KR101068499B1 - A preparation method of Temperature and pH sensitive hydrogel - Google Patents

Abstract

The present invention relates to a method for producing a temperature- and pH-sensitive hydrogel having high swelling and mechanical strength, and more particularly, preparing microcapsules; The cross-linking the microcapsules to produce an IPN (interpenetrating polymer network) hydrogel; and relates to a temperature and pH-sensitive hydrogel manufacturing method comprising a. Temperature and pH sensitive hydrogels according to the present invention can be used in sensors, actuators such as switches, drug delivery agents, implants, artificial skin and artificial muscles.

Microcapsules, IPN, Hydrogels, Drug Delivery Agents

Description

A preparation method of Temperature and pH sensitive hydrogel

The present invention relates to a method for producing a temperature- and pH-sensitive hydrogel having high swelling and mechanical strength, and more particularly, preparing microcapsules; The cross-linking the microcapsules to produce an IPN (interpenetrating polymer network) hydrogel; and relates to a method for producing a temperature- and pH-sensitive hydrogel prepared.

Microcapsule is a technology developed in the United States in the 1950's. It is a size-based but sealed molecule of liquid, solid or gas in a small container (cell) up to several hundred micrometers. Microcapsules have diameters of several millimeters to several nanometers, depending on the manufacturing process. One of the important functions of microcapsules is their retention properties, which protect them from damage and change until the sealed contents are used and isolate them from reacting with other materials. As the retention of microcapsules is important, the release of the contents is also important. Release is mainly caused by the destruction of the cell by pressure or heating. Therefore, the technique of enclosing or coating an unstable or weakly sustained active ingredient with a polymer, ceramic or an organic-inorganic composite is a fundamental technology of microcapsules.

By microencapsulating a material, it is possible to hide a desired material on a desired object without changing the appearance, so there is no design limitation, the desired material can be moved to a minute place, and the loss of material in the manufacturing process can be minimized. In addition, the greatest advantage is that the release rate of the microencapsulated material can be controlled for continuous use. Therefore, it can be applied to pharmaceuticals through microcapsules of biocompatible materials or biodegradable materials. However, microcapsules are problematic because they are easily destroyed or dissolved by external stimuli before delivering the material to the desired place.

Hydrogel generally refers to a material having a three-dimensional hydrophilic polymer network structure that can contain a large amount of water. Hydrogels can absorb at least 20% of the total weight of water, and absorbing more than 95% of water is called a superabsorbent hydrogel. Hydrogels consist of homopolymers or copolymers, forming a structurally stable three-dimensional network structure with little fluidity due to external hysteresis, which has several factors such as covalent bonds, hydrogen bonds, van der Waals bonds, or physical aggregation. Is formed by. It is thermodynamically stable after swelling in an aqueous solution, and has mechanical and physicochemical properties corresponding to the intermediate form of liquid and solid. In addition, the swelling degree of the hydrogel can be adjusted according to the chemical structure and hydrophilicity of the polymer, the degree of crosslinking between the polymer chain, it is possible to manufacture a hydrogel having a variety of forms and properties depending on the composition and the manufacturing method.

When a chemical or biological substance such as drugs, enzymes, tissues, cells or viruses is encapsulated in the polymer gel or particles forming the hydrogel and used as a biological delivery system, the encapsulated substance is inactivated or volatilized by moisture, heat, and oxidation. It is used in the manufacture of pharmaceuticals and cosmetics because it can be prevented, increase the biocompatibility, and can produce a sustained or sustained release formulation.

In addition, hydrogels show various functions depending on the types of functional groups present in the polymer network structure. By introducing these functional groups into the hydrogels, the hydrogels are highly responsive and responsive to external stimuli. Many studies have been conducted. Various studies have been conducted using sustained-release drug delivery using hydrogels in response to physical stimuli such as temperature, electricity, solvents, light, pressure and magnetic force, and chemical stimuli such as ions and specific molecular recognition. It is very important that the polymer gels or particles used in these delivery systems can be released in a timely manner at each desired target location in vivo. Various kinds of methods for controlling the release rate of a polymer for using an active ingredient in a delivery system have been studied.

Recently, research has been actively conducted on pH-sensitive hydrogels as well as temperature.

In general, when a hydrophilic group is introduced into a polymer, the polymer can be dissolved or swelled by water. In general, polymers prepared in this way have increased solubility in water as the temperature increases, whereas polymers composed of hydrophobic moieties such as methyl, ethyl, and propyl decrease in water solubility as the temperature increases. critical solution temperature). Hydrogels made of polymers with LCST condense to gel when the temperature increases above LCST, and this class is called elevated hydrogels. The polymer composed of hydrophilic and hydrophobic moieties dissolves in water because the hydrogen bonding force between the hydrophilic group and the water molecule of the polymer is predominant at low temperature. Agglomeration, ie hydrogel gel occurs. Therefore, the increase of the hydrophobic moiety in the polymer lowers the LCST so that the LCST can be changed by controlling the molecular chain of the hydrophilic and hydrophobic groups. When the polymer is crosslinked, the swelling and shrinkage behavior is shown, but when the polymer is not crosslinked, the phase transition behavior of the sol-gel is shown.

Polymers with acidic or basic counterpart groups can form hydrogels through the migration of protons due to pH changes. Swelling can be controlled by pH, ionic strength and the shape of the corresponding ion. pH-stimulated sensitizing hydrogels are available where different pH levels are present, such as the stomach below pH 3 and the neutral intestine.

Currently, research on hydrogels having both temperature and pH sensitivity is drawing attention, and in particular, amphiphilic polymers exhibiting a sol-gel transition behavior with respect to temperature have been intensively studied in drug delivery systems and medical fields. It is also active.

The method for producing a hydrogel having temperature and pH sensitivity at the same time has been commercialized in various ways. In particular, cited by Sokker. H.H., Abdel Ghaffar. A.M., Gad. Y.H., Aly. A.S., Carbohydrate polymers, v. 75, no. 2, p. 222-229, 2009, describes hydrogel studies using copolymers.

In the cited documents described above, limited experimental conditions such as very pure solvents or monomers, high vacuum, and low temperature are required, and there are limitations in the applicable monomers and limited solvents, crosslinking agents, and polymer selection.

Block copolymer (block copolymer) is a structure in which at least two monomers are connected by covalent bonds and has self-assembly properties, it is difficult to predict the future structure because it is arranged in a spontaneous regular form. In addition, the experimental conditions must be relied on, and the design is not easy.

However, interpenetrating polymer networks (IPNs) refer to polymers having at least two network structures that are at least partially intersected on the molecular scale but are not covalent and not separated until the chemical bond is broken. It is different from a mixture of polymers. The types of IPNs are divided according to the polymerization method and form, and these IPNs form a wide range of attenuating materials or reinforced elastomers to replace thermosetting resins, and some types of IPNs are continuous physical materials that are difficult for other polymers to exhibit. , Mechanical properties. Hydrogels are typically oxygen permeable and biocompatible because they are hydrated crosslinked polymeric systems containing 20 to 90% of water at equilibrium with hydrophilic crosslinked polymers of low crosslink density. Because IPN systems are fast and sensitive to electrical reactions and exhibit good mechanical properties (Kim et al, J. Appl. Polym. Sci, 73, pp 1675-1683, 1999), effective actuators and sensors, muscles and numbers of the human body It can be used as a substance to play a role.

The present invention is to solve the problems of the prior art as described above, and relates to a method for producing a temperature and pH-sensitive hydrogel having a high swelling and mechanical strength, more specifically to prepare a microcapsule; Cross-linking the microcapsules to prepare an IPN (interpenetrating polymer network) hydrogel; to provide a method for producing a temperature- and pH-sensitive hydrogel prepared.

In order to achieve the above object, the present invention provides a method for producing a temperature and pH-sensitive hydrogel having a high swelling degree and mechanical strength. Specifically, the present invention,

a) preparing microcapsules;

b) polymerizing and crosslinking the microcapsules to prepare an IPN (interpenetrating polymer network) hydrogel;

It provides a method for producing a temperature and pH-sensitive hydrogel to be prepared, including.

Hereinafter, the present invention will be described in more detail.

The present invention relates to a method for producing a temperature and pH sensitive hydrogel having high swelling and mechanical strength, and more specifically,

a) preparing microcapsules;

b) polymerizing and crosslinking the microcapsules to prepare an IPN (interpenetrating polymer network) hydrogel;

It relates to a method for producing a temperature and pH sensitive hydrogel to be prepared, including.

The microcapsules of step a) are preferably prepared including poly vinyl alcohol and poly N-isopropylacrylamide.

Polyvinyl alcohol (PVA) is a water-soluble polyhydroxy polymer that is easy to handle, suitable for microcapsules due to its chemical resistance, complete biodegradability and good physical properties. In addition, chemically crosslinked PVA has attracted attention in biomedical and biochemistry because of its good permeability, biocompatibility, and biodegradability.

Poly N-isopropylacrylamide (PNIPAAm) exhibits a lower critical solution temperature (LCST) at about 32 ° C, which is soluble in water below 32 ° C but hydrophobic bonds above 32 ° C. It tends to settle due to the aggregation of. The cross-linked PNIPAAm hydrogel exhibits temperature-responsive properties, with swelling under LCST and shrinkage above LCST.

Step a) is preferably prepared by reacting poly vinyl alcohol and poly N-isopropylacrylamide with a crosslinking agent.

The crosslinking agent is glutaraldehyde, N, N'-methylene-bis-acrylamide (N, N'-methylene-bis-acrylamide), N, N, N ', N'-tetramethyl ethylenediamine ( N, N, N ', N'-tetramethyl ethylene diamine) and ethylene glycol dimethacrylate (ethylene glycol dimethacrylate) is selected from the group consisting of one or two or more, most preferably glutaraldehyde ( glutaraldehyde) and N, N'-methylene-bis-acrylamide (N, N'-methylene-bis-acrylamide) are used.

Chemically crosslinked microcapsules can be prepared by radical polymerization of low molecular weight monomers in the presence of the crosslinking agent. The properties of these microcapsules, in particular the degree of swelling, can be controlled by the amount of crosslinking agent. In addition, microcapsules with temperature stimulation sensitivity can be prepared by the addition of PNIPAAm (temperature stimulation gel).

In step b), a mixed solution of poly vinyl alcohol and a vinyl monomer is added to the microcapsules to provide an IPN structure, wherein the vinyl monomer is acrylic acid, methacrylic acid ( methacrylic acid, methacryl amide, hydroxyethyl methacrylate, glycidyl acrylate, cinnamic acid, vinylpyrrolidone and methylmethacryl It is preferably selected from methacrylate (methyl meta acrylate). Most preferably, acrylic acid is used as the vinyl monomer, and hydrogel having pH stimulus sensitivity may be prepared by the addition of acrylic acid (pH stimulant gel).

Step b) may also be prepared by chemically crosslinking IPN hydrogel by radical polymerization.

In addition to the radical polymerization method using the vinyl monomer, the chemical hydrogel may be prepared by radical polymerization of a polymerizable water-soluble polymer.

The temperature and pH sensitive hydrogels prepared according to the present invention can be used as drug carriers of drug delivery agents.

The drug is processed into a formulation and then administered to the living body in various ways so as to be convenient for application and optimally express pharmacological effect. The temperature and pH sensitive hydrogels prepared according to the present invention are polymers of crosslinked IPN structure, which can withstand strong acid environment, and have good permeability of various drugs. It also has a fabric-like surface structure that can be adjusted to increase the acidity (pH, acidity) to release the swollen drug. Therefore, the acidic gastrointestinal tract well protects the drug, and when the stomach reaches the alkaline small intestine or large intestine will release the drug.

The temperature and pH sensitive hydrogels prepared by the method for preparing the temperature and pH sensitive hydrogels of the present invention simultaneously have temperature-sensitive drug control by microcapsules and pH-sensitive drug control by hydrogels, and have high swelling degree. And has excellent mechanical strength. In addition, the temperature- and pH-sensitive hydrogel has a double encapsulation of the matrix surrounding the material to be transported, and thus has high swelling and excellent mechanical strength, thereby preventing the loss of the material to be transported during the mass transfer process. When used as a drug carrier of the temperature and pH can be prepared a temperature- and pH-sensitive hydrogel that can be sensitively stimulated.

When explaining this invention based on an Example and a comparative example as follows, this invention is not limited by an Example and a comparative example.

Test Methods

1. Swelling degree measurement

In order to measure the average water content (EWC), the dried samples of the IPN hydrogels prepared according to Examples 1 to 3 and Comparative Example 1 were cut into horizontal, vertical and height sizes of 10 mm each. Psalms were made. After measuring the weight of the dried sample, it was immersed in a buffer solution of pH 10 at room temperature to determine the weight of the specimen over time. The measurement of the weight of the specimen removes water on the surface of the specimen with filter paper and measures the weight of the fully swollen specimen. EWC can be obtained from Equation 1 below, where W _s is the weight of the swollen sample and W _d is the weight of the dried sample.

2. Mechanical strength measurement

In order to measure the mechanical strength of IPN hydrogel, the specimens were cut into 10 mm diameter and 5 mm thick circular specimens, immersed in distilled water at room temperature for 2 days, and then swollen to measure mechanical strength. The measuring instrument was an Instron tester model 1122 (Instron Corporation), the measurement conditions were measured at 25 ℃, 50% relative humidity, the total size was measured with a load cell of 2.0 KN.

3. Measurement of Cumulative amount released (%)

By using buffer solutions with different pH, it is possible to measure the cumulative concentration of the released drug of the hydrogel according to pH at a temperature of 25 ℃.

The drug used was Coomasibrillant Blue, and the hydrogel samples prepared according to Examples 1 to 3 and Comparative Example 1 were cut into sizes of 10 mm in diameter and 5 mm in thickness, respectively, to pH 2 buffer solution and pH 7 buffer. The solution was immersed in a buffer solution of pH 10, and 2 mL of each hour was taken and UV measured at 583 nm.

The cumulative concentration of the released drug was measured using a UV spectrometer [Optizen 2120 UV, Mecasys, Korea], the cumulative concentration (%) of the released drug can be expressed as in Equation 2.

In Equation 2, Mt refers to the amount of drug released from the hydrogel sample over time, and M refers to the total amount of coumasibrillant blue.

Example 1

A) Polyvinyl alcohol (A, weight average molecular weight 42,000) and distilled water (B) were mixed and dissolved in a weight ratio (A: B) 1: 9, and then heated at 90 ° C. for 6 hours to prepare an aqueous polyvinyl alcohol solution. The polyvinyl alcohol aqueous solution (A ') prepared above and poly N-isopropylacrylamide (B') were mixed in a weight ratio (A ': B') 1: 1, and then n-hexane (n) as a solvent was added to the mixture. -hexane) 100 mL and emulsifier Span 80 3 mL are added and mixed. In another container, 2 mL of N, N'-methylene-bis-acrylamide (N, N'-methylene-bis-acrylamide), 2 mL of glutaraldehyde (GA), and n-hexane (solvent) 100 mL of n-hexane, 3 mL of emulsifier Span 80, 1.0 mL of hydrochloric acid (HCl) and 1 g of CBB (coomassie brillant blue G-250) are added and stirred. Put the mixture of the two vessels in a homogenizer to prepare a microcapsule by stirring for 1 hour at a homogenizer speed of 1000 rpm. After washing several times with petroleum ether for purification of the microcapsules, the n-hexane solvent is evaporated for 24 hours under a vacuum condition of 50 ℃. And again washed with distilled water several times and dried to prepare a microcapsules;

B) Polyvinyl alcohol (C, weight average molecular weight 42,000) and distilled water (D) was dissolved by mixing in a weight ratio (C: D) 1: 9, and then heated at 90 ℃ for 6 hours to prepare a polyvinyl alcohol aqueous solution. After mixing 20 mL of an aqueous acrylic acid solution (AAc, acrylic acid) to 100 mL of the polyvinyl alcohol solution prepared above, 2 mL of an aqueous solution of ethylene glycol dimethacrylate (EGDMA, ethylene glycol dimethacrylate) and glutaraldehyde were added to the mixture. 2 mL of an aqueous solution (GA, glutaraldehyde) was added and mixed to prepare a hydrogel precursor.

1.0 g of the microcapsules prepared in A) and the mixture prepared in B) were added to the reactor, and 20 mL of potassium persulfate (KPS), an initiator, was added thereto, followed by stirring at room temperature for 30 minutes. The reactor was then made into a nitrogen atmosphere and then crosslinked at 70 ° C. for 2 hours. Temperature- and pH-sensitive hydrogels made in film form are washed again with distilled water, dried, cut into cubes with a length of 0.5 cm, and dried for 24 hours at 60 ° C in a vacuum oven to remove unreacted substances. Sensitive hydrogel (MCH 10) was prepared.

[Example 2]

A temperature and pH sensitive hydrogel (MCH 15) was prepared in the same manner as in Example 1 except that 1.5 g of the microcapsules prepared in A) was added to the reactor.

Example 3

A temperature and pH sensitive hydrogel (MCH 20) was prepared in the same manner as in Example 1 except that 2.0 g of the microcapsules prepared in A) were added to the reactor.

Comparative Example 1

The same procedure as in Example 1 was performed except that the process A) of Example 1 was omitted and only the mixture prepared in B) was used to prepare a hydrogel. Prepared.

1 is a digital camera photograph of a temperature and pH sensitive hydrogel prepared according to the present invention, in which FIG. 1 (a) shows MCH 10, FIG. 1 (b) shows MCH 15 and FIG. 1 (c) shows MCH 20. will be. As shown in FIG. 1, the amount of microcapsules per unit area of the hydrogel increased as the content of the microcapsules increased, and the microcapsules were well dispersed in the hydrogel.

FIG. 2 is a scanning electron microscope (SEM) photograph of a temperature- and pH-sensitive hydrogel according to pH, and FIG. 2 (a) shows a microcapsule present inside a cut section of MCH 10, and FIG. 2 (b) Is MCH 10 at pH 7, FIG. 2 (c) shows MCH 15 at pH 7, and FIG. 2 (d) shows the surface of MCH 20 at pH 7. Through Figure 2 it was confirmed that the microcapsules stably contained in the hydrogel.

Figure 3 shows the mechanical strength of the temperature and pH sensitive hydrogel prepared according to the present invention, MCH 0 is Comparative Example 1, MCH 10 is Example 1, MCH 15 is Example 2 and MCH 20 is Example 3 It is manufactured according to. As shown in FIG. 3, as the content of the microcapsules in the hydrogel increases, the compression coefficient also increases. This means that the temperature- and pH-sensitive hydrogels containing microcapsules prepared according to the invention have excellent mechanical strength.

Figure 4 shows the swelling degree of MCH 20 according to the pH change at a temperature of 25 ℃, it can be confirmed that the temperature and pH-sensitive hydrogel prepared in accordance with the present invention is a hydrogel exhibiting a stimulus to pH.

FIG. 5 is a scanning electron microscope (SEM) photograph of MCH 20 according to pH change. FIG. 5 (a) is pH 2, FIG. 5 (b) is pH 7, and FIG. 5 (c) is MCH 20 at pH 10. The swelling state is shown. As shown in FIG. 5, as the pH of the buffer aqueous solution increased, the degree of swelling also increased. This is because the state of association of ions inside the polymer, the functional groups on the surface of the hydrogel, and the ion repulsion force of the aqueous buffer solution determine the degree of swelling. In other words, as the pH increases, the degree of swelling increases as a result of gel shrinkage along the surface of the hydrogel.

In general, when the degree of swelling increases, the flexibility increases due to the increase in water contained therein, and the skin adhesion increases. Temperature and pH-sensitive hydrogel of the present invention is shown to have a high degree of swelling of 300% or more at a concentration of 0.8 to 0.85% by weight of NaCl in the human body, suitable for use in sensors, actuators and artificial muscles or organs.

Figure 6 shows the swelling degree of the temperature and pH sensitive hydrogel prepared according to the present invention according to the time and temperature change at pH 10, Figure 6 (a) is 4 ℃, Figure 6 (b) is 25 ℃ and Figure 6 (c) shows the swelling degree at 40 ° C., and FIG. 1 (d) shows the swelling degree according to the temperature change of MCH 20. 6, it was confirmed that the hydrogel of the present invention exhibited a stimulus by temperature.

7 is a scanning electron microscope (SEM) photograph of MCH 20 according to temperature change, and shows the swelling state of MCH 20. Figure 7 (a) is 4 ℃, Figure 7 (b) is 25 ℃ and Figure 7 (c) shows the swelling degree at 40 ℃, respectively, through which the swelling difference according to the temperature change of the sample can be confirmed.

8 shows the reversibility of swelling-shrinkage of MCH 20 with pH change at a temperature of 25 ° C. As a result of repeatedly measuring the degree of flatness at pH 2 and pH 10, it was confirmed that it can be used repeatedly without significant change.

Figure 9 shows the drug release change of the temperature and pH-sensitive hydrogel prepared according to the present invention, Figure 9 (a) is a change in drug release by pH, Figure 9 (b) is a change in drug release by temperature Respectively. 9 (a) it can be seen that the temperature and pH-sensitive hydrogel prepared according to the present invention lasts for more than 24 hours depending on the pH tendency, and more drugs are continuously released at pH 10 longer than pH 2 I could confirm that. This is because the spacing between the polymer chains increases as the pH increases due to the ion repulsion of the carboxyl group between the polymer chains of the hydrogel. In addition, the cumulative concentration of the released drug of the hydrogel according to the temperature can be confirmed through FIG. 9 (b), and as the temperature is lower, the hydrogen bonding force between the water and the polymer is increased, and the gap between the polymer chains is widened, as well as the microcapsules. This swelling was also confirmed to release more drug.

1 is a digital camera photograph of a temperature and pH sensitive hydrogel prepared according to the present invention, in which FIG. 1 (a) shows MCH 10, FIG. 1 (b) shows MCH 15 and FIG. 1 (c) shows MCH 20. will be.

2 is a scanning electron microscope (SEM) image of the temperature and pH-sensitive hydrogel according to the pH change, Figure 2 (a) shows a microcapsule present inside the cut section of MCH 10, Figure 2 (b ) Shows MCH 10 at pH 7, FIG. 2 (c) shows MCH 15 at pH 7, and FIG. 2 (d) shows the surface of MCH 20 at pH 7.

Figure 3 shows the mechanical strength of the temperature and pH sensitive hydrogel prepared according to the present invention, MCH 0 is Comparative Example 1, MCH 10 is Example 1, MCH 15 is Example 2 and MCH 20 is Example 3 It is manufactured according to. It can be seen from FIG. 3 that the mechanical strength of the IPN hydrogel increases as the content of the microcapsules increases.

Figure 4 shows the swelling degree of MCH 20 with pH change at a temperature of 25 ℃.

FIG. 5 is a scanning electron microscope (SEM) photograph of MCH 20 according to pH change. FIG. 5 (a) is pH 2, FIG. 5 (b) is pH 7, and FIG. 5 (c) is MCH 20 at pH 10. The swelling state is shown.

Figure 6 shows the swelling degree of the temperature and pH sensitive hydrogel prepared according to the present invention according to time and temperature at pH 10, Figure 6 (a) is 4 ℃, Figure 6 (b) is 25 ℃ and 6 (c) shows each swelling degree at 40 ℃, Figure 1 (d) shows the swelling degree according to the temperature of MCH 20. 6, it can be seen that the hydrogel of the present invention exhibits stimulation by temperature.

7 is a scanning electron microscope (SEM) photograph of MCH 20 according to temperature, and shows the swelling state of MCH 20. Figure 7 (a) is 4 ℃, Figure 7 (b) is 25 ℃ and Figure 7 (c) shows the swelling degree at 40 ℃, respectively, it can be confirmed the difference between the swelling degree according to the temperature of the sample.

8 shows the reversibility of swelling-shrinkage of MCH 20 with pH change at a temperature of 25 ° C.

Figure 9 shows the drug release change of the temperature and pH-sensitive hydrogel prepared according to the present invention, Figure 9 (a) is a change in drug release by pH, Figure 9 (b) is a change in drug release by temperature Respectively.

Claims (8)

a) preparing a microcapsule by reacting polyvinyl alcohol and poly N-isopropylacrylamide with a crosslinking agent; And b) preparing a hydrogel having an IPN (interpenetrating polymer network) structure by radical polymerization by adding a mixed aqueous solution of poly vinyl alcohol and a vinyl monomer to the microcapsules; Method for producing a temperature and pH-sensitive hydrogel prepared by including. delete delete The method of claim 1, The crosslinking agent is glutaraldehyde, N, N'-methylene-bis-acrylamide (N, N'-methylene-bis-acrylamide), N, N, N ', N'-tetramethyl ethylenediamine ( N, N, N ', N'-tetramethyl ethylene diamine) and ethylene glycol dimethacrylate (ethylene glycol dimethacrylate) A method for producing a temperature and pH sensitive hydrogel selected from the group consisting of two or more. delete The method of claim 1, The vinyl monomers are acrylic acid, methacrylic acid, methacrylamide, hydroxyethyl methacrylate, glycidyl acrylate, cinnamic acid. (cinnamic acid), vinylpyrrolidone (vinylpyrrolidone) and methyl methacrylate (methyl meta acrylate) is a method for producing a temperature- and pH-sensitive hydrogel selected from. A temperature and pH sensitive hydrogel prepared according to any one of claims 1, 4 or 6. A drug delivery agent using a temperature and pH-sensitive hydrogel prepared according to any one of claims 1, 4 or 6 as a drug carrier.

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