JP6888980B2 - Polymer material - Google Patents

Description

The present invention relates to a polymer material in which polyhydric alcohols are crosslinked with each other by a structure in which polyglycolic acid and a polyunsaturated carboxylic acid having a trivalent or higher valence or a derivative thereof are ester-bonded.

Polyglycolic acid is a polymer of glycolic acid (HO-CH _2- COOH) and has biodegradability. Polyglycolic acid has a feature that the decomposition rate is faster than that of other biodegradable resins, and it is known that polyglycolic acid rapidly biodegrades even at room temperature. Polyglycolic acid is used in various fields as a raw material for medical materials and food containers because of its biodegradability.

For example, Patent Document 1 discloses crosslinked biodegradable particles in which a water-soluble synthetic polymer is crosslinked with a dicarboxylic acid in which a carboxyl group is introduced into the terminal hydroxyl group of polyglycolic acid. It is described that the crosslinked biodegradable particles can be used as an embolizing material used for blocking blood vessels and blocking blood flow, especially in a living body.

Patent Document 2 discloses further uses of polyglycolic acid and polyglycolic acid derivatives. Specifically, Patent Document 2 describes a main skeleton in which a plurality of polyhydric alcohols are crosslinked with each other, and (a) polyglycolic acid or (b) polyglycolide crosslinked with at least a part of the polyhydric alcohol. A polymer material having a side chain, which is a polyglycolic acid derivative in which another group is added to a carboxyl group at the end of an acid, is disclosed, and this polymer material absorbs a liquid containing a drug or the like. It is described that it can swell and that it exhibits sustained release of drugs and the like by hydrolysis or biodegradation of polyglycolic acid or polyglycolic acid derivative.

Japanese Unexamined Patent Publication No. 2005-314535 Japanese Unexamined Patent Publication No. 2016-53102

A polymer material capable of absorbing a liquid containing a drug or the like and swelling, and exhibiting a sustained release property of the drug or the like by hydrolysis or biodegradation of polyglycolic acid, which is described in Patent Document 2. It is expected that a polymer material having a higher absorption amount of chemicals and the like will be developed as compared with the polymer material of.

In order to solve the above problems, the polymer material according to the embodiment of the present invention is a polymer material in which a plurality of polyhydric alcohols are crosslinked with each other by a plurality of crosslinked structural portions, and the plurality of crosslinkeds. At least a part of the structure is a structure in which polyglycolic acid and a trivalent or higher valent carboxylic acid or a derivative thereof are ester-bonded.

In the polymer material according to one embodiment of the present invention, the trivalent or higher valent carboxylic acid or a derivative thereof is an anhydride of pyromellitic acid, 1,2,3,4-cyclopentanetetracarboxylic acid anhydride, It is preferably selected from the group consisting of 1,2,3,4-butanetetracarboxylic acid anhydride.

In the polymer material according to the embodiment of the present invention, when the total amount of the polyhydric alcohol, the polyglycolic acid constituting the crosslinked structure, and the trivalent or higher polyvalent carboxylic acid or a derivative thereof is 100% by weight. The polyglycolic acid is preferably 30% by weight or more and 75% by weight or less.

In the polymer material according to the embodiment of the present invention, the number average molecular weight of polyglycolic acid in the crosslinked structure is preferably 200 or more and 2000 or less.

The composition according to one embodiment of the present invention includes the above-mentioned polymer material and an agent contained in the polymer material.

In the composition according to one embodiment of the present invention, it is preferable that the above agent is an anionic compound.

The polymer material according to one embodiment of the present invention can absorb a liquid containing a drug or the like and swell, and can exhibit sustained release of the drug or the like by hydrolysis or biodegradation of polyglycolic acid. It is a polymer material that can be produced, and has a better absorption amount of chemicals and the like than the polymer material described in Patent Document 2.

It is a figure which shows the result of the drug (methylene blue) release behavior evaluation in an Example. It is a figure which shows the result of the drug (acid black) release behavior evaluation in an Example. It is a figure which shows the result of the drug inclusion amount test in an Example. It is a figure which shows the result of the swelling test in an Example.

An embodiment of the polymer material according to the present invention will be described below.

[1. Composition and properties of polymer materials]
The polymer material according to this embodiment is
Multiple polyhydric alcohols are crosslinked by multiple crosslinked structures,
At least a part of the plurality of crosslinked structural parts has a structure in which polyglycolic acid and a trivalent or higher valent carboxylic acid or a derivative thereof are ester-bonded.

(Multivalent alcohol)
The number of hydroxy groups of the polyhydric alcohol is not particularly limited as long as it is 3 or more, but it is preferably 4 or more. Further, from the viewpoint of the degree of swelling of the polymer material, it is preferable that the polyhydric alcohol has a large number of carbon atoms between hydroxy groups. When the number of carbon atoms between the hydroxy groups is large, the distance between the cross-linking points becomes long, so that the cross-linking density becomes low, and the free volume in the polymer material increases, so that the degree of swelling becomes higher. Further, the polyhydric alcohol is preferably branched. In the case of a branched polyhydric alcohol, since it is sterically bulky, the free volume increases and the degree of swelling becomes higher.

Examples of the polyhydric alcohol include glycerol, glycerol ethoxylate, polyglycerol, erythritol, pentaerythritol, pentaerythritol ethoxylate and the like. In the case of pentaerythritol ethoxylate, from the viewpoint of the degree of swelling of the polymer material, _{it is preferable that n of the polyethylene glycol moiety (-(CH 2} CH ₂ O) _n- ) is large, and the number average molecular weight Mn of pentaerythritol ethoxylate is large. Is preferably 200 or more, and more preferably 250 or more. Further, in the case of pentaerythritol ethoxylate, in order to obtain a polymer material having a certain strength and not easily deformed or damaged, the _{smaller n of the polyethylene glycol portion (-(CH 2} CH ₂ O) _n- ) is. Preferably, the number average molecular weight (Mn) of pentaerythritol ethoxylate is preferably 10,000 or less, and more preferably 8,000 or less. The number average molecular weight ^{can be measured by 1} H-NMR or the like.

The polyhydric alcohol constituting the polymer material may be one kind or a plurality of kinds.

(Cross-linked structure)
The polyhydric alcohols are crosslinked by a crosslinked structure. The specific structure of the crosslinked structure is not particularly limited, but at least a part of the plurality of crosslinked structures in the polymer material is ester-bonded with polyglycolic acid and a trivalent or higher-valent polycarboxylic acid or a derivative thereof. It is a structure that consists of

(Polyglycolic acid)
Polyglycolic acid (PGA) has the following formula:
H- [O-CH _2- C (= O)] _m- OH
It is represented by.

In the above formula, m is 2 or more. The number average molecular weight (Mn) of PGA in the crosslinked structure is not particularly limited, but is preferably 200 or more from the viewpoint of the degree of swelling of the polymer material. The number average molecular weight (Mn) of PGA in the crosslinked structure is preferably 2000 or less from the viewpoint of suppressing the crystallization of PGA in the polymer material. The polymer material having a larger number average molecular weight (Mn) of PGA in the crosslinked structure has a characteristic that the decomposition rate is higher.

The amount of PGA is not particularly limited, but when the total amount of the polyhydric alcohol, the PGA constituting the crosslinked structure, and the trivalent or higher polyvalent carboxylic acid or its derivative is 100% by weight, for example, 30% by weight or more and 75% by weight. % Or less, and from the viewpoint of rapid decomposition and release of the drug or the like, it is preferably 35% by weight or more and 70% by weight or less, and more preferably 40% by weight or more and 65% by weight or less. When a polymer material is used as the carrier of the cationic compound, the amount of PGA is more preferably 50% by weight or more and 65% by weight or less, and even more preferably 55% by weight or more and 65% by weight or less. When a polymer material is used as the carrier of the anionic compound, the amount of PGA is more preferably 40% by weight or more and 60% by weight or less, and even more preferably 40% by weight or more and 55% by weight or less. When a polymer material is used as a carrier for the uncharged compound, the amount of PGA is more preferably 40% by weight or more and 60% by weight or less, and even more preferably 40% by weight or more and 55% by weight or less.

(Polyunsaturated carboxylic acid of trivalent or higher or its derivative)
The valence of the polyunsaturated carboxylic acid is trivalent or higher, preferably tetravalent or higher. From the viewpoint that PGA and a polyhydric alcohol can be bonded at a ratio of 1: 1 (a regular crosslinked structure is formed), it is preferably tetravalent.

Examples of the trivalent or higher polyvalent carboxylic acid include pyromellitic acid, 1,2,3,4-cyclopentanetetracarboxylic acid, 1,2,4,5-cyclohexanetetracarboxylic acid, 1,2,3. Examples thereof include 4-butanetetracarboxylic acid and 3,3,4,4-benzophenonetetracarboxylic acid.

Examples of the derivative of the trivalent or higher polyvalent carboxylic acid include anhydrides, chlorides, esters, salts and the like of the trivalent or higher polyunsaturated carboxylic acid.

Examples of the trivalent or higher valent carboxylic dianhydride include monohydrides and dianhydrides of trivalent or higher valent carboxylic acids, and specifically, for example, pyromellitic dianhydrides. , Pyromeritic dianhydride, 1,2,3,4-cyclopentanetetracarboxylic dianhydride, 1,2,3,4-cyclopentanetetracarboxylic dianhydride, 1,2,4,5- Cyclohexanetetracarboxylic dianhydride, 1,2,4,5-cyclohexanetetracarboxylic dianhydride, 1,2,3,4-butanetetracarboxylic dianhydride, 1,2,3,4-butanetetra Examples thereof include carboxylic acid dianhydride, 3,3,4,4-benzophenonetetracarboxylic dianhydride, and 3,3,4,4-benzophenonetetracarboxylic dianhydride.

Examples of chlorides of trivalent or higher valent carboxylic acids include pyromellitic acid chloride, 1,2,3,4-cyclopentanetetracarboxylic acid chloride, 1,2,4,5-cyclohexanetetracarboxylic acid chloride, and the like. Examples thereof include 1,2,3,4-butanetetracarboxylic acid chloride and 3,3,4,4-benzophenone tetracarboxylic acid chloride.

Examples of the ester of the trivalent or higher polyvalent carboxylic acid include a methyl ester of a trivalent or higher polyvalent carboxylic acid and an ethyl ester. Specifically, for example, tetramethyl pyromellitic acid and pyromellitic acid. Tetraethyl, 1,2,3,4-cyclopentanetetracarboxylic acid tetramethyl, 1,2,3,4-cyclopentanetetracarboxylic acid tetraethyl, 1,2,4,5-cyclohexanetetracarboxylic acid tetramethyl, 1, Tetraethyl 2,4,5-cyclohexanetetracarboxylic acid, tetramethyl 1,2,3,4-butanetetracarboxylate, tetraethyl 1,2,3,4-butanetetracarboxylate, 3,3,4,5-benzophenone Examples thereof include tetramethyl tetracarboxylate and tetraethyl 3,3,4,4-benzophenone tetracarboxylate.

Examples of the salt of the trivalent or higher-valent polyvalent carboxylic acid include trivalent or higher-valent sodium polyvalent carboxylate, calcium, magnesium, iron and the like, and specifically, for example, sodium pyromellitic acid and calcium pyromellitic acid. , Magnesium pyromellitic acid, iron pyromellitic acid, sodium 1,2,3,4-cyclopentanetetracarboxylate, calcium 1,2,3,4-cyclopentanetetracarboxylate, 1,2,3,4-cyclo Magnesium pentantetracarboxylate, iron 1,2,3,4-cyclopentanetetracarboxylate, sodium 1,2,4,5-cyclohexanetetracarboxylate, calcium 1,2,4,5-cyclohexanetetracarboxylate, 1 , 2,4,5-Cyclohexanetetracarboxylic acid magnesium, 1,2,4,5-cyclohexanetetracarboxylic acid iron, 1,2,3,4-butanetetracarboxylate sodium, 1,2,3,4-butane Calcium tetracarboxylate, magnesium 1,2,3,4-butanetetracarboxylate, iron 1,2,3,4-butanetetracarboxylate, sodium 3,3,4,5-benzophenone tetracarboxylate, 3,3 , 4,4-Benzophenone tetracarboxylate calcium, 3,3,4,4-benzophenone tetracarboxylate magnesium, 3,3,4,4-benzophenone tetracarboxylate iron and the like.

The trivalent or higher valent carboxylic acid or its derivative is preferably a compound capable of leaving a free carboxy group in the crosslinked structure. Further, the polyunsaturated carboxylic acid having a valence of 3 or more or a derivative thereof is preferably a compound having high reactivity with a hydroxy group. Further, from the viewpoint of suppressing the decomposition of the ester group of PGA by a by-product such as water produced by the reaction with the hydroxy group during the production of the polymer material, an anhydride of a polyvalent carboxylic acid having a valence of 3 or more is used. It is preferably an anhydride in which all the carboxylic acids in the molecule are condensed. As a trivalent or higher-valent polyvalent carboxylic acid or a derivative thereof, pyromellitic dianhydride, 1,2,3,4-, from the viewpoint of safety to a living body, reactivity with a hydroxy group, and availability. Cyclopentanetetracarboxylic dianhydride and 1,2,3,4-butanetetracarboxylic dianhydride are preferred, pyromellitic dianhydride, 1,2,3,4-cyclopentanetetracarboxylic dianhydride, And 1,2,3,4-butanetetracarboxylic dianhydride are more preferred, and pyromellitic dianhydride is even more preferred.

The polyunsaturated carboxylic acid having a valence of 3 or more or a derivative thereof constituting the polymer material may be one kind or a plurality of kinds.

The amount of the trivalent or higher polyvalent carboxylic acid or its derivative is not particularly limited, but the total carboxy group of the trivalent or higher polyvalent carboxylic acid or its derivative with respect to the total number of hydroxy groups of the polyhydric alcohol contained in the reaction system ( In the derivative, the number of carboxy group residues) is, for example, 0.9 times or more and 1.5 times or less, and from the viewpoint of suppressing unreacted substances, it is preferably 1.0 times or more and 1.4 times or less.

(Specific structure of the crosslinked structure)
Polyhydric alcohols have multiple hydroxy groups in the molecule. The polyhydric alcohols are crosslinked by the crosslinked structure via these hydroxy groups. Specifically, the hydroxy group of a polyunsaturated alcohol can react with a carboxy group derived from PGA and a carboxy group derived from a trivalent or higher valent carboxylic acid or a derivative thereof to form an ester bond. When the polyhydric alcohol is brought into contact with the PGA, the hydroxy group of the polyhydric alcohol (1) reacts with the carboxy group at the end of the PGA, and (2) the polyhydric alcohol forms an ester bond inside the PGA. Both cases occur when it is cleaved and reacts with the carboxy group generated in the cleaved portion. Therefore, the "carboxy group derived from PGA" here includes both the carboxy group at the end of the PGA and the carboxy group in the ester bond inside the PGA.

Therefore, as a mode of cross-linking in polymer materials,
When X: polyunsaturated alcohol residue, Y: PGA residue, Z: polyunsaturated carboxylic acid residue,
For example
(1) X-OOC-Y-OOC-Z-COO-Y-COO-X
(2) X-OOC-Y-OOC-Z-COO-X
(3) X-OOC-Z-COO-X
And so on. With respect to (1) and (2) above, Y may be further inserted. For example, if -COO- is omitted, XY-Y-Z-X, XY-Y-Z-Y-Y-X, and the like may be possible.

That is, when cross-linking polyhydric alcohols with a cross-linked structure derived from PGA and poly-carboxylic acid, the mode of cross-linking is such that -COO- is omitted.
X-Y _a- Z-Y _b- X (a ≧ 0, b ≧ 0)
Can be expressed as
In the crosslinked structure, if -COO- is omitted,
−Y _a −Z−Y _b − (a ≧ 0, b ≧ 0)
It can be expressed as.

Here, the polymer material according to the present embodiment has a structure in which at least a part of a plurality of crosslinked structural parts is an ester bond between PGA and a trivalent or higher valent carboxylic acid or a derivative thereof. The "structure in which a polyglycolic acid (PGA) and a polyunsaturated carboxylic acid having a valence of 3 or more or a derivative thereof are ester-bonded" is the mode of the above (1) and (2) (Y can be further inserted). , and the is omitted _{-COO-, -Y a -Z-Y b} - represented by (a ≧ 0, b ≧ 0 , a + b ≧ 1). When the polyhydric alcohols are crosslinked by the structure, it can be represented by X-Y _a- Z-Y _b- X (a ≧ 0, b ≧ 0, a + b ≧ 1).

That is, the polymer material according to the present embodiment _{includes a structure represented by −Y a} −Z—Y _b − (a ≧ 0, b ≧ 0, a + b ≧ 1) as a crosslinked structure portion. The polymer material according to the present embodiment may further contain a crosslinked structure (that is, a + b = 0) in the mode of (3) above as a crosslinked structure portion.

Further, the polymer material according to the present embodiment may further have a crosslinked structural portion derived from a substance other than PGA and a trivalent or higher valent carboxylic acid or a derivative thereof, but is hydrolyzable and biodegradable. From the viewpoint of imparting sex, a crosslinked structure derived from PGA and a trivalent or higher polyvalent carboxylic acid or a derivative thereof, and a crosslinked structure derived from a trivalent or higher polyvalent carboxylic acid or a derivative thereof (that is, a crosslinked structure portion). Is _{preferably composed of only −Y a} −Z−Y _b − (a ≧ 0, b ≧ 0).

It should be noted that the polyhydric alcohol does not have to have all the hydroxy groups crosslinked, as long as at least some of the hydroxy groups are crosslinked.

As described above, the polymer material according to the present embodiment has a skeletal structure in which a plurality of polyhydric alcohols are crosslinked with each other by a plurality of crosslinked structural portions. In one aspect, a large number of polyhydric alcohols are configured in a network through a large number of crosslinked structures.

(nature)
The polymer material according to the present embodiment can absorb a liquid, swell, and retain it inside. As liquids, water; alcohols such as methanol, ethanol, propanol, isopropanol, and butanol; alkanes such as hexane, cyclohexane, and octane; aromatic hydrocarbons such as xylene and toluene; esters such as ethyl acetate and butyl acetate. Amides such as dimethylformamide (DMF) and dimethylacetamide (DMAc); ketones such as acetone, methylethylketone, and acetophenone; alkyl halides such as tetrahydrofuran and chloroform; and dimethylsulfoxide (DMSO) and the like. These liquids may contain other substances dissolved or suspended. Other substances include drugs such as pharmaceuticals or pesticides, fertilizers, and agents such as cosmetics.

The degree of swelling of the polymer material can be calculated, for example, by the following formula:
Swelling degree = (W _s −W _d ) / (d × W _d )
Here, W _s is the weight of the polymer material after wetting with the liquid, W _d is the dry weight of the polymer material, and d is the specific gravity of the liquid.

In the polymer material according to the present embodiment, when the liquid is DMF, the degree of swelling obtained by the above formula is, for example, 1 or more, 1 to 5, 1 to 10, or 10 or more. Can be.

In addition, PGA is biodegradable. Therefore, the polymer material according to the present embodiment has sustained release property because PGA, which is a constituent component of the polymer material, is biodegraded. That is, for example, by applying a polymer material impregnated with a liquid containing an agent to a living body or placing it in an environment in which microorganisms are present, PGA in the polymer material is gradually hydrolyzed, and the polymer is polymerized. The agent held by the material is gradually released. PGA also hydrolyzes under abiotic conditions. In the polymer material according to the present embodiment, PGA is contained in the crosslinked structure portion. Therefore, in the polymer material according to the present embodiment, the skeletal structure is disintegrated due to the disintegration of the crosslinked structure, so that the holding agent is easily released and rapid sustained release can be exhibited. The polymer material according to the present embodiment may not only hydrolyze PGA, but also hydrolyze an ester bond between a polyhydric alcohol and a trivalent or higher valent carboxylic acid or a derivative thereof. Further, when pentaerythritol ethoxylate is used as the polyhydric alcohol, hydrolysis of the oxyethylene moiety may occur.

PGA has extremely low affinity with various liquids due to its high packing property. Therefore, it is difficult for PGA alone to absorb and swell the liquid containing the agent and to slowly release the agent by biodegradation. On the other hand, the polymer material according to the present embodiment can exhibit excellent swelling property and sustained release property as described above.

Further, in the polymer material according to the present embodiment, the sustained release property of the agent changes depending on the pH. Specifically, the lower the pH, the more the release of the agent is suppressed, and the higher the pH, the more the release of the agent is promoted. In the polymer material according to the present embodiment, the polyunsaturated carboxylic acid is trivalent or higher. Therefore, unreacted carboxy groups tend to remain in the crosslinked structure. While this unreacted carboxy group is not ionized at low pH, it is ionized (carboxylated) at high pH to increase electrostatic repulsion, causing the polymer material to swell and form a network. It is thought that this is because the agent is easily released by spreading. As described above, the polymer material according to the present embodiment can exhibit good pH responsiveness. Therefore, for example, when the polymer material according to the present embodiment is used as a carrier of a drug to be applied to a living body, the release of the drug is suppressed in a stomach having a low pH (for example, about 1.6) and the pH is high (for example, 7. About 4) The drug is released in the small intestine. Further, since swelling is likely to occur under a high pH, the motility of the molecular chain of the crosslinked structure portion is enhanced by the inclusion of water in the polymer material. As a result, hydrolysis of the ester group derived from PGA or the like in the polymer material is likely to occur, and the release rate of the agent is faster than in the case where the ester group is not hydrolyzed. That is, the polymer material according to this embodiment has high timed release property. Therefore, the polymer material according to the present embodiment can be suitably used, for example, as a carrier for a drug to be absorbed in the small intestine.

The size and shape of the polymer material according to this embodiment are not particularly limited, and may be appropriately set according to the purpose of use. Examples of the shape include a spherical shape, a rectangular parallelepiped, and a sheet shape. The size may be, for example, a size of several tens of cm square or a size on the order of μm. Further, the size may be on the order of nm. Further, a sheet having a thickness of, for example, 10 μm to 10 cm may be used. The "average particle size" can be calculated as a volume-equivalent average particle size by using a measurement method by a laser diffraction / scattering method.

The polymer material according to the present embodiment may be in a dry state or in a state of being impregnated with a liquid (for example, in a gel state).

(Differences from conventional polymer materials)
The structural difference between the conventional (Patent Document 2) polymer material derived from the polyhydric alcohol, PGA, and the polyvalent carboxylic acid or a derivative thereof and the polymer material according to the present embodiment is the conventional (Patent Document 2). In the polymer material of), PGA does not exist in the crosslinked structure part but exists only as a side chain, whereas in the polymer material according to the present embodiment, PGA exists in the crosslinked structure part. It is a point. In the polymer material according to the present embodiment having such a structure, as shown in Examples described later, the absorption amount of the agent is more excellent at the same PGA introduction rate.

[2. Method for manufacturing polymer materials]
An example of the method for producing a polymer material according to the present embodiment will be described below, but the present invention is not limited thereto.

First, the polyhydric alcohol is reacted with PGA. As a result, the hydroxy group of the polyhydric alcohol reacts with the carboxy group derived from PGA (the terminal carboxy group or the internal ester group) to form a structure in which the polyhydric alcohol and PGA are ester-bonded. Theoretically, PGA is ester-bonded to each hydroxy group of the polyhydric alcohol. Next, a polyunsaturated carboxylic acid having a valence of 3 or more or a derivative thereof is added, and the structure is reacted with the polyunsaturated carboxylic acid or a derivative thereof. As a result, the hydroxy group in the PGA ester-bonded to the polyhydric alcohol reacts with the carboxy group derived from the polyvalent carboxylic acid or its derivative, and the structures in which the polyhydric alcohol and the PGA are ester-bonded are trivalent. It is linked via the above polyvalent carboxylic acid or a derivative thereof. The unreacted raw material may be washed and removed. In this way, a plurality of polyhydric alcohols are crosslinked with each other by a plurality of crosslinked structural parts, and at least a part of the plurality of crosslinked structural parts is a PGA and a trivalent or higher valent carboxylic acid or a derivative thereof. The polymer material according to the present embodiment, which has a structure formed by an ester bond, can be produced.

As the raw material polyunsaturated alcohol, PGA, and polyunsaturated carboxylic acid having a trivalent value or higher or a derivative thereof, commercially available ones may be used, or those prepared by a known method may be used.

The reaction may be carried out in the presence of a solvent or in the absence of a solvent. From the viewpoint of increasing the amount of PGA introduced into the crosslinked structure, it is preferable to carry out the reaction in the absence of a solvent capable of increasing the PGA concentration in the reaction system. When a solvent is used, the solvent is not particularly limited as long as it does not react with the raw material, and examples thereof include dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and dimethylacetamide (DMAc), from the viewpoint of solubility. From dimethylformamide and dimethyl sulfoxide are preferred. Polyhydric alcohols, PGAs, and trivalent or higher polyvalent carboxylic acids or derivatives thereof may be added in a state of being previously dissolved in a solvent.

Further, a catalyst may be used in the reaction of the polyhydric alcohol with PGA and the reaction of the structure in which the polyhydric alcohol and PGA are ester-bonded with a trivalent or higher valent carboxylic acid or a derivative thereof. Catalysts include, for example, triethylamine (TEA), dibutyltin dilaurate (DBTDL), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), and 1,4-diazabicyclo [2.2.2]. ] -Octane (DABCO) and the like. The catalyst may be added in a state of being previously dissolved in a solvent. Moreover, the same catalyst may be used for both reactions.

In one example, a polyunsaturated alcohol is added to and reacted with PGA melted in the absence of a solvent, and then a trivalent or higher valent carboxylic acid or a derivative thereof is added and reacted to produce a polymer material. It is preferable to do so.

In this production method, when the raw material PGA reacts with the polyhydric alcohol, the ester bond inside the PGA is cleaved and reacts. Therefore, the following equation holds theoretically between the average molecular weight of PGA used as a raw material and the average molecular weight of PGA in a polymer material:
Average molecular weight of PGA in polymer material = (Average molecular weight of PGA used as raw material) x (Number of moles of PGA as raw material / Number of moles of polyhydric alcohol as raw material) x (1 / Valuation of polyhydric alcohol as raw material)

In one embodiment, the number average molecular weight (Mn) of PGA used as a raw material is not particularly limited, but is 200 or more in order to keep the number average molecular weight (Mn) of PGA in the crosslinked structure portion of the polymer material above a certain level. Is preferable. The number average molecular weight (Mn) of PGA used as a raw material is preferably 100,000 or less, more preferably 70,000 or less, from the viewpoint of suppressing the viscosity of the reaction system during production and promoting the reaction. It is more preferably 30,000 or less.

The amount of PGA is not particularly limited, but is, for example, 30% by weight when the total amount of the polyhydric alcohol as a raw material, the PGA constituting the crosslinked structure, and the trivalent or higher polyvalent carboxylic acid or its derivative is 100% by weight. It is 75% by weight or less, and from the viewpoint of rapid release, it is preferably 35% by weight or more and 70% by weight or less, and more preferably 40% by weight or more and 65% by weight or less. When a polymer material is used as the carrier of the cationic compound, the amount of PGA is more preferably 50% by weight or more and 65% by weight or less, and even more preferably 55% by weight or more and 65% by weight or less. When a polymer material is used as the carrier of the anionic compound, the amount of PGA is more preferably 40% by weight or more and 60% by weight or less, and even more preferably 40% by weight or more and 55% by weight or less. When a polymer material is used as a carrier for the uncharged compound, the amount of PGA is more preferably 40% by weight or more and 60% by weight or less, and even more preferably 40% by weight or more and 55% by weight or less.

The amount of the trivalent or higher polyvalent carboxylic acid or its derivative is not particularly limited, but the total carboxy group of the trivalent or higher polyvalent carboxylic acid or its derivative with respect to the total number of hydroxy groups of the polyhydric alcohol contained in the reaction system ( In the derivative, the number of carboxy group residues) is, for example, 0.9 times or more and 1.5 times or less, and from the viewpoint of suppressing unreacted substances, it is preferably 1.0 times or more and 1.4 times or less.

In the reaction of the polyhydric alcohol with PGA, the temperature is, for example, 60 to 250 ° C, preferably 80 to 240 ° C. The reaction time is, for example, 5 minutes to 48 hours, preferably 10 minutes to 24 hours. Stirring is preferred during the reaction.

In the reaction of the polyunsaturated alcohol and the PGA ester-bonded structure with the polyunsaturated carboxylic acid or a derivative thereof, the temperature is, for example, 60 to 250 ° C, preferably 80 to 240 ° C. The reaction time is, for example, 10 minutes to 48 hours, preferably 30 minutes to 24 hours. It is preferable to add the polyunsaturated carboxylic acid or a derivative thereof, stir, and then allow to stand. It may be molded by pouring it into a mold before allowing it to stand.

In another production method, the reaction of the polyunsaturated alcohol with PGA and the reaction of the structure in which the polyunsaturated alcohol and PGA are ester-bonded with the polyunsaturated carboxylic acid or a derivative thereof may be carried out at the same time.

Moreover, the polymer material may be dried. By drying, the desired liquid can be easily impregnated. Drying may be carried out, for example, under normal pressure or reduced pressure at 20 to 100 ° C. for 1 hour to 7 days.

[3. Examples of use of polymer materials]
The polymer material according to this embodiment can be used as a base material having sustained release properties in a wide range of fields such as medical fields, agricultural fields, and cosmetics fields.

In one example of the use of a polymeric material, the polymeric material is immersed in a liquid in which a chemical such as a drug or pesticide, a fertilizer, or an agent such as a cosmetic is dissolved or suspended. As a result, the liquid in which the agent is dissolved or suspended is absorbed by the polymer material and retained inside. The polymer material may be dried to remove the liquid before use. Therefore, the present invention provides a composition containing the polymer material according to the present embodiment and the agent contained in the polymer material. The composition may further comprise a liquid that dissolves or suspends the agent. The composition can also be a timed release composition. In addition, the composition may be a composition that releases the agent at a constant rate.

In the case of pharmaceuticals, for example, this composition may be orally or parenterally administered to a living body, or may be brought into contact with the skin as a composition for external use on the skin. In the case of pesticides or fertilizers, for example, the composition may be sprinkled on a field or rice field or brought into contact with the plant itself. In the case of cosmetics, for example, this composition may be brought into contact with the skin.

The agent may be any of an anionic compound, a cationic compound, and a non-ionic compound. In a preferred example, the agent is an anionic compound. When the unreacted carboxy group at the polyvalent carboxylic acid residue in the crosslinked structure of the polymer material is ionized (carboxylated), the anionic compound is anionic with the carboxylate in the crosslinked structure of the polymer material. Since the anionic portions of the compound repel each other electrostatically, the anionic compound is easily released to the outside of the polymer material. Therefore, it can exhibit faster sustained release.

Examples are shown below, and embodiments of the present invention will be described in more detail. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects can be used for details. Furthermore, the present invention is not limited to the above-described embodiment, and various modifications can be made within the scope of the claims, and the present invention also relates to an embodiment obtained by appropriately combining the disclosed technical means. It is included in the technical scope of the invention. In addition, all the documents described in the present specification are incorporated by reference.

[Example: Preparation of gel]
PGA (Mw10000, Mn6800 manufactured by Kureha Corporation) was placed in an aluminum dish and heated in an aluminum bead bath at 210 ° C. to melt it. A predetermined amount (Table 1) of pentaerythritol ethoxylate (Mn800) (PEE800) was added thereto, and the mixture was stirred for 30 minutes. Then, a predetermined amount (Table 1) of pyromellitic dianhydride (PMDA) was added, and the mixture was stirred for 1 hour. This was poured into a molding container and allowed to stand at 100 ° C. for 24 hours to prepare a gel. After cooling to room temperature, the prepared gel was cut into 5 mm blocks and washed with dimethylformamide (DMF) for 24 hours and in acetone for 3 days. The washed gel was then dried under conditions of room temperature, normal pressure for 24 hours, followed by reduced pressure (10 Torr) for 24 hours.

[Comparative example: Gel preparation]
PGA (Mw10000, Mn6800 manufactured by Kureha Corporation) was placed in an aluminum dish and heated in an aluminum bead bath at 210 ° C. to melt it. A predetermined amount of PMDA (Table 1) was added thereto, and the mixture was stirred for 6 hours. Then, a predetermined amount of PEE800 (Table 1) was added, and the mixture was stirred for 1 hour. This was poured into a molding container and allowed to stand at 100 ° C. for 24 hours to prepare a gel. After cooling to room temperature, the prepared gel was cut into 5 mm blocks and washed with DMF for 24 hours and in acetone for 3 days. The washed gel was then dried under conditions of room temperature, normal pressure for 24 hours, followed by reduced pressure (10 Torr) for 24 hours. In this gel, PGA does not exist in the crosslinked structure, but exists only as a side chain.

[Test Example 1: Evaluation of drug release behavior]
25 mg of methylene blue (cationic compound) or acid black (anionic compound) was dissolved in 50 mL of DMF. The gel prepared in Example or Comparative Example was immersed in this solution and left at 37 ° C. for 24 hours. The gel was removed from the solution, air-dried for 1 hour, and then dried under reduced pressure at room temperature for 24 hours. Then, it was immersed in 5 mL of pH 1.6 buffer solution for 3 hours, and then immersed in 5 mL of pH 7.4 buffer solution for 7 hours. During this period, the buffer solution is subjected to UV-vis measurement (V-670DS manufactured by JASCO Corporation) every hour, and the amount of drug released is calculated based on the absorbance at the maximum absorption wavelength (methylene blue: 664 nm, acid black: 620 nm). (N = 3 measurement). The buffer solution was replaced with a new one every hour.

The result using methylene blue is shown in FIG. In the examples, the cumulative release rate was higher than that in the comparative examples. In the examples, 60% by weight showed the highest cumulative release rate among the PGA introduction rates tested. Further, in the examples, it was found that the release of the drug tends to be suppressed at pH 1.6 as compared with pH 7.4.

The result of using acid black is shown in FIG. In the examples, the cumulative release rate (rapid release) was higher than that in the comparative example. In the examples, 45% by weight showed the highest cumulative release rate among the PGA introduction rates tested. Further, in the examples, the release of the drug was suppressed at pH 1.6 as compared with pH 7.4, and the effect of suppressing the release at pH 1.6 was higher than that of the comparative example.

[Test Example 2: Drug inclusion amount test]
The gel, which was soaked in a drug and dried in the same manner as in Test Example 1, was soaked in a pH 1.6 buffer solution for 3 hours, then the buffer solution was replaced, and the gel was soaked in a pH 7.4 buffer solution, and the gel was completely completed at 37 ° C. It was decomposed until it was dissolved in. The absorbance of these solutions was measured in the same manner as in Test Example 1, and the amount of the drug contained in the gel was calculated based on the absorbance of the pH 1.6 buffer solution and the 7.4 buffer solution.

The results are shown in FIG. As shown in FIG. 3, it was found that when the PGA introduction rate was the same, the amount of the drug contained in the examples was larger than that in the comparative examples.

[Test Example 3: Swelling test]
The dry weight of the gel prepared in the examples was measured. The dry gel is immersed in pH 7.4 phosphate buffer (PBS) for 3 hours or dimethylformamide (DMF) for 12 hours in an amount that allows the gel to be completely immersed in a constant temperature bath at 40 ° C., and the weight of the swollen gel is increased. Was measured. The degree of swelling was calculated using the following formula.

Swelling degree = (W _s −W _d ) / (d × W _d )
Here, W _s is the weight of the swollen gel, W _d is the dry weight of the gel, and d is the specific density of PBS or DMF.

The degree of swelling of the gel prepared in the examples is shown in FIG.

The present invention can be widely used as a sustained release material in, for example, the medical field and the agricultural field.

Claims (6)

A gel having the following characteristics, in which a plurality of polyhydric alcohols are crosslinked by a plurality of crosslinked structures:
a) The above-mentioned polyhydric alcohol is a trihydric or higher alcohol.
b) In at least a part of the plurality of crosslinked structural parts, the structures in which the polyhydric alcohol and the polyglycolic acid are ester-bonded are the polyglycolic acid and the trivalent or higher polyvalent carboxylic acid or a derivative thereof. It has a structure formed by connecting via an ester bond. The above trivalent or higher valent carboxylic acids or derivatives thereof are pyromellitic acid anhydrides, 1,2,3,4-cyclopentanetetracarboxylic acid anhydrides, and 1,2,3,4-butanetetracarboxylic acids. The gel according to claim 1, which is selected from the group consisting of anhydrides. When the total amount of the polyhydric alcohol, the polyglycolic acid constituting the crosslinked structure, and the trivalent or higher polyvalent carboxylic acid or a derivative thereof is 100% by weight, the polyglycolic acid is 30% by weight or more and 75% by weight. The gel according to claim 1 or 2, which is as follows. The gel according to any one of claims 1 to 3, wherein the number average molecular weight of polyglycolic acid in the crosslinked structure is 200 or more and 2000 or less. And the gel according to any one of claims 1 to 4, and a material that is contained in the gel, composition. The composition according to claim 5, wherein the agent is an anionic compound.

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