JPH07118144A - Heat-sensitive hydrogel and medical external material using the same - Google Patents

Abstract

PURPOSE:To obtain a new heat-sensitive hydrogel of a thermosensitive shrinkage type having excellent transparency, flexibility and adhesiveness and a medical external material using the same heat-sensitive hydrogel. CONSTITUTION:This medical external material is obtained by forming a copolymer of a monomer composition comprising 60-80 pts.wt. of methoxyethyl acrylate and 20-40 pts.wt. of N-vinyl-2-pyrrolidone into a film, cross-linking and subjecting to hydrous treatment.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a temperature-sensitive hydrogel obtained by forming a film of a specific hydrophilic acrylic copolymer, crosslinking and hydrous treatment, and a medical external preparation using the same.
More specifically, it is a temperature-sensitive shrinkable volume-phase-transition phenomenon that is produced by subjecting a hydrophilic acrylic copolymer film, which is flexible, stretchable, and transparent, to crosslinking and water treatment. The present invention relates to a gel and an external medical product using the gel.

[0002]

2. Description of the Related Art Since the discovery of the phase transition phenomenon of gels, interest in organic polymer gels has increased, and a lot of research activities are now being conducted from various angles. There is something to watch.

Among them, hydrogels such as thermosensitive shrinkage type thermoresponsive methyl cellulose, polyvinyl methyl ether, partially saponified polyvinyl acetate, poly-N-isopropylacrylamide, isopropylacrylamide / acrylic acid copolymer and the like are drug delivery. , A wide range of applications such as agricultural and horticultural water retention agents, optical display materials, and mechanochemical materials.

Okano et al. Have proposed an intelligent preparation using a self-regulating heat stimulus responsive drug release system using poly-N-isopropylacrylamide gel. Among them, the mechanism that the drug is released together with water when the temperature rises and the gel contracts, that is, a so-called squeezing effect is explained.

Further, poly-N having temperature sensitivity of Okano et al.
-A hydrogel for wound covering consisting of isopropyl acrylamide and its copolymer (Japanese Patent Laid-Open No. 5-84290) has excellent pain control and adhesion, and can be easily peeled off by cooling the gel after completion of healing. It is a thing.

[0006]

However, this wound-covering hydrogel lacks transparency when the amount of water decreases due to the release or drying of water, and also has poor flexibility and lacks followability in the stretchable portion. In addition, since the adhesion is insufficient, problems such as floating during use and poor absorbability of exudate from the wound are expected.

Up to now, a hydrogel characterized by temperature sensitivity comprising an acrylic ester / N-vinyl-2-pyrrolidone copolymer which is excellent in transparency, flexibility and adhesion, and a medical product using the same No external material was known.

In the present invention, a methoxyethyl acrylate / N-vinyl-2-pyrrolidone copolymer having a specific compounding ratio is formed into a film, crosslinked and treated with water to obtain excellent transparency, flexibility and adhesion. The present invention provides a temperature-sensitive shrinkable temperature-sensitive hydrogel and a medical external-use material using the same.

[0009]

To achieve the above object, in the temperature-sensitive hydrogel of the present invention, 60 to 80 parts by weight of methoxyethyl acrylate and N-vinyl-2 are used.
-Pyrrolidone 20 to 40 parts by weight of a copolymer of a monomer composition is formed into a film, crosslinked and treated with water.

The temperature-sensitive hydrogel of the present invention will be described in detail below. The temperature-sensitive hydrogel of the present invention comprises a copolymer of a monomer composition consisting of 60 to 80 parts by weight of methoxyethyl acrylate and 20 to 40 parts by weight of N-vinyl-2-pyrrolidone, formed into a film, crosslinked, and hydrated. It is obtained by subjecting it to a treatment, and by such a constitution, transparency, water absorption, flexibility, adhesion and temperature sensitivity are excellent.

In the present invention, the content of the monomer composition comprising methoxyethyl acrylate and N-vinyl-2-pyrrolidone is as low as less than 60 parts by weight and the amount of N-vinyl-2-pyrrolidone is less than 60 parts by weight. If it exceeds 40 parts by weight, the water solubility is excessive,
Moreover, it is not preferable because the flexibility at low water content becomes insufficient, and methoxyethyl acrylate exceeds 80 parts by weight,
And when N-vinyl-2-pyrrolidone is less than 20 parts by weight, the water absorption is lowered, and due to the reason that excessive tackiness is exhibited at a low water content, transparency, water absorption, flexibility,
It is difficult to obtain a temperature-sensitive hydrogel having excellent adhesiveness and temperature-sensitivity. Therefore, the mixing ratio is about 70 parts by weight of methoxyethyl acrylate and about 30 parts by weight of N-vinyl-2-pyrrolidone. Is desirable.

The copolymer of the present invention can be produced by copolymerizing a mixture of the above-mentioned monomers by a generally known polymerization method. As the copolymerization method, any of solution polymerization, emulsion polymerization, suspension polymerization, bulk polymerization, and photopolymerization can be used, but solution polymerization is preferably carried out from the viewpoint of reducing the amount of residual monomers.

For example, the solution polymerization can be carried out in a polar solvent or a non-polar solvent in a usual manner. Examples of the polar solvent include water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, and the like, and examples of the nonpolar solvent include methyl acetate, ethyl acetate, toluene, xylene, ethylene glycol monoalkyl ether, and the like. These can be used alone or in admixture of two or more.

In this case, examples of the polymerization initiator include benzoyl peroxide, cumene hydroperoxide, diisopropyl peroxydicarbonate, azobisisobutyronitrile, etc., which may be used alone or in combination of two or more. Can be used.

By subjecting the copolymer obtained by radical polymerization of a mixture of the above-mentioned monomer, solvent and polymerization initiator by a conventional operation to film formation, crosslinking and water-containing treatment, the temperature-sensitive hydrogel of the present invention is obtained. Can be obtained.

As the film-forming method, any generally known method such as a casting method or an extrusion method can be used because the present copolymer has excellent thermoplasticity. However, when the film thickness is 75 μm or less, casting is possible. Method, film thickness is 75
When it exceeds μm, the extrusion method is preferably used.

The cross-linking treatment is carried out by a physical method such as irradiation with γ-rays or electron beams, or a polyfunctional acrylate or methacrylate, an organic peroxide, an isocyanate compound, an organic metal salt, a metal alcoholate, a metal chelate compound or an epoxy group-containing compound. A chemical method using a compound, a compound containing a primary amino group, or the like can be mentioned, and γ-ray irradiation with a dose of 25 kGy or more is suitable because crosslinking and sterilization can be performed at the same time. In the case of photopolymerization, polyfunctional acrylate or methacrylate is also preferably used.

The hydrous treatment is carried out by swelling the crosslinked membrane by immersing it in water, or by crosslinking the aqueous solution of the polymer to make it insoluble. As this water, distilled water, distilled water for injection, sterile purified water, physiological saline, phosphate buffered physiological saline, etc. can be used, and a drug may be further contained.

The drug that can be contained is not particularly limited as long as it is water-soluble, and specific examples thereof include povidone iodine, iodo, sulfadiazine, sulfisomidine sodium, and sulfamethoxa as antibacterial agents. Sodium sol, cetalkonium chloride, benzalkonium chloride,
Antibiotics such as benzethonium chloride, acrinol, chlorhexidine gluconate, neomycin sulfate, potassium benzylpenicillin, cephalosin, cephaloridine, tetracycline hydrochloride, lincomycin hydrochloride, nystacin, vancomycin hydrochloride, kanamycin sulfate, penicillinase-resistant penicillin, and fradiomycin sulfate, salicylic acid Sodium, tramadol hydrochloride, dimethothiazine mesylate, tiaramid hydrochloride, buprenorphine hydrochloride,
Anti-inflammatory analgesics such as sodium hyaluronate, local anesthetics such as tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, antihistamines such as diphenhydramine hydrochloride, propranolol hydrochloride, alprenol hydrochloride, β-blockers such as metoprolol tartrate, clonidine hydrochloride. , Antihypertensive agents such as bunitrolol hydrochloride, antiviral agents such as acyclovir and vidarabine, prostaglandins such as alprostadil, growth factor hormone agents such as TGF, FGF, PDGF and EGF, aqueous collagen, chondroitin sulfate, various water-soluble agents Sex vitamins and the like.

The temperature-sensitive hydrogel of the present invention has the property of contracting and releasing water when the temperature rises. For example, a hydrogel saturated and swollen with distilled water at 20 ° C. (normal temperature) is 37 ° C. When heated to (body temperature), it contracts and releases part of the water.

In this case, when the drug is contained, part of the drug is gradually released due to the squeezing effect together with water. Therefore, it is necessary to control the shape and size of the hydrogel, the concentration of the drug contained, the water content and the temperature difference. It is possible to control the release of the drug.

The moisture content (W / W) of the temperature-sensitive hydrogel of the present invention is 10% or more and 96% or less, and the lower the temperature, the higher the saturated water content, but substantially, The water content at room temperature is preferably 80% or more and 94% or less, and 9
It is more preferably 0% or more and 94% or less.

Since the methoxyethyl acrylate / N-vinyl-2-pyrrolidone copolymer, which is the base material of the temperature-sensitive hydrogel of the present invention, is excellent in flexibility, a large amount of water is released to reduce the water content. Even in, it is possible to maintain satisfactory flexibility.

As described above, according to the present invention, methoxyethyl acrylate / N-vinyl-2 having a specific blending ratio is used.
-By forming a film of pyrrolidone copolymer, crosslinking and hydrous treatment, it is possible to obtain an extremely excellent temperature-sensitive contraction-type temperature-sensitive hydrogel, which is excellent in transparency, flexibility and adhesion.

The medical external preparation of the present invention comprises the temperature-sensitive hydrogel of the present invention in order to achieve the above object.

In the present invention, as the medical external application material,
As will be described later, a wound dressing material, a hydrogel dressing material, herpes, a healing material effective for bandages and erections,
Formulations excellent in drug delivery are included.

That is, the temperature-sensitive hydrogel of the present invention contains an antibacterial agent or an antibiotic at an appropriate concentration to control the sustained release at around body temperature, thereby providing excellent bacterial resistance.
It can be used as a wound dressing effective for wound healing with high contamination.

The temperature-sensitive hydrogel of the present invention contains a healing-promoting substance at an appropriate concentration, such as prostaglandins or EG.
A hydrogel dressing material having excellent curability can be obtained by containing F or the like and controlling the sustained release property near body temperature.

[0029] The temperature-sensitive hydrogel of the present invention contains an antiviral agent at an appropriate concentration to control the sustained-release property at around body temperature, thereby providing a healing material effective for herpes, herpes zoster, and water swelling. Can be obtained.

By incorporating a drug having excellent transdermal absorbability at an appropriate concentration into the temperature-sensitive hydrogel of the present invention and controlling the sustained release at around body temperature, a drug-excellent preparation can be obtained. .

Further, in the external medical material of the present invention,
If necessary, a reinforcing material or a support can be provided. Any material can be used as the reinforcing material or the support. Specific examples of this material include paper, non-woven fabric, cotton cloth, synthetic resin cloth, synthetic resin film, synthetic resin foam, mesh-shaped or net-shaped paper,
Examples include non-woven fabrics, cotton cloths, synthetic resin cloths, synthetic resin films, and surgical tapes, medical adhesive sheets, adhesive bandages and the like having these as a base material.

[0032]

In the temperature-sensitive hydrogel of the present invention, a copolymer of a monomer composition of 60 to 80 parts by weight of methoxyethyl acrylate and 20 to 40 parts by weight of N-vinyl-pyrrolidone is formed into a film, crosslinked and formed. Since it is treated with water, it is a water-soluble acrylic copolymer having a low glass transition point, which is crosslinked to insolubilize it, and is appropriately hydrated to form a gel. Since the phenomenon occurs, it has an effect of being excellent in transparency, water absorption, flexibility, adhesion and temperature sensitivity.

Particularly, in the temperature-sensitive hydrogel of the present invention, since the methoxyethyl acrylate / N-vinyl-2-pyrrolidone copolymer having a specific blending ratio is excellent in flexibility, it releases a large amount of water. Even if the water content is lowered, it has the effect of maintaining satisfactory flexibility.

Since the medical external use material of the present invention comprises the temperature-sensitive hydrogel of the present invention, it has transparency, water absorption, and
It has the effects of excellent flexibility, adhesion and temperature sensitivity.

[0035]

EXAMPLES The present invention will be described below based on examples, but the present invention is not limited thereto. Example 1 In a closed reactor equipped with a 20 L stirrer, 0.2 parts by weight of azobisisobutyronitrile, 70 parts by weight of 2-methoxyethyl acrylate, 30 parts by weight of N-vinyl-2-pyrrolidone and 66.7 parts by weight of toluene. Parts, charged with nitrogen at a flow rate of 500 ml / min for 2 hours, and then stirred and dropped with a solvent (dropping amount 166.7 parts by weight) to bring the inside of the reactor to 58 ° C to 68 ° C.
The reaction was carried out for 4 hours while maintaining

Subsequently, the reaction was completed by stirring at 80 ° C. for 2 hours and then cooled to room temperature to obtain a solution of an acrylic copolymer.

The solution of the acrylic copolymer was applied to a release paper at a constant thickness and then dried at 130 ° C. for 5 minutes to remove the solvent and unreacted monomers, and a transparent film having a thickness of 50 μm. As a result, a hydrophilic acrylic polymer was obtained. This hydrophilic acrylic polymer was dried by a coating machine.

The drying conditions are as follows: coating speed = 1.5 m / min, drying tower length = 6.0 m, drying time = 4 under a fresh air flow.
Min, drying temperature = 120 ° C. to 140 ° C., film thickness = 5
The transparent film obtained was laminated to form a roll having a thickness of 2 cm, and then cut into strips having an appropriate size.

This strip-shaped sample was T-die formed by a single screw extruder. That is, shaft rotation speed = 60 rpm, molding temperature =
A colorless and transparent sheet having an average thickness of 400 μm was obtained by setting 150 ° C. to 170 ° C., die lip width = 0.5 mm, die lip length = 100 mm, and take-up speed = 15 m / min. Furthermore, after cutting this sheet into 5 cm square, the dose is 2
Irradiation with γ ray of 7.7 kGy gave a water absorbent polymer sheet for medical use.

The obtained medical water-absorbent polymer sheet was used as 2
The temperature-sensitive hydrogel of the present invention having a water content of 93.8% was obtained by immersing in distilled water at 0 ° C. for 24 hours to sufficiently swell it with water.

This product was enclosed in a water-impermeable aluminum wrapping material, allowed to stand at 37 ° C. for 5 hours, and then opened. The hydrogel contracted to release water, and the water content was 8%.
It was 6.7%.

Example 2 The medical water-absorbent polymer sheet obtained in Example 1 was treated at 5 ° C.
By immersing it in distilled water for 24 hours to sufficiently swell it with water, the temperature-sensitive hydrogel of the present invention having a water content of 95.5% was obtained.

This product was enclosed in a water-impermeable aluminum packaging material, left at 37 ° C. for 5 hours and then opened, and the hydrogel contracted to release water, and the water content was 8%.
It was 6.7%.

Example 3 20% of the medical water-absorbent polymer sheet obtained in Example 1 was used.
By immersing it in phosphate buffered saline (pH = 7.4) at ℃ for 24 hours and allowing it to absorb and swell it sufficiently, the water content becomes 9%.
A thermosensitive hydrogel of the invention of 3.1% was obtained.

This product was sealed in a water-impermeable aluminum packaging material, left at 37 ° C. for 5 hours and then opened, and the hydrogel contracted to release water, and the water content was 8%.
It was 3.3%.

Example 4 The medical water-absorbent polymer sheet obtained in Example 1 was treated at 5 ° C.
It was immersed in phosphate buffered saline solution (pH = 7.4) for 24 hours for sufficient water swelling to give a water content of 9%.
A thermosensitive hydrogel of the present invention of 5.1% was obtained.

This product was enclosed in a water-impermeable aluminum packaging material, left at 37 ° C. for 5 hours and then opened, and the hydrogel contracted to release water, and the water content was 8%.
It was 3.3%.

Example 5 20% of the medical water-absorbent polymer sheet obtained in Example 1 was used.
As a hydrogel dressing material with bacteria resistance having a water content of 93.5%, it is immersed in a 0.05% (W / W) chlorhexidine gluconate aqueous solution at 24 ° C for 24 hours for sufficient absorption and swelling. The medical external use material of the invention was obtained.

Example 6 20% of the medical water-absorbent polymer sheet obtained in Example 1 was used.
2 in 0.06% (W / W) Vidarabine saline solution at ℃
By immersing for 4 hours for sufficient absorption and swelling, a medical external-use material of the present invention was obtained as an antiviral herpes zoster treatment material having a water content of 93.5%.

Example 7 20% of the medical water-absorbent polymer sheet obtained in Example 1 was used.
As a patch having MRSA resistance having a water content of 93.7% by immersing in a 3% (W / W) acetic acid aqueous solution at a temperature of 24 hours for sufficient absorption and swelling, the medical external use material of the present invention Got

Example 8 6 parts by weight of the dried hydrophilic acrylic polymer obtained in Example 1 was dissolved in 94 parts by weight of distilled water at 20 ° C. to obtain a stripping property of thickness 2 mm, length 10 cm, width 10 cm. The temperature-sensitive hydrogel of the present invention was obtained by bunching in a silicon mold, coating both sides with a peelable PET separator, and then irradiating with 28.5 kGy of γ-rays.

Comparative Example 1 A commercially available hydrogel obtained by gamma-crosslinking a mixture of 4 parts by weight of polyethylene oxide and 96 parts by weight of water was left in distilled water at 20 ° C. for 24 hours to have a water content of 98.4%. there were. When this product was sealed in a hermetically sealed material and left at 37 ° C. for 5 hours, its water content was 98.1%, and no obvious temperature sensitivity was observed.

Comparative Example 2 100 parts by weight of purified N-isopropylacrylamide and 0.4 parts by weight of azobisisobutyronitrile were dissolved in 200 parts by weight of benzene, and the atmosphere was replaced with nitrogen for 2 hours. Polymerization was carried out by stirring for 15 hours. This polymer was dissolved in tetrahydrofuran and reprecipitated with ethyl ether.

Further, it was dried at room temperature for 48 hours under reduced pressure to obtain 78 parts by weight of poly-N-isopropylacrylamide. 95 parts by weight of distilled water was added to 5 parts by weight of the obtained poly-N-isopropylacrylamide and sufficiently stirred at room temperature to obtain a fluid hydrogel.

This hydrogel was enclosed in a moisture-impermeable aluminum packaging material, left at 37 ° C. for 5 hours, and then opened. When the hydrogel contracted and released moisture, it was white opaque and remarkably flexible. Poly-N-isopropylacrylamide, which is inferior in properties, remained.

[0056]

EFFECT OF THE INVENTION The temperature-sensitive hydrogel of the present invention has the above-mentioned constitution and, as a result, is excellent in transparency, flexibility and adhesion.
It has the effect of exhibiting excellent temperature-sensitive contractility.

Since the medical external use material of the present invention comprises the temperature-sensitive hydrogel of the present invention, it has transparency, water absorption, and
As a result of its excellent flexibility, adhesion and temperature sensitivity, it is extremely useful as an external material.

In this case, the drug is contained at an appropriate concentration,
By controlling the sustained release property near body temperature, it becomes possible to control the release of the drug, which is extremely useful as a medical external preparation.

Claims (2)

[Claims] 1. Methoxyethyl acrylate 60-80
A thermosensitive hydrogel obtained by subjecting a copolymer of a monomer composition, which is 20 to 40 parts by weight of N-vinyl-2-pyrrolidone, to a film, crosslinking and water treatment. 2. A medical external preparation comprising the thermosensitive hydrogel according to claim 1.