Antiadhesion gel-forming agent set, method for using antiadhesion gel-forming agent set, and two-liquid mixing type main agent

Abstract

To provide an antiadhesion gel-forming agent set excellent in spray deposition property and spray diffusibility.SOLUTION: The antiadhesion gel-forming agent set of the present invention is used to form an anti-adhesion gel by a two-component mixing spray application and includes a first agent and a second agent, each having a viscosity of 100.0 mPa s or less, which satisfy any of the following conditions (i) to (iii):(i) The first agent contains (X) and (Y), and the second agent contains (Y) but not (X).(ii) The first agent contains (X) and (Y), and the second agent contains (X) and (Y).(iii) The first agent contains (X) but not (Y), and the second agent contains (X) and (Y).(X): A compound having a weight-average molecular weight of 1,000 to 50,000 and two or more hydroxyl groups.(Y): A polymer having a weight-average molecular weight of 10,000 to 35,000 and containing phosphorylcholine groups and phenylboronic acid groups.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an adhesion prevention gel-forming agent set, a method for using the adhesion prevention gel-forming agent set, and a two-part mixed base agent. [Background technology]

[0002] Various adhesion prevention technologies have been developed to date. One known example of this type of technology is the technology described in Patent Document 1. Patent Document 1 describes a material for preventing tissue adhesion and / or joint contracture, the main component of which is a composition containing a compound having a polyvalent hydroxyl group and a polymer containing a phosphorylcholine group and a phenylboronic acid group (Claim 1, etc., of Patent Document 1). Furthermore, in Example 17 of the same document, it is described that a 5% aqueous solution of PMBV (a polymer containing a phosphorylcholine group and a phenylboronic acid group) and a 5% aqueous solution of PVA (polyvinyl alcohol) were mixed to prepare a BV gel (a three-dimensional crosslinked body), and in Example 20, the BV gel was adhered to the area around the suture. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2009 / 066746 Summary of the Invention [Problem to be solved by the invention]

[0004] However, as a result of investigations by the present inventors, it has been found that there is room for improvement in terms of spray film-forming properties in the joint contracture prevention material as described in Patent Document 1 above. [Means for solving the problem]

[0005] Known two-component gel-forming agents are a PMBV aqueous solution (main component) and a PVA aqueous solution (secondary component). In Patent Document 1, a spray is not used for spraying, but a gel is formed by liquid-liquid mixing of a main agent and a secondary agent, and the resulting gel is adhered to the periphery of the sutured area. The inventors have investigated the spraying of the main agent and the auxiliary agent and found that when the main agent and the auxiliary agent are sprayed separately and then mixed on the target surface, dripping occurs in the coating film formed by spraying. On the other hand, it has been found that increasing the viscosity of at least one of the main and auxiliary agents can improve spray film-forming properties, but conversely, it leads to poor diffusion of the spray particles sprayed from the spray nozzle, resulting in a decrease in spray diffusibility. In other words, when only the technical element of the viscosity of the main and auxiliary agents is controlled, there is a trade-off between spray film-forming properties and spray diffusibility. Based on this knowledge, further intensive research led to the discovery that by utilizing a premix product, in which at least a portion of the auxiliary agent is mixed in advance with the main agent, as one or both of the two-component mixed gel-forming agents, and by controlling the viscosity of the two components to a low level, it is possible to improve the spray film-forming properties and spray diffusibility during spraying, which led to the completion of the present invention.

[0006] According to one aspect of the present invention, there are provided the following adhesion prevention gel-forming agent set, method for using the adhesion prevention gel-forming agent set, and two-part mixed base agent. 1. A two-component mixture base used to form an adhesion prevention gel by two-component mixture spray application, (X): a compound having a weight average molecular weight of 1,000 or more and 50,000 or less and having two or more hydroxyl groups; (Y): a polymer having a weight average molecular weight of 10,000 or more and 35,000 or less, and including a phosphorylcholine group and a phenylboronic acid group; The viscosity, measured according to the following procedure, is 100.0 mPa·s or less. Two-component mixed base agent. (procedure) The viscosity is measured using a cone-plate viscometer at room temperature of 25°C, with a cone rotor angle of 1°34' and a rotation speed of 50 rpm. 2. The two-component mixed base material described in 1., A two-component mixture base agent in which the concentration of (X) is 15% by weight or less and the concentration of (Y) is 20% by weight or less. 3. The two-component mixed base material according to 1. or 2. A two-component mixed base resin, in which the polymer (Y) contains a polymer having a skeleton represented by the following general formula (1): [ka] (In the above general formula (1), R1 represents a hydrogen atom, a methyl group, or an ethyl group; R2 represents an alkyl group having 2 to 12 carbon atoms or an oxyethylene group; R3 represents an alkyl group having 2 to 4 carbon atoms; X represents a single bond, a phenyl group which may have a substituent, or a group represented by -C(O)-, -C(O)O-, -O-, -C(O)NH-, or -S-; A represents a hydrogen atom, a halogen atom, or an arbitrary organic substituent; n, m, and l represent, respectively, 0.01 to 0.99, 0.01 to 0.99, and 0 to 0.98 (with the proviso that the sum of n, m, and l is 1.00).) 4. The two-component mixed base material described in 3., A two-component mixed base agent, wherein m / n in the general formula (1) is 0.01 or more and 1.00 or less. 5. A two-component mixed base material according to any one of 1. to 4., A two-component base that contains virtually no thickeners. 6. A two-component mixed base material according to any one of 1. to 5., A two-component mixture base agent, wherein the compound (X) comprises one or more selected from the group consisting of monosaccharides, polysaccharides, low-molecular-weight alcohols, and water-soluble polymer alcohols. 7. An anti-adhesion gel forming agent set used to form an anti-adhesion gel by two-component mixed spray application, comprising: It contains a first agent and a second agent that satisfy any one of the following conditions (i) to (iii): The viscosity of each of the first agent and the second agent, measured according to the following procedure, is 100.0 mPa s or less. Anti-adhesion gel forming agent set. (i) The first agent contains (X) and (Y), and the second agent does not contain (X) but contains (Y). (ii) the first agent contains (X) and (Y), and the second agent contains (X) and (Y) (iii) The first agent contains (X) but not (Y), and the second agent contains (X) and (Y). (X): A compound having a weight-average molecular weight of 1,000 or more and 50,000 or less and having two or more hydroxyl groups. (Y): A polymer having a weight-average molecular weight of 10,000 or more and 35,000 or less, containing a phosphorylcholine group and a phenylboronic acid group. (procedure) The viscosity is measured using a cone-plate viscometer at room temperature of 25°C, with a cone rotor angle of 1°34' and a rotation speed of 50 rpm. 8. The adhesion prevention gel-forming agent set according to 7., An adhesion prevention gel-forming agent set comprising: a first container containing the first agent; and a second container containing the second agent. 9. The adhesion prevention gel-forming agent set according to 7 or 8, a first container containing the first agent; a second container containing the second agent; an anti-adhesion gel-forming agent set, comprising: a spray device connectable to the first container and the second container. 10. The adhesion prevention gel-forming agent set according to any one of 7. to 9., An adhesion prevention gel-forming agent set, wherein the difference in viscosity between the first agent and the second agent is 0 mPa·s or more and 99 mPa·s or less. 11. A method for using an adhesion prevention gel-forming agent set, comprising a preparation step of preparing a first agent and a second agent that satisfy any one of the following conditions (i) to (iii) and each have a viscosity of 100.0 mPa s or less when measured according to the following procedure: (i) The first agent contains (X) and (Y), and the second agent does not contain (X) but contains (Y). (ii) the first agent contains (X) and (Y), and the second agent contains (X) and (Y) (iii) The first agent contains (X) but not (Y), and the second agent contains (X) and (Y). (X): A compound having a weight-average molecular weight of 1,000 or more and 50,000 or less and having two or more hydroxyl groups. (Y): A polymer having a weight-average molecular weight of 10,000 or more and 35,000 or less, containing a phosphorylcholine group and a phenylboronic acid group. (procedure) The viscosity is measured using a cone-plate viscometer at room temperature of 25°C, with a cone rotor angle of 1°34' and a rotation speed of 50 rpm. 12. A method for using the adhesion prevention gel-forming agent set according to 11., comprising: The method for using an adhesion prevention gel-forming agent set, wherein the preparation step includes filling a first container with the first agent and filling a second container separate from the first container with the second agent. 13. A method for using the adhesion prevention gel-forming agent set according to 11 or 12, comprising: The preparation step is a method for using an adhesion prevention gel-forming agent set, the method including filling the first agent into the first container and filling the second agent into the second container in a spray device having a first container and a second container. [Effects of the Invention]

[0007] According to the present invention, there are provided an adhesion prevention gel-forming agent set having excellent spray film-forming properties and spray diffusibility, a method for using the adhesion prevention gel-forming agent set, and a two-component mixed base agent. DETAILED DESCRIPTION OF THE INVENTION

[0008] An outline of the adhesion preventing gel forming agent set of this embodiment will be described.

[0009] The adhesion prevention gel forming agent set of this embodiment is a combination of a first agent and a second agent used to form an adhesion prevention gel by two-component mixing spray application. This anti-adhesion gel forming agent set includes: It contains a first agent and a second agent that satisfy any one of the following conditions (i) to (iii): The viscosity of the first and second parts, measured according to the procedure below, is 100.0 mPa·s or less. (i) The first agent contains (X) and (Y), and the second agent does not contain (X) but contains (Y). (ii) the first agent contains (X) and (Y), and the second agent contains (X) and (Y) (iii) The first agent contains (X) but not (Y), and the second agent contains (X) and (Y). (X): A compound having a weight-average molecular weight of 1,000 or more and 50,000 or less and having two or more hydroxyl groups. (Y): A polymer having a weight-average molecular weight of 10,000 or more and 35,000 or less, containing a phosphorylcholine group and a phenylboronic acid group. (procedure) The viscosity is measured using a cone-plate viscometer at room temperature of 25°C, with a cone rotor angle of 1°34' and a rotation speed of 50 rpm.

[0010] The majority of current adhesion prevention technologies involve applying a film-type anti-adhesion material to the treated tissue. Film-type anti-adhesion materials exert their adhesive properties by utilizing the moisture present in the body, but they are known to be difficult to move after application and to adjust the application site.

[0011] In contrast, the application position of a spray-type adhesion preventive material can be easily adjusted, making it easy to control the position where the adhesion preventive gel is formed around the treated tissue. Furthermore, considering that a spray-type adhesion preventive material can be applied to tissues via a nozzle inserted into the body, it can also be suitably used in laparoscopic surgery and robot-assisted laparoscopic surgery.

[0012] In the case of a spray-type adhesion preventive material, methods that can be used include spraying one of the first and second agents around the treatment tissue and then spraying the other on top of that, spraying a liquid solution of the first and second agents mixed together around the treatment tissue before it gels, or spraying the first and second agents together around the treatment tissue while mixing them, although the spray application methods are not limited to these.

[0013] According to the findings of the present inventors, setting the viscosity of the first and second agents contained in the adhesion prevention gel-forming agent set to the above upper limit or less means that gelation can be prevented from progressing more than necessary. This has been found to prevent nozzle clogging and dripping in the spray device and improve spray diffusibility. Furthermore, the ability to form a high-quality mist improves the uniformity of mixing of the first and second agents at the spray destination.

[0014] Based on this premise, further intensive research was carried out and the following findings were obtained. At least one of the first and second agents is a premix containing component (X) and component (Y), which can promote the gelling reaction when the first and second agents are mixed, thereby preventing a decrease in spray film-forming properties during spray application.

[0015] Furthermore, according to the studies of the present inventors, by decreasing the weight-average molecular weight of component (X) and component (Y), the decomposition rate of the gel increases, and it can be expected that the anti-adhesion properties will improve. Note that even if the weight-average molecular weight of at least one of component (X) and component (Y) is made larger than the above upper limit, dripping of the coating film can be suppressed and spray film-forming properties can be improved, but conversely, the decomposition rate of the gel may decrease and the anti-adhesion properties may be reduced. Although the details are unclear, it is speculated that by setting the weight-average molecular weights of component (X) and component (Y) to the above upper limit or less and using a premix of component (X) and component (Y) as one or both of the two-component gel-forming agents, it is possible to improve both the spray film-forming properties and the adhesion prevention properties.

[0016] The upper limit of the viscosity of the first agent is 100.0 mPa·s or less, preferably 80 mPa·s or less, and more preferably 70 mPa·s or less, which results in finer droplets when sprayed and improves mixing efficiency. On the other hand, the lower limit of the viscosity of the first agent is not particularly limited, but may be 1.0 mPa·s or more.

[0017] The upper limit of the viscosity of the second agent is 100.0 mPa·s or less, preferably 80 mPa·s or less, and more preferably 70 mPa·s or less, which results in finer droplets when sprayed and improves mixing efficiency. On the other hand, the lower limit of the viscosity of the second part is not particularly limited, but may be 1.0 mPa·s or more.

[0018] The upper limit of the difference in viscosity between the first and second parts is, for example, 99 mPa·s or less, preferably 79 mPa·s or less, and more preferably 69 mPa·s or less, which can improve the mixing efficiency during spraying. The lower limit of the viscosity difference between the first and second parts is not particularly limited, but may be, for example, 0 mPa·s or more.

[0019] The adhesion prevention gel-forming agent set may include at least a first container containing a first agent and a second container containing a second agent. The first container and the second container may be directly connected to the spray device, or may be used to fill the first agent and the second agent, respectively, into separate containers attached to the spray device. Here, spraying refers to the release of a liquid in a fine mist using a spray device. In contrast, dripping refers to the dropping of a liquid drop by drop. Spraying is a different application method from dripping.

[0020] The adhesion prevention gel-forming agent set may also include a first container containing the first agent, a second container containing the second agent, and a spray device connectable to the first container and the second container. The spray device may include at least one of a spray nozzle, an air supply tube, a connection mechanism for connecting the spray nozzle to each container, and accessories such as a regulator. However, the configuration of the spray device is not limited to these. Instructions for assembling the spray device may also be included.

[0021] An example of a method for using the adhesion prevention gel-forming agent set of this embodiment includes a preparation step of preparing a first agent and a second agent that satisfy any one of the above conditions (i) to (iii) and each have a viscosity of 100.0 mPa s or less when measured according to the above procedure. For example, the first agent and the second agent can be produced by separately preparing component (X) and component (Y) and mixing one with the other. Specifically, the preparation step may involve filling a first agent into a first container and filling a second agent into a second container separate from the first container. A mixture of component (X) and component (Y) may be filled into the container, or component (X) and component (Y) may be mixed in the container.

[0022] Furthermore, when a spray device having a first container and a second container is used, the preparation step may involve filling the first container with the first agent and the second container with the second agent after or before attaching them to the spray device. The above preparation steps are processes that are carried out before the first agent and the second agent are spray-applied to the target. Note that the method of using the adhesion prevention gel-forming agent set does not necessarily have to include the spray-application step.

[0023] The two-component mixed base agent of this embodiment is used to form an adhesion prevention gel by two-component mixed spray application. Here, in the adhesion prevention gel-forming agent set, one agent containing component (Y) having a functional group (phenylboronic acid group) that serves as a crosslinking point for the gel functions as the main agent, and the other agent not containing component (Y) functions as the auxiliary agent. When both the first agent and the second agent contain component (X) and component (Y), the agent with the higher concentration of component (Y) may be defined as the main agent, and the agent with the lower concentration may be defined as the auxiliary agent. In other words, the first agent and the second agent differ in at least one of the concentrations of component (X) and component (Y).

[0024] The main agent of the two-component mixture may be one of the two agents included in the adhesion prevention gel-forming agent set, but it may also be a first agent that contains the above-mentioned component (X) and component (Y) and has a viscosity of 100.0 mPa s or less, as measured according to the above-mentioned procedure. Such a first agent can prevent gelation from progressing more than necessary by itself, and therefore can be stored and transported before being mixed with the second agent.

[0025] The main agent or the first agent may be one that satisfies the conditions that the concentration of component (X) is 15% by weight or less and the concentration of (Y) is 20% by weight or less, thereby further improving the adhesion prevention ability. The upper limit of the concentration of component (X) is, for example, 15% by weight or less, preferably 12.5% ​​by weight or less, and more preferably 10% by weight or less, based on 100% by weight of the main agent or first agent. The lower limit of the concentration of component (X) is, for example, 0.01% by weight or more, preferably 0.1% by weight or more, and more preferably 0.2% by weight or more, based on 100% by weight of the main agent or first agent, which can improve gelling properties when sprayed.

[0026] The upper limit of the concentration of component (Y) is, for example, 20% by weight or less, preferably 17.5% by weight or less, and more preferably 15% by weight or less, based on 100% by mass of the main agent or first agent. The lower limit of the concentration of component (Y) is, for example, 0.01% by weight or more, preferably 0.5% by weight or more, and more preferably 1.0% by weight or more, based on 100% by weight of the main agent or first agent, which can improve gelling properties when sprayed.

[0027] The gelation time when the first and second agents contained in the adhesion prevention gel-forming agent set are mixed can be measured by the following procedure. Using the dynamic viscoelasticity (DMA) measurement method, a dynamic viscoelasticity measuring device (manufactured by Anton Paar, product name: MCR301) is used to measure the viscoelasticity (gelation process) of a mixture in which the first and second agents are mixed in a volume ratio of 1:1 at room temperature of 25°C, a frequency of 1 Hz, and a strain oscillation angle of 1%. From the viscoelastic spectrum, the storage modulus (G') at 25°C and the loss modulus (G'') at 25°C are determined, and the loss tangent (G'' / G') is calculated using these values. The time (seconds) elapsed from the start of measurement until G'' / G' becomes 1.0 or less is defined as the gelation time. In this embodiment, the gelling time is, for example, 20 seconds or less, preferably 18 seconds or less, and more preferably 15 seconds or less, which can further improve the gelling properties.

[0028] Each component of the adhesion preventing gel forming agent set of this embodiment will be described in detail below.

[0029] As used herein, the term "adhesion" refers to undesirable inter-organ or inter-tissue connection or fusion that occurs between one tissue and another.

[0030] The anti-adhesion gel may be used in any living tissue, such as the abdominal cavity of an "animal." The animal may be either a mammal or a non-mammal, but is preferably a mammal, such as a primate (e.g., human), mouse, guinea pig, rat, cow, horse, pig, goat, dog, rabbit, etc.

[0031] Component (X) contains a compound having a weight average molecular weight of 1,000 or more and 50,000 or less and having two or more hydroxyl groups. As the compound having two or more hydroxyl groups, one that dissolves in an aqueous medium can be used. The compound having two or more hydroxyl groups in the first agent may include one or more selected from the group consisting of monosaccharides, polysaccharides, low-molecular-weight alcohols, and water-soluble polymer alcohols.

[0032] Specifically, examples of monosaccharides include glucose and glucosamine. Examples of polysaccharides include maltose, lactose, amylose, amylopectin, chitin, hyaluronic acid, cellulose, pullulan, dextran, and derivatives thereof. Examples of low molecular weight alcohols include synthetic diols and triols. Examples of the water-soluble polymer alcohol include polyvinyl alcohol, poly(2-hydroxyethyl (meth)acrylate), poly(2,3-dihydroxyethyl (meth)acrylate), and poly((meth)acrylic acid glycoside). These may be used alone or in combination of two or more. The monosaccharides and polysaccharides may be either natural or artificial. Of these, polysaccharides and water-soluble polymer alcohols are preferred, and polyvinyl alcohol is more preferred.

[0033] Component (Y) has a weight average molecular weight of 10,000 or more and 35,000 or less, and includes a polymer containing a phosphorylcholine group and a phenylboronic acid group. A polymer containing a phosphorylcholine group and a phenylboronic acid group can be produced, for example, by mixing a first monomer containing a phosphorylcholine group with a second monomer having a phenylboronic acid group and subjecting the mixture to a polymerization reaction such as a radical polymerization reaction in the presence of a radical generator. A third monomer may be added as needed to adjust the properties of the resulting polymer.

[0034] The first monomer having a phosphorylcholine group can be selected from compounds having a carbon-carbon double bond such as a vinyl group or an allyl group as a polymerizable group and having a phosphorylcholine group in the same molecule. Examples of the first monomer include 2-methacryloyloxyethyl phosphorylcholine, 2-(meth)acryloyloxyethyl-2'-(trimethylammonio)ethyl phosphate, 3-(meth)acryloyloxypropyl-2'-(trimethylammonio)ethyl phosphate, 4-(meth)acryloyloxybutyl-2'-(trimethylammonio)ethyl phosphate, and 5-(meth)acryloyloxypentyl-2'-(trimethylammonio)ethyl phosphate. phosphate, 6-(meth)acryloyloxyhexyl-2'-(trimethylammonio)ethyl phosphate, 2-(meth)acryloyloxypropyl-2'-(trimethylammonio)ethyl phosphate, 2-(meth)acryloyloxybutyl-2'-(trimethylammonio)ethyl phosphate, 2-(meth)acryloyloxypentyl-2'-(trimethylammonio)ethyl phosphate, 2-(meth)acryloyloxyhexyl-2'-(trimethylammonio)ethyl phosphate 2-(meth)acryloyloxyethyl-3'-(trimethylammonio)propyl phosphate, 3-(meth)acryloyloxypropyl-3'-(trimethylammonio)propyl phosphate, 4-(meth)acryloyloxybutyl-3'-(trimethylammonio)propyl phosphate, 5-(meth)acryloyloxypentyl-3'-(trimethylammonio)propyl phosphate, 6-(meth)acryloyloxyhexyl Examples of suitable acryloyloxypropyl esters include 4-(meth)acryloyloxypropyl-3'-(trimethylammonio)propyl phosphate, 3-(meth)acryloyloxypropyl-4'-(trimethylammonio)butyl phosphate, 4-(meth)acryloyloxybutyl-4'-(trimethylammonio)butyl phosphate, 5-(meth)acryloyloxypentyl-4'-(trimethylammonio)butyl phosphate, and 6-(meth)acryloyloxyhexyl-4'-(trimethylammonio)butyl phosphate. These may be used alone or in combination of two or more. Among these, 2-methacryloyloxyethyl phosphorylcholine (hereinafter abbreviated as MPC) may be used. In this specification, "(meth)acrylic" means methacrylic and / or acrylic.

[0035] The second monomer having a phenylboronic acid group can be selected from compounds having a carbon-carbon double bond such as a vinyl group or an allyl group as a polymerizable group and having a phenylboronic acid group in the same molecule. Examples of the second monomer include p-vinylphenylboronic acid, m-vinylphenylboronic acid, p-(meth)acryloyloxyphenylboronic acid, m-(meth)acryloyloxyphenylboronic acid, p-(meth)acrylamidophenylboronic acid, m-(meth)acrylamidophenylboronic acid, p-vinyloxyphenylboronic acid, m-vinyloxyphenylboronic acid, vinylurethanephenylboronic acid, etc. These may be used alone or in combination of two or more. Among these, p-vinylphenylboronic acid or m-vinylphenylboronic acid is preferred in terms of availability of raw materials.

[0036] Examples of the third monomer that can be added include hydrophilic monomers such as (meth)acrylic acid, sodium (meth)acrylate, 2-hydroxyethyl (meth)acrylate, glycerol (meth)acrylate, N-vinylpyrrolidone, acrylonitrile, (meth)acrylamide, polyethylene glycol mono(meth)acrylate, vinylbenzenesulfonic acid, and sodium vinylbenzenesulfonate, methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, lauryl (meth)acrylate, dodecyl (meth)acrylate, stearyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, styrene, Examples of suitable monomers include hydrophobic monomers such as vinyl acetate, monomers having alkyloxysilane groups such as (3-methacryloyloxypropyl)trimethoxysilane, (3-methacryloyloxypropyl)triethoxysilane, (3-methacryloyloxypropyl)methyldimethoxysilane, and trimethoxyvinylsilane, monomers having siloxane groups, monomers having glycyl groups such as glycidyl methacrylate, monomers having amino groups such as allylamine, aminoethyl (meth)acrylate, and 2-methylallylamine, and monomers having groups such as carboxyl, hydroxyl, aldehyde, thiol, halogen, methoxy, epoxy, succinimide, and maleimide. These may be used alone or in combination of two or more. Among these, butyl (meth)acrylate may be used.

[0037] The solvent used in the polymerization reaction may be any solvent capable of dissolving the first and second monomers. It is more preferable that the solvent also be capable of dissolving the polymer produced by polymerization. The solvent may be a single solvent or a mixed solvent of two or more solvents.

[0038] The radical generator can be used without limitation as long as it dissolves in the solvent used in the polymerization reaction and decomposes at a reaction temperature in the range of, for example, 30° C. to 90° C. to generate radicals. From the viewpoint of safety and stability, aliphatic azo compounds such as azobisisobutyronitrile and 4,4′-azobis(4-cyanopentanoic acid), and peroxides such as benzoyl peroxide and succinic acid peroxide are preferred. Furthermore, it is also possible to control the molecular structure and molecular weight by utilizing an initiator that generates radicals upon irradiation with light, an atom transfer living radical polymerization reaction, a reversible addition-fragmentation chain transfer polymerization method, or the like.

[0039] The polymer containing a phosphorylcholine group and a phenylboronic acid group may contain a (meth)acrylate group in the molecule.

[0040] Furthermore, the polymer containing a phosphorylcholine group and a phenylboronic acid group may include a polymer having a skeleton represented by the following general formula (1).

[0041] [ka]

[0042] In the above general formula (1), R1 represents a hydrogen atom, a methyl group, or an ethyl group; R2 represents an alkyl group or an oxyethylene group having 2 to 12 carbon atoms; R3 represents an alkyl group having 2 to 4 carbon atoms; X represents a single bond, a phenyl group which may have a substituent, or a group represented by -C(O)-, -C(O)O-, -O-, -C(O)NH-, or -S-; A represents a hydrogen atom, a halogen atom, or an arbitrary organic substituent; n, m, and l represent, respectively, 0.01 to 0.99, 0.01 to 0.99, and 0 to 0.98 (with the proviso that the total of n, m, and l is 1.00).

[0043] In general formula (1), the upper limit of m / n is, for example, 1.00 or less, preferably 0.95 or less, and more preferably 0.9 or less, which makes it possible to improve biocompatibility. The lower limit of m / n is, for example, 0.01 or more, preferably 0.05 or more, and more preferably 0.1 or more, thereby achieving a gelation time suitable for spray atomization.

[0044] The weight average molecular weight (Mw) of the compound having two or more hydroxyl groups of component (X) is 10,000 or more and 50,000 or less, preferably 12,500 or more and 40,000 or less, and more preferably 15,000 or more and 30,000 or less. The number average molecular weight (Mn) of the compound having two or more hydroxyl groups of component (X) is, for example, 5,000 or more and 20,000 or less, preferably 6,000 or more and 19,000 or less, and more preferably 7,000 or more and 18,000 or less.

[0045] The weight average molecular weight (Mw) of the polymer of component (Y) is 10,000 or more and 35,000 or less, preferably 12,000 or more and 33,000 or less, and more preferably 14,000 or more and 30,000 or less. The number average molecular weight (Mn) of the polymer of component (Y) is, for example, 5,000 or more and 15,000 or less, preferably 6,000 or more and 14,000 or less, and more preferably 7,000 or more and 13,000 or less.

[0046] In this embodiment, the weight average molecular weight and the number average molecular weight can be calculated based on a calibration curve using a standard PEG sample using GPC.

[0047] The first agent and the second agent may each further contain additives such as viscosity modifiers, wetting agents, emulsifiers, lubricants, colorants, release agents, preservatives, antioxidants, pH buffers, etc. These may be used alone or in combination of two or more.

[0048] It is preferable that the first agent and the second agent each contain substantially no thickener as an additive, which can prevent a decrease in the adhesion prevention ability of the adhesion preventing material. "Substantially free" means that the content of thickener is zero or 1% by mass or less relative to 100% by mass of the first agent or second agent.

[0049] One method for producing an anti-adhesion gel is to use an anti-adhesion gel-forming agent set containing a first agent and a second agent, for example, by mixing a compound containing two or more hydroxyl groups contained in the first agent with a polymer containing a phosphorylcholine group and a phenylboronic acid group contained in the second agent, thereby forming an anti-adhesion gel composed of a three-dimensional crosslinked body.

[0050] The temperature for obtaining a three-dimensional crosslinked body is, for example, 4 to 90°C if not limited by the application, preferably 10 to 40°C from the viewpoint of preventing structural changes and activity reduction during immobilization of biological components, and preferably near room temperature, i.e., 20 to 37°C, from the viewpoint of operation.

[0051] The first agent and / or the second agent may contain a solvent. The solvent may be an aqueous solvent, specifically, pure water, physiological saline, buffer solution, cell culture solution, aqueous solution containing 30% or less of an organic solvent, or the like.

[0052] Although the embodiments of the present invention have been described above, these are merely examples of the present invention, and various other configurations may be adopted. Furthermore, the present invention is not limited to the above-described embodiments, and modifications and improvements within the scope of achieving the object of the present invention are included in the present invention. [Example]

[0053] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the descriptions of these examples.

[0054] <Manufacturing of anti-adhesion gel-forming agent set> (Synthesis of PMBV) 30 mL of the reaction solvent, raw material monomers, and reaction initiator were introduced into a glass reaction vessel according to the concentration ratios shown in Table 1, and the mixture was bubbled with nitrogen gas for 15 minutes. After that, the mixture was reacted for approximately 18 hours at the reaction temperature shown in Table 1 of 70°C to obtain a reaction solution. Ethanol (special grade reagent) was used as the reaction solvent. The raw material monomers used were 2-methacryloyloxyethyl phosphorylcholine (MPC, reagent, special grade), butyl methacrylate (BMA), and p-vinylphenylboronic acid (VPBA, reagent, special grade) in the amounts shown in Table 1. As a reaction initiator, 2,2'-azobis(isobutyronitrile) (AIBN, reagent, special grade) was used. Subsequently, the resulting reaction solution was added dropwise to a reprecipitation solvent to precipitate a polymer, which was then subjected to suction filtration and drying under reduced pressure to obtain a white powdery polymer. Here, the reprecipitation solvent used was one or a suitable mixture of two or more selected from the group consisting of hexane, acetone, diethyl ether, and chloroform. The resulting polymer powder was dissolved in pure water and sealed in a dialysis membrane with a molecular weight cutoff of 3500. The solution was purified by dialysis in a glass container filled with pure water for 3 days, with the pure water being replaced once a day. After 3 days, the aqueous solution in the dialysis membrane was freeze-dried to obtain approximately 5 g of a white powdery polymer (PMBV1).

[0055] [Table 1]

[0056] (Preparation of the first agent) A polyhydric hydroxyl group-containing compound as component (X) was dissolved in pure water to a concentration shown in Table 2, a colorant was added to a concentration of 0.01 weight percent, and if necessary, PMBV1 synthesized above as component (Y) was added to a concentration shown in Table 2 to prepare a first agent having a viscosity shown in Table 2. As the polyhydroxyl group-containing compound, polyvinyl alcohol (PVA, reagent, special grade) having the molecular weight shown in Table 2 was used. Brilliant Blue FCF (special grade reagent) was used as the colorant. When used in animal experiments, the first agent was sterilized by filtration.

[0057] (Preparation of second agent) A polymer containing a phosphorylcholine group and a phenylboronic acid group as component (Y) was dissolved in pure water to the concentration shown in Table 2, and if necessary, the above-mentioned PVA as component (X) was added to the concentration shown in Table 2 to prepare a second agent having a viscosity shown in Table 2. The polymer containing a phosphorylcholine group and a phenylboronic acid group was PMBV1 synthesized above. When used in animal experiments, the second agent was sterilized by filtration.

[0058] (Molecular weight analysis) The weight-average molecular weight and number-average molecular weight of the synthesized PMBV1 (powdered polymer after dialysis purification) and the PVA1 used were calculated using GPC (gel permeation chromatography) based on a calibration curve using a standard PEG sample. For the GPC measurement, one TSKgel SuperAWM-H, one TSKgel SuperAW2500, and one TSKgel guard column SuperAW-H (manufactured by Tosoh) were used, and the developing solvent was 70% methanol / 30% HO (with 10 mM LiBr added). The column temperature was 40°C, and the flow rate was 0.6 ml / min.

[0059] (composition analysis) Regarding the synthesized PMBV1, 1 The ratio of each monomer introduced was calculated from the 1 H-NMR spectrum. NMR measurements were performed using a JNM-ECA500 manufactured by JEOL Ltd., using a deuterated ethanol solvent and 32 accumulations.

[0060] The results of the above (molecular weight analysis) and (composition analysis) are shown here. PMBV1: MPC composition ratio n 0.8 BMA composition ratio l 0.092 VPBA composition ratio m 0.108 m / n 0.14 Mw 23.6k Mn 8.6k PVA1 Mw 25k Mn 12k

[0061] (viscosity) The viscosity of each of the first and second parts was measured using a cone-plate viscometer (Toki Sangyo Co., Ltd., TV-100EH) at room temperature of 25°C, with a cone rotor angle of 1°34° and a rotation speed of 50 rpm. The viscosity was measured for the first and second parts immediately after preparation. The results are shown in Table 2.

[0062] (Gelation time) The gel time was measured according to the following procedure. Using the dynamic viscoelasticity (DMA) measurement method, a dynamic viscoelasticity measuring device (manufactured by Anton Paar, product name: MCR301) was used to measure the viscoelasticity (gelation process) of a mixture in which the first and second agents were mixed in a volume ratio of 1:1 at room temperature of 25°C, a frequency of 1 Hz, and a strain oscillation angle of 1%. The storage modulus (G') at 25°C and the loss modulus (G'') at 25°C were determined from the viscoelastic spectrum, and the loss tangent (G'' / G') was calculated using these values. The time (seconds) elapsed from the start of measurement until G'' / G' became 1.0 or less was defined as the gelation time.

[0063] [Table 2]

[0064] The adhesion preventing gel-forming agent set containing the first agent and the second agent obtained above was used to evaluate the following items.

[0065] <Spray diffusion> When the first and second agents obtained above were sprayed using a two-liquid mixing spray nozzle (nozzle inner hole diameter: Φ0.60 mm), the results were rated as "good" if the spray particles turned into a mist and were seen to diffuse in a cone shape, and "poor" if the nozzle was clogged, the droplets dripped, or a continuous stream of droplets was released in a straight line.

[0066] <Spray film formation> When the first and second agents obtained above were sprayed onto paper placed on a 30° inclined surface using a two-liquid mixing spray nozzle, if a gel could be formed at the desired position, it was rated as "good," and if droplets dripped and it was difficult to form a gel at the desired position, it was rated as "poor."

[0067] The results in Table 1 show that the adhesion prevention gel-forming agent sets of Examples 1 to 4 have better spray diffusibility than Comparative Example 1 and better spray film-forming property than Comparative Example 2. It was also found that the first agents of Examples 1 and 2 and the second agents of Examples 3 and 4 can be suitably used as the main agent of a two-part mixture.

Claims

1. A two-component mixed base agent used to form an adhesion prevention gel by two-component mixed spray application, (X): a compound having a weight average molecular weight of 1,000 or more and 50,000 or less and having two or more hydroxyl groups; (Y): a polymer having a weight average molecular weight of 10,000 or more and 35,000 or less, and including a phosphorylcholine group and a phenylboronic acid group; The viscosity, measured according to the following procedure, is 100.0 mPa s or less. Two-component mixed base agent. (procedure) The viscosity is measured using a cone-plate viscometer at room temperature of 25° C., with a cone rotor angle of 1°34′ and a rotation speed of 50 rpm.

2. The two-component base material according to claim 1, A two-component mixture type base agent in which the concentration of (X) is 15% by weight or less and the concentration of (Y) is 20% by weight or less.

3. The two-component mixed base material according to claim 1 or 2, A two-component mixture base resin, wherein the polymer (Y) includes a polymer having a skeleton represented by the following general formula (1): 【Chemical 1】 (In the above general formula (1), R １ represents a hydrogen atom, a methyl group, or an ethyl group; R ２ represents an alkyl group having 2 to 12 carbon atoms or an oxyethylene group, and R ３ represents an alkyl group having 2 to 4 carbon atoms; X represents a single bond, a phenyl group which may have a substituent, or a group represented by -C(O)-, -C(O)O-, -O-, -C(O)NH- or -S-; A represents a hydrogen atom, a halogen atom or any organic substituent; n, m and l represent, respectively, 0.01 to 0.99, 0.01 to 0.99 and 0 to 0.98 (with the proviso that the sum of n, m and l is 1.00).

4. The two-component mixed base material according to claim 3, A two-component mixed base agent, wherein m / n in the general formula (1) is 0.01 or more and 1.00 or less.

5. The two-component mixed base material according to claim 1 or 2, A two-component base that contains virtually no thickeners.

6. The two-component mixed base material according to claim 1 or 2, A two-component mixture base agent, wherein the compound (X) comprises one or more selected from the group consisting of monosaccharides, polysaccharides, low-molecular-weight alcohols, and water-soluble polymer alcohols.

7. An adhesion prevention gel-forming agent set used to form an adhesion prevention gel by two-component mixed spray application, comprising: The composition comprises a first agent and a second agent that satisfy any one of the following conditions (i) to (iii): The viscosity of each of the first agent and the second agent, measured according to the following procedure, is 100.0 mPa s or less. Anti-adhesion gel forming agent set. (i) The first agent contains (X) and (Y), and the second agent does not contain (X) but contains (Y). (ii) The first agent contains (X) and (Y), and the second agent contains (X) and (Y). (iii) The first agent contains (X) but does not contain (Y), and the second agent contains (X) and (Y). (X): A compound having a weight-average molecular weight of 1,000 or more and 50,000 or less and having two or more hydroxyl groups (Y): A polymer having a weight-average molecular weight of 10,000 or more and 35,000 or less, containing a phosphorylcholine group and a phenylboronic acid group. (procedure) The viscosity is measured using a cone-plate viscometer at room temperature of 25° C., with a cone rotor angle of 1°34′ and a rotation speed of 50 rpm.

8. The adhesion prevention gel-forming agent set according to claim 7, An adhesion prevention gel-forming agent set comprising: a first container containing the first agent; and a second container containing the second agent.

9. The adhesion prevention gel-forming agent set according to claim 7, a first container containing the first agent; a second container containing the second agent; an anti-adhesion gel-forming agent set, comprising: a spray device connectable to the first container and the second container.

10. The adhesion prevention gel-forming agent set according to claim 7, An adhesion prevention gel-forming agent set, wherein the difference in viscosity between the first agent and the second agent is 0 mPa·s or more and 99 mPa·s or less.

11. A method for using an adhesion prevention gel-forming agent set, comprising a preparation step of preparing a first agent and a second agent that satisfy any one of the following conditions (i) to (iii) and each have a viscosity of 100.0 mPa s or less when measured according to the following procedure: (i) The first agent contains (X) and (Y), and the second agent does not contain (X) but contains (Y). (ii) The first agent contains (X) and (Y), and the second agent contains (X) and (Y). (iii) The first agent contains (X) but does not contain (Y), and the second agent contains (X) and (Y). (X): A compound having a weight-average molecular weight of 1,000 or more and 50,000 or less and having two or more hydroxyl groups (Y): A polymer having a weight-average molecular weight of 10,000 or more and 35,000 or less, containing a phosphorylcholine group and a phenylboronic acid group. (procedure) The viscosity is measured using a cone-plate viscometer at room temperature of 25° C., with a cone rotor angle of 1°34′ and a rotation speed of 50 rpm.

12. A method for using the adhesion prevention gel-forming agent set according to claim 11, comprising: The method for using an adhesion prevention gel-forming agent set, wherein the preparation step includes filling a first container with the first agent and filling a second container separate from the first container with the second agent.

13. A method for using the adhesion prevention gel-forming agent set according to claim 11, comprising: The preparation step is a method for using an adhesion prevention gel-forming agent set, the method including filling the first agent into the first container and filling the second agent into the second container in a spray device having a first container and a second container.

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