regulator;
5 ... Housing; 5A ... Left housing part; 51 ... Mounting opening;
51A, 51B ... Inward flange; 51C ... Cylindrical part; 52 ... Plate-shaped rib;
52A, 52B ... Horizontal plate-shaped rib opening; 53 ... Claws for assembly between left and right;
54 ... Handle part; 55 ... Battery box; 6 ... On / off mechanism;
61 ... Trigger lever; 61A ... First valve hole;
61B ... Second valve hole; 61C ... Finger rest; 61D ... Rod-shaped part;
61E ... Switch protrusion; 62 ... Valve housing member;
62A ... 1st ventilation pipe part; 62B ... 2nd ventilation pipe part; 62C ... Main body part;
63 ... Coil spring; 7 ... Vial (powder container); 71 ... Bottle mouth
8 ... Bypass airflow pipe; 8A ... Upstream; 8B ... Downstream;
81 ... Second three-way joint; 81A ... Main body; 81B ... Branch;
81C ... Bent part; 82 ... Third three-way joint; 82A ... Main body part;
82B ... Branch

Claims (9)

A first reactant consisting of a powder of aldehyded glucan having a weight average molecular weight of 1000 to 200,000,
Partially carboxylated poly-L obtained by reacting poly-L-lysine having a weight average molecular weight of 1,000 to 20,000 with succinic acid anhydride or glutaric acid anhydride so that the residual amino group ratio becomes 70 to 93%. -With a second reactant consisting of lysine powder,
It consists of a mixed powder mixed so that the molar ratio of aldehyde group / amino group is 0.9 to 2.0.
The aldehyded glucan is obtained by oxidizing dextran or dextrin with periodic acid or periodate to introduce 0.2 to 0.5 aldehyde groups per anhydrous glucose unit.
The aldehyded glucan powder and the partially carboxylated poly-L-lysine powder are both porous bodies having a random shape and have an average particle size of 10 to 150 μm, and the mixed powder has a water content. 2.0% or less,
A medical two-component reactant type adhesive characterized in that the amount of one application using a powder spray device is 20 to 50 mg / cm ² . The medical two-component reactant type adhesive according to claim 1, wherein the residual amino group ratio in the partially carboxylated poly-L-lysine is 87 to 93%. By varying the amount of aldehyde groups introduced in the aldehyded glucan in the range of 0.2 to 0.4 per anhydrous glucose unit, the period until the hydrogel disintegrates is from 2 to 3 days to 4 The medical two-component reactant type adhesive according to claim 1 or 2, which is adjusted and set within a range of one week or longer. The powder spray device is
A funnel member (1) that can be attached to the upper part of the powder container (7) or is provided integrally with the powder container (7).
A three-way joint (3) to which the first opening (31) is connected to the discharge port (11B) at the lower end of the funnel member (1).
The airflow supply pipe (41) and the delivery pipe (42) connected to the second and third openings (32, 33) of the three-way joint (3), respectively.
A housing (5) for storing these members and
Equipped with a vibration motor (2),
The funnel member (1) is integrally provided with a pocket portion (12) or other mounting portion on the outer surface of the funnel main body portion (11), and is pushed into the pocket portion (12) or the other mounting portion. The vibration motor (2) is fixed to the outer surface of the funnel body (11) by being fitted into the funnel body (11).
The medical two-component reactant type according to any one of claims 1 to 3, wherein the funnel member (1) and the three-way joint (3) are attached to the housing (5) so as to be able to swing and swing. glue. The powder spray device further includes
A bypass airflow pipe (8) that branches from the airflow supply pipe (41) and is connected so as to join the delivery pipe (42) without passing through the three-way joint (3).
A standby state in which the compressed gas is sent only through the bypass airflow pipe (8), and a flow path for the compressed gas to be applied through the airflow supply pipe (41), the inside of the three-way joint (3), and the delivery pipe (42). An on / off mechanism (6) for switching between a coating state that passes through the bypass airflow pipe (8) and a bypass airflow pipe (8).
The medical two-component reactant type adhesive according to claim 4. The medical use according to any one of claims 1 to 5, which comprises a step of performing radiation sterilization of 10 to 50 kGy in a state where the mixed powder having a water content of 0.5 to 2.0% is filled in a closed container. A method for producing a two-component reactant type adhesive. A funnel member (1) that can be attached to the upper part of the powder container (7) or is provided integrally with the powder container (7).
A first three-way joint (3) to which the first opening (31) is connected to the discharge port (11B) at the lower end of the funnel member (1).
The airflow supply pipe (41) and the delivery pipe (42) connected to the second and third openings (32, 33) of the first three-way joint (3), respectively.
A vibration motor (2) attached to and fixed to the outer surface of the funnel body (11) in the funnel member (1), and
A bypass airflow pipe (8) that branches from the airflow supply pipe (41) and is connected so as to join the delivery pipe (42).
A standby state in which the compressed gas is sent only through the bypass airflow pipe (8), and a flow path for the compressed gas to be applied through the airflow supply pipe (41), the inside of the three-way joint (3), and the delivery pipe (42). An on / off mechanism (6) for switching between a coating state that passes through the bypass airflow pipe (8) and a bypass airflow pipe (8).
A housing (5) for accommodating these members is provided.
The funnel member (1) and the first three-way joint (3) are powder spraying devices that are attached to the housing (5) so as to be able to swing and swing. The connection portion between the bypass airflow pipe (8) and the delivery pipe (42) is formed by the second three-way joint (81), and the connection portion between the bypass airflow pipe (8) and the airflow supply pipe (41) is the second. Formed by 3 three-way joints (82),
The second three-way joint (81) is provided with a dogleg-shaped bend (91) in a region upstream of the branch (83) to which the bypass airflow pipe (8) is connected, in which the airflow is provided. The powder spray device according to claim 7, wherein the direction of the powder spray device is switched from an obliquely upward direction to an obliquely downward direction. The powder spray apparatus according to claim 7 or 8, for applying the medical two-component reactant type adhesive according to any one of claims 1 to 6.

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