JPH04268359A - Stimulus-responsive hydrogel and production thereof - Google Patents

Abstract

PURPOSE:To produce a functional hydrogel which is based on polyvinyl alcohol and practically applicable to the medical and pharmaceutical fields. CONSTITUTION:An aq. soln. of polyvinyl alcohol having a degree of saponification of 97mol% or higher and an average degree of polymn. of 1000 or higher is freeze-dried to produce a high-strength transparent hydrogel, which is dipped in an aq. alkaline soln. of boric acid or a borate in a concn. of 0.001 mol/l or higher with a pH of 7 or higher for 30min or longer to give the title gel.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention uses polyvinyl alcohol to cause large changes in volume and intensity in response to changes in concentration of monosaccharides and disaccharides such as glucose or divalent metal ions, pH, temperature, and electric field. This invention relates to a completely new high-strength stimulus-responsive hydrogel and a method for producing the same.

0002

[Prior Art] Polyvinyl alcohol gel is one of the most studied hydrogels at present, and has excellent mechanical properties and water retention, is inexpensive, and has extremely low toxicity, so it is also used in the medical and pharmaceutical fields. Various applications have been attempted. However, these attempts have been largely limited to two categories: one is the use of gels as carriers and supports for drugs, enzymes, microorganisms, etc. embedded in them, and the other is for artificial joints and artificial joints. It is used as a substitute for living tissue such as the cornea. However, these merely utilize the substance retention ability, high water content, and elasticity of polyvinyl alcohol gel.

In addition, in recent years, gels that change volume (swell and contract) in response to changes in external pH, temperature, solvent composition, etc. have been prepared using polymers with charged groups (polymer electrolytes). , these are collectively called functional gels. Functional gels have opened up a completely new field of gel application, but most of them use polymer electrolytes that have no track record of medical use and whose toxicity is unconfirmed, making it difficult to apply them to the medical and pharmaceutical fields. It is still a long way off. Furthermore, there have been no reports of hydrogels that swell and contract in response to changes in sugar concentration, even among gels using conventional polymer electrolytes.

0004

SUMMARY OF THE INVENTION An object of the present invention is to provide a functional hydrogel using polyvinyl alcohol that can be used in the medical and pharmaceutical fields and a method for producing the same.

[0005]

SUMMARY OF THE INVENTION The present invention is directed to stimuli-responsive hydrogels made from polyvinyl alcohol.

[0006] As a result of intensive research to solve the above problems, the present inventors have found that by treating a high-strength and transparent polyvinyl alcohol hydrogel produced by an original production method with boric acid and borate, glucose, etc. The present invention was accomplished by discovering a new functional hydrogel that exhibits large swelling and contraction in response to various changes such as changes in the concentration of monosaccharides and disaccharides or divalent metal ions, pH, temperature, and electric field. The stimulus-responsive hydrogel of the present invention has the following functions,
Very useful in the medical and pharmaceutical fields.

(1) Putting the gel in an aqueous solution of borate,
Increase or decrease the glucose concentration in the solution. At this time, when the glucose concentration is increased, the gel contracts, and when the concentration is decreased, the gel swells. Since the amount of change in contraction and swelling increases in proportion to the glucose concentration, this hydrogel can be used as a glucose sensor that can determine the glucose concentration in a solution. It has good sensitivity and can be applied to low-concentration glucose measurements such as blood sugar levels. Glucose sensors currently in common use are complex and expensive ones that use enzymes, and become unusable due to deactivation of the enzyme. If the hydrogel obtained by this production method is used as a glucose sensor, the glucose concentration can be determined easily and inexpensively, and since no deterioration occurs for a long period of time, it can be used repeatedly.

On the other hand, when divalent metal ions such as calcium ions are present in the solution above a certain concentration, the gel swells as the glucose concentration increases, and contracts as the concentration decreases. A new diabetes treatment system can be designed using this property. For example, insulin is encapsulated in a gel and the gel is administered into a living body, or blood is circulated outside the body and brought into contact with the gel. One possible system is that when blood sugar levels rise, the gel swells and its network structure expands, and as a result, the encapsulated insulin is released, suppressing the increase in blood sugar levels. Glucose-responsive drug sustained release systems are also desired by many diabetic patients.

(2) When a gel is placed in an aqueous solution of divalent metal ions such as calcium or barium, it rapidly contracts and its volume decreases to about 30% of its original volume. When an ion chelating agent such as tetrasodium ethylenediaminetetraacetate is added to the contracted gel, the gel quickly swells and completely returns to its original volume. Next, when divalent metal ions are added, contraction occurs again, making it possible to cause a completely reversible volume change (swelling and contraction). Also, if both ends of the gel are fixed, a very strong tension will be generated during contraction. In other words, it can be said to be a hydrogel that has the function of converting chemical stimulation into physical work. Utilizing this function, it is possible to apply it to, for example, artificial muscles.

(3) When the pH of the gel is changed between 6 and 12, the gel contracts as it becomes more acidic and swells as it becomes more alkaline. This volume change is reversible, and the amount of change is 30% or more. Utilizing this, it can be applied to pH-sensitive drug release systems.

(4) When the temperature of the gel is increased, the gel contracts, and when the temperature is returned to the original temperature, it swells. This is a reversible change, and this property can be utilized in temperature-sensitive drug release systems, such as systems that control drug delivery in response to changes in body temperature.

(5) By applying an electric field to the aqueous solution in which the gel is immersed, the gel can be caused to swell, contract, and bend, making it possible to apply it to drug release systems and artificial muscles using electrical stimulation.

The magnitude and speed of the gel volume change and tension change described above can be controlled by the type of polyvinyl alcohol used, the shape of the gel (thin film, rod shape, etc.), the concentration of borate, etc. .

The present invention also provides a method for producing the stimulus-responsive hydrogel. That is, the hydrogel of the present invention has a saponification degree of 97 mol% or more and an average polymerization degree of 100%.
A high-strength and transparent hydrogel is obtained by freeze-drying using an aqueous solution of polyvinyl alcohol with a concentration of 0 or more.
．． It can be obtained by immersion for 30 minutes or more in an alkaline aqueous solution of boric acid or borate salt with a concentration of 0.001 mol/l or more and a pH of 7 or more.

[0015] The production method of the present invention is roughly divided into two steps, and the first step is a step of producing a high-strength, transparent gel by freeze-drying. That is, an aqueous solution of polyvinyl alcohol having a saponification degree of 97 mol % or more and an average polymerization degree of 1000 or more is poured into a container of any shape or a mold, and then dried without freezing. The moisture content at this time is about 5 to 10%. Thereafter, this dried body is left in steam at a constant pressure to adsorb a certain amount of water. This operation results in a moisture content of 20 to 40%. This is a step in which the sample is quickly frozen at -20°C or lower, freeze-dried, and the resulting sample is immersed in water as needed to form a hydrogel. This high-strength, transparent gel can only be obtained through three processes: drying an aqueous polyvinyl alcohol solution, adsorbing water in steam, and freeze-drying, and as shown in the examples below, one of these processes is missing. However, hydrogels with similar properties cannot be obtained. Furthermore, even if a polyvinyl alcohol aqueous solution is dried and concentrated to a moisture content of 20 to 40% and freeze-dried, only a weak gel that cannot maintain its shape is obtained. 1st
The moisture content of the gel obtained in the process varies depending on the type of polyvinyl alcohol and water vapor pressure, and ranges from about 40 to 90%.

[0016] In the second step, the gel obtained in the first step is
．． This is a process of immersing for 30 minutes or more in an alkaline aqueous solution of boric acid or boric acid salts with a pH of 7 or more with a concentration of 0.001 mol/l or more, which forms crosslinks with boric acid ions in the gel and creates charged groups in the gel. It will be granted.

The degree of saponification of the polyvinyl alcohol used in the present invention must be 97 mol% or more, preferably 98 mol% or more. In addition, the average degree of polymerization needs to be 1000 or more, and even if polyvinyl alcohol with a saponification degree and polymerization degree lower than this is used, the strength of the gel obtained is low.
The purpose is not achieved.

[0018] If the concentration of the aqueous solution of polyvinyl alcohol becomes too high, it becomes difficult to remove air bubbles from the solution, so the concentration is preferably about 40% or less.

[0019] The temperature when drying the polyvinyl alcohol aqueous solution must be within a temperature range in which the aqueous solution does not freeze and the polyvinyl alcohol itself does not melt;
A range of 0°C is preferred.

The process of incorporating a small amount of water into the gel in steam also needs to be carried out in a similar temperature range. The water vapor pressure at this time determines the water content of the gel before freezing, and affects the strength and transparency of the final gel. For example 30~80℃
By placing it in a saturated water vapor pressure of 0.04 to 0.3
It can be the water vapor pressure of ATM. Alternatively, the water vapor pressure can be adjusted while keeping the temperature constant.

[0021] The temperature at the time of freezing also affects the strength of the gel, and in order to obtain a gel with high strength, the temperature should be -20°C or lower, preferably -4°C.
A temperature of 0°C or lower is required, and the strength of the gel decreases at -6°C to -20°C.

As the borate, borax (sodium tetraborate decahydrate), sodium metaborate, sodium perborate, etc. can be used.

The concentration, pH and temperature of the aqueous borate solution greatly influence the stimulus responsiveness and strength of the gel. For example, when using boric acid, the concentration needs to be about 0.01 mol/l or more, and when using borax, it needs to be about 0.001 mol/l or more, and if it is less than this, sufficient functionality will not be exhibited. Further, the pH needs to be in an alkaline range where boric acid dissociates, and is adjusted to about 7 or higher, preferably 9 or higher. At temperatures above 50°C, the crosslinks caused by borate dissociate, so
It is necessary to keep the temperature below about 50°C. The function of the stimulus-responsive hydrogel of the present invention is to create a high-strength polyvinyl alcohol gel and cross-link it with borate.
This phenomenon was first demonstrated through the synergistic effect of two steps, and the gel obtained by adding borate to a conventional aqueous solution of polyvinyl alcohol is extremely fragile, and its functionality has not yet been investigated. In addition, a gel prepared by the conventional method of repeatedly freezing and thawing an aqueous solution of polyvinyl alcohol can be used as a substitute for the gel obtained in the first step of this production method, but its use is largely limited due to its low strength and opacity. Ru.

[0024]

[Example] Reference example 1 Commercially available polyvinyl alcohol (saponification degree 98.8 mol%,
An aqueous solution (4w/v%) with an average degree of polymerization of 2000) was cast into a Petri dish, dried in dry air at 30°C,
The sample was left in a saturated water vapor pressure of ~70°C for 24 hours, and the resulting sample was frozen at -40°C for 12 hours and freeze-dried. This was swollen in distilled water to obtain a membrane-like hydrogel. All of the obtained hydrogels were tough and transparent films. This gel was measured for elongation at break and tensile strength test. The measurement results are shown in Table 1.

[0025]

[Table 1]

Example 1 The hydrogel membrane obtained in Reference Example 1 was immersed in a 0.03 mol/l borax aqueous solution for 24 hours for crosslinking treatment. All of the gels obtained were transparent. Table 2 shows the water content and elastic modulus of the gel obtained when 10% tensile strain was applied.

[0027]

[Table 2]

Comparative Example 1 An aqueous solution (10 w/v %) of polyvinyl alcohol (saponification degree 98.8 mol %, average degree of polymerization 2000) was further cast on Petri, and a 0.03 mol/l borax aqueous solution was poured onto it. was added to form a gel. The resulting gel was sticky jelly-like and had extremely low strength.

Comparative Example 2 Commercially available polyvinyl alcohol (saponification degree 98.8 mol%,
A hydrogel was prepared by preparing an aqueous solution (10 w/v %) with an average degree of polymerization of 2000), repeating freezing at -50°C and thawing at 7°C five times, and then swelling it in water. This hydrogel was immersed in a 0.03 mol/l borax aqueous solution for 24 hours for crosslinking treatment. The obtained gel was opaque, and the elastic modulus when tensile strain was applied to this gel was 0.09 MPa, which was much lower in strength than the hydrogel obtained in Example 1.

Example 2 Changes in stress, volume, and water content when calcium ions were added to the hydrogel obtained in Example 1 at a saturated steam temperature of 40° C. were investigated. For stress measurement, a 10% tensile strain was applied to the gel using a 0.03 mol/l borax aqueous solution, and after the stress reached a constant level, the external solution was added to a borax solution (0.03 mol/l)/
The gel film was replaced with a mixed aqueous solution of calcium chloride (0.01 mol/l), and the resulting change in stress in the gel film was measured. Thereafter, the external solution was exchanged with a mixed aqueous solution of borax (0.03 mol/l)/tetrasodium ethylenediaminetetraacetate (0.05 mol/l). Figure 1 shows the stress changes.

A rapid increase in stress was observed upon addition of calcium ions, and reached a constant value in about 10 minutes. Next, the stress was rapidly reduced by replacing the external solution with tetrasodium ethylenediaminetetraacetate, and recovered to the stress value before addition of calcium ions in about 10 minutes. The stress increased by adding calcium ions again, and reversible stress changes occurred thereafter. The stress upon addition of calcium ions increased to about four times the initial stress. The increase in stress due to the addition of calcium ions was about 0.2 MPa, and a very large tension was generated.

FIG. 2 shows the change in volume of the gel. As for the volume change, rapid contraction of the gel occurred simultaneously with the addition of calcium ions, and the gel volume decreased to less than half of its original volume after 20 minutes. The volume of the gel was then completely recovered by exchanging to tetrasodium ethylenediaminetetraacetate.

Table 3 shows the water content of the gel. Addition of calcium ions reduced the water content by more than 20%. Moreover, the water content was recovered by replacing it with tetrasodium ethylenediaminetetraacetate.

[0034]

[Table 3]

Example 3 The hydrogel obtained in Example 1 with a saturated steam temperature of 40°C was
．． A tensile strain of 10% was applied to an aqueous solution of 0.03 mol/l of borax, and the glucose concentration in the solution was increased or decreased between 0 and 125 mM, and changes in stress of the gel were measured. Figure 3 shows the stress changes. Increasing the glucose concentration increased the stress, and decreasing the concentration decreased the stress. The relationship between stress change and glucose concentration was proportional. Therefore, it was shown that this hydrogel can be used as a glucose sensor.

Example 4 The hydrogel obtained in Example 1 with a saturated steam temperature of 40°C was
．． A 10% tensile strain was applied to an aqueous solution of 0.03 mol/l of borax, the pH of the solution was varied between 6 and 12, and changes in stress and volume of the gel were measured at 25°C. pH to 1
By lowering from 2 to 6, the gel stress increased more than three times. When the pH is returned to 12 again, the stress decreases,
The stress returned to its original value, indicating a reversible stress change. On the other hand, when the pH was lowered from 12 to 6, the volume shrunk to less than half. When the pH was returned to 12 again, it swelled to its original volume and exhibited reversible pH responsiveness.

Example 5 The hydrogel obtained in Example 1 with a saturated steam temperature of 40°C was
．． 0.03 mol/l borax aqueous solution to bring the temperature of the solution to room temperature (
When raised from about 22°C to 50°C, the gel shrinks and becomes about 17°C.
% volume decreased. When returned to room temperature, the gel swelled and regained its volume.

Example 6 The hydrogel film obtained in Example 1 with a saturated steam temperature of 40°C was cut into strips and placed in a Petri dish containing a 0.03 mol/l borax aqueous solution, and one end of the film was fixed. . Two platinum electrode plates were placed in parallel with a gel membrane in between, and a voltage of 40 V was applied between the electrode plates. Simultaneously with the application of voltage, the gel film was bent significantly toward the positive electrode.

[0039]

Effects of the Invention The present invention provides a new functional hydrogel that exhibits large swelling and contraction in response to various changes in concentration of monosaccharides and disaccharides such as glucose or divalent metal ions, pH, temperature, electric field, etc. Obtainable.

[Brief explanation of the drawing]

FIG. 1 is a response curve showing the stress change of the hydrogel of the present invention to divalent metal ions.

FIG. 2 is a response curve showing the volume change of the hydrogel of the present invention to divalent metal ions.

FIG. 3 is a response curve showing the stress change of the hydrogel of the present invention to glucose.

Claims (8)

[Claims] 1. A stimulus-responsive hydrogel made from polyvinyl alcohol. 2. The stimulus-responsive hydrogel of claim 1, which responds to changes in concentration of monosaccharides and disaccharides. 3. The stimuli-responsive hydrogel of claim 1, which responds to changes in the concentration of divalent metal ions. 4. The stimuli-responsive hydrogel of claim 1, which is responsive to pH changes. 5. The stimuli-responsive hydrogel of claim 1, which is responsive to temperature changes. Claim 6: Claim 1 which responds to the application of an electric field.
stimulus-responsive hydrogels. 7. Obtain a high-strength, transparent hydrogel by freeze-drying using a polyvinyl alcohol aqueous solution with a saponification degree of 97 mol% or more and an average polymerization degree of 1000 or more. A method for producing a stimulus-responsive hydrogel, which comprises immersing it in an alkaline aqueous solution of boric acid or a borate salt having a pH of 7 or more for 30 minutes or more. 8. The freeze-drying method involves injecting an aqueous solution of polyvinyl alcohol into a container of any shape or into a mold, drying it without freezing, and then placing the dried product in water vapor at a constant pressure. A method of obtaining hydrogel by leaving the sample to absorb a certain amount of water, then immediately freezing it at -20℃ or below, drying it in the frozen state, and immersing the obtained sample in water as necessary. A method for producing a stimuli-responsive hydrogel according to claim 7.