JPH11189624A - Temperature-responsive hydrogel - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a temperature-responsive polyvinyl methyl ether hydrogel which can be applied thinly, evenly, and firmly on the surfaces of many objects at one time and capable of controlled release of a substance in response to a specified temperature change by crosslinking a copolymer obtained by copolymerizing vinyl methyl ether with a monomer having a reactive functional group with a crosslinking agent. SOLUTION: Vinyl methyl ether in an amount of 30 mol.% or above, desirably, 50 mol.% or above is copolymerized with 1-30 mol.%, desirably, 5-20 mol.% monomer having a reactive functional group and, optionally, at least another monomer copolymerizable therewith at 4-90 deg.C, desirably, 20-80 deg.C for 1-72 hr, desirably 12-48 hr to obtain a copolymer. This copolymer is crosslinked with 0.01-5 mol.%, based on the monomer, crosslinking agent at 4-80 deg.C, desirably 20-60 deg.C to obtain a temperature-responsive hydrogen having a crosslinking density of 0.1-10%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a temperature-responsive hydrogel.

[0002]

2. Description of the Related Art In recent years, research on polymers having a stimulus response function has been actively conducted, and one of them is a thermosensitive polymer. As a temperature-sensitive water-soluble polymer, it dissolves in cold water,
Methylcellulose, a partially saponified polyvinyl acetate, and polyN-
Poly N-alkyl-substituted acrylamide represented by isopropylacrylamide and polyvinyl methyl ether are known. Among them, the aqueous solution of polyvinyl methyl ether exhibits temperature responsiveness in which it precipitates by heating around 38 ° C. and dissolves by cooling. The aqueous solution of polyvinyl methyl ether undergoes crosslinking by irradiation with high energy radiation such as γ-rays and electron beams, and a temperature-responsive hydrogel having a lower critical solution temperature of 38 ° C. is also formed. It has been pointed out that this polyvinyl methyl ether hydrogel can be applied as a material for artificial muscle by making it into a fibrous form,
Many attempts have been made for that. In recent biomedical applications, the use of polyvinyl methyl ether hydrogel as an ideal drug release control layer for DDS, which releases the required amount of drug only when a stimulus is applied to the formulation, is being studied. .

[0003]

However, these polyvinyl methyl ether hydrogels are all produced by irradiating high energy radiation such as γ-rays and electron beams during polymerization. In addition, when the method is applied to many objects at once, there is a problem in manufacturing that a hydrogel is not formed in a shadowed portion. Further, since polyvinyl methyl ether hydrogel does not have a reactive functional group, there is a problem that it cannot be stably bonded to the substrate surface.

The present invention solves such a problem and responds to a predetermined temperature change which can be thinly, uniformly and firmly laminated on a large amount of object surface at once without requiring special equipment. It is an object of the present invention to provide a temperature-responsive polyvinyl methyl ether hydrogel capable of controlling the release of a substance by using the same.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in order to solve such problems, and as a result, have found that the temperature of a monomer containing vinyl methyl ether and a monomer having a reactive functional group as a main component is determined. By cross-linking the responsive copolymer with a cross-linking agent on the substrate surface, the present inventors have found that a temperature-responsive hydrogel can be easily and thinly and uniformly laminated on a large number of object surfaces at a time, and the present invention has been achieved. did.

That is, the present invention provides a temperature-responsive hydrogel obtained by crosslinking a copolymer obtained by polymerizing a monomer having a reactive functional group with vinyl methyl ether as a main component with a crosslinking agent. It is an abstract.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be specifically described below. In the present invention, the term “temperature-responsive hydrogel” refers to a hydrogel having a phase transition temperature. Below this temperature, a water-swelled swelling phase is formed by absorbing water, and conversely, the phase transition temperature. Above the transition temperature, water is released to form a contracted contracted phase. This swelling and shrinking behavior occurs reversibly in the presence of water.

The monomer having a reactive functional group used in the present invention has a double bond having a reactive functional group such as an active acyl group such as a succinimide group or an acid anhydride group or an epoxy group in the molecule. It refers to a compound, and specifically includes glycidyl acrylate, N-acryloxysuccinimide, glycidyl methacrylate, N-methacryloxysuccinimide and the like.

The crosslinking agent used in the present invention has at least two active hydrogen groups such as a hydroxyl group, an amino group, a carboxyl group and a thiol group which can react with a reactive functional group in a copolymer. A compound, specifically, a polyol, a polyamine, a polycarboxylic acid and the like.

[0010] The polyol is at least 2 per molecule.
Refers to a compound having one hydroxyl group, for example, ethylene glycol, propylene glycol, butylene glycol, glycerin, pentaerythritol, sorbitol, diglycerin, diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, dipropylene glycol, tripropylene glycol Examples thereof include propylene glycol, polyethylene glycol, polypropylene glycol, and polybutylene glycol, and polyalkylene glycol is particularly preferable.

[0011] The polyamine is defined as at least 2 per molecule.
Refers to compounds having one amino group, for example, diamines such as ethylenediamine, propylenediamine, hexamethylenediamine, poly (oxyethylene) diamine, poly (oxypropylene) diamine, polyvinylamine,
Examples include aminoacetalized polyvinyl alcohol, polyethyleneimine, a reaction product of diamine and epichlorohydrin, and the like.

The term "polycarboxylic acid" refers to a compound having at least two carboxyl groups in one molecule. Examples thereof include terephthalic acid, adipic acid, polyacrylic acid, maleic acid-methyl vinyl ether copolymer, carboxymethyl cellulose and the like. No. These crosslinking agents may be of a low molecular weight or a high molecular weight, but the volume of the hydrogel can be controlled by the structure of the crosslinking agent. That is, the longer the distance between active hydrogen groups, the larger the volume of the resulting hydrogel.

In order to obtain the temperature-responsive hydrogel of the present invention, first, vinyl methyl ether and the above-mentioned monomer having a reactive functional group are polymerized as main components to obtain a copolymer. The vinyl methyl ether used at this time is preferably used in an amount of 30 mol% or more, particularly preferably 5 mol%, of all monomers to be polymerized, from the viewpoint of securing the temperature responsiveness of the gel.
It is preferable to use 0 mol% or more. The monomer having a reactive functional group is preferably used in an amount of 1 to 30 mol%, and particularly preferably 5 to 20 mol%, based on all monomers to be polymerized.

When synthesizing a copolymer comprising these monomers, the method of initiating the polymerization can be carried out only by heating, but in general, better results are obtained by using a polymerization initiator. . The polymerization initiator is not limited as long as it has the ability to initiate radical polymerization, and examples thereof include inorganic peroxides such as hydrogen peroxide, potassium persulfate, and ammonium persulfate, benzoyl peroxide, and t-butyl peroxide. Organic peroxides, such as combinations of these peroxides with reducing agents such as iron, cobalt, copper, etc., sulfites, bisulfites and the like, and azo compounds such as azobisisobutyronitrile. Can be. The addition amount of these polymerization initiators is sufficient within the range employed in ordinary radical polymerization, and is in the range of 0.01 to 5% by weight, preferably 0.05 to 2% by weight, based on the monomers. .

The polymerization temperature and the polymerization time vary depending on the type of initiator used, but are usually 4 to 90 ° C., preferably 20 to 80 ° C., and usually 1 to 72 hours, preferably 12 to 48 hours.

When synthesizing a copolymer of vinyl methyl ether and the above-mentioned monomer having a reactive functional group, these monomers are used in combination with one or more other copolymerizable monomers. can do. Specific examples of such a monomer include hydrophilic monomers such as acrylamide, hydroxyethyl acrylate, acrylic acid, methacrylamide, hydroxyethyl methacrylate, methacrylic acid, and N-n.
N-alkyl (meth) acrylamide derivatives such as -butylacrylamide, Nt-butylacrylamide, Nn-butylmethacrylamide, Nt-butylmethacrylamide, ethyl acrylate, butyl acrylate, methyl methacrylate, butyl methacrylate and the like (Meth) acrylate derivatives, acrylonitrile, methacrylonitrile, vinyl acetate, vinyl chloride, ethylene,
Hydrophobic monomers such as styrene, butadiene, isoprene and the like can be mentioned.

Then, the temperature-responsive hydrogel of the present invention can be obtained by crosslinking the copolymer with the crosslinking agent described above. The crosslink density (the ratio of the number of crosslinked structural units in the polymer to the total number of structural units) of the thermoresponsive hydrogel of the present invention is preferably in the range of 0.1 to 10%. Therefore, in the crosslinking reaction, the crosslinking agent may be added in an amount of 0.01 to 5 mol% based on the monomer.

The temperature and time of the cross-linking reaction differ depending on the combination of the cross-linking agent and the reactive functional group used, and cannot be specified unconditionally. Further, a catalyst such as pyridine, triethylamine, triethylbenzylammonium chloride, etc. may be appropriately added in order to allow the crosslinking reaction to proceed efficiently.

[0019] The phase transition temperature of the thermoresponsive hydrogel of the present invention is specifically in the range of 4 to 80 ° C, preferably in the range of 20 to 60 ° C. Here, the phase transition temperature is determined as the temperature at which the hydrogel starts shrinking rapidly when the temperature-responsive hydrogel is immersed in a thermostat and gradually heated from a low temperature. The phase transition temperature of the temperature-responsive hydrogel of the present invention can be freely changed depending on the type or composition ratio of vinyl methyl ether, a monomer having a reactive functional group and other monomers, and the type or amount of a crosslinking agent. Therefore, it is possible to appropriately prepare a hydrogel having a phase transition temperature as required.
Specifically, the phase transition temperature can be reduced by increasing the composition ratio of the hydrophobic monomer copolymerized with vinyl methyl ether. Further, by increasing the composition ratio of the hydrophilic monomer copolymerized with vinyl methyl ether, the phase transition temperature increases.

Further, the degree of swelling of the temperature-responsive hydrogel of the present invention at a predetermined temperature not higher than the phase transition temperature depends on the type or composition ratio of vinyl methyl ether, a monomer having a reactive functional group and other monomers. , Can be freely changed depending on the type or amount of the crosslinking agent. That is, the swelling degree can be further reduced by increasing the composition ratio of the hydrophobic monomer copolymerized with vinyl methyl ether or increasing the amount of the crosslinking agent added. Further, the swelling degree can be further increased by increasing the composition ratio of the hydrophilic monomer copolymerized with vinyl methyl ether or decreasing the amount of the crosslinking agent added. The degree of swelling here is
It is the so-called weight swelling degree, which is determined by the following equation. Swelling degree = (weight of gel when swollen with pure water) / (absolute dry weight of gel)

The temperature-responsive hydrogel of the present invention can be used after being shaped into a block, pellet, film, fiber, particle, flake, or the like. The shape to be formed is appropriately determined depending on the use situation and cannot be uniformly defined.

The temperature-responsive hydrogel of the present invention can be used as a temperature-responsive release control layer.
In this case, the permeation rate of a substance such as a drug at a predetermined temperature equal to or lower than the phase transition temperature of the temperature-responsive hydrogel of the present invention depends on the thickness of the hydrogel, vinyl methyl ether, a monomer having a reactive functional group and Other monomer types or composition ratios,
It can be freely changed depending on the type or amount of the crosslinking agent. At a given temperature and a given film thickness, the permeation rate should be reduced by increasing the composition ratio of the hydrophobic monomer copolymerized with vinyl methyl ether or increasing the amount of the crosslinking agent added. Can be. Further, by increasing the composition ratio of the hydrophilic monomer copolymerized with vinyl methyl ether or decreasing the amount of the crosslinking agent added, the transmission speed can be further increased.

The substance whose release can be controlled by the temperature-responsive hydrogel of the present invention is not particularly limited as long as it is soluble in water, and examples thereof include drugs, pesticides, catalysts, fragrances, enzymes and the like. For example, pharmaceuticals include antimicrobial agents such as ampicillin, cefazolin, vancomycin, phosphomycin, gentamicin, erythromycin, minocycline, chloramphenicol, ciprofloxacin, rifampicin, sulfamethoxazole, trimethoprim, and isonicotin hydrazide. Is mentioned.

In the temperature-responsive hydrogel of the present invention, in a swelling state, substances such as drugs are released out of the system by diffusion through water present in the hydrogel, and in a contracting state, the surface of the gel becomes hydrophobic. Since a film is formed, the diffusion of the substance is suppressed, and the release to the outside of the system is stopped. Since the hydrophobic film is quickly formed on the gel surface, the release of the substance is quickly controlled. When the temperature-responsive hydrogel of the present invention is applied to controlling the release of substances such as drugs, the presence of water is an essential condition. However, it is not necessary to use only water, and in some cases, the hydrogel can exhibit temperature responsiveness even in an aqueous solution containing appropriate amounts of various surfactants, organic solvents, and salts.

The forms of controlled release are classified into two types: a reservoir type in which a substance holding layer and a release controlling layer are separated, and a monolithic type in which a substance such as a drug is dispersed in the controlled release layer. The temperature-responsive hydrogel of the invention is:
The release control layer can be applied to any of the two types by forming it into a film, plate, fiber or the like as required. That is, when applied to a reservoir type, when the external temperature is lower than the phase transition temperature, the hydrogel becomes a swelling state, and substances such as drugs pass through the release control layer and are released to the outside. When the temperature is higher than the temperature, the hydrogel is in a contracted state, and substances such as drugs cannot permeate the release control layer, and release to the outside stops. Further, a monolithic material can be easily produced by dispersing a substance such as a drug in a liquid or solid state in the hydrogel. As described above, since the hydrogel has a surface rate-determining temperature change, when the external temperature is lower than the phase transition temperature, the drug in the hydrogel is diffused and released to the outside. Since the surface shrinks and a hydrophobic film is rapidly formed, diffusion of the drug is suppressed, and release to the outside is stopped.

In order to form a film made of the temperature-responsive hydrogel of the present invention on the surface of a substrate, it is necessary to obtain a copolymer obtained by polymerizing vinyl methyl ether and a monomer having a reactive functional group as main components. The coalescing and the crosslinking agent are reacted on the surface of the substrate to form the hydrogel film on the surface of the substrate. For this purpose, for example, a method in which the substrate surface is brought into contact with a solution in which the copolymer and the crosslinking agent are dissolved, and then the substrate surface is heated or a catalyst is added is suitable.

Further, since the temperature-responsive hydrogel of the present invention has an unreacted reactive functional group, it can be used as a polyamide such as nylon, polyester such as polyethylene terephthalate, polycarbonate, polyarylate, polyurethane and the like. It can also be covalently bonded to a substrate surface having an active hydrogen group in the molecule.

[0028]

Next, the present invention will be described in detail with reference to examples. The degree of swelling of the temperature-responsive hydrogel obtained in the examples refers to the degree of swelling by weight and is determined by the following equation. Degree of swelling = (weight of gel when swollen with pure water) / (absolute dry weight of gel) The lower critical solution temperature is such that a temperature-responsive hydrogel is immersed in a thermostat and gradually rises from a low temperature. As the temperature increases, the temperature at which turbidity, measured at 500 nm by a spectrophotometer, begins to increase sharply is determined.

Example 1 12.0 g of vinyl methyl ether and 0.5 g of glycidyl methacrylate were dissolved in 50 ml of anhydrous tetrahydrofuran, bubbled with argon gas for 10 minutes, and then azobisisobutyronitrile was degassed by bubbling with argon gas. 0.2 ml of a 1% by weight (polymerization initiator) tetrahydrofuran solution was added with a syringe. After stirring at 50 ° C. for 24 hours in an argon gas atmosphere, hexane 10
0 ml was added to precipitate the copolymer. The precipitate was filtered and dried to obtain 10.4 g of a copolymer. 1 of the obtained copolymer
Ionette Y, a polyamine, is added to a 10% by weight aqueous solution.
56 mg of B-400 (manufactured by Sanyo Chemical Industries) was added, and 2
A transparent gel was obtained by allowing to stand at 5 ° C. for 1 day. When the degree of swelling of this gel at 30 ° C. and 37 ° C. was measured,
It was 4.7 at 30 ° C and 1.5 at 37 ° C. Also,
The phase transition temperature was 34 ° C (see Table 1). Next, the completely dried gel was added to a 1 mg / ml rifampicin aqueous solution for 10 minutes.
The gel was immersed in rifampicin at 24 ° C. for 24 hours. The rifampicin-containing gel was immersed in temperature-controlled pure water, and the amount of rifampicin released from the gel was measured by HPLC. FIG. 1 shows the cumulative release amount of rifampicin when the temperature was changed stepwise at 30 ° C. and 37 ° C.

[0030]

[Table 1]

Example 2 A hydrogel was obtained in the same manner as in Example 1 except that 11.5 g of vinyl methyl ether and 1.0 g of glycidyl methacrylate were used. The phase transition temperature, the degree of swelling, and the cumulative release of rifampicin of these hydrogels were measured in the same manner as in Example 1. The results are summarized in Table 1 and FIG.

Example 3 A hydrogel was obtained in the same manner as in Example 1 except that 11.5 g of vinyl methyl ether, 0.5 g of glycidyl methacrylate and 0.5 g of acrylamide were copolymerized. The phase transition temperature, the degree of swelling, and the cumulative release of rifampicin of these hydrogels were measured in the same manner as in Example 1. The results are summarized in Table 1 and FIG. As is clear from the results of Examples 1 to 3, by changing the composition ratio of the copolymer, polyvinyl methyl ether hydrogels having various phase transition temperatures and swelling characteristics can be obtained. By using the obtained polyvinyl methyl ether hydrogel as a release control layer, it is possible to freely control the release rate of a substance such as a drug depending on the temperature.

[0033]

The temperature-responsive hydrogel of the present invention has an unreacted reactive functional group, so that it can be stably laminated on the substrate surface. The temperature-responsive hydrogel of the present invention can be used as a release control layer that changes the release rate of a substance such as a drug according to the temperature.

[Brief description of the drawings]

FIG. 1 is a diagram showing the release behavior of rifampicin at various temperatures contained in the temperature-responsive hydrogel of the present invention.

Claims (1)

[Claims] 1. A temperature-responsive hydrogel, wherein a copolymer obtained by polymerizing a monomer having a reactive functional group with vinyl methyl ether as a main component is cross-linked by a cross-linking agent.