JP6948160B2 - Hydrogel that can support heterocyclic compounds - Google Patents

Description

The present invention relates to a hydrogel capable of carrying a heterocyclic compound. More specifically, the present invention relates to a hydrogel containing a polymerizable compound having a heterocycle in the molecule as a constituent component, which is useful as a carrier of a heterocyclic compound such as a pyridine derivative, a pyrimidine derivative, a pyridazine derivative, and a pyrazine derivative.

As agents for various diseases, pyrimidine, pyrimidine which is a structural isomer of pyrimidine, pyrimidine derivative which is a derivative of pyrazine, pyridazine derivative and pyrazine derivative are known, and some of them are actually used.

However, some pyrimidine derivatives, pyridazine derivatives, and pyrazine derivatives exhibit excellent medicinal properties, but also exhibit strong toxicity and side effects. Therefore, in order to safely deliver to the treatment target site, a base material that efficiently supports these derivatives is required.

A drug delivery system (DDS), which is one of the methods for delivering a drug to a desired site, is generally composed of a carrier containing the drug inside and a permeable membrane for controlling release. When the drug is a water-soluble drug, hydrogel may be selected as the carrier of the drug. In this case, the inclusion amount of the drug greatly affects the solubility of the drug and therefore depends on the water content of the hydrogel. Therefore, as the water content of the hydrogel improves, the amount of the drug contained tends to increase.

However, when trying to include a drug depending on the water content of such a hydrogel, the drug is only kept in a state of being dissolved in the water in the hydrogel, and the drug is stably put into the hydrogel. There was a problem that it was difficult to hold. Therefore, by forming an ionic bond between the hydrogel base material which is the carrier of the drug and the anionic drug to be included, the retention of the drug in the hydrogel is improved regardless of the water content. Hydrogels for carrying drugs are known (see Patent Document 1).

Japanese Unexamined Patent Publication No. 2004-307574

However, since the hydrogel which is a drug carrier in Patent Document 1 carries a drug by an ionic bond with a functional group of the hydrogel, the included drug is limited to an anionic drug, and further anionic. There is a problem in versatility that the conditions for including sex drugs are restricted.

For example, many of the pyridine derivatives, pyrimidine derivatives, pyridazine derivatives, and pyrazine derivatives that are promising as drugs for various diseases do not have an anionic group or have no intramolecular charge bias. Such a substance is difficult to be supported by the drug-supporting hydrogel described in Patent Document 1.

Therefore, the present invention provides a drug that is difficult to be supported by the drug-carrying hydrogel described in Patent Document 1, in particular, a hydrogel useful as a carrier for a pyridine derivative, a pyrimidine derivative, a pyridazine derivative, or a pyrazine derivative. That is the problem that the invention is trying to solve.

In an attempt to solve the above problems, the present inventors have sought for compounds capable of binding to the pyridine derivative, pyrimidine derivative, pyridazine derivative and pyrazine derivative, which are the target drugs, while diligently examining the binding property. However, attention has been paid to heterocyclic monomers, particularly heterocyclic monomers having a nitrogen atom and a carbon atom having an amino group adjacent to each other in the ring. Through further trial and error, we succeeded in creating a hydrogel containing the heterocyclic monomer as a constituent component. The hydrogel thus created is a pyridine derivative, a pyrimidine derivative, a pyridazine derivative, and a pyrimidine, which has an appropriate intermolecular interaction due to a hydrogen bond formed between the pyrazine derivative and the heterocyclic monomer. Derivatives, pyridazine derivatives and pyrazine derivatives could be supported on the surface and inside of the hydrogel. The present invention is an invention completed based on these findings and successful examples.

（１）
（式中、ｎは０又は１〜５の整数を示し；
Ｚは酸素原子又はＮＨ基を示し；
Ｒ_１は水素原子又はＣＨ_３基を示し；及び、
Ｒ_２及びＲ_３は、それぞれ独立して、水素原子、水酸基、アミノ基又は炭素数１〜５のアルキル基を示す。）
で示される重合性基を有する、［２］〜［３］のいずれか１項に記載のハイドロゲル。
［５］前記複素環式モノマーが、プリン環、トリアジン環、ピリジン環、イミダゾール環及びプテリジン環からなる群より選択される環構造を有する複素環式モノマーである、［２］〜［４］のいずれか１項に記載のハイドロゲル。
［６］前記ハイドロゲルが、疎水性モノマーを構成成分としてさらに含む、又は疎水性モノマーと、該疎水性モノマー以外のシリコーン含有モノマーを構成成分としてさらに含む、［１］〜［５］のいずれか１項に記載のハイドロゲル。
［７］［１］〜［６］のいずれか１項に記載のハイドロゲルと、ピリジン誘導体、ピリミジン誘導体、ピリダジン誘導体及びピラジン誘導体からなる群から選ばれる複素環式化合物とを接触する工程を含む、複素環式化合物の担持方法。
［８］［１］〜［６］のいずれか１項に記載のハイドロゲルと、ピリジン誘導体、ピリミジン誘導体、ピリダジン誘導体及びピラジン誘導体からなる群から選ばれる複素環式化合物とを接触することにより、該複素環式化合物を担持したハイドロゲルを得る工程を含む、複素環式化合物担持ハイドロゲルの製造方法。
［９］ピリジン誘導体、ピリミジン誘導体、ピリダジン誘導体及びピラジン誘導体からなる群から選ばれる複素環式化合物を水素結合により担持したハイドロゲル。 Therefore, according to one aspect of the present invention, the hydrogels and methods of [1] to [9] below are provided.
[1] A hydrogel which is a carrier capable of supporting a heterocyclic compound selected from the group consisting of a pyridine derivative, a pyrimidine derivative, a pyridazine derivative and a pyrazine derivative by hydrogen bonding.
[2] A monocyclic or polycyclic 3- to 12-membered heterocyclic monomer having at least one nitrogen atom in the ring and an atom adjacent to the nitrogen atom in the ring having an amino group. ,
A hydrogel containing a hydrophilic monomer as a constituent component.
[3] The hydrogel according to [2], wherein the hydrogel further contains an anionic monomer as a constituent component.
[4] The heterocyclic monomer is a vinyl group or the following general formula (1).

(1)
(In the formula, n represents an integer of 0 or 1-5;
Z indicates an oxygen atom or NH group;
R ₁ indicates a hydrogen atom or ₃ CH groups; and
R ₂ and R ₃ independently represent a hydrogen atom, a hydroxyl group, an amino group, or an alkyl group having 1 to 5 carbon atoms. )
The hydrogel according to any one of [2] to [3], which has a polymerizable group represented by.
[5] The heterocyclic monomer of [2] to [4], wherein the heterocyclic monomer has a ring structure selected from the group consisting of a purine ring, a triazine ring, a pyridine ring, an imidazole ring and a pteridine ring. The hydrogel according to any one item.
[6] Any of [1] to [5], wherein the hydrogel further contains a hydrophobic monomer as a constituent component, or further contains a hydrophobic monomer and a silicone-containing monomer other than the hydrophobic monomer as a constituent component. The hydrogel according to item 1.
[7] The step of contacting the hydrogel according to any one of [1] to [6] with a heterocyclic compound selected from the group consisting of a pyridine derivative, a pyrimidine derivative, a pyridazine derivative and a pyrazine derivative is included. , A method for carrying a heterocyclic compound.
[8] By contacting the hydrogel according to any one of [1] to [6] with a heterocyclic compound selected from the group consisting of a pyridine derivative, a pyrimidine derivative, a pyridazine derivative and a pyrazine derivative. A method for producing a heterocyclic compound-bearing hydrogel, which comprises a step of obtaining a hydrogel carrying the heterocyclic compound.
[9] A hydrogel in which a heterocyclic compound selected from the group consisting of a pyridine derivative, a pyrimidine derivative, a pyridazine derivative and a pyrazine derivative is supported by a hydrogen bond.

According to the present invention, agents such as pyridine derivatives, pyrimidine derivatives, pyridazine derivatives, and pyrazine derivatives can be supported in hydrogels via hydrogen bonds even if these agents do not have ionic groups. can. Further, according to the present invention, since a hydrogel having a large amount of the drug taken up and / or having excellent sustained release of the taken-in drug is used, the carried drug is supported in the hydrogel. It is possible not only to continue, but also to adsorb the chemicals in the environment to the hydrogel.

FIG. 1 is a diagram showing the results of evaluating the uptake amount of the pyrimidinedione derivative of the hydrogel depending on the presence or absence of the heterocyclic monomer which is VDAT as a constituent component, as described in Examples described later. FIG. 2 is a diagram showing the results of evaluating the uptake amount of the pyrimidinedione derivative of the hydrogel with and without DAMET as a constituent component, as described in Examples described later. FIG. 3 is a diagram showing an evaluation result of an IDU release rate depending on the presence or absence of a heterocyclic monomer which is VDAT as a constituent component, as described in Examples described later. FIG. 4 is a diagram showing the evaluation results of the release rate of 5FU depending on the presence or absence of the heterocyclic monomer which is VDAT as a constituent component, as described in Examples described later.

Hereinafter, the hydrogel and the method according to one aspect of the present invention will be described in detail, but the technical scope of the present invention is not limited to the matters of this item, and the present invention achieves the object. As long as it is limited, various aspects can be taken.

As used herein, the term "monomer" means a term paired with "polymer", which is a molecule that can be polymerized by a polymerizable group in the molecule and can be used as a constituent component of the polymer. Means. As used herein, the term "polymer" means a molecule formed by polymerizing a monomer. In the present specification, "hydrogel" means a substance capable of swelling (hydration swelling) by containing water inside by containing a hydrophilic monomer as a constituent component. As used herein, "supporting" means maintaining a state in which one substance and the other substance are in contact with each other. As used herein, "(meth) acrylate" is a general term that includes both acrylate and methacrylate.

The hydrogel according to one aspect of the present invention is a carrier capable of supporting a heterocyclic compound useful as a therapeutic agent by hydrogen bonding. The heterocyclic compound is preferably a heterocyclic compound having a nitrogen atom and a carbon atom adjacent to the nitrogen atom in the ring, and the carbon atom takes the form of a carbonyl group. That is, the heterocyclic compound preferably has a structure of −N (−H) −C (= O) − in the ring.

In the hydrogel according to one aspect of the present invention, the heterocyclic monomer as a constituent is hydrogen-bonded to the heterocyclic compound to add the heterocyclic compound to the surface of the hydrogel and support the inside of the hydrogel. It is possible to do.

The heterocyclic monomer constituting the hydrogel has at least one nitrogen atom in the ring, and the atom adjacent to the nitrogen atom in the ring has an amino group, and is a monocyclic or polycyclic 3 It is a ~ 12-membered heterocyclic monomer. An atom in which a nitrogen atom in a heterocyclic monomer forms a hydrogen bond with a hydrogen atom in −N (−H) −C (= O) − of a heterocyclic compound and is adjacent to the nitrogen atom in the heterocyclic monomer. The hydrogen atom of the amino group of the compound forms a hydrogen bond with the oxygen atom in −N (−H) −C (= O) − of the heterocyclic compound, so that the hydrogel is complex via the heterocyclic monomer. It is possible to carry a cyclic compound.

In the heterocyclic monomer, in order to form a good hydrogen bond with the heterocyclic compound, the nitrogen atom in the ring and the atom having an amino group adjacent to the nitrogen atom are -N = C (-NH ₂ )-. It is preferable to take the structure of. As a result, the nitrogen atom of −N = C (−NH ₂ ) − in the heterocyclic monomer forms a hydrogen bond with the hydrogen atom in −N (−H) −C (= O) − of the heterocyclic compound. Moreover, the hydrogen atom of −N = C (−NH ₂ ) − in the heterocyclic monomer forms a hydrogen bond with the oxygen atom in −N (−H) −C (= O) − of the heterocyclic compound. The hydrogel can carry the heterocyclic compound via the heterocyclic monomer.

The heterocyclic monomer is a monocyclic or polycyclic 3- to 12-membered heterocycle having at least one nitrogen atom in the ring and an atom adjacent to the nitrogen atom in the ring having an amino group. As long as it is a formula monomer capable of forming a hydrogen bond with a heterocyclic compound, other structures and properties are not particularly limited.

（１）
（式中、ｎは１〜５の整数を示し；
Ｒ_１は水素原子又はＣＨ_３基を示し；
Ｚは酸素原子又はＮＨ基を示し；及び、
Ｒ_２及びＲ_３は、それぞれ独立して、水素原子、水酸基、アミノ基又は炭素数１〜５のアルキル基を示す）
で示される重合性基であることが好ましい。 The polymerizable group of the heterocyclic monomer is not particularly limited as long as it is a functional group subjected to a polymerization reaction as is generally known, but for example, from the viewpoint of copolymerizability, a vinyl group or the following general formula ( 1)

(1)
(In the formula, n represents an integer from 1 to 5;
R ₁ indicates a hydrogen atom or ₃ CH groups;
Z indicates an oxygen atom or NH group; and
R ₂ and R ₃ independently represent a hydrogen atom, a hydroxyl group, an amino group, or an alkyl group having 1 to 5 carbon atoms).
It is preferably a polymerizable group represented by.

Specific examples of the monocyclic heterocycle include 3-membered ring compounds such as aziridine-2-amine; and 4 such as 4-aminoazetidine-2-one and 4-methyl-1-aminoazetidine-2-one. Membered ring compounds; 5-membered ring compounds such as 2-pyrrolidinamine, 3-pyrrolin-2-imine; 2,6-diaminopyridine, 2-aminopyridine, piperidin-2-amine, 2- (2-aminoethylamino) Pyridine, 5-methyl-2-pyridylaminyl radical, 6-aminopyridine-3-carbonitrile, pyridine-2,3,4-triamine, 4-aminopyrimidine, 2-methyl-4-pyrimidineamine, 4,5 -Pyrimidinediamine, 4,6-pyrimidinediamine, 2,4-diaminopyrimidine, 5-methylpyrimidine-4-amine, 4-amino-5-hydroxypyrimidine, 2-fluoro-4-aminopyrimidine, 5-methylpyrimidine- 2-amine, 2-amino-4-methylpyrimidine, 1,3,5-triazine-2-amine, 1,3,5-triazine-2,4-diamine, N-methyl-1,3,5-triazine Examples include, but are not limited to, 6-membered ring compounds such as −2,4-diamine, 4-methyl-1,3,5-triazine-2-amine, 4-ethyl-s-triazine-2-amine and the like. ..

Specific examples of the polycyclic heterocycle include 3-aminoisoquinolin, adenin, 1-methyladenine, 2-methyladenine, 3-methyladenine, 1-aminoadenine, 2,6-diaminopurine, and 3H-purine. 3,6-diamine, 1,2,3,4-tetrahydroquinolin-2-amine, 1,2,3,4-tetrahydroquinolin-8-amine, 1H-benzoimidazole-4-amine, 5-amino-1H -Benzoimidazole, 4-ethyl-1H-benzoimidazole-5-amine, 4-ethyl-1H-benzoimidazole-5-amine, quinoxalin-2-amine, 5-quinoxalineamine, 5,6-diaminoquinoxaline, 1, Examples include, but are not limited to, 5-naphthylidine-4-amine, quinazoline-4-amine, 4-amino-5-methylquinazoline and the like.

The heterocyclic monomer is not particularly limited as long as it has a ring structure capable of forming a hydrogen bond with the heterocyclic compound. For example, as a ring structure capable of easily forming a hydrogen bond, a purine ring, a triazine ring, or a pyridine ring is used. , It is preferable that it has a ring structure selected from the group consisting of an imidazole ring and a pteridine ring, and it is more preferable that it has a ring structure of either a purine ring or a triazine ring. However, if the heterocyclic monomer has a ring structure capable of forming a hydrogen bond with the heterocyclic compound, the atoms in the rings of the purine ring, triazine ring, pyridine ring, imidazole ring and pteridine ring are different. It may be a derivative of a purine ring, a triazine ring, a pyridine ring, an imidazole ring, or a pteridine ring, such as one substituted with an atom, one having an atom having a substituent, and one condensed.

More specific examples of the heterocyclic monomer are 2-vinyl-4,6-diamino-1,3,5-triazine (VDAT) and 2 represented by the general formulas (2) and (3) shown below. , 4-Diamino-6- [2- (methacryloyloxy) ethyl] -1,3,5-triazine (DAMET) and the like, but are not limited thereto.

（２）

(2)

（３）

(3)

As the heterocyclic monomer, one of the above-mentioned ones can be used alone, or two or more kinds can be blended in combination. The method for obtaining the heterocyclic monomer is not particularly limited, and for example, a commercially available heterocyclic monomer or a product produced with reference to publicly known documents can be used as the heterocyclic monomer. Specifically, with reference to the literature of Henry et al. (Henri J. Spijker, A. (Ton) J. Dirks, Jan CM van Hest. Polymer. 2005; 19: 8528-8535), the pyrimidine ring and A heterocyclic monomer having a purine ring can be produced. In addition, a heterocyclic monomer having a pyrimidine ring can be produced by referring to the literature of Saxwan et al. (Acharee Suksuwan, Luelak Lomlim 1, Thayada Rungrotmongkol. J. APPL. Polym. Sci. 2015: 41930).

The blending amount of the heterocyclic monomer is not particularly limited, but for example, it is preferably 5 to 50 wt%, more preferably 10 to 40 wt%, and 15 to 30 wt% with respect to the total amount of the monomer components of the hydrogel. Is more preferable. When the blending amount of the heterocyclic monomer exceeds 50 wt% with respect to the total amount of the monomer components of the hydrogel, the softness of the obtained hydrogel tends to decrease, which is not preferable.

The hydrogel according to one aspect of the present invention can take an aspect as a hydrogel by containing a hydrophilic monomer as a constituent component.

The hydrophilic monomer is not particularly limited as long as it is a monomer having at least one hydrophilic group in the molecule and a polymerizable group such as a (meth) acryloyl group or a vinyl group, and for example, hydroxymethyl (meth) acrylate and 2-hydroxy. Ethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 2,3-dihydroxypropyl (meth) acrylate, 2-polyethylene glycol mono (meth) acrylate, 2-polypropylene glycol (meth) acrylate, methacrylicamide, Examples thereof include N, N-dimethyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, N-vinylpyrrolidone and the like. As the hydrophilic monomer, one of these can be used alone, or two or more of them can be blended in combination.

The blending amount of the hydrophilic monomer is not particularly limited, but for example, it is preferably 5 to 95 wt%, more preferably 10 to 80 wt% with respect to the total amount of the monomer components of the hydrogel. If the blending amount of the hydrophilic monomer is less than 5 wt% with respect to the total amount of the monomer components of the hydrogel, the softness of the obtained hydrogel tends to decrease, which is not preferable, and if it exceeds 95 wt%, a sufficient amount is obtained. It is not preferable because the heterocyclic compound of No. 1 cannot be blended and an effective amount of a pyridine derivative, a pyrimidine derivative, a pyridazine derivative, or a pyrarazine derivative tends to be unbearable.

Heterocyclic monomers generally have extremely low solubility in water and can be dissolved only under acidic conditions. Therefore, from the viewpoint of the solvent, it is preferable to use an anionic monomer together with the heterocyclic monomer, and an anionic monomer having a carboxy group is more preferable.

The anionic monomer is not particularly limited as long as it is a monomer having at least one anionic group in the molecule and a polymerizable group such as a (meth) acryloyl group or a vinyl group, and for example, (meth) acrylic acid, 2- (meth) acrylic acid, 2- (meth). ) Acryloyloxyethyl succinic acid, 2- (meth) acryloyloxyethyl phthalic acid, 2- (meth) acryloyloxyethyl hexahydrophthalic acid and other ethylene-based unsaturated carboxylic acids can be mentioned. As the anionic monomer, one of these can be used alone, or two or more of them can be blended in combination.

The blending amount of the anionic monomer is not particularly limited, but for example, it is preferably 5 to 95 wt%, more preferably 10 to 90 wt%, and 15 to 85 wt% with respect to the total amount of the monomer components of the hydrogel. It is more preferable to have. When the blending amount of the anionic monomer is less than 5 wt% with respect to the total amount of the monomer components of the hydrogel, the solubility of the heterocyclic monomer is deteriorated, the morphology of the hydrogel tends to be impaired, and cloudiness occurs. It is not preferable because it tends to occur.

The hydrogel according to one aspect of the present invention may contain, in addition to the heterocyclic monomer, the hydrophilic monomer and the anionic monomer, other monomers copolymerizable therewith as constituents. Examples of other monomers include, but are not limited to, hydrophobic monomers, silicone-containing monomers, and crosslinkable monomers.

The hydrophobic monomer is not particularly limited as long as it does not have a hydrophilic group in the molecule and has a polymerizable group such as at least one (meth) acryloyl group or a vinyl group. Specific examples of the hydrophobic monomer include (meth) such as trifluoroethyl methacrylate, siloxanyl methacrylate, methyl methacrylate, n-butyl methacrylate, tert-butyl methacrylate, benzyl methacrylate, ethylhexyl methacrylate, and lauryl (meth) acrylate. Acrylic monomers and the like can be mentioned, but the present invention is not limited to these. As the hydrophobic monomer, one of these can be used alone, or two or more of them can be blended in combination.

The silicone-containing monomer is not particularly limited as long as it has a siloxane-bonded structure in the molecule and has a polymerizable group such as a (meth) acryloyl group or a vinyl group. Specific examples of the silicone-containing monomer include α-mono (methacryloyloxymethyl) polydimethylsiloxane, α, ω-di (methacryloxymethyl) polydimethylsiloxane, α-mono (3-methacryloyloxypropyl) polydimethylsiloxane, and α. , Ω-di (3-methacryloyloxypropyl) polydimethylsiloxane, α-mono (3-methacloyloxybutyl) polydimethylsiloxane, α, ω-di (3-methacryloyloxybutyl) polydimethylsiloxane, α-monovinyl poly Dimethylsiloxane, α, ω-divinylpolydimethylsiloxane, 3-tris (trimethylsiloxy) silylmethyl (meth) acrylicate, 3-tris (trimethylsiloxy) silylpropyl (meth) acrylate, 3-methylbis (trimethylsiloxy) silylmethyl ( Meta) acrylate, 3-methylbis (trimethylsiloxy) silylpropyl (meth) acrylate, 3-trimethylsiloxydimethylsilylmethyl (meth) acrylate, 3-trimethylsiloxydimethylsilylpropyl (meth) acrylate, 3-methyldimethoxysilylpropyl (meth) acrylate ) Acrylate and the like can be mentioned, but the present invention is not limited to these. As the silicone-containing monomer, one of these can be used alone, or two or more of them can be blended in combination.

The blending amount of the hydrophobic monomer and the silicone-containing monomer is not particularly limited, and can be appropriately set by those skilled in the art according to the characteristics such as oxygen permeability and water content to be given to the hydrogel.

The crosslinkable monomer can be blended for forming a network structure of a hydrogel, adjusting the mechanical strength, and the like. The crosslinkable monomer is not particularly limited as long as it is a monomer having a polymerizable group such as two or more (meth) acrylic groups or vinyl groups in the molecule, and for example, ethylene glycol di (meth) acrylate and methylenebis (meth) acrylamide. , 2-Hydroxy-1,3-di (meth) acryloxypropane, trimethylolpropane tri (meth) acrylate and the like. As the crosslinkable monomer, one of these can be used alone, or two or more of them can be blended in combination.

The blending amount of the crosslinkable monomer is not particularly limited, but for example, 0.1 to 5 wt% is preferable, and 0.2 to 1 wt% is more preferable with respect to the total amount of the monomer components of the hydrogel. When the blending amount of the crosslinkable monomer exceeds 5 wt%, the flexibility of the obtained hydrogel tends to decrease, which is not preferable.

The hydrogel according to one aspect of the present invention can be obtained by subjecting a monomer as a constituent to a copolymerization reaction. The copolymerization reaction of the monomers is not particularly limited, but can be carried out by, for example, a general method known to those skilled in the art using an electron beam, heat, or the like, and the polymerization initiator used at this time is not particularly limited. For example, as the polymerization initiator, peroxide-based polymerization initiators such as lauroyl peroxide, cumene hydroperoxide, and benzoyl peroxide, which are general radical polymerization initiators; azobisdimethylvaleronitrile, azobisisobutyro, etc. An azo-based polymerization initiator such as nitrile can be used alone or in combination of two or more.

The hydrogel according to one aspect of the present invention can be produced by combining steps generally known to those skilled in the art as a method for producing a hydrogel. The method for producing the hydrogel is not particularly limited, but it can be obtained, for example, by combining the following steps.

As a step of obtaining a polymer, a monomer mixture obtained by mixing the constituent monomers is placed in a molding mold such as metal, glass, or plastic, sealed, and stepwise or continuously in a constant temperature bath or the like at 25 to 120 ° C. A molding mold containing a polymer can be obtained by raising the temperature in the range of 1 and completing the copolymerization reaction in 5 to 120 hours. For polymerization, ultraviolet rays, electron beams, gamma rays and the like can be used. In addition, solution polymerization can be applied by adding water or an organic solvent to the monomer mixture. In the preparation of the monomer mixed solution, since the heterocyclic monomer has low solubility in water, it is preferable to use an acidic solvent, and it is more preferable to use an anionic monomer as the acidic solvent.

As a step of obtaining a hydrogel, the molding die after completion of polymerization is cooled to room temperature, the polymer contained in the molding die is peeled off from the molding die, and if necessary, cut and polished, and then the polymer is hydrated and swollen. Use a hydrogel. Examples of the liquid (swelling liquid) to be used include, but are not limited to, water, physiological saline, an isotonic buffer solution, and a solution obtained by mixing an organic solvent such as ethanol with the liquid. The swelling liquid is heated to 60 to 100 ° C., and the polymer is immersed in the swelling liquid for a certain period of time to bring it into a swelling state. Further, it is preferable to remove the unreacted monomer adhering to the polymer during the swelling treatment. The obtained hydrogel can be stylized by subjecting it to high-pressure steam sterilization at 110 to 130 ° C. for 10 to 60 minutes in a state of being immersed in a swelling solution such as physiological saline.

The hydrogel according to one aspect of the present invention functions as a carrier of a heterocyclic compound such as a pyridine derivative, a pyrimidine derivative, a pyridazine derivative, and a pyrazine derivative. The heterocycle is formed by forming a strong interaction between the nitrogen atom of the heterocyclic monomer and the amino group which is the substituent of the heterocyclic side chain in the hydrogel of one aspect of the present invention and the heterocyclic compound by hydrogen bonding. The formula compound is carried on the surface and inside of the hydrogel.

The heterocyclic compound has a skeleton selected from the group consisting of a pyridine skeleton, a pyrimidine skeleton, a pyridazine skeleton and a pyrazine skeleton. In a heterocyclic compound, a hydrogen atom at −N (−H) − in the ring forms a hydrogen bond with a nitrogen atom in the ring of the heterocyclic monomer in the hydrogel of one embodiment of the present invention.

In the heterocyclic compound, it is preferable that the atom adjacent to −N (−H) − in the ring takes the form of a carbonyl group (−C (= O) −) in order to form a further hydrogen bond. That is, the heterocyclic compound preferably has a structure of −N (−H) −C (= O) − in the ring.

The heterocyclic compound having a structure of −N (−H) −C (= O) − in the ring is not particularly limited, and for example, a pyridone derivative, a pyridinedione derivative, a pyrimidine derivative, a pyrimidinedione derivative, a pyridazineion derivative, and the like. Examples thereof include pyridazinedione derivatives, pyrazinedione derivatives, pyrazinedione derivatives, and specifically, pyrimidinedione derivatives, pyridazinedione derivatives, pyrazinedione derivatives, and pyridinediones represented by any of the following general formulas (4) to (7). Examples include derivatives.

（４）
（式中、Ｒ_１及びＲ_２は、それぞれ独立して、水素原子、Ｆ、Ｃｌ、Ｂｒ、Ｉといったハロゲン原子、置換基を有してもよい炭素数１〜６の直鎖状、分岐鎖状若しくは環状の炭化水素化合物、アミド基、カルボキシル基、カルボニル基、オキシカルボニル基、シリル基、ホスフィンオキサイド基又は複素環基を示し；及び、
Ｒ_３及びＲ_４は、それぞれ独立して、水素原子又は置換基を有してもよい炭素数１〜６の直鎖状、分岐鎖状若しくは環状の炭化水素化合物を示す。）

(4)
(In the formula, R ₁ and R ₂ are linear and branched chains having 1 to 6 carbon atoms which may independently have a hydrogen atom, a halogen atom such as F, Cl, Br, and I, and a substituent. Shows a cyclic or cyclic hydrocarbon compound, an amide group, a carboxyl group, a carbonyl group, an oxycarbonyl group, a silyl group, a phosphine oxide group or a heterocyclic group;
R ₃ and R ₄ each independently represent a linear, branched or cyclic hydrocarbon compound having 1 to 6 carbon atoms which may have a hydrogen atom or a substituent. )

（５）
（式中のＲ_１、Ｒ_２、Ｒ_３及びＲ_４は、一般式（４）と同一のものを示す。）

(5)
_{(R 1, R 2, R} 3 and _{R 4} in the formula represents the same as the general formula (4).)

（６）
（式中のＲ_１、Ｒ_２、Ｒ_３及びＲ_４は、一般式（４）と同一のものを示す。）

(6)
_{(R 1, R 2, R} 3 and _{R 4} in the formula represents the same as the general formula (4).)

（７）
（式中のＲ_１、Ｒ_２、Ｒ_３及びＲ_４は、一般式（４）と同一のものを示す。）

(7)
_{(R 1, R 2, R} 3 and _{R 4} in the formula represents the same as the general formula (4).)

Specific examples of the heterocyclic compound include 1,3-dimethyl-5-chloropyrimidine-2,4-dione, 1,3-dimethyl-5-bromopyrimidine-2,4-dione, and 2,3-dihydro-. 2-Iminopyrimidine-4,6-dione, 5-fluoropyrimidine-2,4-dione, 5-fluoro-1-[(tetra)-2-yl] pyrimidine-2,4-dione, 1- (2-) Deoxy-β-D ribofuranosyl) -5-iodopyrimidine-2,4-dione and other pyrimidinedione derivatives; 4-methyl-3,6-pyridazinedione, 4,5-dibromo-1,2-diethyl-3,6 Pyrimidinedione derivatives such as −pyridazinedione, 4,5-dimethyl-3,6-pyridazinedione; pyrazinedione derivatives such as 6-hydroxymethyl-1-methyl-2,3-pyridazinedione; 4-amino-2,6 Examples thereof include, but are not limited to, pyrimidinedione derivatives such as (1H, 3H) -pyrimidinedione.

Specific examples of the combination of the heterocyclic compound and the heterocyclic monomer in the hydrogel of one aspect of the present invention are shown by the following combination examples 1-1 to 6-2, but are not particularly limited. The dotted line in the combination example indicates a hydrogen bond.

The method for supporting the heterocyclic compound on the hydrogel according to one aspect of the present invention is not particularly limited. For example, the hydrogel according to one aspect of the present invention is heated at room temperature or in a solution in which the heterocyclic compound is dissolved. Examples thereof include a method including contacting the hydrogel according to one aspect of the present invention with the heterocyclic compound method by immersing the compound in a state. The immersion time can be appropriately set depending on the concentration of the solution and the liquid temperature, but is preferably about 12 to 48 hours, for example.

The method of one aspect of the present invention is a method of carrying a heterocyclic compound, which comprises at least a step of contacting the hydrogel of one aspect of the present invention with the heterocyclic compound. The method of another aspect of the present invention comprises at least a step of contacting the hydrogel of one aspect of the present invention with a heterocyclic compound to obtain a hydrogel carrying the heterocyclic compound. A method for carrying a formula compound. In the method of one aspect of the present invention, various steps and operations can be added to the first stage or the second stage of the above-mentioned steps or during the steps as long as the object of the present invention can be achieved.

The amount of the heterocyclic compound held by the hydrogel of one aspect of the present invention can be determined, for example, by placing the hydrogel after holding the heterocyclic compound in a phosphate buffer according to the method described in Examples described later. The amount of the eluted heterocyclic compound can be confirmed by quantifying the amount of the eluted heterocyclic compound by high performance liquid chromatography.

The hydrogel according to one aspect of the present invention can slowly release the retained heterocyclic compound by containing the heterocyclic monomer as a constituent component. The sustained release properties of the heterocyclic compound retained by the hydrogel according to one aspect of the present invention are not particularly limited, and for example, 2-hydroxyethyl methacrylate, 2-methacryloyloxyethyl succinic acid, acrylic acid and ethylene glycol di. It is superior to the sustained release property of the heterocyclic compound held by the control hydrogel obtained by copolymerizing the monomer component composed of methacrylate, and the release rate for 1 hour after the start of release is relative to the release rate of the control hydrogel. It is preferably 0.7 times or less and has a certain degree of sustained release, more preferably 0.5 times or less and has a certain degree of sustained release, and 0.4 times or less and has a certain degree of sustained release. Is more preferable, and it is even more preferable that the sustained release property is 0.3 times or less and has a certain degree of sustained release. Further, considering the release rate of the heterocyclic compound held by the hydrogel of one aspect of the present invention as a reference, for example, the release rate for 1 hour after the start of release is 70% or less, preferably 60% or less. Yes, more preferably 50% or less, still more preferably 40% or less, and even more preferably 30% or less. The release rate of the heterocyclic compound retained by the hydrogel according to one aspect of the present invention can be calculated by the method described in Examples described later.

The hydrogel according to one aspect of the present invention contains a heterocyclic monomer as a constituent component of the hydrogel, whereby a nitrogen atom and a substitution in a heterocyclic compound such as a pyridinedione derivative, a pyridazinedione derivative, a pyrimidinedione derivative, and a pyrazinedione derivative are used. Since the heterocyclic compound can be supported on the surface and inside of the hydrogel by the hydrogen bond with the amino group, it can be used as an ophthalmic lens such as a DDS medium, a separation film, an adsorbent, and a contact lens. can. In particular, when the hydrogel according to one aspect of the present invention is used as a contact lens, the heterocyclic compound held before being worn in the eye can be slowly released into the eye, and the heterocyclic compound existing in the eye can be sustained. By adsorbing the cyclic compound with the hydrogel of one aspect of the present invention, the excess heterocyclic compound can be removed and side effects can be reduced.

The hydrogel of another aspect of the present invention is a hydrogel in which a heterocyclic compound selected from the group consisting of a pyridine derivative, a pyrimidine derivative, a pyridazine derivative and a pyrazine derivative is supported by a hydrogen bond.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples, and the present invention may take various aspects as long as the problems of the present invention can be solved. can.

[1. Preparation of hydrogels (1) to (5)]
2-Hydroxyethyl methacrylate (HEMA), 2-methacryloyloxyethyl succinic acid (HOMS), acrylic acid (AA) and 2-vinyl-4,6-diamino- 1,3,5-Triazine (VDAT) (manufactured by Tokyo Kasei Kogyo Co., Ltd.) and 2,4-diamino-6- [2- (methacryloyloxy) ethyl] -1,3,5-triazine (DAMET) ( After weighing (manufactured by Wako Pure Chemical Industries, Ltd.), ethylene glycol dimethacrylate (EGDMA) (manufactured by Mitsubishi Rayon Co., Ltd.) is added, and azobis (external) of 3,500 ppm (external) is added to the total weight of the monomer. A monomer mixture was prepared by adding isobutyronitrile (AIBN) and stirring and mixing.

The obtained monomer mixture was placed in a disk-shaped molding mold and heated in the range of 30 to 110 ° C. over 15 hours to obtain a polymer. The obtained polymer was returned to room temperature, taken out from a mold, and then immersed in an ethanol-containing aqueous saline solution and an aqueous saline solution at 70 ° C. for 1 hour to hydrate and swell to obtain a hydrogel. The obtained hydrogel was immersed in a physiological saline solution and sterilized by high-pressure steam at 121 ° C. for 30 minutes to obtain hydrogels (1) to (5) as standard devices.

[2. Preparation of pyrimidinedione derivative solution]
Weigh 1- (2-deoxy-β-D ribofuranosyl) -5-iodopyrimidine-2,4-dione (IDU) into physiological saline to a concentration of 1,000 μg / mL, and stir at room temperature for 30 minutes. To prepare an IDU solution.

A 5FU solution was prepared by weighing 5-fluoropyrimidine-2,4-dione (5FU) into physiological saline to a concentration of 1,000 μg / mL and stirring at room temperature for 30 minutes.

[3. Preparation of pyrimidinedione derivative-supported hydrogel]
(Example 1)
Hydrogels (1) Five sheets of hydrogels (1) were immersed in IDU solutions separated by 2 ml each, and then allowed to stand at room temperature for 24 hours to obtain IDU-supported hydrogels.

(Example 2)
5 hydrogels (2) were immersed in 2 ml of each IDU solution and then allowed to stand at room temperature for 24 hours to obtain an IDU-supported hydrogel.

(Example 3)
Hydrogels (2) Five sheets were immersed in 5FU solutions separated by 2 ml each, and then allowed to stand at room temperature for 24 hours to obtain 5FU-supported hydrogels.

(Example 4)
Five hydrogels (3) were immersed in 2 ml of each IDU solution and then allowed to stand at room temperature for 24 hours to obtain an IDU-supported hydrogel.

(Example 5)
Five hydrogels (4) were immersed in 2 ml of each IDU solution and then allowed to stand at room temperature for 24 hours to obtain an IDU-supported hydrogel.

(Comparative Example 1)
Five hydrogels (5) were immersed in 2 ml of each IDU solution and then allowed to stand at room temperature for 24 hours to obtain an IDU-supported hydrogel.

(Comparative Example 2)
5 hydrogels (5) were each immersed in a 5FU solution prepared by 2 ml each, and then allowed to stand at room temperature for 24 hours to obtain a 5FU-supported hydrogel.

[4. Hydrogel evaluation method]
<Measurement of uptake of pyrimidinedione derivative>
The pyrimidinedione derivative-bearing hydrogels of Example 1, Example 2, Example 4, Example 5, and Comparative Example 1 were immersed in phosphate buffer (PBS) and allowed to stand at room temperature for 24 hours. By immersing in PBS, the pyrimidinedione derivative supported on the hydrogel was eluted in the solution. The pyrimidinedione derivatives contained in the eluted physiological saline were quantified by high performance liquid chromatography (HPLC, manufactured by JASCO Corporation) according to a conventional method.

The value obtained by quantification was taken as the IDU uptake amount (μg / g) per unit hydrogel. The results of the IDU uptake amount for each hydrogel used are shown in Tables 2 and 3, and the results of the average IDU uptake amount are shown in FIGS. 1 and 2.

As shown in Tables 2 and 3 and FIGS. 1 and 2, a hydrogel containing a heterocyclic monomer having a nitrogen atom and a carbon atom having an amino group adjacent to each other in the ring, such as VDAT and DAMET, as a constituent component (implementation). It was confirmed that Examples 1 to 2 and 4 to 5) can carry a large amount of pyrimidinedione derivative as compared with the hydrogel (Comparative Example 1) which does not contain the heterocyclic monomer as a constituent.

<Evaluation of pyrimidinedione derivative support>
The pyrimidinedione derivative-supported hydrogels of Examples 2 and 3 and Comparative Examples 1 and 2 were immersed in 2 ml of physiological saline at room temperature for a certain period of time (0.5, 1, 2, 4, 8 and). 24 hours). The amount of the drug contained (eluted) in the physiological saline after immersion was quantified using an ultra-trace spectrophotometer (manufactured by Thermo Fisher Scientific Co., Ltd.) according to a conventional method.

The release rate was determined from the quantified values according to the following formula, and the pyrimidinedione derivative supportability was evaluated based on this release rate. The results of the average release rate at each time are shown in Tables 4 and 3 for IDU and in Tables 5 and 4 for 5FU.
Release rate (%) = (release amount / uptake amount at each time) x 100

As shown in Tables 4 to 5 and FIGS. 3 to 4, a hydrogel containing a heterocyclic monomer having a nitrogen atom and a carbon atom having an amino group adjacent to each other in the ring as a constituent component, such as VDAT (Example 2). In 3), the release rate of the pyrimidinedione derivative over time is smaller than that of the hydrogel (Comparative Examples 1 and 2) which does not contain the heterocyclic monomer as a constituent component, and the pyrimidinedione derivative is supported for a long time. It was confirmed that the pyrimidinedione derivative can be gradually released (sustained release) as well as being able to continue.

From the above results, the hydrogel containing a heterocyclic monomer having a nitrogen atom and a carbon atom having an amino group adjacent to each other in the ring as a constituent component is excellent in the uptake of the pyrimidinedione derivative and has been taken up. It was found that the pyrimidinedione derivative was excellent in sustained release.

The hydrogel according to one aspect of the present invention or the hydrogel according to the method according to one aspect of the present invention can efficiently carry a desired amount of a drug such as a pyridine derivative, a pyrimidine derivative, a pyridazine derivative, or a pyrazine derivative, and can support the drug. Since it is a hydrogel that exhibits excellent sustained release of drugs, it can contribute to the health and welfare of those who are expected to undergo drug therapy or regenerative medicine by using it as a medical device such as an ocular lens. ..

Claims (7)

Monocyclic or polycyclic 3- to 12-membered heterocyclic monomers having at least one nitrogen atom in the ring and an atom adjacent to the nitrogen atom in the ring having an amino group.
Hydrophilic monomer and
A hydrogel containing an anionic monomer and <br /> as constituents. The heterocyclic monomer is a vinyl group or the following general formula (1).

(1)
(In the formula, n represents an integer of 0 or 1-5;
Z indicates an oxygen atom or NH group;
R ₁ indicates a hydrogen atom or ₃ CH groups; and
R ₂ and R ₃ independently represent a hydrogen atom, a hydroxyl group, an amino group, or an alkyl group having 1 to 5 carbon atoms. )
The hydrogel according to claim 1 , which has a polymerizable group represented by. The heterocyclic monomer is a heterocyclic monomer having a ring structure selected from the group consisting of a purine ring, a triazine ring, a pyridine ring, an imidazole ring and a pteridine ring, according to any one of claims 1 and 2. The hydrogel described. The method according to any one of claims 1 to 3 , wherein the hydrogel further contains a hydrophobic monomer as a constituent component, or further contains a hydrophobic monomer and a silicone-containing monomer other than the hydrophobic monomer as a constituent component. Hydrogel. Monocyclic or polycyclic 3- to 12-membered heterocyclic monomers having at least one nitrogen atom in the ring and an atom adjacent to the nitrogen atom in the ring having an amino group.
Hydrophilic monomer and
A method for supporting a heterocyclic compound, which comprises a step of contacting a hydrogel containing the above as a constituent component with a heterocyclic compound selected from the group consisting of a pyridine derivative, a pyrimidine derivative, a pyridazine derivative and a pyrazine derivative. Monocyclic or polycyclic 3- to 12-membered heterocyclic monomers having at least one nitrogen atom in the ring and an atom adjacent to the nitrogen atom in the ring having an amino group.
Hydrophilic monomer and
A step of contacting a hydrogel containing the above-mentioned as a constituent component with a heterocyclic compound selected from the group consisting of a pyridine derivative, a pyrimidine derivative, a pyridazine derivative and a pyrazine derivative to obtain a hydrogel carrying the heterocyclic compound. A method for producing a heterocyclic compound-supporting hydrogel, which comprises. Monocyclic or polycyclic 3- to 12-membered heterocyclic monomers having at least one nitrogen atom in the ring and an atom adjacent to the nitrogen atom in the ring having an amino group.
Hydrophilic monomer and
A hydrogel containing a pyridine derivative, a pyrimidine derivative, a pyridazine derivative, and a pyrazine derivative, wherein a heterocyclic compound selected from the group consisting of a pyridine derivative, a pyrimidine derivative, a pyridazine derivative, and a pyrazine derivative is supported by a hydrogen bond.

Images