JP6944263B2 - Cyclodextrin derivative modified hydrogel - Google Patents

Description

The present invention relates to a cyclodextrin derivative-modified hydrogel obtained by modifying the surface of the hydrogel with a cyclodextrin derivative.

The therapeutic drug is generally delivered into the body by an administration method such as oral administration, injection, or patching. However, depending on the administration method, there is a problem that side effects occur due to contact of the drug with a site other than the treatment target site, and the drug concentration decreases before reaching the treatment target site, so that the drug effect cannot be fully exerted. There is a problem such as.

There is a drug delivery system (DDS) as a method of delivering a drug to a treatment target site in a limited manner. DDS is a method of improving the drug effect at a treatment target site and enhancing the therapeutic effect by controlling the drug distribution in the body quantitatively, spatially or temporally. As a specific method of DDS, there is a method of delivering a carrier containing a drug to a treatment target site orally or by absorption through the skin or mucous membrane. When this method is adopted, hydrogel may be selected as the carrier from the viewpoint of safety and handleability.

Hydrogels contain water inside the three-dimensional structure. When the hydrogel is used as a carrier of a drug in DDS, the drug is contained inside the hydrogel by filling the inside of the hydrogel with a drug dissolved in water. Therefore, a water-soluble drug is selected as a drug that can be used when included in the hydrogel (see Patent Document 1), and a poorly water-soluble drug is not an option.

Therefore, various methods for including a poorly water-soluble drug in a hydrogel and using it in DDS instead of the water-soluble drug have been studied.

On the other hand, cyclodextrin is known to have an action of encapsulating poorly water-soluble molecules. Cyclodextrin is a type of cyclic oligosaccharide in which several molecules of D-glucose are bound by α-1,4 glycosidic bonds to form a cyclic structure. Cyclodextrin has a unique structure in which the inside of the cyclic structure is hydrophobic and the outside is hydrophilic. Due to such a structure, cyclodextrin has a characteristic property that a poorly water-soluble molecule is incorporated into the cyclic structure and the cyclodextrin exhibits solubility in water by the action of hydrophilicity on the outside.

Utilizing this property of cyclodextrin, a method of incorporating a complex of a poorly water-soluble drug-cyclodextrin into a hydrogel, which is obtained by encapsulating a poorly water-soluble drug in cyclodextrin in advance (see Patent Document 2). A method for carrying a poorly water-soluble drug using a hydrogel in which cyclodextrin is arranged in a side chain is known (see Patent Document 3).

Japanese Unexamined Patent Publication No. 2004-307574 Special Table 2006-508940 Japanese Patent Application Laid-Open No. 2011-528998

However, the method described in Patent Document 2 includes a complex of a poorly water-soluble drug-cyclodextrin, which is formed by incorporating a poorly water-soluble drug into the ring of cyclodextrin, depending on the water content of the hydrogel. Therefore, for example, when the hydrogel is brought into contact with the body surface such as skin or mucous membrane, most of the complex of the poorly water-soluble drug-cyclodextrin contained in the hydrogel comes into contact with the body surface immediately. There is a problem that a so-called initial burst occurs, which is emitted. Then, due to this initial burst, there is a concern that overdose of the drug or insufficient therapeutic effective concentration at the treatment target site may occur.

Further, in the method described in Patent Document 3, a monomer having a glycidyl group is used as a constituent monomer of the hydrogel as a means for introducing cyclodextrin into the side chain in the hydrogel prepared in advance by a subsequent step. In the method described in Patent Document 3, in order to increase the amount of cyclodextrin introduced, the amount of the monomer having a glycidyl group must be increased. However, when the amount of the monomer having a glycidyl group is increased, the water content of the hydrogel depends on the content of the glycidyl group. Therefore, there is a problem that the shape retention property is lowered by increasing the water content of the hydrogel. be.

Furthermore, according to the investigation by the present inventors, in the method described in Patent Document 3, most of the cyclodextrin is introduced into the inside of the hydrogel, but the cyclodextrin introduced into the inside of the hydrogel is used. Has the problem that poorly water-soluble drugs are not included. On the other hand, even if cyclodextrin on the surface of the hydrogel tries to encapsulate a poorly water-soluble drug, there is a problem that such inclusion is inhibited by steric hindrance of the polymer chain of the hydrogel. Therefore, there is a problem that a desired amount of the drug cannot be supported on the hydrogel depending on the method described in Patent Document 3.

In view of the above-mentioned problems of the prior art, in the present invention, a desired amount of the poorly water-soluble agent can be efficiently supported as compared with the techniques described in Patent Documents 2 and 3. It is an object of the present invention to provide a hydrogel exhibiting excellent sustained release of a drug.

In view of the above problems, the present inventors have earnestly studied the carrier of the poorly water-soluble drug, and have come to pay attention to the distance between the hydrogel and the cyclodextrin to be introduced into the hydrogel.

By introducing cyclodextrin into the hydrogel via a compound having a carbon chain having a certain length, a poorly water-soluble drug can be placed inside the cyclodextrin without suffering steric damage to the polymer chain of the hydrogel. I hypothesized that it could be included.

While repeating studies based on this hypothesis, the present inventors efficiently encapsulate a poorly water-soluble drug inside cyclodextrin in a hydrogel having a cyclodextrin derivative synthesized from diaminoalkane and cyclodextrin on the surface. It was found that the drug that was in contact with the drug and further included was excellent in the supportability and the sustained release property. Then, the present inventors have succeeded in creating a cyclodextrin derivative-modified hydrogel having a predetermined cyclodextrin derivative on the surface of the hydrogel. The present invention is an invention completed based on these findings and successful examples.

（１）
（式中、
Ｒ_１は、−ＮＨ−又は−ＣＯＯ−であり；
Ｒ_２は、炭素数２〜１０の直鎖状、分枝状若しくは環状のアルキレン基又はアセチレン基であり；
Ｒ_３は、アミノ基又はカルボキシ基であり；及び、
ＣＤは、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン又は９単位以上のα−１，４−グルコピラノース結合型シクロデキストリンである。）
で表わされるシクロデキストリン誘導体をハイドロゲルの表面に有する、シクロデキストリン誘導体修飾ハイドロゲルが提供される。
好ましくは、前記シクロデキストリン誘導体が、下記一般式（２）

（２）
（式中、
ｎは４〜８の整数であり；及び、
ＣＤは、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン又は９単位以上のα−１，４−グルコピラノース結合型シクロデキストリンである。）
で表わされる、シクロデキストリン誘導体である。
好ましくは、前記シクロデキストリン誘導体が、（１，４−ジアミノブチル）−６−β−シクロデキストリン、（１，５−ジアミノペンチル）−６−β−シクロデキストリン又は（１，６−ジアミノへキシル）−６−β−シクロデキストリンである。
好ましくは、前記ハイドロゲルが、構成成分としてカルボキシ基を分子内に有するモノマーと、これと共重合可能な親水性モノマーとを含み、かつ、前記カルボキシ基を分子内に有するモノマーの量が、前記親水性モノマーの量に対し、５ｗｔ％以上１０ｗｔ％以下である。 Therefore, according to the present invention, the following general formula (1)

(1)
(During the ceremony,
R ₁ is -NH- or -COO-;
R ₂ is a linear, branched or cyclic alkylene group or acetylene group having 2 to 10 carbon atoms;
R ₃ is an amino or carboxy group; and
CD is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or α-1,4-glucopyranose-bound cyclodextrin of 9 units or more. )
Provided is a cyclodextrin derivative-modified hydrogel having a cyclodextrin derivative represented by (1) on the surface of the hydrogel.
Preferably, the cyclodextrin derivative has the following general formula (2).

(2)
(During the ceremony,
n is an integer of 4-8; and
CD is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or α-1,4-glucopyranose-bound cyclodextrin of 9 units or more. )
It is a cyclodextrin derivative represented by.
Preferably, the cyclodextrin derivative is (1,4-diaminobutyl) -6-β-cyclodextrin, (1,5-diaminopentyl) -6-β-cyclodextrin or (1,6-diaminohexyl). -6-β-cyclodextrin.
Preferably, the amount of the monomer containing a monomer having a carboxy group in the molecule as a constituent component and a hydrophilic monomer copolymerizable therewith, and having the carboxy group in the molecule is the above. It is 5 wt% or more and 10 wt% or less with respect to the amount of the hydrophilic monomer.

According to the present invention, there is provided a cyclodextrin derivative-modified hydrogel in which cyclodextrin is arranged at a predetermined distance from the surface of the hydrogel as a base material. In the cyclodextrin derivative-modified hydrogel according to one aspect of the present invention, since cyclodextrin exists at a predetermined distance from the surface of the substrate, steric hindrance due to the polymer chain of the hydrogel occurs in the inclusion of a poorly water-soluble drug. Since it is difficult to receive, it is possible to efficiently carry a desired amount of the poorly water-soluble drug, and it is possible to exhibit further excellent sustained release of the drug. Further, since the cyclodextrin derivative-modified hydrogel according to one aspect of the present invention is excellent in shape stability, there is an advantage that the cyclodextrin derivative-modified hydrogel can be easily attached and detached when used as a contact lens.

FIG. 1 is a diagram showing the results of evaluating the uptake amount and uptake rate of the poorly water-soluble drug in the hydrogel depending on the presence or absence of cyclodextrin derivative modification as described in Examples described later. FIG. 2 is a diagram showing the evaluation results of the release rate of the poorly water-soluble drug in the hydrogel depending on the presence or absence of cyclodextrin derivative modification, as described in Examples described later.

Hereinafter, the details of the cyclodextrin derivative-modified hydrogel which is one aspect of the present invention will be described, but the technical scope of the present invention is not limited to the matters of this item, and the present invention achieves the object. As long as it does, it can take various aspects.

The cyclodextrin derivative-modified hydrogel is obtained by modifying the surface of a preformed hydrogel with a cyclodextrin derivative represented by the following general formula (1), and as a result, the cyclodextrin derivative is applied to the surface of the hydrogel. It is characterized by having.

（１）
（式中、
Ｒ_１は、−ＮＨ−又は−ＣＯＯ−であり；
Ｒ_２は、炭素数２〜１０の直鎖状、分枝状若しくは環状のアルキレン基又はアセチレン基であり；
Ｒ_３は、アミノ基又はカルボキシ基であり；及び、
ＣＤは、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン又は９単位以上のα−１，４−グルコピラノース結合型シクロデキストリンである。）

(1)
(During the ceremony,
R ₁ is -NH- or -COO-;
R ₂ is a linear, branched or cyclic alkylene group or acetylene group having 2 to 10 carbon atoms;
R ₃ is an amino or carboxy group; and
CD is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or α-1,4-glucopyranose-bound cyclodextrin of 9 units or more. )

（２）
（式中、
ｎは４〜８の整数であり；及び
ＣＤは、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン又は９単位以上のα−１，４−グルコピラノース結合型シクロデキストリンである。） The cyclodextrin derivative is, for example, represented by the following general formula (2), preferably (1,4-diaminobutyl) -6-β-cyclodextrin, (1,5-diaminopentyl) -6-β. -Cyclodextrin and (1,6-diaminohexyl) -6-β-cyclodextrin.

(2)
(During the ceremony,
n is an integer of 4-8; and CD is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or 9 or more units of α-1,4-glucopyranose-linked cyclodextrin. )

The method for producing the cyclodextrin derivative is not particularly limited. For example, the cyclodextrin derivative can be obtained by the method described in Examples described later, and specifically, the OH group of the cyclodextrin, preferably at the 6-position. The OH group is tosylated to obtain a cyclodextrin having an activated OH group, and then one end has a functional group capable of binding to the activated OH group of the cyclodextrin, and It can be obtained by binding a linear, branched or cyclic alkylene compound or acetylene compound having an amino group or a carboxy group at the other end to a cyclodextrin having an activated OH group.

The mode of introduction of the cyclodextrin derivative is not particularly limited, and examples thereof include a mode in which the cyclodextrin derivative is introduced into the surface of the hydrogel by covalently bonding the functional group of the cyclodextrin derivative and the functional group on the surface of the hydrogel. , A mode in which the cyclodextrin derivative is introduced on the surface of the hydrogel by forming an amide bond between the amino group or the carboxy group in the cyclodextrin derivative and the carboxy group or the amino group in the hydrogel base material. Is preferable. A cyclodextrin derivative has a structure in which an amino group or a carboxy group and a cyclodextrin are located at one end and the other end, respectively. Since the cyclodextrin derivative has such a structure, the cyclodextrin in the molecule can be hydrogel (base material) via a linear, branched or cyclic alkylene group or acetylene group having 2 to 10 carbon atoms. ) It will be arranged at a predetermined distance from the surface. As a result, the inclusion of the poorly water-soluble drug on the cyclodextrin on the surface of the hydrogel is less susceptible to steric hindrance of the polymer chain of the hydrogel. As a result, the poorly water-soluble agent can be efficiently encapsulated in the cyclodextrin ring on the surface of the hydrogel.

In the cyclodextrin derivative, the linear, branched or cyclic alkylene group or acetylene group having 2 to 10 carbon atoms is not particularly limited as long as it applies to these structures, and for example, an ethylene group and an n-propylene group. Group, isopropylene group, n-butylene group, isobutylene group, n-pentylene group, n-hexylene group, n-heptylene group, n-octylene group, 2-ethylhexylene group, n-nonylene group, n-decylene group And other alkylene groups; acetylene groups such as n-butynyl group, n-pentynyl group, n-hexynyl group, n-heptinyl group, n-octynyl group, etc., among these, straight chain having 4 to 8 carbon atoms. The shape of the alkylene group is preferable.

Cyclodextrin is not particularly limited as long as it is a cyclic oligosaccharide in which several molecules of D-glucose, as is usually known, are bound by α-1,4 glycosidic bonds to form a cyclic structure, but α-cyclodextrin, β-Cyclodextrin, γ-cyclodextrin and 9 or more units of α-1,4-glucopyranose-linked cyclodextrin are used.

The hydrogel contains at least a monomer having a carboxy group or an amino group as a binding site of the cyclodextrin derivative in the molecule and a hydrophilic monomer other than the monomer having the carboxy group or the amino group in the molecule as a constituent component.

The monomer having a carboxy group in the molecule is not particularly limited as long as it is a compound having a carboxy group and a polymerizable group such as a (meth) acryloyl group or a vinyl group, and for example, methacrylic acid, acrylic acid, and 2-methacry. Examples thereof include leuroxyethyl succinic acid, 2-methacryloyloxyethyl hexahydrophthalic acid, 2-acryloyloxyethyl-phthalic acid, 2-acryloyloxyethyl hexahydrophthalic acid, etc., and one of them is used alone. Or, two or more kinds can be mixed and used.

The monomer having an amino group in the molecule is not particularly limited as long as it is a compound having an amino group and a polymerizable group such as a (meth) acryloyl group or a vinyl group, and for example, (meth) acrylamide and N- (2). -Aminoethyl) methacrylamide, N- (3-aminopropyl) methacrylicamide, N- (6-aminohexyl) methacrylamide, N-aminocarbonylmethacrylamide, 3-methyl-3-butenamide, N-aminocarbonylmethacrylamide , 3- (methacryloylamino) propanamide, N-methacryloylglycinamide, 3- (vinyloxy) propylamine, etc., and one of these can be used alone or in combination of two or more. can.

The hydrophilic monomer is not particularly limited as long as it is a compound having a hydrophilic group and a polymerizable group such as a (meth) acryloyl group or a vinyl group, and for example, hydroxymethyl (meth) acrylate and 2-hydroxyethyl (meth). ) Acrylate, 2-hydroxypropyl (meth) acrylate, 2,3-dihydroxypropyl (meth) acrylate, 2-hydroxybutyl (meth) acrylate and 2-polyethylene glycol mono (meth) acrylate, 2-polypropylene glycol (meth) acrylate , N, N-dimethyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, N-vinylpyrrolidone, etc., and one of these is used alone or in combination of two or more. be able to.

The preferable blending amount of the monomer having a carboxy group or an amino group in the molecule is 5 wt% or more and 10 wt% or less with respect to the blended amount of the hydrophilic monomer. When the blending amount of the monomer having a carboxy group or amino group in the molecule is less than 5 wt% with respect to the blending amount of the hydrophilic monomer, the carboxy group or amino group serving as the binding site of the cyclodextrin derivative is sufficiently on the surface of the hydrogel. Since it is absent, it tends to be impossible to place the desired amount of cyclodextrin derivative on the surface of the hydrogel. Further, when the blending amount of the monomer having a carboxy group or an amino group in the molecule is 10 wt% or more with respect to the blending amount of the hydrophilic monomer, the water content of the obtained hydrogel is high and the hydrophilicity of the hydrogel surface is high. It is not preferable because it tends to affect the inclusion efficiency of the poorly water-soluble drug.

The preferable blending amount of the hydrophilic monomer is 70 to 95 wt%, more preferably 80 to 92 wt%, based on the total polymerization component. When the blending amount of the hydrophilic monomer is less than 70 wt%, the flexibility of the hydrogel tends to be low, which is not preferable when the hydrogel is used orally or attached to the skin or mucous membrane, for example. Further, when the compounding amount of the hydrophilic monomer exceeds 95 wt%, the compounding amount of the monomer having a carboxy group or an amino group tends to be small, so that the binding site of the cyclodextrin derivative tends to be insufficient, which is desirable. It may not be possible to place an amount of cyclodextrin derivative on the surface of the substrate.

In the present invention, for example, in addition to the above components, a crosslinkable monomer can be blended in order to form a network structure of the hydrogel and adjust the mechanical strength. The crosslinkable monomer is not particularly limited as long as it is a compound having two or more (meth) acrylic groups, vinyl groups, or other polymerizable groups in the molecule, and is, for example, ethylene glycol di (meth) acrylate or methylenebis (meth). Acrylamide, 2-hydroxy-1,3-di (meth) acryloxipropane, trimethylolpropane tri (meth) acrylate and the like can be mentioned, and one of these can be used alone or in combination of two or more. can do.

The blending amount of the crosslinkable monomer is not particularly limited, but for example, it is preferably 0.3 to 5 wt% and more preferably 0.7 to 2 wt% with respect to the total mole of the polymerization component. When the blending amount of the crosslinkable monomer exceeds 5 wt%, the softness of the obtained hydrogel tends to decrease, which is not preferable.

A polymerization initiator is used to provide these monomers for copolymerization. Examples of the polymerization initiator include peroxide-based polymerization initiators such as lauroyl peroxide, cumene hydroperoxide, and benzoyl peroxide, which are general radical polymerization initiators, and azobisdimethylvaleronitrile and azobisisobutyronitrile. Azo-based polymerization initiators such as the above can be used alone or in combination of two or more. The amount of the polymerization initiator added is not particularly limited as long as it is a sufficient amount to promote the copolymerization reaction of the monomer. For example, as an externally added component, 10 to 7,000 ppm is preferable with respect to the total weight of the monomer of the polymerization component. ..

The hydrogel can be produced by combining steps known to those skilled in the art, and the production method thereof is not particularly limited, but can be obtained, for example, by the following method:
As a step of obtaining a copolymer, a monomer mixed solution containing a monomer having a carboxy group or an amino group in the molecule, a hydrophilic monomer, and optionally a crosslinkable monomer is placed in a molding mold such as metal, glass, or plastic. The copolymer is obtained by gradually or continuously raising the temperature in the range of 25 to 120 ° C. using a constant temperature bath or the like and completing the polymerization in 5 to 120 hours. Regarding polymerization, it is also possible to use ultraviolet rays, electron beams, gamma rays and the like. It is also possible to adapt solution polymerization by adding water or an organic solvent to the monomer mixture.

As a step of obtaining a hydrogel, the molding die after completion of polymerization is cooled to room temperature, the obtained polymer is peeled from the molding die, and if necessary, cut or polished, and then the polymer is immersed in a liquid. It is hydrated and swollen to form a hydrogel. Examples of the liquid (swelling liquid) to be used include water, physiological saline, and isotonic buffer. It is preferable to bring the copolymer into a swollen state by immersing it in a swollen liquid heated to 60 to 100 ° C. for a certain period of time. It is also possible to remove the unpolymerized monomer contained in the polymer during the swelling treatment.

As a specific example of the hydrogel, as a constituent component, a monomer having a carboxy group such as (meth) acrylic acid in the molecule 5 to 10 wt%, 2-hydroxyethyl (meth) so that the total amount of the monomers is 100 wt%. Contains 70-95 wt% hydrophilic monomers such as acrylates and 2-hydroxybutyl (meth) acrylates and 0.3-5 wt% crosslinkable monomers such as ethylene glycol di (meth) acrylates, with carboxy groups in the molecule. Examples include, but are not limited to, hydrogels in which the amount of monomer contained is 5-10 wt% with respect to the amount of hydrophilic monomer.

The method for producing the cyclodextrin derivative-modified hydrogel is not particularly limited. For example, the cyclodextrin derivative-modified hydrogel can be obtained by the method described in Examples described later. Specifically, the hydrogel is carboxy. When the cyclodextrin derivative has a group and the cyclodextrin derivative has an amino group at the terminal, the carboxy group of the hydrogel is N. -A hydrogel having an activated carboxy group by binding to hydroxysuccinimide or the like is obtained, and then a cyclodextrin derivative-containing solution in which the cyclodextrin derivative is dissolved in a buffer solution such as borate buffer (pH 8.5) is prepared. It can be obtained by immersing a hydrogel having an activated carboxy group or the like to co-bond the activated carboxy group of the hydrogel and the amino group of the cyclodextrin derivative.

The cyclodextrin derivative-modified hydrogel exhibits a function as a carrier of the poorly water-soluble drug by supporting the poorly water-soluble drug inside the cyclodextrin introduced on the surface of the hydrogel.

The poorly water-soluble drug is not particularly limited, and is, for example, a prostaglandin preparation, a steroid, a radical supplement, an antioxidant, a stain, a natural and synthetic anesthetic, an analgesic, an antagonist, an antiadrenergic agent, and an antiarrhythmia. Drugs, antibiotics, anticholinergic and cholinergic drugs, anticonvulsants, antidepressants, antiepileptic drugs, antibacterial and antiviral drugs, antiinflammatory drugs, antimuscarinic drugs and muscarinic drugs, antineoplastic drugs, Antipsychotics, anxiolytics, hormones, sleeping pills, immunosuppressants and immunoactive drugs, neuroleptics, neuronal blockers, antihypertensive drugs, nutritional supplements, sedatives and their derivatives, etc. The seeds can be used alone or in combination of two or more.

Specific examples of poorly water-soluble drugs include steroidal drugs triamcinolone acetonide, fluorometholone, and testosterone; nonsteroidal drugs diclofenac, indomethacin, ibuprofen, ketoprofen; prostaglandin derivatives travoprost, latanoprost, and tafluprost. , Bimatoprost; Examples of other drugs include edaravon, levamipide, natamycin, aminopyrin and the like, and are preferably used.

In the step of including the poorly water-soluble drug in the cyclodextrin derivative-modified hydrogel, the cyclodextrin derivative-modified hydrogel is dissolved or dispersed in a mixed solution of water and an organic solvent in the cyclodextrin derivative-modified hydrogel. It can be carried out by immersing in a water solution and stirring the mixture at 20 to 40 ° C. In the step of encapsulating the poorly water-soluble drug, it is preferable to carry out the stirring treatment because the poorly water-soluble drug is efficiently encapsulated in the cyclic structure of cyclodextrin. In the mixed solution of water and an organic solvent, the organic solvent is preferably a lower alcohol, more preferably methanol, ethanol, 1-propanol, 2-propanol and the like. The concentration of the organic solvent in the mixed solution is preferably 1 to 10 wt%, for example. If it exceeds 10 wt%, a poorly water-soluble agent is easily taken into the inside of the hydrogel, and whitening due to phase separation tends to occur, which is not preferable.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples, and the present invention may take various aspects as long as the problems of the present invention can be solved. can.

スキーム（１） [1. Synthesis of Aminoalkyl-Cyclodextrin]
Based on the following scheme (1), (1,6-diaminohexyl) -6-β-cyclodextrin was synthesized.

Scheme (1)

1.95 g (10.25 mol) of p-toluene dissolved in 3.5 ml of acetonitrile in a dispersion of 11.35 g (10 mmol) of β-cyclodextrin (CD) in 70.9 mL of purified water. A TsCl-containing CD dispersion was prepared by adding sulfonyl chloride (TsCl) while cooling with ice water.

The TsCl-containing CD dispersion was stirred at room temperature for 2 hours. A reaction solution was prepared by adding 31 ml of 1N sodium hydroxide to the stirred TsCl-containing CD dispersion in 3 portions. At that time, in order to maintain the pH of the reaction solution at 8 to 9, an appropriate amount of ammonium chloride was added to the reaction solution at the same time. The reaction solution was obtained by stirring the reaction solution for 30 minutes at room temperature to allow the reaction to proceed. The reaction solution at which the reaction was completed was cooled with ice water. Precipitation was generated by pouring 100 mL of purified water and 100 mL of acetone into the obtained reaction solution. The resulting precipitate was filtered, and the obtained precipitate was washed with acetone three times for purification, and then dried under reduced pressure to obtain 7.62 g of a white powder of tosylated β-cyclodextrin.

To a TsCD solution prepared by dissolving 1.0 g of tosylated β-cyclodextrin (TsCD) obtained by the above method in 10 mL of dehydrated dimethylformamide (DMF), add 4.5 mL of hexadiamine by argon airflow. , The reaction solution was obtained by advancing the reaction with stirring overnight at 80 ° C. Precipitation was generated by pouring 500 mL of cold acetone into the obtained reaction solution. The resulting precipitate was filtered, and the resulting precipitate was washed 3 times with 100 mL of cold diethyl ether, purified, and then dried under reduced pressure to (1,6-diaminohexyl) -6-β-cyclodextrin brown. 0.92 g of powder was obtained.

[2. Preparation of hydrogel]
2-Hydroxyethyl methacrylate (HEMA), 2-hydroxybutyl acrylate (HOB-A) and methacrylic acid (MAA) are weighed in the proportions shown in Table 1, and then polyethylene glycol diacrylate (A-200) is added. Further, 3000 ppm (external) of azobisisobutyronitrile (AIBN) was added to the total weight of the monomers, and the mixture was stirred and mixed to prepare a monomer mixture. The monomer mixture solution after the completion of stirring and mixing was placed in a disk-shaped molding mold and heated in the range of 30 to 110 ° C. over 15 hours to obtain a polymer. The obtained polymer was returned to room temperature, taken out from a mold, and then immersed in an ethanol-containing phosphate buffer solution and a phosphate buffer solution at 70 ° C. for 1 hour each for hydration and swelling to obtain a hydrogel. .. The hydrogel after hydration and swelling was immersed in a phosphate buffer solution and subjected to high-pressure steam sterilization at 121 ° C. for 30 minutes to obtain a hydrogel. The hydrogels were divided into two groups and designated as hydrogels (1) and hydrogels (2), respectively, in order to treat them with two types of poorly water-soluble chemical solutions described later.

The meanings of the abbreviations in the table are as follows;
HEMA: 2-Hydroxyethyl methacrylate HOB-A: 2-Hydroxybutyl acrylate MAA: A-200 methacrylic acid: Polyethylene glycol diacrylate AIBN: Azobisisobutyronitrile Hexaamino CD: (1,6-diaminohexyl)- 6-β-cyclodextrin

スキーム（２） [3. Preparation of Aminoalkyl-Cyclodextrin-Modified Hydrogel]
Based on the following scheme (2), a (1,6-diaminohexyl) -6-β-cyclodextrin-modified hydrogel was synthesized.

Scheme (2)

In a solution obtained by dissolving 0.115 g of N-hydroxysuccinimide (NHS) and 0.192 g of 1-ethyl-3-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) in 10 mL of DMF. 5 sheets each of the hydrogels (1) and (2) obtained by the method described in 2 above were immersed therein. The hydrogels (1) and (2) after immersion are shaken at room temperature for 1 hour using a vortex mixer so that NHS is bonded to the carboxy group (-COOH) exposed on the surface of the hydrogel. The reaction group was activated (hydrogel-COO-NHS).

Then, 3,000 ppm of (1,6-diaminohexyl) -6-β-cyclodextrin obtained by the method described in 1 above was dissolved in borate buffer to give a pH of 8.5 (1,6). -Diaminohexyl) -6-β-cyclodextrin solution was prepared. Each of the hydrogels in which the reactive groups were activated was immersed in 1 ml of the prepared (1,6-diaminohexyl) -6-β-cyclodextrin solution, and allowed to stand overnight at room temperature to proceed with the reaction. The reaction solution containing the hydrogel in which the NHS of the hydrogel was replaced with (1,6-diaminohexyl) -6-β-cyclodextrin was obtained. By taking out the hydrogel from the obtained reaction solution and immersing it in pure water at room temperature for 24 hours to remove the unreacted compounds generated in each of the above steps, (1,6-diaminohexyl) -6. -Β-Cyclodextrin-modified hydrogels (1) and (2) were obtained.

[4. Preparation of poorly water-soluble chemical solution]
An edaravone dispersion was prepared by weighing 3000 ppm of edaravone into pure water and stirring at room temperature for 30 minutes.

A triamcinolone dispersion was prepared by weighing 3000 ppm of triamcinolone (triamcinolone acetonide) into a hydrous ethanol solution (pure water: ethanol = 98: 2) and stirring at room temperature for 30 minutes.

[5. Preparation of drug inclusion hydrogel]
(Example 1)
(1,6-diaminohexyl) -6-β-cyclodextrin-modified hydrogel (1) By immersing 5 sheets in 1 ml of each triamcinolone dispersion and then stirring at room temperature for 5 hours. , Triamcinolone-encapsulated hydrogel in which triamcinolone was encapsulated in the ring structure of β-dextrin was obtained.

(Example 2)
(1,6-diaminohexyl) -6-β-cyclodextrin-modified hydrogel (2) After immersing 5 sheets in 1 ml of edaravone dispersion, the mixture was stirred at room temperature for 5 hours. An edaravone-encapsulating hydrogel in which edaravone was encapsulated in the ring structure of β-dextrin was obtained.

(Comparative Example 1)
Triamcinolone and hydrogel were prepared by the same method as in Example 1 except that the hydrogel used was hydrogel (1) before the (1,6-diaminohexyl) -6-β-cyclodextrin modification reaction. To obtain a triamcinolone-treated hydrogel.

(Comparative Example 2)
The hydrogel used was edaravone and hydrogel by the same method as in Example 2 except that the hydrogel used was (2) before the (1,6-diaminohexyl) -6-β-cyclodextrin modification reaction. To obtain an edaravone-treated hydrogel.

The obtained hydrogel was evaluated according to the following evaluation method.

[6. Hydrogel evaluation method]
<Evaluation of drug uptake>
The hydrogels of Examples 1 and 2 and Comparative Examples 1 and 2 were immersed in a hydrous ethanol solution (water: ethanol = 20: 80), allowed to stand at room temperature for 24 hours, and then the hydrous ethanol solution (water:: By immersing in ethanol = 20:80), the poorly water-soluble drug encapsulated or brought into contact with the hydrogel was eluted in the solution. The poorly water-soluble drug in the hydrated ethanol solution (water: ethanol = 20:80) after elution was quantified using an ultra-trace spectrophotometer (manufactured by Thermo Fisher Scientific Co., Ltd.) according to a conventional method. The value obtained by quantification was defined as the amount of poorly water-soluble drug taken up per unit hydrogel (μg / g), and was evaluated as a percentage of 3000 ppm of the drug contained in the poorly water-soluble drug solution. The results are shown in Table 2 and FIG.

<Evaluation of drug-carrying effect>
The hydrogels of Example 1 and Comparative Example 1 were immersed in 2 ml of physiological saline at room temperature for a certain period of time (0.5, 1, 2, 4, 8 and 24 hours). The amount of the drug contained (eluted) in the physiological saline after immersion was quantified using an ultra-trace spectrophotometer (manufactured by Thermo Fisher Scientific Co., Ltd.) according to a conventional method. The value obtained by quantification was expressed as a percentage of the total amount of uptake according to the following formula, and the supportability was evaluated. The results are shown in Table 3 and FIG.
Release rate (%) = (release amount / uptake amount at each time) x 100

[7. Evaluation results]
As shown in Table 2 and FIG. 1, the uptake amount and uptake rate of the poorly water-soluble drug by the (1,6-diaminohexyl) -6-β-cyclodextrin-modified hydrogel (Practical Examples 1 and 2) are It was much larger than the usual hydrogels (Comparative Examples 1 and 2). In particular, it was found that the uptake amount and uptake rate of extremely difficult water-soluble drugs, such as triamcinolone, which are considered to be almost insoluble in water, differ by 10 times or more between the two.

Further, as shown in Table 3 and FIG. 2, in a normal hydrogel (Comparative Example 1), 75% of triamcinolone was eluted 0.5 hours after the start of immersion, and 92% of triamcinolone was eluted 1 hour after the start of immersion. Therefore, the initial burst was confirmed. On the other hand, in the (1,6-diaminohexyl) -6-β-cyclodextrin-modified hydrogel (Practical Example 1), less than 70% of triamcinolone remained in the hydrogel until 4 hours after the start of immersion. , The expected burst was not seen. Thus, it was found that the (1,6-diaminohexyl) -6-β-cyclodextrin-modified hydrogel was excellent in drug sustained release.

Based on the above results, (1,6-diaminohexyl) -6-β-cyclodextrin-modified hydrogel is excellent in taking up poorly water-soluble drugs, especially extremely poorly water-soluble drugs, and drug gradual. It turned out to be excellent in release.

The cyclodextrin derivative-modified hydrogel according to one aspect of the present invention is a hydrogel that can efficiently carry a desired amount of a poorly water-soluble drug and exhibits excellent sustained release of the drug. By using it as a medical device such as a gel, it can contribute to the health and welfare of those who are expected to undergo drug therapy or regenerative medicine.

Claims (3)

The following general formula (1)

(1)
(During the ceremony,
R ₁ is -NH- or -COO-;
R ₂ is a linear, branched or cyclic alkylene group or acetylene group having 2 to 10 carbon atoms;
R ₃ is an amino or carboxy group; and
CD is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or α-1,4-glucopyranose-bound cyclodextrin of 9 units or more. )
A cyclodextrin derivative-modified hydrogel having a cyclodextrin derivative represented by (1) on the surface of the hydrogel .
The hydrogel contains a monomer having a carboxy group or an amino group in the molecule as a constituent component and a hydrophilic monomer copolymerizable therewith, and the amount of the monomer having the carboxy group or the amino group in the molecule is , A cyclodextrin derivative-modified hydrogel which is 5 wt% or more and 10 wt% or less with respect to the amount of the hydrophilic monomer . The cyclodextrin derivative has the following general formula (2).

(2)
(During the ceremony,
n is an integer of 4-8; and CD is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or 9 or more units of α-1,4-glucopyranose-linked cyclodextrin. )
The cyclodextrin derivative-modified hydrogel according to claim 1, which is a cyclodextrin derivative represented by. The cyclodextrin derivative is (1,4-diaminobutyl) -6-β-cyclodextrin, (1,5-diaminopentyl) -6-β-cyclodextrin or (1,6-diaminohexyl) -6-. The cyclodextrin derivative-modified hydrogel according to claim 1 or 2, which is β-cyclodextrin.

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