Technical field
[0001]
The present invention relates to a polymer material kit for hemostasis, vascular occlusion, tissue coating, or body fluid coagulation, and further relates to a hemostatic method, vessel occlusion method, tissue coating method, or body fluid coagulation method using the polymer material kit.
Background technology
[0002]
Conventional blood coagulation means mainly include a method of accelerating the hemostatic reaction using the pharmacological action of a biological blood coagulation factor represented by fibrin glue (for example, Patent Document 1), or a method of physically increasing the blood flow. A technique is used in which blood is blocked and blood is coagulated by the coagulability of the blood itself.
[0003]
However, in the former method of using biological materials, there is a risk of infection because it is not easy to control the infection of the animal that is the raw material and the donor. In fact, problems such as drug-related AIDS cases and iatrogenic Creutzfeldt-Jakob disease are occurring. On the other hand, the latter method using physical blockage requires the use of a sheet-like material due to the nature of the principle of hemostasis, and is difficult to apply to an affected area having a complicated structure. Furthermore, as a common problem for both, since the final state of hemostasis depends on the blood coagulability of the patient, it is difficult to obtain a blood coagulation effect for patients who are being administered drugs such as anticoagulants. It is also pointed out that it is difficult to
prior art documents
patent literature
[0004]
Patent Document 1: JP 2017-66150 A
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0005]
Therefore, an object of the present invention is to provide a safe and efficient hemostasis method, blood vessel occlusion method, tissue coating method, or body fluid coagulation method using a polymer material that is a non-living compound.
Means to solve problems
[0006]
As a result of intensive studies to solve the above problems, the present inventors have found a solution containing a hydrophilic polymer capable of forming a hydrogel through intermolecular cross-linking under specific concentration conditions and having specific pH conditions and ionic strength. We have found that excellent blood coagulation and hemostatic effects can be obtained by preparing a (pre-gel solution) and gelling it in-situ in an environment where blood is present, such as at a bleeding site or in a blood vessel. The present invention has been completed.
[0007]
That is, in one aspect, the present invention relates to a kit for forming a hydrogel in an environment where blood exists, specifically
<1> A polymer material kit comprising a polymer solution A containing a first polymer and a second polymer solution B containing a second polymer, wherein the first polymer and the second polymer are A combination of hydrophilic polymers having a polyalkylene glycol backbone or a polyvinyl backbone that can be crosslinked to form a hydrogel; having an average molecular weight (Mw); the concentrations of the first polymer and the second polymer in the polymer solutions A and B range from 10 to 300 g/L; mixing the polymer solutions A and B The polymer material kit, wherein the pH of the mixed solution obtained by
<2> The polymer material kit according to <1> above, wherein the first polymer and the second polymer are bi-, tri-, or tetra-branched polyethylene glycol;
<3> The first polymer has one or more nucleophilic functional groups in side chains or terminals; The second polymer has one or more electrophilic functional groups in side chains or terminals; The polymer material kit according to <1> or <2> above;
<4> the nucleophilic functional group is selected from the group consisting of a thiol group and an amino group, and the electrophilic functional group is a maleimidyl group, an N-hydroxy-succinimidyl (NHS) group, a sulfosuccinimidyl group; , a phthalimidyl group, an imidazoyl group, an acryloyl group, a nitrophenyl group, and —CO 2 PhNO 2 , the polymer material kit according to any one of the above <1> to <3>;
<5> The polymer material kit according to any one of <1> to <4> above, wherein the pH of the polymer solutions A and B is in the range of 3 to less than 7;
<6> In an environment where a liquid having a pH of 6.5 to 8.0 exists, the polymer solution A and the polymer solution B are mixed, so that the first polymer and the second polymer are mixed with each other. The polymer material kit according to any one of <1> to <5> above, in which a crosslinked hydrogel is formed;
<7> The polymer material kit according to <6> above, wherein the gelation time of the hydrogel formed by the first polymer and the second polymer is in the range of 1 to 30 seconds;
<8> The above-described <6> or <7>, wherein the hydrogel formed by the first polymer and the second polymer has an equilibrium swelling degree in the range of 0.9 to 3.5. polymer material kit;
<9> Any one of <6> to <8> above, wherein the hydrogel formed by the first polymer and the second polymer has a Young's modulus in the range of 0.1×10 4 to 4×10 4 Pa. A polymeric materials kit as described in .
<10> The polymer material kit according to any one of <1> to <9> above, which is for hemostasis, vascular occlusion, tissue coating, or body fluid coagulation;
<11> A hemostatic agent comprising the polymer material kit according to any one of <1> to <10> above;
<12> A vasoocclusive agent comprising the polymer material kit according to any one of <1> to <10> above;
<13> A tissue covering comprising the polymer material kit according to any one of <1> to <10> above; and
<14> Body fluid coagulant comprising the polymer material kit according to any one of <1> to <10> above
It provides
[0008]
In another aspect, the present invention relates to a method for producing a hemostatic agent or the like containing hydrogel using the kit, specifically,
<15> A method for producing a hemostatic agent, a vasoocclusive agent, a tissue coating agent, or a body fluid coagulant containing a hydrogel, comprising a polymer solution A containing a first polymer and a second polymer solution containing a second polymer A step of applying the mixed solution with B to an environment in which a liquid having a pH of 6.5 to 8.0 is present; the first polymer and the second polymer are crosslinked with each other to form a hydrogel. a combination of hydrophilic polymers having a polyalkylene glycol backbone or a polyvinyl backbone, said first polymer and said second polymer having a weight average molecular weight (Mw) in the range of 1x10 3 to 1x10 5 the concentrations of the first polymer and the second polymer in the polymer solutions A and B are in the range of 10 to 300 g/L; and the mixture obtained by mixing the polymer solutions A and B The production method, wherein the pH is less than 3 to 7 and the ionic strength is in the range of 10 to 100 mM;
<16> The method according to <15> above, comprising mixing the polymer solution A and the second polymer solution B in an environment in which a liquid having a pH of 6.5 to 8.0 exists;
<17> The above-described <15>, comprising contacting the carrier with an environment in which a liquid having a pH of 6.5 to 8.0 exists after dropping the polymer solution A and the polymer solution B onto the carrier. the method of; and
<18> The method according to any one of <15> to <17>, wherein the pH of the polymer solutions A and B is in the range of 3 to less than 7.
It provides
[0009]
In a further aspect, the present invention also relates to a method for hemostasis using the kit, and specifically,
<19> A hemostasis method using the polymer material kit according to any one of <1> to <10> above;
<20> A blood vessel occlusion method using the polymer material kit according to any one of <1> to <10> above;
<21> A tissue covering method using the polymer material kit according to any one of <1> to <10> above;
<22> A body fluid coagulation method using the polymer material kit according to any one of <1> to <10> above;
<23> A medical device comprising the polymer material kit according to any one of <1> to <10> above; and
<24> The medical device according to <23> above, wherein at least one of polymer solution A and polymer solution B is stored in a sprayer.
The invention's effect
[0010]
According to the polymer material kit of the present invention, by applying two polymer solutions to an environment where blood is present, such as a bleeding site or a blood vessel, the pH of the polymer solution changes, causing in-situ gelation. The reaction proceeds and a gel-blood complex incorporating blood can be formed in a short period of time. As a result, it is possible to provide not only an excellent blood coagulation effect by incorporating blood into the gel, but also a physical hemostatic effect by coating a bleeding site or the like with the gel.
[0011]
The polymer material used in the present invention is not an animal-derived material like the conventional technology, so risks such as infection can be avoided. In addition, the present invention has the advantage of being able to maintain a liquid state for a certain period of time after mixing two polymer solutions, so that it can be applied to tissue with a complicated structure. Furthermore, unlike conventional methods, excellent blood coagulability can be provided without depending on the coagulability of the blood itself, so there is also the advantage that it can be applied to patients receiving anticoagulant agents and the like.
[0012]
As for its application target, vascular occlusion can also be performed by applying the in-situ gel formation of the present invention to blood vessels such as veins and arteries. In addition, since it is a gel formation mechanism that utilizes the pH change due to application to the biological environment, it is possible to exert a coagulation action not only on blood but also on body fluids having a pH near neutrality.
Brief description of the drawing
[0013]
[Fig. 1] Fig. 1 is a graph showing the effects of concentration and pH on gelation time.
[Fig. 2] Fig. 2 is a graph showing changes in gelation time depending on ionic strength.
3] Fig. 3 is a graph showing changes in pH depending on ionic strength. [Fig.
4] Fig. 4 is a graph showing the relationship between gelation time and pH. [Fig.
[Fig. 5] Fig. 5 is a graph showing changes in Young's modulus due to mixing with milk.
[Fig. 6] Fig. 6 is a graph showing changes over time in the degree of swelling in milk.
[Fig. 7] Fig. 7 is a graph showing the degree of equilibrium swelling at each prepolymer concentration in water.
[FIG. 8] FIG. 8 is an image of a gel applied to a rat femoral venous vessel.
[FIG. 9] FIG. 9 is an image of a gel applied to an arterial blood vessel in the abdomen of a rat.
MODE FOR CARRYING OUT THE INVENTION
[0014]
Embodiments of the present invention will be described below. The scope of the present invention is not restricted by these descriptions, and other than the following examples can be appropriately changed and implemented without impairing the gist of the present invention.
[0015]
1. The polymeric material kit of the invention
The polymer material kit of the present invention comprises a polymer solution A containing a first polymer and a second polymer solution B containing a second polymer, and the polymer solution forms a hydrogel through intermolecular cross-linking. It is characterized by containing a formable hydrophilic polymer at specific concentration conditions and having specific pH conditions and ionic strength.
[0016]
By adopting such solution conditions, the gelation reaction does not proceed in a short time by simply mixing the polymer solutions A and B as they are, but the two solutions are mixed in a solution having a pH near neutrality such as blood. As a result, gelation is promoted and gelation occurs in-situ in a relatively short time, and a hydrogel that incorporates the blood inside the gel (this is called a “gel-blood complex” or a “gel-body fluid complex”) ) can be formed. By forming such a gel-blood complex in-situ, the blood itself is incorporated into the gel to provide a blood coagulation effect, and at the same time, a physical hemostatic effect is provided by coating the bleeding site with the gel. It can be said that this is a new method that has not existed conventionally.
[0017]
The polymer materials and solution conditions used in the polymer material kit of the present invention will be described in detail below.
[0018]
(1-1) Polymer material
　The first polymer and the second polymer used in the polymer solutions A and B of the present invention areBoth are hydrophilic polymers having a polyalkylene glycol skeleton or a polyvinyl skeleton that can form hydrogels by cross-linking with each other. As the hydrophilic polymer, those known in the art can be used as long as they can form a hydrogel by a gelation reaction (crosslinking reaction, etc.) in an aqueous solution. In the organic gel, it is preferable that the polymer is a polymer capable of forming a network structure, particularly a three-dimensional network structure, by cross-linking with each other.
[0019]
Polymers having a polyethylene glycol skeleton typically include polymer species having a plurality of branched polyethylene glycol skeletons, and particularly preferred are bi-, tri-, or tetra-branched polyethylene glycols. In particular, a gel composed of a tetra-branched polyethylene glycol skeleton is generally known as Tetra-PEG gel, and each terminal has an electrophilic functional group such as an active ester structure and a nucleophilic functional group such as an amino group. A network structure is constructed by an AB-type cross-end coupling reaction between two tetra-branched polymers having groups (Matsunaga et al., Macromolecules, Vol. 42, No. 4, pp. 1344-1351, 2009). In addition, Tetra-PEG gel can be easily prepared on the spot by simple two-liquid mixing of each polymer solution, and it is also possible to control the gelation time by adjusting the pH and ionic strength during gel preparation. be. And since this gel has PEG as a main component, it is also excellent in biocompatibility.
[0020]
In addition, examples of hydrophilic polymers having a polyvinyl skeleton include polyalkylmethacrylates such as polymethylmethacrylate, polyacrylates, polyvinyl alcohols, polyN-alkylacrylamides, and polyacrylamides.
[0021]
The first polymer and said second polymer have a weight average molecular weight (Mw) in the range of 1x10 3 to 1x10 5, preferably in the range of 0.5x10 4 to 5x10 4, more preferably in the range of 1x10 4 to 2x10 4 have
[0022]
Preferably, the first polymer and the second polymer are a combination of a polymer having one or more nucleophilic functional groups in side chains or terminals and a polymer having one or more electrophilic functional groups in side chains or terminals. is. For example, it is preferred that the first polymer has one or more nucleophilic functional groups on its side chains or terminals, and the second polymer has one or more electrophilic functional groups on its side chains or terminals. A gel is formed by cross-linking such a nucleophilic functional group and an electrophilic functional group. Here, the total number of nucleophilic functional groups and electrophilic functional groups is preferably 5 or more. These functional groups are more preferably present at the ends.
[0023]
Examples of the nucleophilic functional groups present in the first and second polymers include a thiol group (—SH), an amino group, or the like, and those skilled in the art can appropriately use known nucleophilic functional groups. be able to. Preferably, the nucleophilic functional group is a -SH group. The nucleophilic functional groups may be the same or different, but are preferably the same. When the functional groups are the same, the reactivity with the electrophilic functional groups that form cross-links becomes uniform, making it easier to obtain a gel with a uniform three-dimensional structure.
[0024]
An active ester group can be used as the electrophilic functional group present in the first and second polymers. Such active ester groups include maleimidyl, N-hydroxy-succinimidyl (NHS), sulfosuccinimidyl, phthalimidyl, imidazoyl, acryloyl, nitrophenyl, —CO 2 PhNO 2 (Ph is o-, m-, or p-phenylene groups), etc., and those skilled in the art can appropriately use other known active ester groups. Preferably, the electrophilic functional group is a maleimidyl group. The electrophilic functional groups may be the same or different, but are preferably the same. When the functional groups are the same, the reactivity with the nucleophilic functional groups that form cross-linked bonds becomes uniform, making it easier to obtain a gel with a uniform three-dimensional structure.
[0025]
Preferred non-limiting examples of the polymer having a terminal nucleophilic functional group include, for example, a compound represented by the following formula (I) having four polyethylene glycol skeleton branches and a terminal thiol group is mentioned.
[Chemical 1]

[0026]
In formula (I), R 11 to R 14 are the same or different, and are a C 1-C 7 alkylene group, a C 2-C 7 alkenylene group, -NH-R 15-, -CO-R 15-, -R 16-O-R 17-, -R 16-NH-R 17-, -R 16-CO 2-R 17-, -R 16-CO 2-NH-R 17-, -R 16-CO-R 17 -, or -R 16-CO-NH-R 17-, where R 15 represents a C 1-C 7 alkylene group, R 16 represents a C 1-C 3 alkylene group, and R 17 represents a C It denotes a 1-C5 alkylene group. )
[0027]
n11 to n14 may be the same or different. The closer the values of n 11 to n 14 are, the more uniform the steric structure can be and the higher the strength. Therefore, it is preferable that they are the same in order to obtain a high-strength gel. If the values of n 11 to n 14 are too high, the strength of the gel will be weak. Therefore, n 11 to n 14 include integer values of 5 to 600, preferably 25 to 250, more preferably 50 to 120, and even more preferably 110 to 120.
[0028]
In formula (I) above, R 11 to R 14 are linker moieties that connect the functional group and the core portion. R 11 to R 14 may be the same or different, but are preferably the same in order to produce a high-strength gel having a uniform three-dimensional structure. R 11 to R 14 are a C 1-C 7 alkylene group, a C 2-C 7 alkenylene group, -NH-R 15-, -CO-R 15-, -R 16-OR 17-, -R 16 -NH-R 17-, -R 16-CO 2-R 17-, -R 16-CO 2-NH-R 17-, -R 16-CO-R 17-, or -R 16-CO-NH- R 17- is shown. Here, R 15 represents a C 1-C 7 alkylene group. R 16 represents a C 1-C 3 alkylene group. R 17 represents a C 1-C 5 alkylene group.
[0029]
Here, the “C 1-C 7 alkylene group” means an alkylene group having 1 or more and 7 or less carbon atoms which may be branched, and is a linear C 1-C 7 alkylene group or one or two It means a C2-C7 alkylene group having one or more branches (2 or more and 7 or less carbon atoms including branches). Examples of C 1 -C 7 alkylene groups are methylene, ethylene, propylene, butylene groups. Examples of C1-C7 alkylene groups are -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)-, -(CH2)3-, -( CH(CH3))2-, -(CH2)2-CH(CH3)-, -(CH2)3-CH(CH3)-, -(CH2)2-CH(C2H5) -, -(CH 2) 6-, -(CH 2) 2-C(C 2H 5) 2-, and -(CH 2) 3C(CH 3) 2CH 2-.
[0030]
The “C 2-C 7 alkenylene group” is a branched or branched alkenylene group having 2 to 7 carbon atoms and having one or more double bonds in the chain. A divalent group having a double bond formed by removing 2 to 5 hydrogen atoms of adjacent carbon atoms from an alkylene group can be mentioned.
[0031]
On the other hand, preferred non-limiting specific examples of the polymer having an electrophilic functional group at the terminal include the following, which has four polyethylene glycol backbone branches and an N-hydroxy-succinimidyl (NHS) group at the terminal. Compounds represented by formula (II) are included.
[Chemical 2]

[0032]
In the above formula (II), n21 to n24 may be the same or different. The closer the values of n 21 to n 24 are, the more the gel can have a uniform three-dimensional structure and the higher the strength. If the values of n 21 to n 24 are too high, the strength of the gel will be weak, and if the values of n 21 to n 24 are too low, gel formation will be difficult due to steric hindrance of the compound. Therefore, n 21 to n 24 include integer values of 5 to 600, preferably 25 to 250, more preferably 50 to 120, and even more preferably 110 to 120.
[0033]
In the above formula (II), R 21 to R 24 are linker moieties that connect the functional group and the core portion. R 21 to R 24 may be the same or different, but are preferably the same in order to produce a high-strength gel having a uniform three-dimensional structure. In formula (II), R 21 to R 24 are each the same or different, a C 1-C 7 alkylene group, a C 2-C 7 alkenylene group, -NH-R 25-, -CO-R 25-, -R 26-OR 27-, -R 26-NH-R 27-, -R 26-CO 2-R 27-, -R 26-CO 2-NH-R 17-, -R 26-CO-R 27 -, or -R 26-CO-NH-R 27-. Here, R 25 represents a C 1-C 7 alkylene group. R 26 represents a C 1-C 3 alkylene group. R 27 represents a C 1-C 5 alkylene group.
[0034]
In the present specification, the alkylene group and alkenylene group may have one or more arbitrary substituents. The substituents include, for example, an alkoxy group, a halogen atom (which may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group, a mono- or di-substituted amino group, a substituted silyl group, an acyl groups, or aryl groups, etc., but are not limited to these. When an alkyl group has more than one substituent, they may be the same or different. The same applies to the alkyl moieties of other substituents containing alkyl moieties (for example, alkyloxy groups and aralkyl groups).
[0035]
Further, in the present specification, when a certain functional group is defined as "optionally having a substituent", the type of substituent, the substitution position, and the number of substituents are not particularly limited, When having two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxyl groups, carboxyl groups, halogen atoms, sulfo groups, amino groups, alkoxycarbonyl groups, and oxo groups. These substituents may further have a substituent.
[0036]
As another aspect, it is also possible to replace either the first polymer or the second polymer with a low-molecular-weight compound. In this case, the low-molecular compound has one or more nucleophilic functional groups or electrophilic functional groups in the molecule. As a result, for example, instead of the first polymer, a low-molecular-weight compound having a nucleophilic functional group in the molecule is used, and a second polymer having one or more electrophilic functional groups in the side chain or terminal is used. By reacting with, the second polymer can be gelled. Examples of such a "low-molecular-weight compound having a nucleophilic functional group in the molecule" include compounds having a thiol group in the molecule, such as dithiothreitol.

The scope of the claims
[Claim 1]
A polymer material kit consisting of a polymer solution A containing a first polymer and a second polymer solution B containing a second polymer,
The first polymer and the second polymer are a combination of hydrophilic polymers having a polyalkylene glycol skeleton or a polyvinyl skeleton that can form a hydrogel by cross-linking with each other;
the first polymer and the second polymer have a weight average molecular weight (Mw) in the range of 1x10 3 to 1x10 5;
the concentrations of the first polymer and the second polymer in the polymer solutions A and B are in the range of 10 to 300 g/L;
The polymer material kit, wherein the mixed solution obtained by mixing the polymer solutions A and B has a pH in the range of 3 to less than 7 and an ionic strength in the range of 10 to 100 mM.
[Claim 2]
The polymer material kit according to claim 1, wherein said first polymer and said second polymer are bi-, tri- or tetra-branched polyethylene glycol.
[Claim 3]
Claim 1, wherein the first polymer has one or more nucleophilic functional groups on a side chain or terminal; and the second polymer has one or more electrophilic functional groups on a side chain or terminal. 3. or the polymer material kit according to 2.
[Claim 4]
The nucleophilic functional group is selected from the group consisting of thiol groups and amino groups, and the electrophilic functional group is maleimidyl group, N-hydroxy-succinimidyl (NHS) group, sulfosuccinimidyl group, phthalimidyl group. , imidazoyl groups, acryloyl groups, nitrophenyl groups, and —CO 2 PhNO 2 .
[Claim 5]
The polymer material kit according to any one of claims 1 to 4, wherein the pH of the polymer solutions A and B are both in the range of 3 to less than 7.
[Claim 6]
In an environment where a liquid having a pH of 6.5 to 8.0 exists, the polymer solution A and the polymer solution B are brought into a mixed state, thereby forming a hydrogel in which the first polymer and the second polymer are crosslinked to each other. A kit of polymeric materials according to any preceding claim, wherein a gel is formed.
[Claim 7]
The polymer material kit according to claim 6, wherein the hydrogel formed by the first polymer and the second polymer has a gelling time in the range of 1 to 30 seconds.
[Claim 8]
The polymer material kit according to claim 6 or 7, wherein said hydrogel formed by said first polymer and said second polymer has an equilibrium swelling degree in the range of 0.9 to 3.5.
[Claim 9]
A polymeric material kit according to any one of claims 6 to 8, wherein said hydrogel formed by said first polymer and said second polymer has a Young's modulus in the range of 0.1x104 to 4x104Pa. .
[Claim 10]
The polymer material kit according to any one of claims 1 to 9, which is for hemostasis, vascular occlusion, tissue coating, or body fluid coagulation.
[Claim 11]
A hemostatic agent comprising the polymer material kit according to any one of claims 1 to 10.
[Claim 12]
A vasoocclusive agent comprising the polymer material kit according to any one of claims 1 to 10.
[Claim 13]
A tissue covering comprising the polymer material kit according to any one of claims 1 to 10.
[Claim 14]
A body fluid coagulant comprising the polymer material kit according to any one of claims 1 to 10.
[Claim 15]
A method for producing a hemostatic agent, vasoocclusive agent, tissue coating agent, or body fluid coagulant containing hydrogel,
A step of applying a mixture of a polymer solution A containing a first polymer and a second polymer solution B containing a second polymer to an environment in which a liquid having a pH of 6.5 to 8.0 is present;
The first polymer and the second polymer are a combination of hydrophilic polymers having a polyalkylene glycol backbone or a polyvinyl backbone that can form a hydrogel by cross-linking with each other;
the first polymer and the second polymer have a weight average molecular weight (Mw) in the range of 1x10 3 to 1x10 5;
the concentrations of the first polymer and the second polymer in the polymer solutions A and B are in the range of 10 to 300 g/L;
The production method, wherein the mixed solution obtained by mixing the polymer solutions A and B has a pH of 3 to less than 7 and an ionic strength in the range of 10 to 100 mM.
[Claim 16]
The method according to claim 15, comprising mixing the polymer solution A and the second polymer solution B in an environment in which a liquid having a pH of 6.5 to 8.0 is present.
[Claim 17]
The method according to claim 15, comprising contacting the carrier with an environment in which a liquid having a pH of 6.5 to 8.0 exists after dropping the polymer solution A and the polymer solution B onto the carrier.
[Claim 18]
The method according to any one of claims 15 to 17, wherein the pH of the polymer solutions A and B are both in the range of 3 to less than 7.
[Claim 19]
A hemostasis method using the polymer material kit according to any one of claims 1 to 10.
[Claim 20]
A blood vessel occlusion method using the polymer material kit according to any one of claims 1 to 10.
[Claim 21]
A tissue covering method using the polymer material kit according to any one of claims 1 to 10.
[Claim 22]
A body fluid coagulation method using the polymer material kit according to any one of claims 1 to 10.
[Claim 23]
A medical device comprising the polymer material kit according to any one of claims 1 to 10.
[Claim 24]
The medical device according to claim 23, wherein at least one of polymer solution A and polymer solution B is stored in the nebulizer.