Biodegradable polymers and shape-memory hydrogels

Abstract

The present invention provides a polymer material that exhibits sufficient shape memory while maintaining the advantages of hydrogels (flexibility, transparency, material encapsulation, biocompatibility, etc.), and is also biodegradable. [Solution] A shape-memory hydrogel containing a polymer matrix and water. The polymer matrix is ​​a biodegradable polymer having carboxyl groups, some of which are modified with glycinamide, and the carboxyl groups that are not modified with glycinamide are crosslinked with a crosslinking agent. An example of a biodegradable polymer having carboxyl groups is polyglutamic acid. An example of a crosslinking agent is ethylenediamine. Because the hydrogel of the present invention retains biodegradability, it is extremely safe and does not burden the environment when disposed of. Furthermore, it has extremely high hydrophilicity and can absorb and retain a large amount of water.

Description

[Technical Field]

[0001] This invention relates to a novel biodegradable polymer, and more particularly to a hydrogel having shape memory function containing the biodegradable polymer. [Background technology]

[0002] In recent years, from the perspective of the SDGs (Sustainable Development Goals), there has been a growing demand for the development of environmentally friendly polymer materials that have a low impact on the environment and ecosystems and enable sustainable production. Among these, hydrogels have high water content, transparency, structural flexibility similar to biological tissues, and material encapsulation capabilities, and are applied in a wide range of fields such as medicine, cosmetics, and engineering materials. In recent years, the development of hydrogels with functions such as self-healing and stimulus responsiveness has also progressed. For example, polymer materials that exhibit gel-sol transition in response to changes in temperature and pH have already been put into practical use.

[0003] Patent Document 1 discloses an adhesive gel comprising a matrix of hydrophilic polymer and acrylamide polymer containing a polyhydric alcohol and water. This adhesive gel has the characteristic of maintaining its adhesiveness and being able to adhere to biological surfaces even when its water content decreases.

[0004] Patent Document 2 discloses an adhesive gel in which a water-soluble polymer and water are held within a polymer matrix obtained by copolymerizing acrylamide as a polymerizable monomer and N,N'-methylenebisacrylamide as a crosslinkable monomer. This adhesive gel has low skin irritation properties and is conductive due to the inclusion of an electrolyte salt.

[0005] On the other hand, because hydrogels are mostly composed of water, their structural flexibility makes it difficult to deform, fix, and retain their shape like plastics. Hydrogels, with their unique property of remembering their initial shape and then recovering to their original shape in response to external stimuli such as pH and temperature, are attractive as new high-performance soft materials.

[0006] The present inventors developed a hydrogel that can remember its initial shape and can be fixed / recovered in shape by temperature stimulation by utilizing the reversible hydrogen bonds of a chemically crosslinked temperature-responsive amino acid-derived vinyl polymer (Patent Document 3). However, since this hydrogel has a vinyl polymer (carbon-carbon bond) as its network main chain, it does not inherently have biodegradability. Particularly for cosmetic materials, since marine outflow is likely to occur, dealing with the microplastic problem is an important issue.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0008] The present invention has been made in view of such problems, and an object thereof is to provide a biodegradable polymer material that sufficiently exhibits shape memory while maintaining the advantages (flexibility / transparency / substance encapsulation / bio-compatibility, etc.) of the hydrogel and also has biodegradability.

Means for Solving the Problems

[0009] The biodegradable polymer according to the present invention is a biodegradable polymer having a carboxyl group, and a part of the carboxyl group is modified with glycine amide.

[0010] The shape memory hydrogel according to the present invention is a shape memory hydrogel comprising a polymer matrix and water, wherein the polymer matrix is ​​a biodegradable polymer having carboxyl groups, a portion of which is modified with glycinamide, and the unmodified carboxyl groups are crosslinked with a crosslinking agent, characterized in that it is a biodegradable polymer. [Effects of the Invention]

[0011] According to the present invention, a hydrogel is obtained that exhibits sufficient shape memory while maintaining the advantages of hydrogels, and is also biodegradable. Because the hydrogel according to the present invention retains biodegradability, it is extremely safe and does not burden the environment when disposed of. Furthermore, it has extremely high hydrophilicity and can absorb and retain large amounts of water. Therefore, it is expected to be applicable to adhesives usable in living organisms, wound dressings, cell culture gels, water retention materials for agriculture, and moisturizers and water absorbers incorporated into cosmetics, etc. [Brief explanation of the drawing]

[0012] [Figure 1] This figure shows the measurement results of the storage modulus (G') and loss coefficient (tanδ) for hydrogels (Px-EDAy) with varying proportions of glycinamide moieties x. [Figure 2] This figure shows the measurement results of the swelling rate with temperature for the hydrogel (Px-EDAy) according to the present invention. [Figure 3] This figure shows the measurement results of the storage modulus (G') and loss coefficient (tanδ) for hydrogels (Px-EDAy) with varying amounts of EDA used for crosslinking. [Figure 4] This is a schematic diagram illustrating a method for measuring the shape retention of a hydrogel according to the present invention. [Figure 5] This is a schematic diagram illustrating a method for measuring the shape recovery of a hydrogel according to the present invention. [Figure 6] This figure shows the measurement results for the shape memory and shape recovery properties of the hydrogel according to the present invention. [Figure 7] This figure shows the results of measuring the enzymatic degradability of the hydrogel according to the present invention. [Figure 8] This figure shows the evaluation results of the shape memory and shape recovery properties of the polyaspartic acid-based hydrogel according to the present invention. [Figure 9] This figure shows the evaluation results of the temperature responsiveness of the hydrogel with polyaspartic acid as the main chain according to the present invention. [Modes for carrying out the invention]

[0013] The embodiments of the present invention will be described below with reference to the attached drawings. However, these embodiments are provided to facilitate understanding of the principles of the present invention, and the scope of the present invention is not limited to the embodiments described below. Other embodiments in which those skilled in the art appropriately substitute the configurations of the embodiments below are also included in the scope of the present invention.

[0014] (1) Biodegradable polymer The biodegradable polymer according to the present invention is a biodegradable polymer having carboxyl groups, characterized in that a portion of the carboxyl groups are modified with glycinamide.

[0015] A glycinamide-modified carboxyl group is represented, for example, by the following formula -Y-CONH-CH2-CONH2, where Y is a chemical bond, a heteroatom consisting of N, O, or S, or -N(R 1 )CO-, -CON(R 1 )-, or -N(R 1 )CON(R 1 )-(Here, R 1 The element is a hydrogen atom, a C1-C4 alkyl group, an alkoxy group, or an alkoxyalkyl group, or -CO-, or -COO-, or a branched C1-6 alkyl group or C2-6 alkenyl group which may have a functional group (which is a hydroxyl group, a carboxyl group, an amino group, an amide group, a carbamate group, or a ketone group) or a heteroatom.

[0016] The biodegradable polymer according to the present invention has a main chain with side chains represented as -Y-CONH-CH2-CONH2.

[0017] [ka]

[0018] The biodegradable polymer according to the present invention is preferably characterized by being represented by the following formula (1). Here, p is an integer from 0 to 2, q is an integer from 0 to 2, and x is from 0.01 to 0.99. n represents a repeating unit defined by the molecular weight of the compound, and the weight-average molecular weight of the biodegradable polymer according to the present invention is not particularly limited, but is for example from 50,000 to 800,000.

[0019] [ka]

[0020] The biodegradable polymer according to the present invention is more preferably characterized by being represented by the following formula (2). That is, in the case of formula (1) described above, p=2 and q=0, and when polyglutamic acid is modified with glycinamide. Here, x is 0.01 to 0.99, and n represents a repeating unit defined by the molecular weight of the compound.

[0021] [ka]

[0022] Furthermore, the biodegradable polymer according to the present invention is a biodegradable polymer having carboxyl groups, characterized in that a portion of the carboxyl groups are modified with glycinamide, and the biodegradable polymer having carboxyl groups is not particularly limited. An example of a biodegradable polymer having carboxyl groups is polyaspartic acid. Polyaspartic acid can be obtained by polycondensation of aspartic acid via polyscinimide, which is an intermediate substance.

[0023] The biodegradable polymer according to the present invention, represented by the following formula (3), is the case when polyaspartic acid is modified with glycinamide. Here, x is between 0.01 and 0.99, and n represents a repeating unit defined by the molecular weight of the compound.

[0024] [ka]

[0025] Furthermore, glycan polymers are examples of biodegradable polymers having carboxyl groups, and polyglucuron is a specific example. The biodegradable polymer according to the present invention, shown in formula (4) below, is the case when polyglucuronic acid is modified with glycinamide. Here, x is between 0.01 and 0.99, and n represents a repeating unit defined by the molecular weight of the compound.

[0026] [ka]

[0027] (2) Method for synthesizing biodegradable polymers Next, a method for synthesizing biodegradable polymers according to the present invention will be described.

[0028] First, as shown in the formula below, glycinamide modification is performed by condensing glycinamide (H-Gly-NH2) onto the side chain of a biodegradable polymer having a carboxyl group in the form of a sodium salt, using DMT-MM as a condensing agent. By adjusting the amount of glycinamide (H-Gly-NH2), x can be appropriately adjusted from 0.01 to 0.99.

[0029] [ka]

[0030] Next, biodegradable polymers containing carboxyl groups can be synthesized by performing cation exchange.

[0031] [ka]

[0032] Next, we will explain the method for synthesizing the biodegradable polymer according to the present invention when p=2 and q=0.

[0033] Polyglutamic acid (PGA) can be produced by either microbial fermentation or chemical polymer synthesis. Furthermore, polyglutamic acid (PGA) can be composed solely of L-type glutamic acid, solely of D-type glutamic acid, or of both L-type and D-type glutamic acid.

[0034] First, as shown in the formula below, glycinamide modification is performed by condensing glycinamide (H-Gly-NH2) onto the side chain of a biodegradable polymer having a carboxyl group in the form of a sodium salt, using DMT-MM as a condensing agent.

[0035] [ka]

[0036] Next, biodegradable polymers containing carboxyl groups can be synthesized by performing cation exchange.

[0037] [ka]

[0038] (3) Hydrogel The hydrogel according to the present invention is a shape-memory hydrogel containing a polymer matrix and water. The polymer matrix is ​​a biodegradable polymer having carboxyl groups, some of which are modified with glycinamide, and the carboxyl groups that are not modified with glycinamide are crosslinked with a crosslinking agent.

[0039] The hydrogel according to the present invention preferably has a polymer matrix which is a biodegradable polymer represented by formula (5). Here, p is an integer from 0 to 2, q is an integer from 0 to 2, x is from 0.01 to 0.99, y is from 0.01 to 0.99, z is from 0.01 to 0.99, where x + y + z = 1, X represents a bond crosslinked with a crosslinking agent having an amino group (-NH2), and n represents a repeating unit defined by the molecular weight of the compound.

[0040] [ka]

[0041] Crosslinking agents having an amino group include, for example, diamine crosslinking agents. Diamine crosslinking agents may also have a functional group (this functional group may be a hydroxyl group, a carboxyl group, an amino group, an amide group, a carbamate group, or a ketone group). The diamine crosslinking agent is not particularly limited, but examples include aliphatic diamine compounds such as ethylenediamine, hexamethylenediamine, lysine and its derivatives, hexamethylenediamine carbamate, N,N-disinnamyridene-1,6-hexanediamine, and hexamethylenediamine cinnamaldehyde adduct; and diamine compounds having a phenyl group such as 4,4-methylenedianiline, m-phenylenediamine, 4,4-diaminodiphenyl ether, 3,4-diaminodiphenyl ether, 4,4-(m-phenylenediisopropylidene)dianiline, 4,4-(p-phenylenediisopropylidene)dianiline, 2,2-bis[4-(4-aminophenoxy)phenyl]propane, 4,4-bis(4-aminophenoxy)biphenyl, m-xylylenediamine, and p-xylylenediamine. Among these, ethylenediamine is preferably used. In addition, polymeric diamine crosslinking agents can also be used. The polymeric diamine crosslinking agent is not particularly limited, but examples include polyethylene glycol diamine (PEG diamine), polypropylene glycol diamine (PPG diamine), polyethylene glycol / propylene glycol diamine, and others, with PEG diamine being preferred. Furthermore, a mixture of the polymeric diamine crosslinking agent and a non-polymeric diamine crosslinking agent such as ethylenediamine can also be used.

[0042] Furthermore, crosslinking agents containing amino groups include, for example, alkyl monoamine crosslinking agents. In the case of diamine crosslinking agents, the amino groups at the ends react with the carboxyl groups of the polymer side chains to bond the polymers together and crosslink them. However, in the case of alkyl monoamine crosslinking agents, the hydrophobic alkyl groups aggregate together, forming crosslinking sites that then gel.

[0043] The number of carbon atoms in the alkylmonoamine is not particularly limited, but a long-chain alkylmonoamine is preferred from the viewpoint of forming crosslinking points. Furthermore, the alkylmonoamine may be a primary amine, a secondary amine, or a tertiary amine.

[0044] As the long-chain alkyl monoamine, a long-chain alkyl having 4 to 25 carbon atoms is preferred, particularly preferred to have 6 to 20 carbon atoms, and even more preferably 8 to 18 carbon atoms.

[0045] Examples of primary alkylmonoamines include n-octylamine, n-decaneamine, n-isodecylamine, n-tridecylamine, n-laurylamine, n-cetylamine, and n-stearylamine.

[0046] Examples of secondary alkylmonoamines include N-octylmethylamine, N-laurylmethylamine, N-tridecylmethylamine, N-stearylmethylamine, N-laurylethylamine, dilaurylamine, and distearylamine.

[0047] Examples of alkylmonoamine tertiary amines include dimethyl laurylamine, dimethyl myristylamine, dimethyl stearylamine, dimethyl decaneamine, dimethyl isodecylamine, dimethyl tridecylamine, diethyl laurylamine, and polyoxyethylene laurylamine.

[0048] The hydrogel according to the present invention is more preferably characterized in that the polymer matrix is ​​a biodegradable polymer represented by formula (6). That is, in formula (5) above, p=2 and q=0. Here, x is 0.01 to 0.99, y is 0.01 to 0.99, z is 0.01 to 0.99, where x+y+z=1, X represents a bond crosslinked by a crosslinking agent having an amino group, and n represents a repeating unit defined by the molecular weight of the compound.

[0049] [ka]

[0050] The hydrogel according to the present invention is more preferably characterized in that the polymer matrix is ​​a biodegradable polymer represented by formula (7). That is, in the case where p=2 and q=0 in formula (5) above, and ethylenediamine is used as the crosslinking agent. Here, x is 0.01 to 0.99, y is 0.01 to 0.99, z is 0.01 to 0.99, where x+y+z=1, X represents a bond crosslinked by a crosslinking agent having an amino group, and n represents a repeating unit defined by the molecular weight of the compound.

[0051] [ka]

[0052] In the hydrogel of the present invention, the ratio of the polymer matrix content to the water content is not particularly limited, but for example, the polymer matrix content is preferably in the range of 5 to 50 parts by weight, and more preferably in the range of 10 to 30 parts by weight, per 100 parts by weight of the total amount of hydrogel. If the polymer matrix content is less than 5 parts by weight per 100 parts by weight of the total amount of hydrogel, the hydrogel may not maintain its shape well and may become too soft or easily torn. If it exceeds 50 parts by weight per 100 parts by weight of the total amount of hydrogel, the hydrogel may become hard, lose its flexibility, or lose its transparency.

[0053] The hydrogel of the present invention may optionally contain a water-soluble polymer. The usable water-soluble polymers are not particularly limited, but examples include vinylpyrrolidone homopolymers (i.e., polyvinylpyrrolidone); vinylpyrrolidone copolymers such as copolymers of vinyl alcohol and vinylpyrrolidone, ether-modified copolymers of vinyl alcohol and vinylpyrrolidone, and copolymers of vinylpyrrolidone and vinyl acetate; polyvinyl alcohol, polyacrylic acid, sodium polyacrylate, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium alginate, dextran, various proteins, nucleic acids, etc.

[0054] Furthermore, the hydrogel of the present invention may contain, as necessary, preservatives, disinfectants, rust inhibitors, antioxidants, stabilizers, fragrances, surfactants, colorants, anti-inflammatory agents, vitamins, whitening agents, and other medicinal ingredients, to the extent that they do not inhibit the effects of the present invention. These additives may be used individually or in combination of two or more.

[0055] (4) Method for producing hydrogels The method for producing the hydrogel according to the present invention is not particularly limited, but for example, a glycinamide-modified biodegradable polymer Px according to the present invention and a crosslinking agent having an amino group are dissolved in water, and a dehydrating condensation agent is added and stirred. DMT-MM is used as the dehydrating condensation agent to promote amidation in water.

[0056] For example, in the aforementioned equation (1), when p=2, q=0, and ethylenediamine is used as the crosslinking agent, a condensation reaction is carried out according to the following equation to produce the hydrogel according to the present invention. Here, x is 0.01 to 0.99, y is 0.01 to 0.99, z is 0.01 to 0.99, where x+y+z=1, and n represents a repeating unit defined by the molecular weight of the compound.

[0057] [ka]

[0058] For example, in the aforementioned formula (1), when p=2 and q=0, and lysine methyl ester (a diamine crosslinking agent having a functional group) is used as the crosslinking agent, a condensation reaction is carried out according to the following formula to produce the hydrogel according to the present invention. Here, x is 0.01 to 0.99, y is 0.01 to 0.99, z is 0.01 to 0.99, where x + y + z = 1, and n represents a repeating unit defined by the molecular weight of the compound.

[0059] [ka] [Examples]

[0060] (Example 1) Synthesis of glycinamide-modified γPGA (Px) Glycineamide-modified γPGA was synthesized by condensing poly(γ-glutamic acid) sodium (γPGA-Na) with glycinamide (H-Gly-NH2) as the side chain using DMT-MM(4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-Hydrate) as the coupling agent. The synthesis route is shown in Scheme 1 below.

[0061] [ka]

[0062] As shown in Table 1, 1.51 g of γPGA-Na (10 mmol of GA units) was dissolved in 10 mL of water, and 0.33 g of H-Gly-NH2·HCl (3 mmol) was dissolved in 10 mL of water. These solutions were mixed, 40 mL of N-methylmorpholine (NMM) was added to adjust the pH to 7, and the mixture was stirred for 30 minutes to completely dissolve the mixture. After stirring, 0.83 g of DMT-MM (3 mmol) dissolved in 10 mL of water was added, and the mixture was stirred at 50°C for 24 hours to carry out condensation. After condensation, unreacted H-Gly-NH2·HCl, DMT-MM, and condensation by-products were removed by reprecipitation using methanol as a poor solvent, and the glycinamide-modified γPGA-Na was isolated as a precipitate. Methanol was removed from the resulting precipitate by drying under reduced pressure in a desiccator. The unreacted γPGA-Na side chains were protonated by treating the obtained polymer with a cation exchange resin. The resulting solution was freeze-dried to obtain the target polymer Px.

[0063] As shown in Table 1, five different polymers were synthesized using similarly different ingredient ratios.

[0064] [Table 1]

[0065] (Example 2) Preparation of hydrogel (Px-EDAy) by ethylenediamine crosslinking As an example, P shown in Table 2 20 -EDA 15 The synthesis route for the preparation method is shown in Scheme 2 below.

[0066] [Table 2]

[0067] 0.11 g of Px (0.8 mmol) and 160 μL of an aqueous solution of ethylenediamine (EDA) diluted 20-fold (0.12 mmol) were dissolved in 1 mL of water. 40 μL of NMM (4-methylmorpholine) was added to adjust the pH to 7, and then 0.098 g (0.35 mmol) of the dehydrating condensing agent DMT-MM was added and stirred. To use as a spacer, a silicon rubber sheet with a thickness of 1 mm with a cut was prepared and adhered onto a glass plate with a hydrophobized surface. The solution was poured into the cut portion of the spacer, and the glass plate was placed thereon in close contact and clamped with a clip. The hydrogel was prepared by leaving it standing at 50 °C for 24 hours in this state.

[0068] [Chemical formula]

[0069] (Example 3) Preparation of hydrogel (Px-Lysy) by lysine methyl ester crosslinking As an example, the synthetic route of the preparation method of P 20 -Lys 15 is shown in Scheme 3 below. 0.11 g of Px (0.8 mmol) and 0.028 g of lysine methyl ester hydrochloride (0.12 mmol) were dissolved in 1 mL of water. 20 μL of NMM was added to adjust the pH to 7, and then 0.098 g (0.35 mmol) of DMT-MM was added and stirred. To use as a spacer, a silicon rubber sheet with a thickness of 1 mm with a cut was prepared and adhered onto a glass plate with a hydrophobized surface. The solution was poured into the cut portion of the spacer, and the glass plate was placed thereon in close contact and clamped with a clip. This was left standing at 50 °C for 24 hours to prepare a hydrogel.

[0070] [Chemical formula]

[0071] (Example 4) Dynamic viscoelasticity measurement of Px-EDAy hydrogel The storage modulus (G') and loss modulus (G") of the hydrogel (Px-EDAy) according to the present invention were determined by rheological measurement. A Discover HR-1 rheometer manufactured by TA-Instruments was used for the rheological measurement, and a 20 mm diameter parallel plate was used as the measurement plate. A solvent trap cover was used during the measurement to minimize water evaporation from the gel. The measurement conditions were 25°C, 1% strain, and pH 5.6. The hydrogel (Px-EDAy) is shown in Table 2. 20 -EDA 15 , P 33 -EDA 15 , P 45 -EDA 15 , P 55 -EDA 15 , P 65 -EDA 15 And, P0-EDA where x=0 15 I used [this].

[0072] Figure 1 shows the measurement results of the storage modulus (G') and loss factor (tanδ) for the hydrogel (Px-EDAy) according to the present invention. For each hydrogel, the left side of the graph represents the storage modulus (G'), and the right side of the graph represents the loss factor (tanδ). The loss factor (tanδ) is expressed as loss modulus (G") / storage modulus (G'). From Figure 1, P0-EDA 15 , P 20 -EDA 15 , P 33 -EDA 15 , P 45 -EDA 15 , P 55 -EDA 15 , P 65 -EDA 15The data shows that as the proportion of x increases, the storage modulus (G') tends to increase, indicating an increase in the adhesive and holding power of the hydrogel. This is thought to be partly due to an increase in hydrogen bonding between polymers as the proportion of x increases. Furthermore, Figure 1 shows that as the proportion of x decreases, the loss coefficient (tanδ) tends to increase, indicating an increase in the shock absorption and diffusivity of the hydrogel. From Figure 1, it was found that the hydrogel (Px-EDAy) according to the present invention has the ability to appropriately set predetermined physical properties by changing the proportion of x.

[0073] (Example 5) Swelling rate of hydrogel The swelling rate with respect to temperature was measured for the hydrogel (Px-EDAy) according to the present invention.

[0074] The swelling rate was measured by the following method. The hydrogel (Px-EDAy) is shown in Table 2. 20 -EDA 15 , P 33 -EDA 15 , P 45 -EDA 15 , P 55 -EDA 15 , P 65 -EDA 15 And, P0-EDA where x=0 15 The following was used: A sample gel (10 mm × 10 mm × 1 mm) was alternately immersed in water (pH 2.0) at 4°C and 70°C for one hour. The mass (Ws) of the hydrogel was measured at each temperature. The hydrogel was also freeze-dried, and its dry mass (Wd) was measured. From these measurements, the swelling rate of the hydrogel at each temperature was calculated using the following formula.

[0075] Swelling rate (%) = (Amount of water absorbed by the hydrogel at each temperature) / (Weight of the gel in dry state) × 100 = (Ws - Wd) / Wd × 100 Figure 2 shows the results of temperature-dependent swelling rate measurements for the hydrogel (Px-EDAy) according to the present invention. As shown in Figure 2, the hydrogel (Px-EDAy) according to the present invention exhibited swelling and shrinking behavior when alternately immersed in water at 4°C and 70°C. That is, it showed UCST-type temperature responsiveness, swelling at high temperatures and shrinking at low temperatures.

[0076] (Example 6) Preparation of hydrogels (Px-EDAy) with different crosslinking ratios As shown in Table 3, hydrogels (Px-EDAy) with different crosslinking rates were prepared by varying the amount of EDA used for crosslinking. The synthesis route was the same as Scheme 2 shown in Example 2 above. The method for preparing the hydrogels was also as described in Example 2 above.

[0077] [Table 3]

[0078] For these hydrogels with different crosslinking ratios (Px-EDAy), the storage modulus (G') and loss modulus (G") were measured rheologically. The measuring equipment and conditions were the same as those used in Example 4 described above.

[0079] Figure 3 shows the measurement results of the storage modulus (G') and loss coefficient (tanδ) for the hydrogel (Px-EDAy) according to the present invention. The hydrogel (Px-EDAy) is P shown in Table 3. 45 -EDA 15 , P 45 -EDA 20 , P 45 -EDA 25 , P 45 -EDA 28 In each hydrogel, the left side of the graph represents the storage modulus (G'), and the right side represents the loss coefficient (tanδ).

[0080] Figure 3 shows that as EDA increases and the crosslinking ratio rises, the storage modulus (G') tends to increase, and the adhesive strength and holding power of the hydrogel tend to increase. Also, Figure 3 shows that as EDA decreases and the crosslinking ratio falls, the loss coefficient (tanδ) tends to increase, and the shock absorption and diffusivity of the hydrogel tend to increase. From Figure 3, it was found that the hydrogel (Px-EDAy) according to the present invention can have its predetermined physical properties appropriately set by changing the crosslinking ratio.

[0081] (Example 7) Method for measuring the shape memory and shape recovery properties of hydrogels The shape memory properties of the hydrogel according to the present invention were measured. Figure 4 is a schematic diagram showing the method for measuring the shape retention of the hydrogel according to the present invention. The hydrogel is prepared into a straight rod shape in a glass tube. The angle of the initial rod-shaped hydrogel was θ0, which is close to 180 degrees. Next, it is bent to 90 degrees in water at 70°C. Next, the bent state is fixed at 4°C. In the low-temperature range, hydrogen bonds between polymers work effectively to fix the shape. Next, the fixed state is removed and the outer angle that is maintained is defined as θ1. The shape retention rate F (%) is defined as θ1 / 90 × 100. For example, if θ1 is 90 degrees, the shape retention rate F is 100%.

[0082] Next, Figure 5 is a schematic diagram showing a method for measuring the shape recovery of a hydrogel according to the present invention. The hydrogel, which maintains an angle θ1 at 4°C as described above, is maintained in water at 70°C. In the high-temperature region, hydrogen bonds are gradually released, and the hydrogel recovers to a shape close to its initial rod shape. The angle of the open interior angle after recovering to this shape close to the initial rod shape is defined as θ2. The shape recovery rate R (%) is defined as θ2 / θ0 × 100. For example, if θ2 is θ0, the shape recovery rate R is 100%.

[0083] (Example 8) Measurement of shape memory and shape recovery properties of hydrogels The shape memory and shape recovery properties of the hydrogel according to the present invention were measured according to the measurement method described in Example 7. The measured hydrogel (Px-EDAy) is shown in Table 3. 45-EDA 15 , P 45 -EDA 20 , P 45 -EDA 25 , P 45 -EDA 28 Figure 6 shows the measurement results of the shape memory and shape recovery properties of the hydrogel according to the present invention. As shown in Figure 6, it was found that as EDA increases and the crosslinking rate increases, the shape fixation rate F tends to increase. It was also found that as EDA decreases and the crosslinking rate decreases, the shape recovery rate R tends to increase. From Figure 6, it was found that the shape memory and shape recovery properties of the hydrogel (Px-EDAy) according to the present invention can be controlled by changing the crosslinking rate.

[0084] (Example 9) Measurement of enzymatic degradability of hydrogels The enzymatic degradability of the hydrogel according to the present invention was measured. The hydrogel is P, which indicates the proportion of the glycinamide moiety at x=0.93. 0.93 The enzyme used was actinase E. Actinase E is a proteolytic enzyme product derived from the culture filtrate of the actinomycete Streptomyces griseus and is widely used to remove peptide components from samples such as sugars and nucleic acids. The molecular weight of the polymer that decreases with enzymatic degradation was evaluated by the relative viscosity η / η0 of the polymer solution. Relative viscosity η / η0 correlates with molecular weight. Here, η is the viscosity of the polymer solution and η0 is the viscosity of the solvent.

[0085] 6.1 g of tris(hydroxymethyl)aminomethane and 3.6 mL of hydrochloric acid were diluted to 500 mL with water to prepare 0.1 M tris HCl buffer (pH 7.4). Hydrogel P 0.93 0.4 g was dissolved in 0.1 M tris HCl buffer, and 0.003 g of actinase E (1,000,000 tyrosine units / g) was added. The reaction was carried out at 37°C. The relative viscosity η / η0 was measured using an Ostwald viscometer.

[0086] Figure 7 shows the results of measuring the enzymatic degradability of the hydrogel according to the present invention. As shown in Figure 7, the relative viscosity decreases with enzymatic degradation, confirming the biodegradability of the hydrogel according to the present invention.

[0087] (Example 10) Synthesis of glycinamide-modified polyaspartic acid In the previously mentioned examples, a hydrogel of glycinamide-modified poly(γ-glutamic acid) was used. In Example 10, a hydrogel of glycinamide-modified polyaspartic acid was used.

[0088] First, polyscinimide (PSI) was synthesized as shown in Scheme 4. 25 g (188 mmol) of L-aspartic acid and 0.8 g (9.4 mmol) of 85 wt% phosphoric acid were dissolved in 80 g of a mesitylene / sulfolane mixed solvent (v / v = 7 / 3) and stirred for 4.5 hours under an N2 atmosphere at 165°C. Water produced in the reaction mixture was removed using a Dean-Stark trap. The precipitate was washed with methanol and then with water. After washing again with methanol, it was dried under reduced pressure.

[0089] [ka]

[0090] Next, glycinamide modification was carried out as shown in Scheme 5. 5 g (51.5 mmol) of PSI and 11.4 g (103 mmol) of glycinamide hydrochloride were dissolved in DMF, and 28.6 ml (206 mmol) of triethylamine was added as a base. The mixture was stirred at 50°C for 12 hours. After the reaction, the mixture was reprecipitated with methanol as a poor solvent and dried under reduced pressure.

[0091] [ka]

[0092] Next, a hydrogel with polyaspartic acid as the main chain was prepared as shown in Scheme 6. 0.11 g (0.8 mmol) of glycinamide-modified PSI with a glycinamide introduction rate of 57% and 1.6 μL (0.022 mmol) of ethylenediamine were dissolved in 1 mL of DMF, and 50 μL (0.36 mmol) of triethylamine was added as a base and the mixture was stirred. A 1 mm thick silicone rubber sheet with a cutout was prepared to be used as a spacer and adhered to a glass plate whose surface had been hydrophobically treated. The solution was poured into the cutout of the spacer, and the glass plate was placed on top, ensuring close contact, and then clipped. This was left to stand at 50°C for 12 hours. After thoroughly washing the resulting gel with water, the desired hydrogel (crosslinking rate 3%) was obtained by swelling it in water.

[0093] [ka]

[0094] Next, the shape memory properties of the prepared hydrogel with polyaspartic acid as the main chain were evaluated. A rod-shaped gel (θ0 = 180°) was swollen in water at 70°C, then bent to 180°, and its shape was fixed by immersion in water at 4°C. After that, it was immersed again in water at 70°C, and its shape recovery was evaluated. Figure 8 shows the evaluation results of the shape memory and shape recovery properties of the hydrogel with polyaspartic acid as the main chain. As shown in Figure 8, the shape fixed at 4°C recovered to its original shape when the temperature was increased to 70°C. This confirmed that the hydrogel of glycinamide-modified polyaspartic acid also possesses shape memory properties.

[0095] Furthermore, in Schemes 4-6, instead of ethylenediamine, ethylenediamine 1 μL (0.014 mmol) / PEG-diamine (M) is used as the diamine compound. wA hydrogel (crosslinking rate 2%) was prepared using the same method with 0.025 g (0.00125 mmol) (9 / 1) (=20,000). The temperature responsiveness of the hydrogel with polyaspartic acid as the main chain prepared in this way was evaluated. Figure 9 shows the evaluation results of the temperature responsiveness of the hydrogel with polyaspartic acid as the main chain. As shown in Figure 9, it showed UCST-type temperature responsiveness, swelling at 70°C and contracting at 4°C. [Industrial applicability]

[0096] It can be used in cosmetics, medical materials, quasi-drugs, engineering materials, hobby materials, etc.

Claims

1. A biodegradable polymer having carboxyl groups, characterized in that a portion of the carboxyl groups are modified with glycinamide.

2. A biodegradable polymer according to claim 1, characterized by being represented by the following formula (1) (where p is an integer from 0 to 2, q is an integer from 0 to 2, x is from 0.01 to 0.99, and n represents a repeating unit determined by the molecular weight of the compound). 【Chemistry 1】

3. A biodegradable polymer according to claim 1, characterized by being represented by the following formula (2) (where x is 0.01 to 0.99, and n is a repeating unit determined by the molecular weight of the compound). 【Chemistry 2】

4. A shape memory hydrogel containing a polymer matrix and water, The shape memory hydrogel is characterized in that the polymer matrix is ​​a biodegradable polymer having carboxyl groups, wherein a portion of the carboxyl groups are modified with glycinamide, and the carboxyl groups that are not modified with glycinamide are crosslinked with a crosslinking agent.

5. The shape memory hydrogel according to claim 4, characterized in that the polymer matrix is ​​a biodegradable polymer represented by formula (5) (where p is an integer from 0 to 2, q is an integer from 0 to 2, x is from 0.01 to 0.99, y is from 0.01 to 0.99, z is from 0.01 to 0.99, where x + y + z = 1, X represents a bond crosslinked by a crosslinking agent having an amino group, and n represents a repeating unit defined by the molecular weight of the compound). 【Transformation 3】

6. The shape memory hydrogel according to claim 4, characterized in that the polymer matrix is ​​a biodegradable polymer represented by formula (6) (where x is 0.01 to 0.99, y is 0.01 to 0.99, z is 0.01 to 0.99, x + y + z = 1, X represents a bond crosslinked with a crosslinking agent having an amino group, and n represents a repeating unit defined by the molecular weight of the compound). 【Chemistry 4】

7. The shape memory hydrogel according to claim 6, characterized in that the crosslinking agent having the amino group is a diamine crosslinking agent.

8. The shape memory hydrogel according to claim 6, characterized in that the crosslinking agent having the amino group is an alkyl monoamine crosslinking agent.

9. The shape memory hydrogel according to claim 4, characterized in that the polymer matrix is ​​a biodegradable polymer represented by formula (7) (where x is 0.01 to 0.99, y is 0.01 to 0.99, z is 0.01 to 0.99, x + y + z = 1, and n represents a repeating unit defined by the molecular weight of the compound). 【Transformation 5】

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