JPH06306250A - Polymer gel containing working substance - Google Patents

Abstract

PURPOSE:To provide a polymer gel containing an active substance having anionic functional group, firmly holding the active substance in the gel and capable of exhibiting remarkable sustained release effect and easily moldable to a desired form. CONSTITUTION:The polymer gel containing an active substance having anionic substituent is produced by adsorbing and holding the active substance in a copolymer gel produced by copolymerizing a monomer mixture at least containing (A) a (meth)acrylate containing one or more hydroxyl groups and having hydrocarbon group optionally containing ether bond in the chain, (B) a (meth)acrylate having alkyl group or fluorinated alkyl group and (C) a monomer having a quaternary ammonium salt on the side chain.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a polymer gel containing an active substance, and more particularly to a drug delivery system (DD).
The present invention relates to an active substance-containing polymer gel useful for S). The active substance-containing polymer gel of the present invention can be preferably used for, for example, soft contact lenses and DDS for ocular mucosa (eg, product name: Oxate, manufactured by Fujisawa Pharmaceutical Co., Ltd.).

[0002]

2. Description of the Related Art A hydrogel obtained by swelling a polymer having a three-dimensional network structure with an aqueous solvent has elasticity similar to that of a biological system, and therefore has been extensively applied and developed as a medical material. A typical example thereof is a soft contact lens mainly made of polyhydroxyethyl methacrylate or the like, which gives an extremely excellent wearing feeling due to elasticity similar to a living body.

On the other hand, the concept of a drug delivery system (DDS), which realizes an optimum dose and administration method in consideration of the in vivo kinetics of a drug, has been around since 1970, and in recent years, it has been highly functional in a wide range of fields. Research and development for DDS is in progress.

As a means for controlling this type of drug release, there is one described in JP-A-52-56148. That is, a hydrous gel of polyvinyl alcohol (hereinafter referred to as PVA) in the form of an aqueous solution or in a state swollen with water or a previously prepared crosslinked PVA hydrogel is used in the form of a salt form of a carboxyl group, a salt form of a sulfonic acid group, or a salt form. Treated with actinic radiation in the presence of radically polymerizable monomers having an electrolytic group such as a phosphoric acid group or a quaternary ammonium salt group, or a polar group such as an amino group, a carbonyl group, a sulfone group, or a nitro group. P grafted with a monomer having an electrolytic group or a polar group
After forming a water-containing gel of VA, it is impregnated with an active substance such as a drug to obtain an active substance-containing polymer gel. This is because the active substance is incorporated into the network structure of crosslinked PVA and
By introducing an electrolytic group or a polar group into the compound, a weak bond is formed between the electrolytic group or the polar group of the PVA molecule and the functional group in the active substance to delay the release of the active substance. is there.

However, in the above-mentioned active substance-containing polymer gel, an extremely special γ-ray is used as an actinic ray for crosslinking the PVA as a base material. It is not a general method. Moreover, in the active substance-containing polymer gel,
In order to slow down the release rate of the active substance, it is necessary to set the γ-ray irradiation dose high, but due to the increase in crosslink density and the occurrence of side reactions, the polymer gel has a reduced mechanical strength as a material. It was difficult to obtain good sustained release while maintaining good strength.

As a means for solving these problems, there is an invention disclosed in Japanese Patent Application No. 4-293362 filed by the present inventors. That is, after preparing a hydrogel composed of a monomer having 2-hydroxyethyl methacrylate and a quaternary ammonium salt in a side chain, an active substance having an anionic group is strongly retained inside the hydrogel, and an active substance-containing polymer gel is prepared. Is what you get. This is because the base material 2-hydroxyethyl methacrylate is excellent in mechanical strength and processability, and a hydrogel having good strength can be produced, and at the same time, an ammonium group present in the hydrogel and an anion in the active substance are present. It is intended to delay the release of the active substance by forming a bond due to an electrostatic interaction with the functional group to give the active substance a sustained release property.

[0007]

SUMMARY OF THE INVENTION The present invention has been made in order to further improve the invention disclosed in Japanese Patent Application No. 4-293362 filed by the present inventors.
The object of the present invention is to adjust the swelling rate and water content of the hydrogel, which makes it possible to obtain a better sustained release effect, and it is possible to form a desired shape very easily. An object is to provide an active substance-containing polymer gel.

[0008]

The present invention has been made to achieve the above object, and comprises a hydrocarbon group-containing (meth) acrylate containing at least one hydroxyl group and optionally having an intrachain ether bond, Anionic substitution is performed in a copolymer gel obtained by copolymerizing a monomer mixture containing at least a (meth) acrylate having an alkyl group or a fluorinated alkyl group and a monomer having a quaternary ammonium salt in its side chain. It is an active substance-containing polymer gel in which an active substance having a group is adsorbed and held.

The present invention will be specifically described below. Since the active substance-containing polymer gel of the present invention comprises an active substance adsorbed and held in a copolymer gel, the copolymer gel will be described first, and then the active substance will be described.

Copolymer gel A hydrocarbon group-containing (meth) acrylate (hereinafter referred to as "meth" acrylate, which is one of the first monomer components constituting the copolymer gel in the present invention, contains at least one hydroxyl group and optionally has an in-chain ether bond. H (M) A) is, for example, 2-
Examples thereof include hydroxymethyl (meth) acrylate, 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 2,3-dihydroxypropyl (meth) acrylate, and mono (meth) acrylate of 2-polyethylene glycol. However, two or more of them may be used in combination (in the present specification, “(meth) acrylate” means both acrylate and methacrylate). Of these, 2-hydroxyethyl methacrylate (hereinafter referred to as HEMA) is preferable. The reason is that HEMA has excellent processability, and the water content of the hydrogel obtained when used as a comonomer can be easily adjusted.

The (meth) acrylate having an alkyl group or a fluorinated alkyl group, which is the second monomer component constituting the copolymer gel in the present invention, adjusts the swelling rate and the water content of the hydrogel to give an anionic property. It has a function of controlling the release rate of an active substance having a substituent.

The (meth) acrylate having an alkyl group or a fluorinated alkyl group used in the present invention (hereinafter R)
As (M) A)), those represented by the following general formula (I) are preferable.

[0013]

[Chemical 4]

[0014] The above in formula (I), R ₁ is a methyl group or a hydrogen atom, R ₂ is a hydrogen atom, C ₁ -C ₁₂ alkyl group or a fluorine atom C ₁ may be substituted with -C ₁₂
It is an alkyl group.

Specific examples of R (M) A represented by the general formula (I) include, for example, methacrylic acid, methyl (meth) acrylate, ethyl (meth) acrylate, n-propyl (meth) acrylate, isopropyl (meth). Acrylate, n-butyl (meth) acrylate, isobutyl (meth) acrylate, tert-butyl (meth) acrylate, n-hexyl (meth) acrylate, n-octyl (meth) acrylate, n-heptyl (meth) acrylate, n- Nonyl (meth) acrylate, 2,
2,2-trifluoroethyl (meth) acrylate,
2,2,3,3-tetrafluoropropyl (meth) acrylate, 2,2,3,3,3-pentafluoropropyl (meth) acrylate, 1,1,1,3,3,3-hexafluoroisopropyl ( Examples thereof include (meth) acrylate.

The amount of R (M) A added is preferably 1 to 30 mol% based on all monomers. Particularly preferably 3 to 25
It is mol%. If it is less than 1 mol%, the release rate of the active substance having an anionic substituent cannot be controlled due to lack of R (M) A, and if it exceeds 30 mol%, the swelling rate and water content of the hydrogel are significantly lowered. ,
In some cases, the active substance having an anionic substituent may be difficult to be released.

In the present invention, the third monomer component constituting the copolymer gel, that is, the monomer having a quaternary ammonium salt in the side chain, the quaternary ammonium ion in the hydrogel has an anionic group due to ionic interaction. It has a function of strongly retaining the active substance it has and exhibiting a remarkable sustained-release effect.

The monomer having a quaternary ammonium salt in the side chain used in the present invention is a vinylbenzyltrialkylammonium salt represented by the following general formula (II):
Alternatively, ethyl (meth) acrylate represented by the following general formula (III) is preferable.

[0019]

[Chemical 5]

[Chemical 6] In the above general formulas (II) and (III), R ₃ and R ₆
Is a C ₅ -C ₁₂ alkyl group, R ₄ , R ₅ , R ₇ and R ₈ are the same or different C ₁ -C ₂ alkyl groups, or
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are the same or different C _{1 to} C ₄ alkyl groups, and in general formula (III),
X is a methyl group or a hydrogen atom. That is, among the three alkyl groups in the general formulas (II) and (III), 1
When one alkyl group becomes a long-chain alkyl group having 5 to 12 carbon atoms, the remaining two alkyl groups are limited to one or two extremely short-chain alkyl groups, but three alkyl groups. When all the groups are short-chain alkyl groups having 4 or less carbon atoms, the number of carbon atoms in these alkyl groups can range from 1 to 4.

Examples of the vinylbenzyltrialkylammonium salt represented by the general formula (II) include vinylbenzyltrimethylammonium salt (particularly ammonium chloride), vinylbenzyltriethylammonium salt (particularly ammonium chloride), vinylbenzyldimethylethylammonium salt ( Particularly, ammonium chloride), vinylbenzyldimethylisopropylammonium salt (particularly ammonium chloride), vinylbenzyl n-butyldimethylammonium salt (particularly ammonium chloride), vinylbenzyldimethylpentylammonium salt (particularly ammonium chloride) and the like can be mentioned.

Ethyl (meta) represented by the general formula (III)
Examples of the acrylate include 2-methacryloxyethyltrimethylammonium salt (particularly ammonium chloride), 2-methacryloxyethyldimethylethylammonium salt (particularly ammonium chloride), 2-methacryloxyethyldimethyl n-pentylammonium salt (particularly ammonium chloride). , 2-acryloylethyltrimethylammonium salt (especially ammonium chloride), 2-acryloylethyldimethylethylammonium salt (especially ammonium chloride), 2-acryloylethyltriethylammonium salt (especially ammonium chloride), 2-acryloylethyldimethyl n-pentylammonium Examples thereof include salts (particularly ammonium chloride).

The amount of H (M) A, R (M) A and the monomer having a quaternary ammonium salt in the side chain (composition ratio) is the molar concentration of the monomer having a quaternary ammonium salt in the side chain. C], H (M) A molar concentration [H], R
(M) Molar concentration of A is [R], monomer composition ratio (F) =
([C] / ([H] + [R] + [C])),
It is preferably in the range of 0.001 ≦ F ≦ 0.1. Particularly preferably, 0.005 ≦ F ≦ 0.05. 0.
When it is less than 001, [H] and [R] in the hydrogel are
The amount of [C] is small, and the amount of the active substance retained is small, and when it exceeds 0.1, the mechanical strength of the resulting hydrogel may decrease.

In the present invention, a crosslinkable monomer may be used as a constituent component of the copolymer gel in addition to the above essential components. The crosslinkable monomer is used for the purpose of forming a network structure of the hydrogel and further improving the mechanical strength of the gel, and includes bismethyleneacrylamide, ethylene glycol dimethacrylate (hereinafter abbreviated as EDMA), 2-hydroxy-1,3-. Examples thereof include dimethacryloxypropane and trimethylolpropane triacrylate.

The amount of the crosslinkable monomer used is preferably 0.1 to 10 mol% based on all the monomers. Particularly preferably, it is 0.1 to 3 mol%. If the amount is less than 0.1 mol%, the shape retention of the hydrogel tends to be deteriorated due to lack of cross-linking monomer, and if the amount exceeds 10 mol%, the number of cross-linking points increases, resulting in brittleness and deterioration of mechanical strength. Processing may be difficult.

In the present invention, a hydrophilic monomer can be used as an optional component as a constituent component of the copolymer gel. This hydrophilic monomer has the function of adjusting the water content of the resulting hydrogel, and may also contribute to the adjustment of the amount of the active substance adsorbed on the hydrogel.

The hydrophilic monomer is a hydrophilic monomer having biocompatibility and excellent compatibility with monomers having H (M) A, R (M) A and a quaternary ammonium salt in its side chain. Any material can be used, but N, N-dimethylacrylamide, N, N-dimethylmethacrylamide, vinylpyrrolidone and the like are preferable.

Agents In the present invention, the agent to be adsorbed and retained in the above-mentioned copolymer gel includes a substituent having a carboxylic acid group, a sulfonic acid group, a phenolic hydroxy group or a salt structure thereof in the molecular structure. Any one having a selected anionic substituent can be used, but when the active substance-containing polymer gel is used as an ocular wear product, one that exhibits a preferable pharmacological effect is, for example, sodium prednisolone phosphate. , Dexamethasone sodium phosphate,
Dexamethasone metasulfobenzoate, dexamethasone sodium sulfate (adrenocortical hormone agent), sodium sulfenicillin, carbenicillin sodium (antibiotic), dipotassium glycyrrhizinate, sodium guaizulenesulfonate (nonsteroidal anti-inflammatory agent), sodium cromoglycate (antiallergic agent) ), Glutathione, catalin (therapeutic agent for cataract), N-acetyl cysteine (an agent for promoting corneal healing) and the like.

The active substance-containing polymer gel of the present invention can be used for various purposes other than the above-mentioned eyewear. Such applications include various drug delivery systems (DDS),
Examples include sterilizing sheets, insecticidal sheets, poultices, etc., and the active substance to be used is also appropriately selected according to each application.

As an example of the use of the active substance-containing polymer gel of the present invention, when used as an eyewear, the present invention impregnated with a drug such as an anti-inflammatory agent when there is a lesion such as inflammation of the eye If a soft contact lens made of the active substance-containing polymer gel is attached to the eye, effects such as treatment of the eye can be expected with or without the contact lens.

In the field of other medicines, a patch of nitroglycerin for treating angina, a patch of scopolamine for sickness prevention, etc. are well known and put into practical use. In addition, it is difficult to keep the blood level constant by oral administration such as diabetes, high blood pressure, and menopause, and at the same time, a drug whose rapid increase in blood level poses a risk to the patient can be used for a long time. There is also a lot of research on adhesive patches that can be supplied in Japan.

The active substance-containing polymer gel of the present invention is extremely useful as a so-called "transdermal drug" for administering the above-mentioned drug expected to be sustained release to the living body.

In addition, molds and the like tend to be generated due to moisture and the like in the household indentation, and insects that feed on the fibers of clothes are also likely to be generated. As a means for controlling these molds and insects over a long period of time, a sheet impregnated with a bactericidal agent or an insecticide has been put on the market and is now widely used.

When a bactericidal agent and an insecticide are present in the air at a high concentration, they adversely affect humans such as poisoning, but if they are held in the active substance-containing polymer gel of the present invention, they are released into the air in trace amounts, A bactericidal or insecticidal effect can be obtained over a long period of time at an air concentration that is safe for humans.

The active substance-containing polymer gel of the present invention can be applied in various situations in daily life as described above.

Next, the method for producing the active substance-containing polymer gel of the present invention will be described by taking an eyewear as an example. In producing the hydrogel for an eyewear of the present invention, first, a polymerization initiator is added to the above mixture of monomers and sufficiently stirred to form a homogeneous monomer mixture liquid.

As the radical polymerization initiator used here, peroxides such as lauroyl peroxide, cumene hydroperoxide and benzoyl peroxide, which are known as general radical polymerization initiators, azobisvaleronitrile and azo are known. Although bisisobutyronitrile (hereinafter abbreviated as AIBN) can be used, AIBN is preferable among them. The amount of the initiator used is preferably about 0.02 to 0.5 mol% with respect to the total amount of the monomers.

Then, the above-mentioned mixed solution is placed in a container having a desired shape such as metal, glass, or plastics, and the container is sealed, and in a thermostat or the like 25 to 1 stepwise or continuously.
The temperature is raised in the temperature range of 20 ° C. and the polymerization is completed in 12 to 120 hours. At the time of polymerization, it is also possible to apply a photopolymerization method using ultraviolet rays or visible rays. It is also possible to mix the above-mentioned monomer mixed liquid with an organic solvent and perform solution polymerization. As the organic solvent at this time, for example, methanol, ethanol, acetone or the like is preferable. Next, after the completion of the polymerization, it is cooled to room temperature, the obtained polymer is cut, and then, if necessary, it is polished to obtain a desired shape. The desired shape at this time may be, for example, a normal contact lens shape, an eye-wearable shape similar thereto, a film shape, or a sheet shape. Further, for example, by previously performing the above-mentioned polymerization operation in a container having a desired shape such as a container having a substantially contact lens shape, it becomes unnecessary to perform cutting and polishing.

Then, the polymer having a desired shape is hydrated and swollen to form a hydrogel. Examples of the liquid used for the hydration swelling (hereinafter referred to as hydration liquid) include water,
Examples include physiological saline and isotonic buffer. By heating the hydration solution and immersing the polymer under the conditions of a temperature of 40 ° C. to 100 ° C. and atmospheric pressure, the hydrated and swollen state can be rapidly obtained.

By the hydration swelling treatment, the residual monomers contained in the polymer can be removed at the same time.

Next, an active substance solution in which an active substance having an anionic substituent is dissolved is prepared, and the hydrogel is immersed in the active substance solution to impregnate the active substance into the hydrogel. , A hydrogel in which the active substance is adsorbed and retained is obtained.

The solvent used to dissolve the active substance includes water, a hydrophilic solvent, and a mixed solvent of water and a hydrophilic solvent. Examples of the hydrophilic solvent include methanol, ethanol, isopropanol, and the like. Examples thereof include alcohols such as n-butanol, dimethyl sulfoxide, and the like. Examples of the mixed solvent of water and the hydrophilic solvent include a mixed solvent of water and alcohol, a mixed solvent of water and dimethyl sulfoxide, and the like.

The concentration of the active substance contained in the active substance solution depends on the solubility of the active substance, the minimum effective concentration for exhibiting a medicinal effect as a drug, the maximum safe concentration, etc.
Although it is appropriately determined for each active substance, 1.
0 × 10 ⁻⁶ (mol / l) to 1.0 × 10 ⁻² (mol / l)
The concentration of l) is generally preferred.

[0043]

EXAMPLES The present invention will be further described below with reference to examples, but the present invention is not limited to these examples.

Example 1 23.7 g of HEMA (0.
182 mol), methyl methacrylate (hereinafter abbreviated as MMA) 2 g (0.02 mol), vinylbenzyltrimethylammonium salt (hereinafter abbreviated as QBm) 0.42 g
(0.002 mol), EDMA 0.202 g (0.5 mol% based on all monomers), AIBN 0.027 g
(0.08 mol% with respect to all monomers) was added, and the mixture was stirred for 1 hour while sufficiently substituting with nitrogen. At this time, the monomer composition ratio is F = 0.01. After completion of stirring, the mixture was put in a polyethylene container (diameter 15 mm, height 17 mm) and polymerized at 50 to 100 ° C. for 72 hours. The polymer was taken out of the container, cut into a flat disk shape having a diameter of 13 mm and a thickness of 0.5 mm, and the surface thereof was polished to obtain a smooth transparent flat disk. The flat disk was immersed in distilled water at 80 ° C. for 2 hours for hydration and swelling to form a hydrogel, and residual monomers in the hydrogel were removed. Distilled water 10m
5.12 mg (1 × 10 ⁻⁵ mol) of sodium cromoglycate (hereinafter abbreviated as DSCG) as an active substance in 1
In addition, the hydrogel was placed in 10 ml of an aqueous DSCG solution obtained by mixing and stirring, and was immersed at 25 ° C. for 24 hours to adsorb DSCG in the hydrogel. Then DSC
By immersing the hydrogel having G adsorbed therein in 50 ml of distilled water at 37 ° C. for 48 hours, free DSCG not bound to the cation in the hydrogel was released.

[Measurement of linear swelling rate and water content of polymer]
A polymer having a dry size of 13 mm in diameter and 0.5 mm in thickness was immersed in distilled water at 25 ° C. for 48 hours (confirmed to be parallel swelling), and the diameter of the polymer before hydration swelling (D
d), diameter after hydration and swelling (Dw), weight after hydration and swelling (Wω) and weight after re-drying (Wd) were measured, and linear swelling rate (hereinafter referred to as swelling rate) and water content were calculated from the following equations. The rate was calculated. Swelling rate (%) = [(Dw−Dd) × 100] / Dd Moisture content (%) = [(Wω−Wd) × 100] / Wω

[Measurement of Adsorption Amount of DSCG Adsorbed on Hydrogel] As described above, the hydrogel was immersed in 10 ml of an aqueous DSCG solution (1.0 × 10 ⁻³ (mol / l)) at 25 ° C. for 24 hours. (It has been confirmed that it is equilibrium adsorption)
After that, in order to measure the adsorption amount of DSCG adsorbed in the hydrogel, the DSCG aqueous solution residual liquid (liquid A) after soaking for 24 hours and the hydrogel having DSCG adsorbed therein were soaked in distilled water for 48 hours, and then For distilled water containing released free DSCG (Liquid B), wavelength 239n
The DSCG content of each of the liquid A and the liquid B was quantified by measuring the absorbance of DSCG at m, and the difference was calculated to calculate the amount of D bound to the cation in the hydrogel.
The amount of SCG adsorbed was determined. The spectrophotometer used was U-3210 manufactured by Hitachi, Ltd. The amount of DSCG adsorbed in the hydrogel of this example was 0.218 × 10 ⁻⁴ (m
ol / g).

[Change in DSCG Release Amount Released from Hydrogel Adsorbing DSCG with Time] The hydrogel whose DSCG adsorption amount was measured as described above was immersed in 20 ml of physiological saline at 37 ° C. The immersion liquids were sampled over time (1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 24 hours, 48 hours and 72 hours) and the D at wavelength 239 nm for them was sampled.
By measuring the absorbance of SCG, DS in the immersion liquid
DS released from hydrogel by quantifying CG content
The total amount of CG released (DSCG cumulative release amount) was determined, and the percentage relative to the amount of DSCG adsorbed was shown as the DSCG release rate released from the hydrogel.

The release rate of DSCG from the hydrogel of this example was as follows. Elapsed time Release rate 1 hour later 23.2% 2 hours later 31.8% 3 hours later 38.4% 4 hours later 44.6% 5 hours later 49.6% 24 hours later 84.0% 48 hours later 94 . 1% 72 hours later 97.8%

Example 2 In the same manner as in Example 1, AIBN was added to a monomer mixture consisting of HEMA, MMA, QBm and EDMA for radical polymerization, and the resulting polymer was hydrated and swollen to obtain a hydrogel. It was The amounts of the monomer, the crosslinkable monomer and the radical polymerization initiator are shown in Table 1. Then, the same operation as in Example 1 was performed on the obtained hydrogel to adsorb DSCG in the hydrogel, and then to release free D not bound to the cation in the hydrogel.
The SCG was released. DSCG adsorbed on hydrogel
Measurement of adsorption amount and DSC released from hydrogel
The total G release amount was measured in the same manner as in Example 1. Table 2 shows the swelling ratio of the polymer, the water content measurement result, and the DSCG adsorption amount adsorbed on the hydrogel. The time-dependent change in the DSCG release rate released from the hydrogel is shown in FIG.

Examples 3 to 4 In the same manner as in Example 1, AIBN was added to a monomer mixture consisting of HEMA, n-butyl methacrylate (hereinafter abbreviated as BMA), QBm and EDMA to carry out radical polymerization to obtain a polymer. Was hydrated and swollen to obtain hydrogels of Examples 3 to 4. The amounts of the monomer, the crosslinkable monomer and the radical polymerization initiator are shown in Table 1. Then, Example 1 was applied to the obtained hydrogel.
The same operation as above was carried out, and DS was added to the hydrogel of each Example.
The CG was adsorbed and then free DSCG not bound to the cations in the hydrogel was released. The measurement of the amount of DSCG adsorbed on the hydrogel and the measurement of the total amount of DSCG released from the hydrogel were carried out in the same manner as in Example 1. Table 2 shows the swelling rate of the polymer, the water content measurement result, and the DSCG adsorption amount adsorbed on the hydrogel.
It was shown to. In addition, DSCG released from hydrogel
The change with time in the release rate is shown in FIG.

Examples 5 to 6 In the same manner as in Example 1, HEMA, 2,2,2-trifluoroethyl methacrylate (hereinafter abbreviated as 3FE), Q
AIB in a monomer mixture consisting of Bm and EDMA
N was added and radical polymerization was performed, and the obtained polymer was hydrated and swollen to obtain hydrogels of Examples 5 to 6. The amounts of the monomer, the crosslinkable monomer and the radical polymerization initiator are shown in Table 1. Then, the same operation as in Example 1 was performed on the obtained hydrogel to adsorb DSCG in the hydrogel of each Example, and then to release free DSCG not bound to the cation in the hydrogel. It was The measurement of the amount of DSCG adsorbed on the hydrogel and the measurement of the total amount of DSCG released from the hydrogel were carried out in the same manner as in Example 1. Table 2 shows the swelling ratio of the polymer, the water content measurement result, and the DSCG adsorption amount adsorbed on the hydrogel. In addition, the change with time of the release rate of DSCG released from the hydrogel is shown in FIG.

Reference Example 1 According to the description of Japanese Patent Application No. 4-293362, which is the prior application of the present inventors, an ampoule tube having a capacity of 50 ml was charged with the composition shown in Table 1.
25.7 g of HEMA (0.198 mo
l), QBm 0.42 g (0.002 mol), EDM
A 0.198 g (0.5 mol based on all monomers)
%), AIBN 0.026 g (0.
(08 mol%) was added, and the mixture was stirred for 1 hour while sufficiently substituting with nitrogen. After completion of stirring, the hydrogel of Reference Example 1 was obtained in the same manner as in Example 1. The same operation as in Example 1 was performed on this hydrogel to adsorb DSCG in the hydrogel, and then release the free DSCG not bound to the cation in the hydrogel. The measurement of the amount of DSCG adsorbed on the hydrogel and the measurement of the total amount of DSCG released from the hydrogel were carried out in the same manner as in Example 1. Table 2 shows the swelling ratio of the polymer, the water content measurement result, and the DSCG adsorption amount adsorbed on the hydrogel. Further, changes in the DSCG release rate released from the hydrogel with time are shown in FIGS.

[0053]

[Table 1]

[0054]

[Table 2] As shown in Table 2, as compared with Reference Example 1, Examples 1 to 6
It can be seen that the hydrogels of the respective examples 1 and 2 have almost no difference in the DSCG adsorption amount, although the swelling rate and the water content are reduced. As shown in the release rate curves of FIGS. 1 to 3, most of DSCG adsorbed in the hydrogel was released from the hydrogel of Reference Example 1 in 24 hours. On the other hand, in Examples 1 to 6, all 7
It showed extremely remarkable sustained release over a long period of about 2 hours.

This is because, by introducing R (M) A into the high-gel gel, the diffusion rate of DSCG in the hydrogel was suppressed and a remarkable sustained release property as shown in FIGS. 1 to 3 was obtained. Is.

[0056]

INDUSTRIAL APPLICABILITY According to the present invention, an active substance having an anionic functional group is strongly retained inside the hydrogel, and the swelling rate and water content of the hydrogel are adjusted to exert a remarkable sustained release effect. It is possible to obtain an active substance-containing polymer gel which can be molded into a desired shape very easily. Therefore, the active substance-containing polymer gel of the present invention can be used in various drug delivery systems (DD).
S), a sterilizing sheet, an insecticidal sheet, a poultice, etc. are preferably used, but in particular, they are preferably used as an eyewear, for example, a DDS for soft contact lenses and ocular mucosa.

[Brief description of drawings]

FIG. 1 is a comparative diagram of changes with time of the DSCG release rate released from the hydrogels obtained in Examples 1 and 2 and Reference Example 1.

FIG. 2 is a comparison diagram of changes with time of the DSCG release rate released from the hydrogels obtained in Examples 3 to 4 and Reference Example 1.

FIG. 3 is a comparative diagram of changes with time of the DSCG release rate released from the hydrogels obtained in Examples 5 to 6 and Reference Example 1.

Claims (8)

[Claims] 1. A hydrocarbon group-containing (meth) acrylate having at least one hydroxyl group and optionally having an in-chain ether bond, a (meth) acrylate having an alkyl group or a fluorinated alkyl group, and a quaternary ammonium salt. A polymer gel containing an active substance, wherein an active substance having an anionic substituent is adsorbed and retained in a copolymer gel obtained by copolymerizing a monomer mixture containing at least a monomer having a chain. . 2. The active substance-containing polymer gel according to claim 1, wherein the hydrocarbon group-containing (meth) acrylate having at least one hydroxyl group and optionally having an in-chain ether bond is 2-hydroxyethyl methacrylate. 3. The active substance-containing polymer gel according to claim 1, wherein the monomer having an alkyl group or a fluorinated alkyl group is a (meth) acrylate represented by the following general formula (I). [Chemical 1] [In the formula, R ₁ is a methyl group or a hydrogen atom, R ₂ is a hydrogen atom, C ₁ -C ₁₂ alkyl group or optionally substituted with fluorine atoms C ₁ -C ₁₂ alkyl group. ] 4. The active substance-containing polymer gel according to claim 1, wherein the monomer having a quaternary ammonium salt in a side chain is a vinylbenzyltrialkylammonium salt represented by the following general formula (II). [Chemical 2] [Wherein R ₃ is a C _{5 to} C ₁₂ alkyl group, R ₄ and R ₅ are the same or different C _{1 to} C ₂ alkyl groups, or
R ₃ , R ₄ and R ₅ are the same or different C ₁ -C ₄ alkyl groups. ] 5. The active substance-containing polymer gel according to claim 1, wherein the monomer having a quaternary ammonium salt in a side chain is ethyl (meth) acrylate represented by the following general formula (III). [Chemical 3] [In the formula, X is a methyl group or a hydrogen atom, and R ₆ is C _{5 to} C ₁₂
Alkyl groups, R ₇ and R ₈ are the same or different and are C ₁ -C ₂
It is an alkyl group or R ₆ , R ₇ and R ₈ are the same or different C ₁ -C ₄ alkyl groups. ] 6. An agent having an anionic substituent,
The organic compound having at least one anionic substituent selected from the group consisting of a carboxylic acid group, a sulfonic acid group, a phenolic hydroxy group, and a substituent having a salt structure thereof in the molecule. The polymer gel containing the active substance according to 1. 7. The agent-containing polymer gel according to claim 1, wherein the monomer mixture further contains at least one crosslinkable monomer. 8. The method according to claim 1, which is used as an eyewear.
7. The active substance-containing polymer gel according to claim 7.