JP3167057B2 - Temperature-responsive hydrogel - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a high-strength temperature-responsive hydrogel capable of delivering a required amount of a drug to a required place by a temperature change only when needed.

[0002]

2. Description of the Related Art Conventionally, administration of drugs to animals, including humans,
For administration of pesticides to plants and pests, supply of catalysts for chemical reactions, etc., release of fragrances to foul odor environments, etc., dosage of drugs with fast decomposition rate, drugs with poor stability, drugs with short onset of drug effect, etc. And it is difficult to control the amount of release.

On the other hand, in recent years, basic and practical research on a drug which acts in a necessary amount at a necessary place and only when necessary, that is, a so-called drug delivery system (DDS) has been actively conducted. Practical applications include scopolamine for motion sickness, nitroglycerin for the treatment of angina, and other nitrites, transdermal preparations such as nicotine for smoking cessation, and diazinon. And microcapsule-type preparations of agricultural chemicals.

[0004] However, most of them merely aim at sustained release of the drug, and do not fulfill the entire concept of DDS.

[0005] Recently, research has begun on the use of a stimulus-responsive hydrogel to realize an ideal DDS that releases a required amount of a drug to a required place only when a stimulus is applied to a preparation. I have. In particular, attention has been paid to a temperature-responsive DDS represented by an N-alkyl-substituted (meth) acrylamide-based hydrogel.

[0006]

However, these hydrogels have a problem in that they generally have low mechanical strength and cannot be put to practical use.

Accordingly, it is an object of the present invention to provide a high-strength temperature-responsive hydrogel capable of controlling the release of a drug in response to a predetermined temperature change.

[0008]

Means for Solving the Problems The present inventors have made intensive studies to solve the above problems, and as a result, have found that N-substituted (meth) acrylamide monomer is particularly useful for controlling the release of a drug. A high-strength temperature-responsive hydrogel containing a polymer insoluble in water and having as a main polymerization component was found, and the present invention was completed.

That is, the present invention provides: A water-insoluble polymer obtained by polymerizing an N-alkyl or N-alkylene-substituted (meth) acrylamide monomer (alkylene may be interrupted by an ether bond) as a main component; The breaking strength at the time of equilibrium swelling with water at a temperature below the temperature is
A temperature-responsive hydrogel of 1.0 kg / cm ² or more,

[0010] 2. A water-insoluble polymer obtained by polymerizing an N-alkyl or N-alkylene-substituted (meth) acrylamide monomer (alkylene may be interrupted by an ether bond) as a main component; 2. a temperature-responsive hydrogel, which is an alternating infiltration network polymer structure composed of a water-insoluble polymer having a monomer as a polymer component; A compound represented by the formula (1) and / or a compound represented by the formula (2), wherein the N-alkyl or N-alkylene-substituted (meth) acrylamide monomer is

[0011]

Embedded image

(Wherein R ₁ is a hydrogen atom or a methyl group,
R ₂ and R ₃ represent a hydrogen atom or a lower alkyl group;
R ₂ and R ₃ may be the same or different, but at least one of them represents a lower alkyl group. )

[0013]

Embedded image

(Wherein R ₁ is a hydrogen atom or a methyl group,
A is n is 4-6 or _{(CH 2) n (CH 2} ) 2 O
(CH ₂ ) ₂ is shown. 3.) The temperature-responsive hydrogel according to 1 or 2 above, 4. A temperature-responsive hydrogel according to the above item 1, 2 or 3 for controlling drug release.

In the present invention, the term “temperature-responsive hydrogel” refers to a hydrogel having a phase transition temperature, absorbs water at a temperature lower than the phase transition temperature and swells, and releases water at a temperature higher than the phase transition temperature. Refers to a gel that can shrink by shrinkage.

This swelling and shrinking behavior occurs reversibly in the presence of water. Furthermore, since this reversible change is surface-limited, a quick change can be made.

In the temperature-responsive hydrogel of the present invention, in a swelling state, substances such as drugs are easily diffused through water existing in the hydrogel and released to the outside of the system. Water is depleted, diffusion of the substance is suppressed, and release to the outside of the system is stopped.

Therefore, when the temperature-responsive hydrogel of the present invention is applied to the control of drug release, the presence of water is an essential condition. However, it is not necessary to use only water.
Even if a mixed solution of 0% or less of various surfactants or 50% or less of an organic solvent and water is used, the hydrogel has the above-mentioned temperature responsiveness and can control the release of the drug.

In general, the release control method can be classified into a reservoir type in which the drug and the release control member are separated and a monolithic type in which the drug is dispersed in the liquid or solid state in the release control member. The temperature responsive type hydrogel can be applied to any of the two methods as a release control member by forming it into a film, plate, fiber, or the like as necessary.

That is, when applied to a reservoir type,
When the external temperature is lower than the phase transition temperature, the hydrogel is in a swelling state and the drug permeates the membrane and is released to the outside.When the external temperature is higher than the phase transition temperature, the hydrogel is in a contracted state and the drug is The film cannot pass through the membrane, and the release to the outside stops.

Also, by dispersing the drug in the hydrogel, a monolithic type can be easily prepared. As described above, the surface of the hydrogel is rate-determined by a change in temperature, so that the hydrogel is in contact with the environment. When the temperature is lower than the phase transition temperature, the drug in the hydrogel diffuses and is released to the environment. When the temperature is higher than the phase transition temperature, the surface shrinks, so that the diffusion of the drug is suppressed and the release to the environment is stopped.

A typical example of the temperature-responsive hydrogel is a water-insoluble polymer obtained by polymerizing the compound represented by the formula (1) and / or the compound represented by the formula (2) as a main component. An alternately infiltrated network polymer structure of a coalesced polymer and a water-insoluble polymer having a vinyl monomer as a polymerization component can be exemplified.

Such a structure may be, for example, a water-insoluble polymer obtained by polymerizing the compound represented by the above formula (1) and / or the compound represented by the formula (2) as a main component.
After impregnating with a solution containing one or more vinyl monomers,
It is obtained by polymerization and insolubilization in water.

Specific examples of the compound represented by the formula (1) or (2) include N-methylacrylamide and N-methylacrylamide.
-N-propylacrylamide, N-isopropylacrylamide, N-ethylacrylamide, N, N-dimethylacrylamide, N-acryloylpyrrolidine, N
-Acryloylpiperidine, N-acryloylmorpholine, Nn-propylmethacrylamide, N-isopropylmethacrylamide, N-ethylmethacrylamide,
N, N-dimethylmethacrylamide, N-methacryloylpyrrolidine, N-methacryloylpiperidine, N-methacryloylmorpholine and the like can be mentioned.

The above-mentioned compounds can be used in combination with other monomers copolymerizable therewith, and such monomers include hydrophilic monomers and hydrophobic monomers. And one or more monomers thereof can be used.

Specifically, examples of the hydrophilic monomer include acrylamide, methacrylamide, diacetone acrylamide, hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, N-vinyl-2-pyrrolidone, Various methoxy polyethylene glycol acrylates, various methoxy polyethylene glycol methacrylates,

Acrylic acid, methacrylic acid, vinylsulfonic acid, allylsulfonic acid, methacrylsulfonic acid, styrenesulfonic acid, 2-acrylamido-2-phenylpropanesulfonic acid, 2-acrylamido-2-methyl-
Acids such as propanesulfonic acid and salts thereof, amines such as N, N-dimethylaminoethyl methacrylate, N, N-dimethylaminoethyl acrylate, N, N-dimethylaminopropyl methacrylamide, N, N-dimethylaminopropyl acrylamide And salts thereof.

As the hydrophobic monomer, for example, Nn-
Butylacrylamide, Nt-butylacrylamide, Nn-hexylacrylamide, Nn-octylacrylamide, Nt-octylacrylamide,
Nn-dodecyl acrylamide, Nn-butyl methacrylamide, Nt-butyl methacrylamide, N-
n-hexyl methacrylamide, Nn-octyl methacrylamide, Nt-octyl methacrylamide, N
N-alkyl (meth) acrylamide derivatives such as -n-dodecyl methacrylamide,

N, N-diglycidylacrylamide, N
-(4-glycidoxybutyl) acrylamide, N-
(5-glycidoxypentyl) acrylamide, N-
(6-glycidoxyhexyl) acrylamide, N, N
N- (ω) such as diglycidyl methacrylamide, N- (4-glycidoxybutyl) methacrylamide, N- (5-glycidoxypentyl) methacrylamide, N- (6-glycidoxyhexyl) methacrylamide; -Glycidoxyalkyl) (meth) acrylamide derivatives,

(Meth) acrylate derivatives such as ethyl acrylate, methyl methacrylate, butyl methacrylate, butyl acrylate, lauryl acrylate, 2-ethylhexyl methacrylate, glycidyl acrylate, glycidyl methacrylate, acrylonitrile, methacrylonitrile, vinyl acetate, vinyl chloride, vinyl chloride, ethylene, Olefins such as propylene and butene, styrene, α-methylstyrene, butadiene, isoprene and the like,
Can be mentioned.

When a hydrophobic monomer is used, after copolymerization with the formula (1) or (2), if necessary, the structural portion derived from the hydrophobic monomer in the copolymer is hydrolyzed, The copolymer may be provided with hydrophilicity.

As a method for obtaining a water-insoluble polymer from the above-mentioned monomers, there are a method of insolubilizing at the time of polymerization and a method of insolubilizing by a treatment after polymerization. Any method may be used as long as the finally obtained polymer becomes insoluble in water.

Specifically, a method of copolymerizing with a crosslinkable monomer having at least two double bonds in a molecule (first method), a method of introducing a polyvalent copolymer into an ionic functional group-introduced copolymer. A method of adding a metal ion to form an ion-bonding complex (second method), a method of reacting a copolymer into which a hydroxyl group or an amino group is introduced with a polyfunctional compound such as epichlorohydrin or glutaraldehyde to crosslink ( Third method), a method of self-crosslinking by increasing the monomer concentration and performing rapid polymerization (fourth method), a method of cross-linking by irradiating light or radiation (fifth method), and the like. be able to.

As the crosslinkable monomer used in the first method,
For example, N, N'-methylenebisacrylamide, N,
N'-diallylacrylamide, N, N'-diacryloylimide, N, N'-dimethacryloylimide, triallyl formal, diallyl naphthalate, ethylene glycol diacrylate, ethylene glycol dimethacrylate, various polyethylene glycol di (meth) acrylates , Propylene glycol diacrylate, propylene glycol dimethacrylate, various polypropylene glycol di (meth) acrylates,

1,3-butylene glycol diacrylate, 1,3-butylene glycol dimethacrylate,
1,4-butylene glycol dimethacrylate, various polybutylene glycol di (meth) acrylates, glycerol dimethacrylate, neopentyl glycol dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, tetramethylolmethanetetramethacrylate, divinylbenzene, etc. And the like, but are not particularly limited thereto. Preferred crosslinking monomers are compounds having two or more acryloyl groups, methacryloyl groups and / or allyl groups in total.

In the second method, an anionic monomer such as (meth) acrylic acid or vinyl sulfonic acid or a cationic monomer having a quaternary ammonium base or the like and a compound represented by the formula (1) And / or insoluble in water by forming an ionic bonding complex from a polymer obtained by copolymerizing the compound represented by the formula (2) with a polyvalent cationic or polyvalent anionic compound.

In the third method, the amino group can be introduced by copolymerization, and the hydroxyl group can be introduced by copolymerization with hydroxymethacrylate or the like or by hydrolysis after copolymerization with vinyl acetate or the like. These amino groups or hydroxyl groups can be reacted with a polyfunctional compound such as epichlorohydrin or glutaraldehyde in the presence of a basic or acidic catalyst to make them insoluble in water.

In the fourth method, the compound represented by the formula (1) and / or the compound represented by the formula (2) or an acrylic acid salt or the like is rapidly polymerized or copolymerized at a high concentration to form self-crosslinking. To make it insoluble in water.

In the fifth method, after the compound represented by the formula (1) and / or the compound represented by the formula (2) or a monomer copolymerizable with these compounds is polymerized or copolymerized, the light is It can be insolubilized by adding a polymerization initiator or the like and irradiating ultraviolet rays or gamma rays or the like, or by adding a photopolymerization initiator or the like to a monomer before polymerization and irradiating it with ultraviolet rays or gamma rays or the like. Can be insolubilized.

The compound represented by the formula (1) and / or the compound represented by the formula (2) is used in all monomers to be polymerized.
It is preferably used in an amount of at least 50 mol%, particularly preferably at least 50 mol%. The crosslink density (the ratio of the number of crosslinked structural units to the total number of structural units in the polymer) is preferably in the range of 0.1 to 10%, particularly preferably 0.5 to 3%. is there.

The temperature-responsive hydrogel obtained as described above may be in the form of a block, pellet, film, fiber,
It can be used in the form of particles, flakes or the like. Depending on how the temperature-responsive hydrogel is used or the environment in which it is applied,
It cannot be uniformly defined because it is determined appropriately.

The method of molding can be (1) a method of molding at the same time as the polymerization, and (2) a method of molding after the polymerization, and is not particularly limited as long as the desired shape is finally obtained. Specifically, in the method (1),
A method in which a monomer having a desired shape is cast and polymerized and molded, a method in which a material having a desired shape is impregnated or coated with a monomer and polymerized or graft-polymerized, and a method in which a monomer is molded. Examples include a method of molding by polymerization after maintaining a stable shape with a dispersant or the like,
In the method (2), a method of forming a polymer into a desired shape by pulverization, cutting, or the like can be given.

At this time, as a method for initiating the polymerization,
Although it can be carried out only by heating, the use of a polymerization initiator generally gives better results. The polymerization initiator is not limited as long as it has the ability to initiate radical polymerization, and examples thereof include inorganic peroxides, organic peroxides, combinations of those peroxides and reducing agents, and azo compounds. No.

Specifically, hydrogen peroxide, potassium persulfate, ammonium persulfate, benzoyl peroxide, t
There are peroxides such as -butyl peroxide, t-butyl peroxy-2-ethylhexanoate and butyl perbenzoate, and as a reducing agent to be used in combination therewith, a sulfite,
Examples thereof include bisulfite, salts such as iron, cobalt, and copper, organic acids such as ascorbic acid, and organic amines such as aniline. Examples of the azo compound include azobisisobutyronitrile, 2,2′-azobis-2-amidinopropane hydrochloride, and 2,2′-azobis-2,4-dimethylvaleronitrile.

The addition amount of these polymerization initiators is sufficient within the range employed in ordinary radical polymerization. For example, 0.01 to 5% by weight, preferably 0.05 to 5% by weight, based on the monomer.
It is in the range of 2% by weight. The polymerization temperature and the polymerization time vary depending on the type of initiator used, but each is usually 4 to
90 ° C., preferably 40-80 ° C., and usually 1-72
Hours, preferably 12 to 48 hours. The gel thus obtained can be washed by impregnating the gel with a solvent capable of dissolving unreacted substances and allowing the gel to swell for at least one day, and then removing the solvent from the solvent and drying it to obtain a purified gel.

The above-mentioned method is a typical example. When a water-insoluble polymer is obtained, a method of polymerizing a monomer and a method of the first to fifth methods are used. The method of insolubilizing in water at the time of polymerization or after polymerization can be performed according to a known method.

As a method for obtaining the alternately infiltrated network polymer structure, a method in which the above-mentioned dried gel (purified gel) is impregnated with a vinyl monomer and polymerized to form a water-insoluble polymer. No. At this time, a polymerization initiator may be simultaneously impregnated if necessary. The vinyl polymer may be impregnated as it is, or may be impregnated after being mixed with a solvent.

Examples of the vinyl monomer include a compound represented by the above formula (1) or (2), a monomer copolymerizable therewith, and a crosslinkable monomer, and are not particularly limited. . The method of impregnating the dry gel with a vinyl monomer is as follows:
The drying can be performed by a conventional method. For example, the gel is impregnated with the vinyl-based monomer or a solution containing the same, usually for 1 to 48 hours, preferably for 12 to 24 hours.

The amount of the vinyl monomer to be impregnated into the dry gel is preferably in the range of 0.1 to 70% by weight, more preferably 1 to 50% by weight, based on the dry gel. Preferably it is in the range of 5 to 30% by weight.

As a method of polymerizing the impregnated vinyl monomer to form a water-insoluble polymer, a known method can be employed. For example, the above-mentioned polymerization method and insolubilization method (first method to first method) 5).
In the case of performing in the same manner as in the first method, as the vinyl monomer, only a crosslinkable monomer may be used,
Moreover, you may use together with another monomer. The crosslink density of the polymer of the impregnated vinyl monomer is 0.1 to 100%.
Is preferably within the range. The alternately infiltrated network polymer structure thus obtained is washed with a solvent capable of dissolving the unreacted material and swelling the gel for one day or more, then taken out of the solvent and dried to obtain a temperature-responsive type of the present invention. A hydrogel can be obtained.

The drug whose release is controlled by the temperature-responsive hydrogel of the present invention is not particularly limited as long as it is soluble in water. For example, in the case of drugs, anti-inflammatory analgesics such as indomethacin, ketoprofen and salicylic acid, tetracycline,
Chloramphenicol, antibiotics such as penicillin, antibacterial agents such as benzacorconium chloride, clotrimazole, pyrrolnitrin, anesthetics such as lidocaine and pentobarbital, cold drugs such as aminoacetophenone, etenzazamide, aspirin,

Antihistamines such as diphenhydramine hydrochloride, promethazine hydrochloride, and clemastine fumarate; antianginal agents such as nitroglycerin, isosorbide dinitrate, and nitromannitol; antihypertensive drugs such as clonidine, hydralazine, methyldopa, testosterone, estradiol,
Hormones such as thiamine, riboflavin, pyridoxine, vitamins such as ascorbic acid, bleomycin,
Anticancer agents such as cisplatin, bestatin, etoposide and the like can be mentioned.

In pesticides, sodium pentachlorophenol, zinc ethylenebisdithiocarbamate, O, O
-Diisopropyl-S-benzylthiophosphate, 5
Fungicides such as -methyl-1,2,4-triazolo (3,4-b) benzothiazole, nicotine sulfate, dimethyl (3
-Methyl-4-nitrophenyl) thiophosphate,
Insecticides such as (2-isopropyl-4-methylpyrimidyl-6) -diethylthiophosphate;

Herbicide such as 2,4-dichlorophenoxyacetic acid sodium salt, 2,4-dinitroortho-sec-butylphenol isopropanolamine, 3- (5-tert-butyl-3-isooxazolyl) -1,1-dimethylurea Agents, plant growth regulators such as indolebutyric acid, nicotinamide and potassium maleate hydrazide;
Preservatives such as (4-thiazolyl) benzimidazole and the like can be mentioned.

Examples of catalysts in chemical reactions and the like include:
Reducing agents such as sodium borohydride, lithium borohydride, ascorbic acid, and methylamine; oxidizing agents such as hydrogen peroxide, N-bromosuccinimide and sodium metaperiodate; 2-methylimidazole;
Epoxy curing accelerator such as tris (diethylaminomethyl) phenol, ammonium peroxide, 2,
Polymerization initiators such as 2′-azobis (2-methylpropionamidine) dihydrochloride and 2,2′-azobis (2- (2-imidazolin-2-yl) propane) dihydrochloride;

Examples of the enzyme include alpha-amylase, papain, chymopapain, lipase, cellulase, pectinase, glucose oxidase, catalase, lactase, lysozyme, pepsin, L-asparaginase, and protease.

Examples of air fresheners for malodorous environments include muscone, cibetone, cinnamic acid, benzoic acid, castramine,
Litrol, linalool, camphen, santa roll,
Examples thereof include d-limonene, citral, 1-menthol, cinnamaldehyde, vanillin, heliotropin, and lilial.

The phase transition temperature of the thermoresponsive hydrogel of the present invention is specifically in the range of 4 ° C. to 80 ° C., preferably in the range of 20 ° C. to 60 ° C. The temperature at which release is controlled is determined by the drug used or the environment in which it is applied, but in the present invention, it is possible to design a hydrogel having a phase transition temperature as required, so that it can be used in a wide range of applications. It is.

That is, the phase transition temperature of the temperature-responsive hydrogel of the present invention depends on the type of the compound represented by the formula (1) or (2), the type or the composition ratio of the monomer to be copolymerized, and the It can be freely changed depending on the kind or composition ratio, furthermore, the kind or composition ratio of the monomer and the kind or composition ratio of the cross-linking agent used for forming the alternately infiltrated network polymer structure.

Specifically, by copolymerizing a hydrophobic monomer, a phase transition temperature lower than the phase transition temperature of a hydrogel obtained from the compound represented by the formula (1) or (2) is designed. can do. In addition, by copolymerizing a hydrophilic monomer, a phase transition temperature higher than that of a hydrogel obtained from the compound represented by the formula (1) or the formula (2) can be designed. For example, the phase transition temperature of the hydrogel of Example 1 shown below is 29 ° C., and the phase transition temperature of the hydrogel of Comparative Example 1 is 36 ° C.

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 of the compound represented by the formula (1) or (2) and the monomer to be copolymerized. Type or composition ratio, type or composition ratio of crosslinking agent,
Furthermore, it can be freely changed depending on the type or composition ratio of the monomer and the type or composition ratio of the cross-linking agent used when making the alternately infiltrated network polymer structure.

Specifically, the swelling of the hydrogel obtained from the compound represented by the formula (1) or (2) is carried out by copolymerizing a hydrophobic monomer or increasing the composition ratio of a crosslinking agent. It can be designed to have a degree of swelling smaller than that. Further, by copolymerizing a hydrophilic monomer or reducing the composition ratio of the crosslinking agent, the swelling degree of the hydrogel obtained from the compound represented by the formula (1) or (2) can be increased to a value larger than the swelling degree. Can be designed.

For example, the swelling degree at 32 ° C. of the hydrogel of Example 2 shown below is 1.8, and the swelling degree at 39 ° C. is 0.3. The degree of swelling of the hydrogel of Example 3 at 32 ° C. was 3.0, and the degree of swelling at 39 ° C. was 0.4.

The degree of swelling was determined by immersing a weighed dry gel sample (Wp) in distilled water at a predetermined temperature, and measuring the weight (Ws + Wp) of the temperature of the swelled gel sample that did not change in weight with time. And the degree of swelling Q were determined according to the following equation. Q = Ws / Wp

Further, the release rate of the drug at a predetermined temperature lower than the phase transition temperature of the temperature-responsive hydrogel of the present invention depends on the thickness of the hydrogel, the type of the compound represented by the formula (1) or (2), The type or composition ratio of the monomer to be copolymerized, the type or composition ratio of the cross-linking agent, and the type or composition ratio of the monomer or the type or composition of the cross-linking agent used when making the alternately infiltrated network polymer structure It can be freely changed by the ratio.

Specifically, by copolymerizing a hydrophobic monomer or increasing the composition ratio of the crosslinking agent, the formula (1) or the formula (1) is obtained at a predetermined temperature and a predetermined film thickness. The hydrogel can be designed to have a lower permeation rate than the permeation rate of the hydrogel obtained from the compound represented by 2). Further, by copolymerizing a hydrophilic monomer or reducing the composition ratio of the crosslinking agent, the compound represented by the formula (1) or (2) at a predetermined temperature and a predetermined film thickness is obtained. Can be designed into a hydrogel having a higher permeation rate than the permeation rate of the hydrogel obtained from.

For example, the permeation rate of nitroglycerin at 32 ° C. of the hydrogel of Example 15 shown below is 2.8.
× 10 ⁻⁵ cm / sec, and the permeation rate of nitroglycerin at 39 ° C. was 6.1 × 10 ⁻⁶ cm / sec. The permeation rate of nitroglycerin at 32 ° C. of the hydrogel of Comparative Example 1 was 4.1 × 10 ⁻⁶ cm / sec, and the permeation rate of nitroglycerin at 39 ° C. was 1.3.
× 10 ⁻⁷ cm / sec.

The breaking strength of the temperature-responsive hydrogel of the present invention at a predetermined temperature is determined by copolymerizing with a hydrophobic monomer, increasing the composition ratio of a crosslinking agent, or forming an alternately infiltrated network polymer structure. To improve. For example, in the hydrogel of Example 3, it is 11.0 kg / cm ² ,
In the hydrogel of Comparative Example 1, it is 0.5 kg / cm ² .
The use of the alternately infiltrated network polymer structure improved the 22-fold breaking strength.

Although the temperature-responsive hydrogel of the present invention has excellent breaking strength, the preferred breaking strength is 1.0 kg / c.
m ² or more, more preferably 3 kg / cm ² or more, and particularly preferably 5 kg / cm ² or more. In the present invention, the breaking strength of the hydrogel was 2 cm.
× 2cm × 0.05cm, cut in a thermostatic water bath with a hardness meter (plunger diameter 0.25mm) at 0.1mm /
A point at which the sample was broken by applying a load at a speed of sec was defined as a breaking load, and a value obtained by dividing the cross-sectional area of the plunger by the breaking strength (k
g / cm ² ).

[0070]

EXAMPLES Next, the contents of the present invention will be described specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 10 g of N-isopropylacrylamide, 0.526 g of n-butyl methacrylate, 0.186 g of ethylene glycol dimethacrylate and t-butyl-peroxy-2
-0.018 g of ethylhexanoate was dissolved in 10 ml of 1,4-dioxane, and bubbled with nitrogen gas for 10 minutes, and then poured under a nitrogen atmosphere between glass plates sandwiching a spacer of 0.05 to 0.5 mm, and poured in an oven.
The mixture was reacted at 24 ° C. for 24 hours to obtain a film-like gel. This was washed with methanol, water-methanol (one-to-one) and water for 2 days each, and N-isopropylacrylamide 94% by weight, n-
A film-like hydrogel (IB5 film) having a composition of 5% by weight of butyl methacrylate and 1% by weight of ethylene glycol dimethacrylate was obtained.

Next, 0.189 g of ethylene glycol dimethacrylate and 0.005 g of t-butyl-peroxy-2-ethylhexanoate were dissolved in 10 ml of methanol, and dried under reduced pressure to a solution bubbled with nitrogen gas for 10 minutes. The IB5 film was immersed all day and night, sandwiched between glass plates under a nitrogen atmosphere, and reacted at 75 ° C. for 24 hours to obtain a gel film of an alternately infiltrated network polymer structure. This was washed as described above to obtain a hydrogel film of the alternately infiltrated network polymer structure.

When the transmittance of the obtained hydrogel film to a temperature change at 700 nm was measured with a spectrophotometer equipped with a temperature controller (U-3210, manufactured by Hitachi, Ltd.), the phase transition temperature was 29. ° C. Furthermore, after measuring the weight (Ws + Wp) of the hydrogel membrane sample piece impregnated in constant temperature water at 32 ° C. and 39 ° C. for 24 hours, the sample piece was dried under reduced pressure and the weight was measured (Wp). When the swelling degree Q was calculated based on the above equation, it was 0.3, 39 at 32 ° C.
It was 0.2 at ° C. Next, creep meter (Ltd.)
It was 31.5 kg / cm ² when measured for breaking strength in constant temperature water at 32 ° C. using Yamaden Corporation.

Example 2 10 g of N-isopropylacrylamide, 0.526 g of N-vinylpyrrolidone, 0.186 g of ethylene glycol dimethacrylate and tert. 0.018 g of -butyl-peroxy-2-ethylhexanoate was dissolved in 10 ml of 1,4-dioxane, and polymerized in the same manner as in Example 1.
Washed to give 94% by weight of N-isopropylacrylamide,
A film-like hydrogel (IV5 film) having a composition of 5% by weight of N-vinylpyrrolidone and 1% by weight of ethylene glycol dimethacrylate was obtained.

Next, 0.378 g of ethylene glycol dimethacrylate, tert. -Butyl-peroxy-2
0.011 g of ethylhexanoate in methanol 10
The IV5 film was dried under reduced pressure in a solution dissolved in 10 ml of nitrogen and bubbled with nitrogen gas for 10 minutes. The film was immersed in the solution for 24 hours. Obtained. For this, the phase transition temperature, swelling degree, and breaking strength were measured in the same manner as in Example 1. Table 1 shows the results.

Example 3 0.189 g of ethylene glycol dimethacrylate, t
-Butyl-peroxy-2-ethylhexanoate
005 g was dissolved in 10 ml of methanol, and the IV5 membrane of Example 2 dried under reduced pressure was immersed in a solution of 10 minutes of methanol and bubbling with nitrogen gas for 24 hours, polymerized and washed in the same manner as in Example 1, and alternately infiltrated network polymer structure. Was obtained. For this, the phase transition temperature, swelling degree, and breaking strength were measured in the same manner as in Example 1. Table 1 shows the results.

Examples 4 to 14 Alternately infiltrated network polymer hydrogel films were obtained in the same manner as in Example 1 except for the preparation conditions shown in Tables 2-1 and 2-2. The swelling degree and breaking strength of these films were determined in Example 1.
The measurement was performed in the same manner as described above. Table 3 summarizes the results.

Example 15 10 g of N-isopropylacrylamide, 0.811 g of N, N-dimethylacrylamide, 0.188 g of ethylene glycol dimethacrylate and 0.018 g of t-butyl-peroxy-2-ethylhexanoate were added to 1,4-
The polymer was dissolved in 10 ml of dioxane, polymerized and washed in the same manner as in Example 1, and N-isopropylacrylamide 91.5 was dissolved.
Thus, a film-shaped hydrogel (ID7.5 film) having a composition of 1% by weight, 7.5% by weight of N, N-dimethylacrylamide, and 1% by weight of ethylene glycol dimethacrylate was obtained.

Next, n-butyl methacrylate 0.53
0 g, ethylene glycol dimethacrylate 0.062
g, t-butyl-peroxy-2-ethylhexanoate (0.019 g) was dissolved in methanol (10 ml).
The ID7.5 film dried under reduced pressure in a solution bubbled with nitrogen gas for 5 minutes was immersed in the solution for 24 hours to obtain a hydrogel film of an alternately infiltrated network polymer structure in the same manner as in Example 1. For this, the phase transition temperature, swelling degree, and breaking strength were measured in the same manner as in Example 1. Table 1 shows the results.

Next, this hydrogel membrane was sandwiched between jacketed glass two-chamber cells, a phosphate buffer solution of pH 7.4 was placed in each chamber, and nitroglycerin was suspended in one chamber. . The concentration of nitroglycerin was measured by HPLC by sampling over time from the other chamber. Temperature 39
Table 4 shows the change over time of the accumulated nitroglycerin permeation when the temperature was changed stepwise at 32 ° C and 32 ° C. The transmission coefficient obtained from the cumulative transmission amount is 6.1 × 10 ⁻⁶ cm / 39 ° C.
2.8 × 10 ⁻⁵ cm / sec at 32 ° C.
Met.

Comparative Example 1 The phase transition temperature, swelling degree and breaking strength of the IV5 film of Example 2 were measured in the same manner as in Example 1. The results are summarized in Table 1. Further, the change with time of the accumulated amount of nitroglycerin was measured in the same manner as in Example 15, and the results are shown in Table 4. The transmission coefficient obtained from the accumulated transmission amount is 3
At 9 ° C., it was 1.3 × 10 ⁻⁷ cm / sec, and at 32 ° C., it was 4.8 × 10 ⁻⁶ cm / sec.

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Table 1 Table 1 Phase transition temperature Swelling degree (g / g) Breaking strength (° C) 32 ° C 39 ° C (kg / cm ² ) Example 1 29.0 0.3 0.2 31.5 Example 236 0.0 1.8 0.3 13.1 Example 3 36.5 3.0 0.4 11.0 Example 15 37.0 3.2 0.3 15.6 Comparative Example 36.5 7.30 .4 0.5

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Table 2-1 Composition (wt%) of gel film before forming into an alternately infiltrated network polymer structure Example 4 5 6 7 8 9 10 11 12 13 14 IPAAm 94 94 94 94 94 94 94 94 94 94 94 VP 5 5 5 5 5 5 5 5 BMA 5 5 5 EGDMA 1 1 1 1 1 1 1 1 1 1 1

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Table 2-2 Charge concentration (mmol / ml) of a monomer for forming an alternating infiltration network polymer structure Example 4 5 6 7 8 9 10 11 12 13 14 IPAAm 10 10 VP 10 0.5 HEMA 10 DMAA 10 10 5 3.3 EGDMA 0.5 1 1 1 1 1 1 1 1 PEG (200) DA 1 PEG (400) DA 1

Description of abbreviations in Tables 2-1 and 2-2 IPAAm; N-isopropylacrylamide VP; N-vinylpyrrolidone BMA; n-butyl methacrylate HEMA; 2-hydroxyethyl methacrylate DMAA; N, N-dimethylacrylamide EGDMA; Ethylene glycol dimethacrylate PEG (200) DA; polyethylene glycol (200) diacrylate PEG (400) DA; polyethylene glycol (400) diacrylate

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[Table 4]

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[Table 5]

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According to the present invention, the temperature-responsive hydrogel composed of, for example, an alternatingly infiltrated network polymer structure can control reversible release of a drug by swelling and shrinking in response to environmental temperature changes. Thus, it is possible to provide a high-strength practical self-controlling preparation.

Claims (3)

(57) [Claims] 1. A water-insoluble polymer obtained by polymerizing an N-alkyl or N-alkylene-substituted (meth) acrylamide monomer (alkylene may be interrupted by an ether bond) as a main component. And a water-insoluble polymer having a vinyl monomer as a polymerization component, and a temperature-responsive hydrogel which is an alternately infiltrated network polymer structure. 2. A compound represented by the formula (1) and / or a compound represented by the formula (2) wherein the N-alkyl or N-alkylene-substituted (meth) acrylamide monomer is: (Wherein R ₁ is a hydrogen atom or a methyl group, R ₂ and R ₃
Represents a hydrogen atom or a lower alkyl group, and R ₂ and R ₃
May be the same or different, but at least one of them represents a lower alkyl group. ) (Wherein, R ₁ is a hydrogen atom or a methyl group, A is (C
H _{2) n n} is 4-6 or _{(CH 2) 2 O (CH} 2)
₂ is shown. The temperature-responsive hydrogel according to claim 1, wherein 3. The temperature-responsive hydrogel according to claim 1 for controlling the release of a drug.