JPH01230659A - Tacky pva hydrogel composition - Google Patents

Abstract

PURPOSE:To obtain the title composition excellent in water retentivity low- temperature flexibility and ionic conductivity and useful for, e.g., a percutaneously absorbable preparation or a gel for a bioelectrode, by dissolving a bivalent metal salt and PVA in water by heating under specified conditions and cooling the solution. CONSTITUTION:A metal chloride which is a bivalent metal salt which does not form any complex with a molecular chain of PVA by a coordination bond and is selected from among CaCl2, ZnCl2, SrCl2, PdCl2, BaCl2, BiCl2, BeCl2, MgCl2, MnCl2 and NiCl2 in such an amount that the content in the desired hydrogel is 2-90wt.% is dissolved in water, and PVA of a viscosity-average degree of polymerization >=500 and a degree of saponification >=80mol% is added to the solution in an amount to give a PVA content of 5-80wt.% in the hydrogel, dissolved by heating, cast on, for example, a glass plate and allowed to gel by cooling.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to an ion conductive adhesive for biological electrodes for biological research, biological treatment, or biological diagnosis, and for transdermal absorption preparations and cooling adhesives. The present invention relates to a hydrogel composition with excellent adhesive properties that can be used as a base for water-containing patches for therapeutic purposes.

[Prior Art] A hydrogel is a gel that does not dissolve in water but contains a large amount of water. Although such hydrogels have been known for a long time, interest in monofunctional materials has increased in recent years, and their properties have been attracting attention. For example, they are used as medical materials such as soft contact lenses and sustained-release carriers for medicines, as immobilized carriers for enzymes and microbial cells, as heat carriers for cold storage, and as sustained-release carriers for fragrances.

A typical synthetic polymer used as a hydrogel is poly-2-hydroxyethyl methacrylate-1.
-, polyacrylate, polyvinylpyrrolidone, polyethylene oxide, hydrolyzed polyacrylonitrile, etc., but recently, hydrogels of polyvinyl alcohol (hereinafter abbreviated as PVA) have particularly been attracting attention.

To improve the mechanical strength of PVA hydrogel.

Formalization with formaldehyde, a method of chemically crosslinking PVA using a crosslinking agent such as glutaraldehyde, a method of gelling a PVA aqueous solution by adding a thickener such as boric acid, Congo red, or glycerin, or γ A method of crosslinking PVA by irradiating it with radiation, electron beam, ultraviolet light, etc.;

A known method is to add a metal compound such as titanium, aluminum, zirconium, tin, vanadium, chromium, copper, or cobalt to form a coordinate bond. however,
Since the PVA hydrogel obtained by these methods has crosslinks introduced between molecular chains, it has improved mechanical strength and hot water resistance, but is inferior in stickiness or flexibility at low temperatures (below zero degrees).

[Problems to be solved by the invention] As described above, although conventional PVA hydrogels have high water content and excellent transparency, they have no adhesiveness at all. When used as a conductive gel for diagnostic purposes, it is necessary to use other means such as adhesive tape when fixing it to a living body, and conventional PVA hydrogel has a high water content. However, if it is left in the air, water will scatter quickly and its water retention properties will be poor. Furthermore, due to its high water content, it freezes at low temperatures below 0° C., resulting in loss of flexibility.

The present invention addresses the shortcomings of conventional PVA hydrogels.

That is, the purpose is to improve low adhesion to living tissues, water retention, flexibility at low temperatures, ionic conductivity, etc.

[Means to achieve the purpose] We found that the PVA hydrogel had a sticky property.

As a result of intensive research aimed at imparting water retention, low-temperature flexibility, and ionic conductivity, it was discovered that the above objectives could be achieved by dissolving PVA in an aqueous divalent metal salt solution and cooling it to gel. Ta.

[Function and Examples] The PVA gel of the present invention has excellent water retention, low-temperature flexibility, and ionic conductivity, as well as excellent adhesiveness.

The reason why such a sticky PVA hydrogel is obtained is not clear, but it is thought to be as follows.

When divalent metal salts such as titanium, aluminum, zirconium, tin, vanadium, chromium, copper 5, or cobalt are used, these metal salts are highly reactive with the hydroxyl groups of PVA, so low concentrations of metals may be used. Even salts form complexes between molecular chains due to coordination bonds and become insolubilized, and -valent metal salts such as potassium chloride, silver chloride, cesium chloride, thallium chloride, sodium chloride, lithium chloride, etc. have poor reactivity, and in addition, aqueous solutions of these salts act as precipitants for PVA, making it difficult to obtain uniform gels from highly concentrated solutions. However, zinc chloride, calcium chloride, strontium chloride, palladium chloride,
In the case of divalent metal salts such as barium chloride, bismuth chloride, beryllium chloride, magnesium chloride, manganese chloride, and nickel chloride, unlike the monovalent metal salts mentioned above, PVA does not precipitate even in concentrated solutions of these metal salts. , and no complexes are formed due to coordination bonds.

It is thought that a weak cross-linked structure between PVA molecular chains is formed and gelation occurs, resulting in excellent water retention, low-temperature flexibility, and ionic conductivity, as well as transparency and adhesive properties.

[Example] The PVA used in the present invention has a degree of saponification of 80 mol% or more, preferably 90 mol% or more.

The average degree of polymerization is viscosity average of 500 or more, especially 1,000
The above is preferable.

The divalent metal salt used in the present invention is a metal salt that does not form a complex with the molecular chain of PVA due to coordination bonds. , magnesium chloride, manganese chloride,
Alternatively, nickel chloride is preferable. Among these metal salts, calcium chloride is particularly preferred in view of its solubility in PVA and the relationship between the mixing ratio with water and freezing point depression.

A feature of the present invention is that a divalent metal salt aqueous solution is used when PVA is gelled, and among the various divalent metal salts mentioned above, calcium chloride is most preferred. However, calcium compounds other than these divalent metal salts, such as calcium acetate, calcium benzoate, calcium bromide, and calcium carbide.

Calcium carbonate, calcium citrate, calcium fluoride, calcium hydroxide, calcium hypophosphite, calcium lactate, calcium nitrate, calcium oxalate, calcium dihydrogen phosphate, calcium hydrogen phosphate, tricalcium phosphate, calcium salicylate, silicic acid Calcium, calcium stearate, calcium sulfate, etc. can be used alone or in combination. Although the mixing ratio of these metal salts and water can be selected arbitrarily, the mixing ratio of water and metal salts greatly influences the strength and adhesiveness of the obtained P'VA gel. Therefore, the mixing ratio should be selected appropriately depending on the purpose, but usually the ratio of water to metal salt is 98:2 to 2.
0:80 (weight ratio), preferably 90:10-40:
It is 60.

In the present invention, a metal salt aqueous solution is first prepared to a predetermined concentration according to the purpose, and then a PVA solution is prepared.
Preparation of such a concentrated solution, preferably in the range of ~50% by weight, is generally carried out by heating and dissolving the PVA.

Simply heating while stirring or using an autoclave or microwave oven may be used.

The gel of the present invention can be obtained by casting a completely dissolved PVA solution onto a container, mold, glass plate, or plastic film of any shape, and then allowing it to gel by leaving it at a low temperature below room temperature. . In that case, the lower the temperature, the stronger the gel at the same PVA concentration? j) It is preferable to gel it in a freezer at around -20°C.

If it is necessary to further enhance the strength, heat resistance, etc. of the gel thus obtained, use a divalent metal salt other than the divalent metal salt used in the present invention after gel formation.

For example, it is possible to use chlorinated steel, titanium chloride, etc., and it is also possible to use borax or boric acid, or to irradiate with radiation or electron beams.

The adhesive PVA gel of the present invention can be molded into various shapes required depending on the intended use.

For example, it is possible to freely mold anything from films, sheets, ronds, blocks, tapes, tubes, fibers, to complex shapes. In addition, fibers, nonwoven fabrics 1
It can also be processed into foam sheets, knitted fabrics, or composites with textiles.

The PVA gel of the present invention has excellent water retention, but in order to further increase the water retention, polyhydric alcohols such as glycerin and ethylene glycol may be added, or other water-soluble polymers such as gelatin, cyclodextrin, carboxymethyl cellulose, and starch may be added. , Carbo Ball, Karayago 11,
It is also possible to use starch-sodium acrylate copolymer, vinyl alcohol-sodium acrylate copolymer, polysodium acrylate, and the like. The PVA gel of the present invention has excellent ionic conductivity, but in order to further improve the ionic conductivity, lithium chloride, lithium perchlorate, ferrous chloride, ammonium sulfate, potassium nitrate, sodium nitrate,
It is also possible to add inorganic salts such as sodium carbonate, sodium thiocyanate, and lithium trifluoromethanesulfonate.

Furthermore, when the adhesive PVA gel of the present invention is applied as a transdermal absorption preparation, a physiologically active substance that can be applied transdermally can be added. The physiologically active substances include, for example, menthol, peppermint, salicylic acid ester, camphor, kabsaicin, and chili pepper extract as drugs for poultices, xylocaine, pensicaine, and procyone as local anesthetics, and nitroglycerin as an angina drug. , isosorbide nitrate, etc., steroids such as prezonisolone, dexamethacin, hydrocortisone, dexamethacin acetate, hydrocortisone acetate, etc., β-blockers such as propranolol, alprenolol, pindolol, antihypertensive agents such as clonidine hydrochloride, bunitrol hydrochloride, nifedipine, captopril, etc., bronchial Extensive drugs such as methylephedrine, chlorbrenaline, salbutamol, and terbutaline; asthma drugs such as cromoglycic acid; allergic rhinitis drugs such as ketotifen fumarate; antipyretic and anti-inflammatory agents such as diclofenac sodium and indomethacin sodium; and hormone drugs such as: prostaglandin, varnish 1
-Radiol, etc. Antibiotics include glortetracycline, oxytetracycline, doxycycline, penicillins, cephalosporins, sulfonamides, erythromycin, toframycin, dibekacin hydrochloride, and the like. Furthermore, peptide drugs such as insulin, somatostatin, luteinizing hormone-releasing hormone (Ll-IRH), prolactin, calhitonin, and growth hormone have NF activity, but these high molecular weight drugs have poor skin permeability. Constant current iontophoresis can efficiently increase skin permeability. These physiologically active substances can be used alone or in combination.

In order to produce the above-mentioned adhesive PvΔ hydrogel containing a physiologically active substance:A, it is assembled, for example, as follows. Add PvΔ powder to a concentration of 10 to 16% by weight in an aqueous solution of 25 to 35% by weight of calcium chloride, completely dissolve in an autoclave, cool to 50 to 60°C, and then add 1 to 10% of the above physiologically active substances. After adding 30% by weight and dissolving with stirring, the mixture is cast onto a suitable material and left overnight in a freezer at -20°C to gel.

In this case, if it is necessary to increase the skin permeability of the physiologically active substance, it is also possible to add polyhydric alcohol or the like.

Example 1 Commercially available PVA (saponification degree 99.5 mol%, average polymerization degree 1
, 700) were added with the metal salt shown in Table 1 and a solvent with an aqueous solution concentration of the metal salt so as to have the PVA concentration shown in the same table, and heated in an autoclave at 110°C for -30 minutes.
A VA solution was prepared. The resulting solution was then cast onto a polyethylene film.

This product was gelled overnight in a -20°C freezer to obtain a sheet-like PVA gel with a thickness of about 1 mm.
- For each PVA gel obtained, PVA gel samples (5X5 cm) were placed on the eyebrows of 5 volunteers without fixation of adhesive tape.
24 hours later, the adhesion area between the I'VA gel sample and the skin was examined. The results are also shown in Table 1.

[Margin below] Table 1 Comparative Example 1゜Commercially available PVA (saponification degree 99.5 mol%, average polymerization degree
1.700) were added with the metal salt shown in Table 2 and a solvent with an aqueous solution concentration of the metal salt at a P V A of 1 degree shown in the same table, and an attempt was made to dissolve it by heating in an autoclave.
In the case of comparative experiment numbers 1 to 3, PVA was hardly dissolved. Moreover, in the case of Comparative Experiment Nos. 4 to 6, although some of the gels were dissolved, non-uniform gels were formed. Therefore, when a solution was prepared by lowering the concentration of the metal salt aqueous solution to 2 to 10% and a gel was prepared in the same manner as in Example, a milky white gel was obtained.
They showed no stickiness at all.

Table 2 Example 2 Commercially available PVA (degree of saponification 95 mol%, average degree of polymerization 2.2
00) 75 g was added to 425 g of a 30% aqueous solution of calcium chloride dihydrate prepared separately in advance, heated and dissolved in an autoclave at 110°C for 30 minutes, then sealed in a polyethylene bag and placed in a freezer at -20°C. A cold bag was prepared by leaving it in the bag overnight. This gel exhibited flexibility without freezing even at -20°C, and did not cause any discomfort due to its hardness when it touched the head or skin. Also.

A cycle of leaving at -20° C. overnight and leaving at room temperature overnight was tried 30 times, but although the strength of the gel increased slightly, no phenomenon of water separation in the gel occurred.

Example 3 VA gel obtained in Experiment No. 3 in Example 1 was cut into approximately 5 x 5 mm pieces and dehydrated for approximately 3 days in a vacuum dryer to obtain a white dried PVA gel containing calcium chloride. Ta. Place approximately 50g of this dry gel into a 10L piece.
When the humidity was measured by placing it in the bottom of a glass desiccator, the humidity was about 80% at first, but it reached 0% in a few hours and remained at that humidity for more than three months.

Example 4 The volume resistivity of the P■Δ gel obtained in Experiment No. 5 in Example 1 was measured in accordance with JIS K-6911, Section 5-13, and it was found to be 4X10' Ωcm.
The value of Also, when an electrode connector was attached to this gel and an electrocardiogram was measured, good results were obtained.

Example 5 Commercially available PVA (saponification degree 99.5 mol%, average polymerization degree
1,700) 13 g of calcium chloride dihydrate 30% aqueous solution 87. and heated and dissolved in an autoclave at 110°C for 30 minutes. The concentrated solution was cooled to 50-60°C, and then added 1 g of glycol salicylate and 1. ,,DL
- Add 0.5 g of camphor and 0.3 g of tocopherol acetate, stir and dissolve and cast onto polyester film J-,
After placing a nonwoven fabric thereon, an anti-inflammatory/analgesic poultice was prepared by leaving it in a -20°C freezer overnight. When this poultice (10X L Ocm) was applied to the back of a person, it had excellent adhesion to the skin without the aid of other adhesive tapes, and even after 24 hours, it maintained its initial adhesive strength, and it showed no resistance to the skin. There was little irritation and almost no skin irritation was observed.

Example 6 2.6 g of commercially available r'VA (degree of saponification 99.5 mol%, average degree of polymerization 1,700) was added to 17.4 g of a 30% by weight aqueous solution of calcium chloride dihydrate prepared separately in advance, The mixture was heated and dissolved in an autoclave at 110°C for 30 minutes. The solution was cooled to 50-60°C, then 0.5 g of diclofenac sodium and 1.5 g of octyl nicotinate were added, dissolved under stirring, and placed in a glass petri dish, then kept in a -20°C freezer overnight. A transdermal absorption preparation was prepared by leaving it to stand, and the control effect of this preparation on carrageenan paw edema was investigated in male Wi star cattle (body weight approximately 2 sOg).8
After several hours, the effect of galagenin on controlling paw edema was clearly observed.

Example 7 Commercially available PVA (saponification degree 99.5 mol%, average polymerization degree
1,700) 2.6g was added to a separately prepared 30% aqueous solution of calcium chloride hydrate], 7.4°, and dissolved by heating at 110"C for 30 minutes in an autoclave.The solution was cooled to 50 to 60°C, 0.2 g of glonidine hydrochloride was added, dissolved under stirring, and cast onto a polyester film (thickness: 20 μm).
A transdermal absorption preparation was prepared by leaving it in a freezer at 20°C overnight. W
When examined in male istar rats (body weight approximately 250 g), a decrease in blood pressure was observed over 48 hours.

Example 8 Commercially available PVA (saponification degree 99.5 mol%, average polymerization degree 1
．． 200) was added to 80 g of a 30% by weight aqueous solution of calcium chloride dihydrate prepared separately in advance, and the mixture was heated and dissolved in an autoclave at 1.10'C for 30 minutes. After cooling the solution to 50 to 60°C, add commercially available jasmine fragrance Log, disperse it uniformly under stirring, and put it in a plastic container, and then leave it in a -20°C freezer overnight to deodorize the gel. A fragrance was created. When this product was installed in the rear of a passenger car and the persistence of the fragrance was examined, it was found that the fragrance remained effective for about 3 months.

[Effects of invention The adhesive PVA hydrogel composition of the present invention.

Since no highly toxic chemical cross-linking agents or catalysts are used during the gelation of pvA, there is almost no irritation to living tissues, and there is no reduction in the activity or alteration of physiologically active substances. In addition, it has excellent mechanical strength, adhesiveness, transparency, flexibility at low temperatures, water retention, and ionic conductivity, so it can be applied as ice packs, transdermal absorption preparations, and gels for bioelectrodes.

In addition, we also use immobilized carriers for enzymes and bacterial cells, as well as insect repellents,
It can be widely applied as a sustained release carrier for insecticides, fungicides, pheromones, agricultural chemicals, and fragrances, deodorants, mats for sick people, desiccants, etc.

Patent applicant: Biomaterial Universe Co., Ltd.

Claims (1)

[Scope of Claims] 1) An adhesive PVA hydrogel composition characterized by containing polyvinyl alcohol and a divalent metal salt as main components in addition to water. 2) The adhesive PVA hydrogel composition according to claim 1, wherein the viscosity average degree of polymerization of polyvinyl alcohol is 500 or more. 3) The adhesive PVA hydrogel composition according to claim 1, wherein the degree of saponification of polyvinyl alcohol is 80 mol% or more. 4) The adhesive PVA hydrogel composition according to claim 1, wherein the content of polyvinyl alcohol in the hydrogel is 5 to 80% by weight. 5) The adhesive according to claim 1, wherein the divalent metal salt is zinc chloride, calcium chloride, strontium chloride, palladium chloride, barium chloride, bismuth chloride, beryllium chloride, magnesium chloride, manganese chloride, or nickel chloride. PVA hydrogel composition. 6) The content of metal chloride in the hydrogel is 2~
The adhesive P according to claim 1, which is 90% by weight.
VA hydrogel composition.