WO2021225144A1 - 止血用ポリマー材料キット - Google Patents
止血用ポリマー材料キット Download PDFInfo
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- WO2021225144A1 WO2021225144A1 PCT/JP2021/017403 JP2021017403W WO2021225144A1 WO 2021225144 A1 WO2021225144 A1 WO 2021225144A1 JP 2021017403 W JP2021017403 W JP 2021017403W WO 2021225144 A1 WO2021225144 A1 WO 2021225144A1
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Images
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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- C—CHEMISTRY; METALLURGY
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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Definitions
- the present invention relates to a polymer material kit for hemostasis, vascular occlusion, tissue coating or body fluid coagulation, and further relates to a hemostasis method, vascular occlusion method, tissue coating method or body fluid coagulation method using the polymer material kit.
- Conventional blood coagulation means mainly use a method of accelerating the blood-stopping reaction by using the pharmacological action of a biological blood coagulation factor typified by fibrin glue (for example, Patent Document 1), or physically blood flow.
- a method of blocking and coagulating blood by the coagulation ability of the blood itself is used.
- the present inventors have made a solution containing a hydrophilic polymer capable of forming a hydrogel by cross-linking between molecules under a specific concentration condition and having a specific pH condition and ionic strength.
- a hydrophilic polymer capable of forming a hydrogel by cross-linking between molecules under a specific concentration condition and having a specific pH condition and ionic strength.
- excellent blood coagulation effect and hemostatic effect can be obtained by preparing (pregel solution) and gelling it in-situ in an environment where blood is present, such as in a bleeding site or in a blood vessel. This is the result of completing the present invention.
- the present invention relates to a kit for forming a hydrogel in an environment in which blood is present, specifically, ⁇ 1> a polymer solution A containing a first polymer and a second polymer.
- a polymer material kit comprising a second polymer solution B comprising, wherein the first polymer and the second polymer have a polyalkylene glycol skeleton or a polyvinyl skeleton capable of forming a hydrogel by cross-linking with each other.
- said first polymer and said second polymer has a weight average molecular weight in the range of 1x10 3 ⁇ 1x10 5 (Mw) ; the in the polymer solutions a and B in the The concentration of the polymer 1 and the second polymer is in the range of 10 to 300 g / L; the pH of the mixture obtained by mixing the polymer solutions A and B is less than 3 to 7, and the ionic strength is high.
- the polymer material kit in the range of 10-100 mM; ⁇ 2> The polymer material kit according to ⁇ 1> above, wherein the first polymer and the second polymer are 2-branched, 3-branched or 4-branched polyethylene glycol; ⁇ 3> The first polymer has one or more nucleophilic functional groups in the side chain or terminal; the second polymer has one or more electrophilic functional groups in the side chain or terminal.
- 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.
- ⁇ 5> The polymer material kit according to any one of ⁇ 1> to ⁇ 4>, wherein the pHs of the polymer solutions A and B are both in the range of 3 to less than 7.
- ⁇ 6> In an environment in which a liquid having a pH of 6.5 to 8.0 is present, the polymer solution A and the polymer solution B are in a mixed state, so that the first polymer and the second polymer become mutually exclusive.
- the polymer material kit according to 1. ⁇ 10> The polymer material kit according to any one of ⁇ 1> to ⁇ 9> above, which is used 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 vascular occlusion agent comprising the polymer material kit according to any one of ⁇ 1> to ⁇ 10>above; ⁇ 13> Tissue coating agent comprising the polymer material kit according to any one of ⁇ 1> to ⁇ 10>above; and ⁇ 14> The polymer material kit according to any one of ⁇ 1> to ⁇ 10> above. It is intended to provide a body fluid coagulant.
- the present invention relates to a method for producing a hemostatic agent or the like containing a hydrogel using the above kit, specifically.
- a method for producing a hemostatic agent, a vascular obstructing agent, a tissue coating agent, or a body fluid coagulant containing a hydrogel which is a polymer solution A containing a first polymer and a second polymer solution containing a second polymer.
- 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 mixture obtained by mixing the polymer solutions A and B.
- the production method wherein the pH is less than 3-7 and the ion intensity is in the range of 10-100 mM; ⁇ 16>
- the method according to ⁇ 15> above which comprises 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; ⁇ 17>
- the above ⁇ 15> wherein the polymer solution A and the polymer solution B are added dropwise to the carrier, and then the carrier is brought into contact with an environment in which a liquid having a pH of 6.5 to 8.0 is present.
- the present invention also relates to a hemostatic method or the like using the above kit, specifically, ⁇ 19> A hemostatic method using the polymer material kit according to any one of ⁇ 1> to ⁇ 10>above; ⁇ 20> A method for vascular occlusion using the polymer material kit according to any one of ⁇ 1> to ⁇ 10>above; ⁇ 21> A tissue coating 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>
- the medical device comprising the polymer material kit according to any one of ⁇ 1> to ⁇ 10>; and ⁇ 24> at least one of the polymer solution A and the polymer solution B is stored in the atomizer. It provides the medical device according to ⁇ 23>.
- the polymer material kit of the present invention by applying the two polymer solutions to an environment where blood is present, such as in a bleeding site or in a blood vessel, the pH of the polymer solution changes, resulting in in-situ gelation.
- the reaction proceeds and a gel-blood complex that has taken up blood can be formed in a short time.
- the polymer material used in the present invention is not an animal-derived material as in the prior art, the risk of infection or the like can be avoided. Further, the present invention has an advantage that it can be applied to a structure having a complicated structure because it can maintain a liquid state for a certain period of time after mixing the two polymer solutions. Further, unlike the conventional method, it can provide an excellent blood coagulation ability without depending on the coagulation ability of the blood itself, and therefore has an advantage that it can be applied to a patient who is receiving an anticoagulant or the like.
- 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.
- it is a gel forming mechanism that utilizes a pH change when applied to a biological environment, it can exert a coagulation action not only on blood but also on body fluids having a pH near neutral.
- FIG. 1 is a graph showing the effects of concentration and pH on the gelation time.
- FIG. 2 is a graph showing the change in gelation time due to ionic strength.
- FIG. 3 is a graph showing a change in pH due to ionic strength.
- FIG. 4 is a graph showing the relationship between gelation time and pH.
- FIG. 5 is a graph showing changes in Young's modulus due to mixing with milk.
- FIG. 6 is a graph showing the change over time in the degree of swelling in milk.
- FIG. 7 is a graph showing the equilibrium swelling degree at each prepolymer concentration in water.
- FIG. 8 is an image in which the gel is applied to the venous blood vessels of the rat thigh.
- FIG. 9 is an image in which the gel is applied to the arterial blood vessels of the abdomen of the rat.
- 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 is intermolecular. It is characterized by containing a hydrophilic polymer capable of forming a hydrogel by cross-linking with a specific concentration condition, and having a specific pH condition and ionic strength.
- the gelation reaction does not proceed in a short time simply by mixing these 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.
- a solution having a pH near neutrality such as blood.
- gelation is promoted and gelation occurs in-situ in a relatively short time, and a hydrogel in which the blood is taken into the gel (this is called “gel-blood complex” or “gel-body fluid complex”). ”)
- gel-blood complex or “gel-body fluid complex”
- the first polymer and the second polymer used in the polymer solutions A and B of the present invention can both form a hydrogel by cross-linking with each other, a polyalkylene glycol skeleton or polyvinyl. It is a hydrophilic polymer having a skeleton.
- a hydrophilic polymer a polymer known in the art can be used as long as it can form a hydrogel by a gelation reaction (crosslinking reaction or the like) in an aqueous solution.
- crosslinking reaction or the like crosslinking reaction or the like
- the polymers can form a network structure, particularly a three-dimensional network structure, by cross-linking the polymers with each other.
- Typical examples of the polymer having a polyethylene glycol skeleton include polymer species having a plurality of branches of a polyethylene glycol skeleton, and a bifurcated, 3-branched or 4-branched polyethylene glycol is particularly preferable.
- a gel composed of a tetrabranched polyethylene glycol skeleton is generally known as a Terra-PEG gel, and has a nucleophilic functional group such as an active ester structure and a nucleophilic functional group such as an amino group at the terminals, respectively.
- a network-structured network is constructed by an AB-type cross-end coupling reaction between two four-branched polymers having a group (Massunaga et al., Macromolecules, Vol.42, No.4, pp.1344-1351, 2009).
- Tetra-PEG gel can be easily prepared on the spot by a simple two-component mixture of each polymer solution, and the gelation time can be controlled by adjusting the pH and ionic strength at the time of gel preparation. be. And since this gel contains PEG as a main component, it is also excellent in biocompatibility.
- hydrophilic polymer having a polyvinyl skeleton examples include polyalkyl methacrylate such as polymethyl methacrylate, polyacrylate, polyvinyl alcohol, poly N-alkylacrylamide, and polyacrylamide.
- the first polymer and the second polymer is in the range of 1x10 3 ⁇ 1x10 5, preferably, 0.5 ⁇ 10 4 ⁇ 5x10 4 range, a weight average molecular weight of more preferably in the range of 1x10 4 ⁇ 2x10 4 (Mw) Have.
- the first polymer and the second polymer are a combination of a polymer having one or more nucleophilic functional groups in the side chain or terminal and a polymer having one or more electrophilic functional groups in the side chain or terminal.
- the first polymer has one or more nucleophilic functional groups in the side chain or terminal and the second polymer has one or more electrophilic functional groups in the side chain or terminal.
- a gel is formed by cross-linking the nucleophilic functional group and the electrophilic functional group.
- the total of the nucleophilic functional group and the electrophilic functional group is preferably 5 or more. It is more preferred that these functional groups are present at the ends.
- nucleophilic functional group present in the first and second polymers examples include a thiol group (-SH), an amino group, or the like, and a nucleophilic functional group known to those skilled in the art is appropriately used. be able to.
- the nucleophilic functional group is a -SH group.
- the nucleophilic functional groups may be the same or different, but they are preferably the same. When the functional groups are the same, the reactivity with the electrophilic functional group that forms a cross-linking bond becomes uniform, and it becomes easy to obtain a gel having a uniform three-dimensional structure.
- Active ester groups can be used as the electrophilic functional groups present in the first and second polymers.
- an active ester group include a maleimidyl group, an N-hydroxy-succinimidyl (NHS) group, a sulfosuccinimidyl group, a phthalimidyl group, an imidazole group, an acryloyl group, a nitrophenyl group, and -CO 2 PhNO 2 (Ph is , O-, m-, or p-phenylene group) and the like, and other known active ester groups can be appropriately used by those skilled in the art.
- the electrophilic functional group is a maleimidyl group.
- the electrophilic functional groups may be the same or different, but they are preferably the same. When the functional groups are the same, the reactivity with the nucleophilic functional group that forms a cross-linking bond becomes uniform, and it becomes easy to obtain a gel having a uniform three-dimensional structure.
- Non-limiting specific examples preferable as a polymer having a nucleophilic functional group at the end include, for example, a compound represented by the following formula (I) having a branch of four polyethylene glycol skeletons and having a thiol group at the end. Can be mentioned.
- R 11 ⁇ R 14 are the same or respectively, C 1 -C 7 alkylene group, 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. shows the 1 -C 5 alkylene group. )
- n 11 to n 14 may be the same or different from each other. The closer the values of n 11 to n 14, the more uniform the three-dimensional structure can be obtained, and the higher the strength becomes. Therefore, in order to obtain a high-strength gel, it is preferable that they are the same. If the values of n 11 to n 14 are too high, the strength of the gel will be weakened, and if the values of n 11 to n 14 are too low, the gel will not be easily formed due to steric hindrance of the compound. 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.
- R 11 to R 14 are linker sites that connect the functional group and the core portion.
- R 11 to R 14 may be the same or different from each other, but are preferably the same in order to produce a high-strength gel having a uniform three-dimensional structure.
- R 11 ⁇ R 14 is, C 1 -C 7 alkylene group, 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 -is shown.
- 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.
- C 1 -C 7 alkylene group carbon atoms, which may have a branch means 1 to 7 alkylene group, or one linear C 1 -C 7 alkylene group or 2
- One or more C 2 -C 7 alkylene group having branching (number of carbon atoms including branching 2 to 7) means.
- C 1- C 7 alkylene groups are -CH 2 -,-(CH 2 ) 2 -,-(CH 2 ) 3- , -CH (CH 3 )-,-(CH 2 ) 3 -,-( CH (CH 3 )) 2 -,-(CH 2 ) 2- CH (CH 3 )-,-(CH 2 ) 3- CH (CH 3 )-,-(CH 2 ) 2- CH (C 2 H 5) )-,-(CH 2 ) 6 -,-(CH 2 ) 2- C (C 2 H 5 ) 2 -,-(CH 2 ) 3 C (CH 3 ) 2 CH 2-, and the like.
- the "C 2 -C 7 alkenylene group” is a one or two or more Jo or branched having 2 to 7 carbon atoms alkenylene group having a double bond in the chain, for example, the Examples thereof include a divalent group having a double bond formed by removing 2 to 5 hydrogen atoms of adjacent carbon atoms from an alkylene group.
- non-limiting specific examples preferable as a polymer having an electrophilic functional group at the terminal include, for example, the following having a branch of four polyethylene glycol skeletons and an N-hydroxy-succinimidyl (NHS) group at the end.
- examples thereof include compounds represented by the formula (II).
- n 21 to n 24 may be the same or different from each other. The closer the values of n 21 to n 24 are, the more uniform the three-dimensional structure can be obtained and the higher the strength of the gel, which is preferable, and it is preferable that the gels are the same. If the values of n 21 to n 24 are too high, the strength of the gel will be weakened, and if the values of n 21 to n 24 are too low, the gel will not be easily formed due to steric hindrance of the compound. Therefore, n 21 to n 24 may be an integer value of 5 to 600, preferably 25 to 250, more preferably 50 to 120, and even more preferably 110 to 120.
- R 21 to R 24 are linker sites that connect the functional group and the core portion.
- R 21 to R 24 may be the same or different from each other, but are preferably the same in order to produce a high-strength gel having a uniform three-dimensional structure.
- R 21 ⁇ R 24 are the same or respectively, C 1 -C 7 alkylene group, C 2 -C 7 alkenylene group, -NH-R 25 -, - CO-R 25 -, - R 26 -O-R 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 -is indicated.
- 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.
- the alkylene group and the alkaneylene group may have one or more arbitrary substituents.
- substituents include 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, and an acyl group.
- Groups, aryl groups and the like can be mentioned, but are not limited thereto. If the alkyl group has two or more substituents, they may be the same or different. The same applies to the alkyl moiety of other substituents containing the alkyl moiety (eg, alkyloxy group, aralkyl group, etc.).
- a certain functional group may have a substituent
- the type of the substituent, the position of the substituent, and the number of the substituents are not particularly limited. If they have two or more substituents, they may be the same or different.
- the substituent include, but are not limited to, an alkyl group, an alkoxy group, a hydroxyl group, a carboxyl group, a halogen atom, a sulfo group, an amino group, an alkoxycarbonyl group, an oxo group and the like. Further substituents may be present in these substituents.
- the small molecule compound has one or more nucleophilic or electrophilic functional groups in the molecule.
- a low molecular weight compound having a nucleophilic functional group in the molecule is used, and a second polymer having one or more nucleophilic functional groups in the side chain or the terminal thereof is used.
- the second polymer can be gelled by reacting with.
- Examples of such a "low molecular weight compound having a nucleophilic functional group in the molecule” include a compound having a thiol group in the molecule, and for example, dithiothreitol can be used.
- the polymer solution A and polymer solution B constituting the polymer material kit of the present invention satisfy the following conditions such as polymer concentration, pH, and ionic strength.
- 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, preferably in the range of 30 to 200 g / L, and more preferably in the range of 50 to 150 g / L. Is the range of.
- the gelation time can be set within a desired range.
- the concentrations of the first and second polymers may be the same or different as long as the above ranges are satisfied, but the concentrations are preferably the same.
- the polymer solutions A and B are adjusted so that the mixture obtained by mixing these solutions is in an acidic region (pH less than 7), and the pH is preferably in the range of 3 to less than 7, more preferably 3.2 to. It is adjusted to be in the range of 5.0. Further, the pH of either one of the polymer solutions A and B is preferably in the range of 3 to less than 7, and preferably in the range of 3.2 to 5.0. However, as long as the mixture of the polymer solutions A and B satisfies the acidic pH range, the pH of the other solution may exceed 8. In a typical embodiment, it is preferred that both the polymer solutions A and B are within these pH ranges.
- the gelation reaction does not occur in a short time just by mixing the polymer solutions A and B as they are (preferably, the gelation reaction does not proceed), but blood or the like is present and the pH is neutral.
- the pH of the polymer solution rises and the gelation reaction proceeds. can do.
- the gel can be formed in-situ in a relatively short time in an environment in which blood or the like is present and has a pH near neutral.
- the pH of the polymer solutions A and B may be the same or different as long as the above range is satisfied, but the pH is preferably the same.
- a pH buffer known in the art can be used for the pH of the polymer solutions A and B.
- the pH can be adjusted to the above range by using a citric acid-phosphate buffer (CPB) and changing the mixing ratio of citric acid and disodium hydrogen phosphate.
- CPB citric acid-phosphate buffer
- the polymer solutions A and B are adjusted so that the ionic strength of the mixed solution obtained by mixing them is in the range of 10 to 100 mM, preferably in the range of 10 to 40 mM.
- the gelation time can be set within a desired range.
- the ionic strengths of the individual polymer solutions A and B may be the same or different as long as the above ranges are satisfied, but the ionic strengths are preferably the same.
- each condition of the polymer concentration, pH, and ionic strength in the polymer solutions A and B are set in an environment in which a liquid having a pH corresponding to a body fluid such as blood of 6.5 to 8.0 is present.
- a hydrogel in which the first polymer and the second polymer are crosslinked with each other can be formed in-situ.
- the gelation time at that time is preferably in the range of 1 to 30 seconds, and more preferably in the range of 1 to 10 seconds.
- the gelation time can be adjusted mainly by appropriately setting the polymer concentration, pH, and ionic strength in the polymer solution.
- the solvent in the polymer solutions A and B is water, but in some cases, it may be a mixed solvent containing alcohols such as ethanol and other organic solvents.
- the polymer solutions A and B are aqueous solutions using water as a single solvent.
- the volumes of the polymer solutions A and B in the polymer material kit of the present invention can be appropriately adjusted according to the area and structural complexity of the bleeding site, blood vessel, etc. to which they are applied, but typically. Each is in the range of 0.1 to 20 ml, preferably 1 to 10 ml.
- the hydrogel can be formed by cross-linking the first polymer and the second polymer with each other.
- the "gel” is generally a dispersion system of a polymer that has lost its fluidity, and has a state in which a storage elastic modulus G'and a loss elastic modulus G "have a relationship of G' ⁇ G". say.
- the "hydrogel” is a gel containing water.
- the hydrogel formed by the first polymer and the second polymer preferably has an equilibrium swelling degree in the range of 0.9 to 3.5, more preferably 0.9 to 2.5. ..
- the "equilibrium swelling degree” is a value of the swelling degree when the change in the swelling degree with the passage of time after gel formation reaches an equilibrium state.
- the degree of swelling can be measured by a method commonly used in the art. As the degree of swelling, a value measured at 25 ° C. can be used.
- the hydrogel formed by the first polymer and the second polymer preferably has a Young's modulus in the range of 0.1x10 4 to 4x10 4 Pa, more preferably 0.5x10 4 to 2x10 4 Pa. Has.
- the hydrogel formed in the bleeding site, blood vessel, or the like can be made to have appropriate strength to stay in the affected area for a certain period of time.
- the hemostatic agent and the like of the present invention, the hemostatic method, etc. also relates to a hemostatic agent, a vascular obstructing agent, a tissue coating agent, or a body fluid coagulant, which comprises a polymer material kit.
- the polymer solutions A and B are applied to an environment where blood is present, such as a bleeding site or a blood vessel, to form a gel in-situ.
- a gel-blood complex that has taken up blood can be formed.
- it is possible to provide not only an excellent blood coagulation action by taking blood into the gel but also a physical hemostatic action by covering the bleeding site or the like with the gel.
- by applying such in-situ gel formation to blood vessels such as veins and arteries it can be used for vascular occlusion, and it can also be used for coagulating body fluids having a pH near neutral, not limited to blood. can.
- tissue that is the subject of the present invention can broadly include biological tissues and organs in which a liquid having a pH near neutral is present, and includes, for example, organs, nerves, muscles, and these. Some are mentioned. However, even if the surface is generally considered to be acidic, if it is temporarily or permanently modified to a pH near neutral by prior treatment, it should be included in the tissue targeted by the present invention. Can be done. This includes, but is not limited to, gastric mucosa.
- the present invention also relates to a method for producing such a hemostatic agent, a vascular occlusion agent, a tissue coating agent, or a body fluid coagulant.
- a polymer solution A containing the first polymer and a second polymer solution B containing the second polymer are mixed with a liquid having a pH near neutrality, that is, a pH of 6.5 to 8.0. It is characterized by including a step of applying to the environment.
- the types of the first and second polymers and the conditions of the polymer solutions A and B are as described above.
- the "environment in which a liquid having a pH of 6.5 to 8.0 exists” is preferably a place where blood or body fluid exists, for example, blood vessels such as arteries or veins, or blood or body fluid.
- the pH range can preferably be 6.5-7.5.
- the step of "applying" a mixture of the polymer solution A and the second polymer solution B to an environment in the presence of a liquid having a pH of 6.5 to 8.0 is typically in such a pH environment.
- the polymer solution A and the second polymer solution B are mixed.
- it includes directly dropping or spraying the polymer solutions A and B directly onto the affected area where blood is present.
- the polymer solutions A and B may be dropped or sprayed at the same time.
- the polymer solutions A and B are set to solution conditions in which the gelation reaction does not occur in a short time (preferably, the gelation reaction does not proceed) when the polymer solutions A and B are mixed as they are. Therefore, it is also possible to mix the polymer solutions A and B in advance to form one solution, and then apply the polymer solutions to an environment in which a liquid having a pH of 6.5 to 8.0 exists.
- the carrier is brought into contact with an environment in which a liquid having a pH of 6.5 to 8.0 is present.
- a liquid having a pH of 6.5 to 8.0 is present.
- each polymer solution is once held in a carrier, and then the affected area (for example, the affected area after suturing surgery) in which blood is present is covered or protected with the carrier.
- a carrier is not particularly limited as long as it is made of a material capable of holding a polymer solution, and examples thereof include a cloth member such as gauze and an absorbent member such as sponge.
- the carrier in a state where either one of the polymer solutions A and B is held on the carrier, the carrier is brought into contact with the affected area and the like, and then the remaining one polymer solution is dropped or sprayed onto the carrier. It is also possible.
- a two-component mixing syringe as disclosed in WO2007 / 083522 can be used.
- the temperature of the two liquids at the time of mixing is not particularly limited, and may be any temperature as long as the precursor units are dissolved and each liquid has fluidity.
- the temperatures of the two liquids may be different, but it is preferable that the two liquids have the same temperature because the two liquids are easily mixed.
- a sprayer containing the solution can be used as a means for spraying the polymer solution A and / or B.
- the atomizer those known in the art can be appropriately used, and a medical atomizer is preferable. Therefore, such a nebulizer can be used as the container in the kit of the present invention, in which case one aspect of the present invention can be a medical device containing the polymer solutions A and B, preferably a nebulizer. Twice
- executing the production method of the present invention corresponds to a hemostasis method, a blood vessel occlusion method, a tissue coating method, and a body fluid coagulation method using the above polymer material kit.
- the tissues and blood vessels that can be targeted are not necessarily in vivo, and this method also includes application to tissues and the like after being removed from the body by surgery or the like.
- Tetra-PEG-SH tetrathiol-polyethylene glycol
- Tetra-PEG-MA tetramaleimidyl-polyethylene having a maleemidyl group at the end. Glycol
- Mw weight average molecular weight
- Citric acid-phosphate buffer (CPB) was used as a buffer for the polymer solution.
- the pH is adjusted by changing the mixing ratio of citric acid and disodium hydrogen phosphate.
- the buffer capacity was adjusted by changing the molar concentration of citric acid and disodium hydrogen phosphate (called ionic strength).
- the gelation time is defined as the time until the solution does not fall even if the container containing the solution is turned upside down.
- the polymer concentration, buffer pH and ionic strength were varied.
- the results of polymer concentration and pH dependence at the gelation time are shown in FIG. 1, and the results of the ionic strength dependence at the gelation time are shown in FIG.
- the gelation time was found to depend on the concentration of prepolymer and the pH of the buffer. Also, changing the ionic strength of the buffer (which is an indicator of the strength of the ability to maintain pH) also changes the gelation time, but this simply means that the pH cannot be maintained as the ionic strength decreases. This is because of the fact. In fact, the same relationship can be obtained by plotting the relationship between pH and gelation time obtained from Figures 2 and 3 on the graph of the relationship between pH and gelation time at the same concentration (Fig. 4).
- a milk gelling test was conducted.
- a prepolymer solution for this milk gelation test was prepared (prepolymer concentration: 150 g / L, solvent: pH 3.4, 200 mM).
- This prepolymer solution was added to milk (milk 10: prepolymer solution 1; volume ratio), and the fluidity of milk was evaluated macroscopically.
- the gelation time at this time was 3 minutes.
- another prepolymer solution was prepared (prepolymer concentration: 200 g / L, solvent: pH 3.4, 40 mM).
- the gelation time was shortened to 10 seconds.
- a gelation test of whole rat blood was performed. First, a prepolymer solution for this gelation test was prepared (prepolymer concentration: 200 g / L, solvent: pH 3.4, 40 mM). Whole blood collected from rats was pre-treated with heparin. The heparinized whole blood was divided into two parts, and the previously prepared prepolymer solution was added to one of them (whole blood 10: prepolymer solution 1; volume ratio). No prepolymer solution was added to the other. At this time, gelation was observed only in the group to which the prepolymer solution was added.
- a gelation test was conducted by replacing Tetra-PEG-SH with dithiothreitol (molecular weight 154.253 g / mol) having two SH groups.
- a prepolymer solution of Tetra-PEG-MA was prepared (prepolymer concentration: 200 g / L, solvent: pH 3.4, 40 mM).
- a new dithiothreitol solution was prepared so that the terminal MA group of this prepolymer solution and the SH group of dithiothreitol had the same molar concentration. When these two liquids were mixed in the same volume, fluidity was lost and gelation was confirmed.
- a gelation test was conducted by replacing Tetra-PEG-SH with Linear-PEG-SH, which has 2 branches and has an SH group at the end.
- a prepolymer solution of Tetra-PEG-MA was prepared (prepolymer concentration: 200 g / L, solvent: pH 3.4, 40 mM).
- a new Linear-PEG-SH solution was prepared so that the terminal MA group of this prepolymer solution and the SH group of Linear-PEG-SH had the same molar concentration. When these two liquids were mixed in the same volume, fluidity was lost and gelation was confirmed.
- the gelation test was performed by replacing Tetra-PEG-MA with Linear-PEG-MA having 2 branches and having an MA group at the end.
- a prepolymer solution of Tetra-PEG-SH was prepared (prepolymer concentration: 200 g / L, solvent: pH 3.4, 40 mM).
- a new Linear-PEG-MA solution was prepared so that the terminal SH group of this prepolymer solution and the MA group of Linear-PEG-MA had the same molar concentration. When these two liquids were mixed in the same volume, fluidity was lost and gelation was confirmed.
- the gel preparation procedure is the same as above. After mixing the two liquids, they gelled and after the reaction was completed, they were placed in milk and examined how much they swelled. Both concentrations of gel reached equilibrium swelling in about 4 hours (Fig. 6). The equilibrium swelling degree is 1.7 for 60 g / L and 2.3 for 120 g / L, and this value is the same as when swelling in water (Fig. 7), using the results of the swelling experiment in water. Also suggests that it is good.
- the gel preparation procedure is the same as above. After mixing the two liquids, if left standing, gelation takes about 3 minutes (this gelation time can be changed depending on the pH), so about 100 microliters were injected into the venous blood vessels of the rat thigh by then. At this time, the upstream part of the blood vessel was compressed to stop the blood flow and prevent the gel from flowing immediately after the injection. In addition, by lowering the ionic strength of the buffer to 20 mM, the pH was easily raised by mixing the solution with blood after injection, and gelation occurred immediately. After keeping the pressure for about 30 seconds, I let go and confirmed that the gel had solidified and did not flow. In addition, after a certain period of time, the affected area was opened again and it was confirmed that the gel did not flow out. The image at that time is shown in FIG. It was confirmed that the effect of vascular occlusion by the gel lasted for at least 2 to 3 weeks.
- Solvent pH 3.0, CPB of 20 mM, prepolymer concentration: When using the conditions of 100 g / L (10 wt%), after mixing the two liquids; In short, due to the low ionic strength, after mixing with rat blood, the pH increased and gelation occurred immediately.
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Abstract
Description
<1>第1のポリマーを含むポリマー溶液Aと、第2のポリマーを含む第2のポリマー溶液Bよりなる、ポリマー材料キットであって、前記第1のポリマー及び前記第2のポリマーは、互いに架橋することでハイドロゲルを形成し得る、ポリアルキレングリコール骨格又はポリビニル骨格を有する親水性ポリマーの組み合わせであり;前記第1のポリマー及び前記第2のポリマーは、1x103~1x105の範囲の重量平均分子量(Mw)を有し;前記ポリマー溶液A及びB中における前記第1のポリマー及び前記第2のポリマーの濃度は、10~300g/Lの範囲であり;前記ポリマー溶液AとBを混合して得られる混合液のpHが3~7未満であり、イオン強度が10~100mMの範囲である、該ポリマー材料キット;
<2>前記第1のポリマー及び前記第2のポリマーが、2分岐、3分岐又は4分岐のポリエチレングリコールである、上記<1>に記載のポリマー材料キット;
<3>前記第1のポリマーが、側鎖又は末端に1以上の求核性官能基を有し;前記第2のポリマーが、側鎖又は末端に1以上の求電子性官能基を有する、上記<1>又は<2>に記載のポリマー材料キット;
<4>前記求核性官能基が、チオール基及びアミノ基よりなる群から選択され、前記求電子性官能基が、マレイミジル基、N-ヒドロキシ-スクシンイミジル(NHS)基、スルホスクシンイミジル基、フタルイミジル基、イミダゾイル基、アクリロイル基、ニトロフェニル基、及び-CO2PhNO2よりなる群から選択される、上記<1>~<3>のいずれかに記載のポリマー材料キット;
<5>前記ポリマー溶液A及びBのpHが、いずれも3~7未満の範囲である、上記<1>~<4>のいずれかに記載のポリマー材料キット;
<6>pHが6.5~8.0の液体が存在する環境において、前記ポリマー溶液Aと前記ポリマー溶液Bが混合状態となることにより、前記第1のポリマーと前記第2のポリマーが互いに架橋したハイドロゲルが形成される、上記<1>~<5>のいずれかに記載のポリマー材料キット;
<7>前記第1のポリマーと前記第2のポリマーにより形成される前記ハイドロゲルのゲル化時間が、1~30秒の範囲である、上記<6>に記載のポリマー材料キット;
<8>前記第1のポリマーと前記第2のポリマーにより形成される前記ハイドロゲルが、0.9~3.5の範囲の平衡膨潤度を有する、上記<6>又は<7>に記載のポリマー材料キット;
<9>前記第1のポリマーと前記第2のポリマーにより形成される前記ハイドロゲルが、0.1x104~4x104Paの範囲のヤング率を有する、上記<6>~<8>のいずれか1に記載のポリマー材料キット。
<10>止血用、血管閉塞用、組織被覆用、又は体液凝固用である、上記<1>~<9>のいずれか1に記載のポリマー材料キット;
<11>上記<1>~<10>のいずれか1に記載のポリマー材料キットよりなる、止血剤;
<12>上記<1>~<10>のいずれか1に記載のポリマー材料キットよりなる、血管閉塞剤;
<13>上記<1>~<10>のいずれか1に記載のポリマー材料キットよりなる、組織被覆剤;及び
<14>上記<1>~<10>のいずれか1に記載のポリマー材料キットよりなる、体液凝固剤
を提供するものである。
<15>ハイドロゲルを含む止血剤、血管閉塞剤、組織被覆剤、又は体液凝固剤の製造方法であって、第1のポリマーを含むポリマー溶液Aと第2のポリマーを含む第2のポリマー溶液Bとの混合液を、pHが6.5~8.0の液体が存在する環境に適用する工程を含み;前記第1のポリマー及び前記第2のポリマーは、互いに架橋することでハイドロゲルを形成し得る、ポリアルキレングリコール骨格又はポリビニル骨格を有する親水性ポリマーの組み合わせであり;前記第1のポリマー及び前記第2のポリマーは、1x103~1x105の範囲の重量平均分子量(Mw)を有し;前記ポリマー溶液A及びB中における前記第1のポリマー及び前記第2のポリマーの濃度は、10~300g/Lの範囲であり;前記ポリマー溶液AとBを混合して得られる混合液のpHが3~7未満であり、イオン強度が10~100mMの範囲である、該製造方法;
<16>pHが6.5~8.0の液体が存在する環境において、前記ポリマー溶液Aと前記第2のポリマー溶液Bを混合することを含む、上記<15>に記載の方法;
<17>前記ポリマー溶液Aと前記ポリマー溶液Bを担体に滴下した後に、当該担体をpHが6.5~8.0の液体が存在する環境に接触させることを含む、上記<15>に記載の方法;及び
<18>前記ポリマー溶液A及びBのpHが、いずれも3~7未満の範囲である、<15>~<17>のいずれかに記載の方法
を提供するものである。
<19>上記<1>~<10>のいずれか1に記載のポリマー材料キットを用いる、止血方法;
<20>上記<1>~<10>のいずれか1に記載のポリマー材料キットを用いる、血管閉塞方法;
<21>上記<1>~<10>のいずれか1に記載のポリマー材料キットを用いる、組織被覆方法;
<22>上記<1>~<10>のいずれか1に記載のポリマー材料キットを用いる、体液凝固方法;
<23>上記<1>~<10>のいずれか1に記載のポリマー材料キットよりなる、医療機器;及び
<24>ポリマー溶液A及びポリマー溶液Bの少なくとも1つが噴霧器に格納されている、上記<23>に記載の医療機器を提供するものである。
本発明のポリマー材料キットは、第1のポリマーを含むポリマー溶液Aと、第2のポリマーを含む第2のポリマー溶液Bよりなるものであり、当該ポリマー溶液は、分子間の架橋によりハイドロゲルを形成し得る親水性ポリマーを特定の濃度条件で含有し、特定のpH条件及びイオン強度を有することを特徴とする。
本発明のポリマー溶液A及びBに用いられる第1のポリマー及び第2のポリマーは、いずれも、互いに架橋することでハイドロゲルを形成し得る、ポリアルキレングリコール骨格又はポリビニル骨格を有する親水性ポリマーである。当該親水性ポリマーは、水溶液中でのゲル化反応(架橋反応等)によってハイドロゲルを形成し得るものであれば、当該技術分野において公知のものを用いることができるが、より詳細には、最終的なゲルにおいて、当該ポリマーが互いに架橋にすることにより網目構造、特に、3次元網目構造を形成し得るポリマーであることが好ましい。
本発明のポリマー材料キットを構成するポリマー溶液A及びポリマー溶液Bは、以下に示すポリマー濃度、pH、イオン強度等の各条件を満たすものである。
上述のように、第1のポリマー及び第2のポリマーが互いに架橋することによりハイドロゲルを形成することができる。本明細書中において、「ゲル」とは、一般に、流動性を失ったポリマーの分散系であり、貯蔵弾性率G’と損失弾性率G”においてG’≧G”の関係性を有する状態をいう。また、「ハイドロゲル」は、水を含有するゲルである。
本発明は、別の観点において、ポリマー材料キットよりなる、止血剤、血管閉塞剤、組織被覆剤、又は体液凝固剤にも関する。
原料ポリマーとして、末端に-SH基を有するTetra-PEG-SH(テトラチオール-ポリエチレングリコール)及び末端にマレイミジル基を有するTetra-PEG-MA(テトラマレイミジル-ポリエチレングリコール)を用いた。これら原料ポリマーは、それぞれ日油株式会社から市販されているものを用いた。重量平均分子量(Mw)は、どちらも20000である。
1. 200 mM のクエン酸水溶液とリン酸水素二ナトリウム水溶液を作る。
2. クエン酸水溶液 : リン酸水素二ナトリウム水溶液 = 32.3 : 35.4 の割合で混合する。
血液と同程度のpHを有する牛乳(pH=7.4)を用いて、上記Tetra-PEGポリマーのゲル化挙動の評価を行った。
2液混合後のプレポリマー溶液は、体内へ注射後、血液と混ざってゲル化する。このときの血液の含有量による、固さ (ヤング率) の変化を調べた。上述の手順によってプレポリマー溶液を作成した (プレポリマー濃度: 50 g/L、溶媒: pH 3.8、200 mM)。2種類のプレポリマーを混合後、さらに牛乳を割合を変えて混ぜ、ゲル化し反応が完了したのちに、そのヤング率を圧縮試験によって求めた (図5)。例えば、プレポリマー溶液に対して同体積の牛乳を加えた場合に50%と表される。牛乳を添加するほど最終的なヤング率は低下した。これは、牛乳の添加によってプレポリマー溶液が希釈され、ゲルの架橋点密度が低下したためである。
実験手順
溶媒: pH 3.0、20 mMのCPB
プレポリマー濃度: 60, 120 g/L (6, 12 wt%)
実験手順
溶媒: pH 4.6、20 mMのCPB (pH 3.8、20 mM CPB : pH 5.8、20 mM CP = 1:2 で混合)
プレポリマー濃度: 50 g/L (5 wt%)
溶媒: pH 3.4、40 mMのCPB
プレポリマー濃度: 200 g/L (20 wt%)
ラットの腹部大動脈を外径0.2 mmの注射針で穿刺し、出血を促した。出血点に対して2液混合後のプレポリマー溶液を添加した(図9)。そのまま1分間圧迫止血を行ったところ、止血が確認された。このとき比較対象群として、プレポリマー溶液を添加せずに同様の圧迫止血を1分行ったところ、止血は認められなかった。
Claims (24)
- 第1のポリマーを含むポリマー溶液Aと、第2のポリマーを含む第2のポリマー溶液Bよりなる、ポリマー材料キットであって、
前記第1のポリマー及び前記第2のポリマーは、互いに架橋することでハイドロゲルを形成し得る、ポリアルキレングリコール骨格又はポリビニル骨格を有する親水性ポリマーの組み合わせであり;
前記第1のポリマー及び前記第2のポリマーは、1x103~1x105の範囲の重量平均分子量(Mw)を有し;
前記ポリマー溶液A及びB中における前記第1のポリマー及び前記第2のポリマーの濃度は、10~300g/Lの範囲であり;
前記ポリマー溶液AとBを混合して得られる混合液のpHが3~7未満の範囲であり、イオン強度が10~100mMの範囲である、該ポリマー材料キット。 - 前記第1のポリマー及び前記第2のポリマーが、2分岐、3分岐又は4分岐のポリエチレングリコールである、請求項1に記載のポリマー材料キット。
- 前記第1のポリマーが、側鎖又は末端に1以上の求核性官能基を有し;前記第2のポリマーが、側鎖又は末端に1以上の求電子性官能基を有する、請求項1又は2に記載のポリマー材料キット。
- 前記求核性官能基が、チオール基及びアミノ基よりなる群から選択され、前記求電子性官能基が、マレイミジル基、N-ヒドロキシ-スクシンイミジル(NHS)基、スルホスクシンイミジル基、フタルイミジル基、イミダゾイル基、アクリロイル基、ニトロフェニル基、及び-CO2PhNO2よりなる群から選択される、請求項1~3のいずれかに記載のポリマー材料キット。
- 前記ポリマー溶液A及びBのpHが、いずれも3~7未満の範囲である、請求項1~4のいずれかに記載のポリマー材料キット。
- pHが6.5~8.0の液体が存在する環境において、前記ポリマー溶液Aと前記ポリマー溶液Bが混合状態となることにより、前記第1のポリマーと前記第2のポリマーが互いに架橋したハイドロゲルが形成される、請求項1~5のいずれかに記載のポリマー材料キット。
- 前記第1のポリマーと前記第2のポリマーにより形成される前記ハイドロゲルのゲル化時間が、1~30秒の範囲である、請求項6に記載のポリマー材料キット。
- 前記第1のポリマーと前記第2のポリマーにより形成される前記ハイドロゲルが、0.9~3.5の範囲の平衡膨潤度を有する、請求項6又は7に記載のポリマー材料キット。
- 前記第1のポリマーと前記第2のポリマーにより形成される前記ハイドロゲルが、0.1x104~4x104Paの範囲のヤング率を有する、請求項6~8のいずれか1に記載のポリマー材料キット。
- 止血用、血管閉塞用、組織被覆用、又は体液凝固用である、請求項1~9のいずれか1に記載のポリマー材料キット。
- 請求項1~10のいずれか1に記載のポリマー材料キットよりなる、止血剤。
- 請求項1~10のいずれか1に記載のポリマー材料キットよりなる、血管閉塞剤。
- 請求項1~10のいずれか1に記載のポリマー材料キットよりなる、組織被覆剤。
- 請求項1~10のいずれか1に記載のポリマー材料キットよりなる、体液凝固剤。
- ハイドロゲルを含む止血剤、血管閉塞剤、組織被覆剤、又は体液凝固剤の製造方法であって、
第1のポリマーを含むポリマー溶液Aと第2のポリマーを含む第2のポリマー溶液Bとの混合液を、pHが6.5~8.0の液体が存在する環境に適用する工程を含み;
前記第1のポリマー及び前記第2のポリマーは、互いに架橋することでハイドロゲルを形成し得る、ポリアルキレングリコール骨格又はポリビニル骨格を有する親水性ポリマーの組み合わせであり;
前記第1のポリマー及び前記第2のポリマーは、1x103~1x105の範囲の重量平均分子量(Mw)を有し;
前記ポリマー溶液A及びB中における前記第1のポリマー及び前記第2のポリマーの濃度は、10~300g/Lの範囲であり;
前記ポリマー溶液AとBを混合して得られる混合液のpHが3~7未満であり、イオン強度が10~100mMの範囲である、該製造方法。 - pHが6.5~8.0の液体が存在する環境において、前記ポリマー溶液Aと前記第2のポリマー溶液Bを混合することを含む、請求項15に記載の方法。
- 前記ポリマー溶液Aと前記ポリマー溶液Bを担体に滴下した後に、当該担体をpHが6.5~8.0の液体が存在する環境に接触させることを含む、請求項15に記載の方法。
- 前記ポリマー溶液A及びBのpHが、いずれも3~7未満の範囲である、請求項15~17のいずれかに記載の方法。
- 請求項1~10のいずれか1に記載のポリマー材料キットを用いる、止血方法。
- 請求項1~10のいずれか1に記載のポリマー材料キットを用いる、血管閉塞方法。
- 請求項1~10のいずれか1に記載のポリマー材料キットを用いる、組織被覆方法。
- 請求項1~10のいずれか1に記載のポリマー材料キットを用いる、体液凝固方法。
- 請求項1~10のいずれか1に記載のポリマー材料キットよりなる、医療機器。
- ポリマー溶液A及びポリマー溶液Bの少なくとも1つが噴霧器に格納されている、請求項23に記載の医療機器。
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US20230218797A1 (en) | 2023-07-13 |
CN115515658A (zh) | 2022-12-23 |
JP2021176422A (ja) | 2021-11-11 |
EP4147731A4 (en) | 2024-06-19 |
EP4147731A1 (en) | 2023-03-15 |
AU2021268414A1 (en) | 2023-01-19 |
JP7550390B2 (ja) | 2024-09-13 |
CA3182001A1 (en) | 2021-11-11 |
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