WO2006038326A1

WO2006038326A1 - Method for controlling release of acting substance and material for use therein

Info

Publication number: WO2006038326A1
Application number: PCT/JP2005/005008
Authority: WO
Inventors: Masahiro Miyauchi; Hiromasa Tokudome
Original assignee: Toto Ltd.
Priority date: 2004-10-01
Filing date: 2005-03-18
Publication date: 2006-04-13
Also published as: TW200611713A

Abstract

A method for controlling the release of an acting substance which comprises providing a hollow article being made of at least one material selected from a titanium oxide, titanium hydroxide and a titanic acid salt and being packed with the acting substance, and exposing the hollow article packed with the acting substance to a stimulus from outside such as the irradiation of light or the change of pH, to thereby release the acting substance to the outside of the hollow article; and materials for use in the above method.

Description

Specification

Release of active substances 1 method and materials used therefor

Background of the Invention

[0001] Field of the Invention

The present invention relates to a method for controlling release of an active substance and a material used therefor.

Specifically, the present invention relates to a method and a material in which an inside is filled with an active substance and the active substance is released by an external stimulus such as light irradiation or pH change. Such methods and materials can be preferably used for pharmaceuticals, cosmetics, food additives, fragrances, agricultural chemicals, etc., particularly drug delivery materials or cosmetics.

[0002] Putujutsu

Sustained-release materials that can gradually and controlledly release active substances such as drugs, cosmetic facial ingredients, and food nutritional ingredients in the fields of pharmaceuticals, cosmetics, food additives, fragrances, and agricultural chemicals It has been known. For example, in the case of a drug, by gradually releasing the active substance, it is possible to maintain a medicinal effect for a long time and perform an effective treatment even with a small dose of drug. In addition, side effects can be reduced because the concentration of medicinal ingredients in the body and blood does not increase excessively. In addition, a technology called a drug delivery system has been proposed that allows medicinal ingredients to work in the pathogenic part. On the other hand, in the case of cosmetics, the whitening effect can be maintained for a long time by gradually releasing the active substance. The following are known as such technologies.

[0003] A. Harada, K. Kataoka, Science, 283, 65 (1999) discloses a technique for sustained release of a drug using a sustained release material using polymeric micelles. This sustained-release material is one in which a drug is carried in a hydrophilic part that is the central part of a micelle formed by molecular association.

[0004] Japanese Patent Application Laid-Open No. 2002-173319 discloses a technique for sustained release of a drug by a sustained release material using mesoporous silica. Mesoporous silica has multiple holes with specific pore sizes, and can carry molecules that can enter the holes.

[0005] JP-A-2004-91421 discloses a cosmetic using a layered double hydroxide salt containing ascorbic acid. In this cosmetic, there is an ascorbide layer between double hydroxides. Since the acid is included, ascorbic acid can be stably present.

[0006] On the other hand, biocompatibility is high! As a substance, titanium-based oxides are known. Conventionally, the synthesis of titanium oxides with specific pore sizes has been considered difficult due to unstable starting materials. In recent years, hollow fibers of titanium oxide or titanate by hydrothermal synthesis have been used. Has been reported (see, for example, JP-A-10-152323 and LM Peng et al, Adv. Mater. 14, 1208 (2002)).

Summary of the Invention

[0007] The inventors of the present invention have now been charged with titanium oxide, titanium hydroxide, and a group force selected from the group power of titanate power, with a certain kind of active substance filled in the hollow body. It was found that by applying external stimuli such as light irradiation and pH change, the active substance is released out of the hollow body, that is, the release of the active substance can be controlled by the external stimulus.

[0008] Therefore, an object of the present invention is to control the release of an active substance by an external stimulus.

[0009] And, the method for controlling the release of an active substance according to the present invention comprises:

Prepare at least one hollow body selected from the group force consisting of titanium oxide, titanium hydroxide, and titanate filled with active substance,

An external stimulus is applied to the hollow body filled with the active substance to release the active substance out of the hollow body.

Is included.

[0010] The active substance release controlling material according to the present invention includes titanium oxide, titanium hydroxide, and at least one hollow body selected from the group force consisting of titanate power, And an active substance filled in the part.

Brief Description of Drawings

FIG. 1 is a diagram showing the zeta potential of hollow fibers at various pH values measured in Example 3.

FIG. 2 is a graph showing methylene blue release characteristics at various pH values measured in Example 4.

FIG. 3 is a graph showing ibuprofen release characteristics at various pH values measured in Example 5. is there.

FIG. 4 is a graph showing ascorbic acid release characteristics at each ultraviolet irradiation time measured in Example 6.

FIG. 5 is a graph showing the binaphthalenediol emission characteristics measured in Example 6 for each ultraviolet irradiation time.

FIG. 6 is a graph showing the relationship between the double value (2R) of the molecular length of ammine ions and the amount of fixed amount of alkylamine measured in Example 7.

FIG. 7 is a photograph of a hollow fiber with a silane coupling agent fixed, taken in Example 8.

FIG. 8 is a diagram showing an FT-IR of a hollow fiber in which alkylamine is fixed, measured in Example 9.

FIG. 9 is a photograph of a hollow fiber in which the active substance obtained in Example 10 is immobilized.

FIG. 10 is a graph showing the reflectance of a hollow fiber in which the active substance obtained in Example 10 is immobilized.

FIG. 11 is a diagram showing the results of a methylene blue staining test conducted in Example 11. Detailed description of the invention

[0012] Methods and materials for controlling the release of agent soot

In the method for controlling release of an active substance according to the present invention, first, at least one hollow body selected from titanium oxide, titanium hydroxide, and a group force consisting of titanate is prepared. Next, this hollow body is filled with an active substance. That is, a certain kind of active substance for controlling the release (controlled release) can be filled through the opening of the hollow body. In this way, many of the active substances pre-filled in the hollow body can be held in the hollow body for a long time because they are housed, fixed, or adhered to the hollow body to prevent release. At this time, a part of the active substance may be released gradually and slowly as long as the release rate does not hinder controlled release. By holding the active substance in the hollow fiber, it is also expected to prevent thermal chemical alteration of the active substance to some extent by the masking effect of the hollow body.

[0013] Then, by applying an external stimulus such as light irradiation and pH change to the hollow body, the active substance Is released out of the hollow body. In other words, the force at which release of the active substance that has not been performed until then starts to be released to the outside of the hollow body, or the release of the active substance that has been gradually performed until then becomes faster. Therefore, by applying an external stimulus at the timing when the function of the active substance is most desired to be exerted to promote the release of the active substance, the function of the active substance can be maximized at the optimal timing. For this reason, the method and material of the present invention have utility value for applications where it is desired to exert the function of the active substance at a specific timing, for example, drug delivery systems, cosmetics, and food additives. High.

[0014] Hollow body

The hollow body used in the present invention is composed of at least one selected from titanium oxide, titanium hydroxide, and titanate force, and is limited as long as it has an opening capable of filling and releasing the active substance. Although not, it is preferred to use hollow fibers. As this hollow fiber, for example, those disclosed in JP-A-10-152323 and LM Peng et al., Adv. Mater. 14, 1208 (2002) can be used. It is a part of the disclosure of this specification. Since the constituent material of the hollow body used in the present invention is responsive to external stimuli such as light irradiation and _P H change, it is possible to release the active substance filled inside according to the external stimuli. is there. In addition, these materials are known as non-toxic and highly biocompatible materials with high dispersibility, and are therefore suitable for use in drug delivery systems, cosmetics, food additives, and the like.

[0015] The titanium oxide usable in the hollow body of the present invention may be either crystalline or amorphous, but is preferably crystalline acid titanium. Preferable examples of crystalline acid titanium include rutile type, anatase type, brookite type, and Ti02 (B), and more preferable is anatase type acid titanium with the highest photocatalytic activity. . Titanium oxide contains a reductant such as Ti 0 or Ti 0 or a magnetic phase in which this reductant is regularly arranged.

2 3 3 5

It may be. Preferred examples of titanates include polytitanic acid containing protons such as trititanic acid, tetratitanic acid, pentatitanic acid, hexatitanic acid, heptitanic acid, octatitanic acid, potassium titanate, and calcium titanate. , Cesium titanate, sodium titanate, magnesium titanate, aluminum titanate, strontium titanate, and titanate Examples thereof include polyvalent titanates such as norium.

[0016] The shape of the hollow fiber in the present invention is not limited as long as it has an opening capable of filling and releasing the active substance at both ends in the long axis direction, but it is preferably a scroll-like layered shape. According to a preferred embodiment of the present invention, the force of using a scroll-like layered titanate as a hollow fiber can be synthesized in a large amount at a low cost, and the force is also uniform pore diameter, large specific surface area, non-toxicity, And high biocompatibility. In addition, the scroll-like layered titanate may be heat-treated in order to enhance crystallinity and improve thermal chemical stability. The preferred heat treatment temperature at that time is 50 ° C— 600 ° C.

[0017] The preferred inner diameter of the hollow fiber used in the present invention is lnm-50nm, more preferably 3nm-8nm. Within this range, since the material has a nanostructure, it is excellent in dispersibility in a solvent, and as a result, the active substance can be released more efficiently when an external stimulus is applied. The inner diameter of the hollow fiber can be determined by direct observation using a transmission electron microscope (TEM) or by measuring the pore size distribution by the BET method. According to a more preferred embodiment of the present invention, the size of the hollow fiber is preferably in the range of 3-8 nm inner diameter, 8-30 nm outer diameter, and lOOnm-1 μm length. A method for producing such a hollow fiber is not limited, but it can be preferably produced by hydrothermal treatment of acid titanium particles in a sodium hydroxide aqueous solution.

[0018] According to a preferred embodiment of the present invention, the hollow body may include an anion other than oxygen in its chemical structure. For example, the oxygen position of the hollow body is replaced with an ion other than oxygen. It is also possible to interpose a gas ion other than oxygen between the lattices, or to arrange a gas ion other than oxygen at the grain boundary of the hollow body. Thereby, the photocatalytic activity of the hollow body can be expressed by visible light, or the solid acidity of the surface can be increased to increase the binding force with the modifying molecule.

According to a preferred embodiment of the present invention, a metal such as Pt, Pd, Ag, Cu, Au, or Ni can be supported on the hollow body. Thereby, the electron-hole pair photoexcited at the time of light irradiation can be efficiently separated, and the hydrophilization activity and the acid-decomposition activity can be increased. In addition, when Ag or Cu is supported on the hollow body, antibacterial properties can be exhibited in addition to the above effects. [0020] According to a preferred aspect of the present invention, the sustained release rate of the active substance may be precisely controlled by providing an opening / closing mechanism such as a molecular door at both ends of the opening of the hollow fiber. Preferred examples of the material constituting the molecular door include gold fine particles; quantum dots such as CdS and CdSe; and photoisomeric materials such as azobenzene, spiropyran and coumarin. For example, when a photoisomer material is used, the opening / closing of the molecular door can be controlled by the wavelength of light irradiation. It is also possible to remove the substance corresponding to the door by chemical treatment and release the contained active substance.

[0021] Active substance

In the present invention, the hollow body is filled with an active substance. The method is not limited as long as the active substance can be filled into the hollow body, but it can be simply carried out by immersing the hollow body in a solution containing the active substance.

[0022] The active substance used in the present invention is not limited as long as it is a substance that can be filled into the hollow body and can be released to the outside of the hollow body by external stimulation such as light or pH change. Various substances such as (facial ingredients), nutrients, fragrances, agricultural chemicals, and fertilizers can be used. Therefore, the size of the active substance is desired to be smaller than the inner diameter of the hollow body.

[0023] Preferable drugs include, for example, fluorouracil, gemcitabine, methotrexate, cyclophosphamide, daunorubicin hydrochloride, adriamycin, idarubicin hydrochloride, bleomycin, mitomycin, actinomycin, vincristine, cisplatin, force norepoplatin, etoposide, netaxurax Anticancer agents such as irinotecan hydrochloride; Penicillin, Macrolide, New quinolone, Tetracycline and other antibacterial agents; Lamivudine, Nelfinavir, Indinavir, Saquinavir, Interferon, Amantadine, Acyclovir and other antiviral drugs; New prorelin, Drugs for hormonal diseases such as buserelin, goserelin, triptorelin and nafarelin; analgesics such as ibuprofen That. Preferred examples of cosmetics (facial ingredients) include vitamins A, vitamin B, vitamin C, vitamin 0, vitamin E, vitamin! ⁷ , vitamin K, etc .; anthocyanins; collagen; hyaluronic acid; chalcone derivatives, etc. Is mentioned. Examples of preferred oral nutrients include docosahexaenoic acid, eisacopentaenoic acid, linoleic acid, γ-linolenic acid, α-linolenic Acid, evening primrose oil, borage oil, lecithin, octacosanol, rosemary, sage, γ-oryzanol, j8-carotene, palm carotene, perilla oil, chitin, chitosan, royal jelly, propolis, gimmegma, heme iron, etc. . Preferable examples of the fragrances include essential oils such as oranges, limes, lemons, grapefruits and citrus oils; plant essential oils such as peppermint oil, spearmint oil, spice oil; cola nuts, coffee, rice bran, cocoa, black tea, green tea, Examples include spices and flavors derived from various animals and plants. Preferable examples of agricultural chemicals include various insecticides, repellent agents, fungicides, herbicides, rodenticides, plant growth regulators and the like. Preferable examples of the fertilizer include ammonium sulfate, glass draft, sodium nitrate, lime nitrate, potassium sulfate, potassium chloride, potassium sulfate bitter soil, and soluble.

[0024] According to a preferred embodiment of the present invention, it is preferable to use a substance capable of binding to the inner wall of the hollow body by dehydration condensation as the active substance. As a result, the active substance can be bonded to the inner wall of the hollow body by dehydration condensation, and the bond is decomposed by the photocatalytic activity of the hollow body that appears in response to light irradiation, and the active substance is released to the outside. Can be made.

[0025] According to a more preferred embodiment of the present invention, it is preferable to use a molecule having a hydroxyl group as the active substance capable of binding to the inner wall of the hollow body by dehydration condensation. This makes it possible to prevent decomposition of the active substance itself due to the photocatalytic activity of the hollow body. That is, the bond formed by dehydration condensation of the hydroxyl group with the hydroxyl group of the hollow body is relatively weak and easily broken by the photocatalytic activity, so that the hydroxyl group of the active substance is released in a reproducible form.

[0026] According to a further preferred embodiment of the present invention, it is preferable to use a molecule having a diol group as the active substance bonded to the inner wall of the hollow body by dehydration polycondensation. This molecule is colorless and transparent when it dissolves in water, but when two hydroxyl groups contained in the diol group are dehydrated and polycondensed with the hollow fiber, it is colored by the interface state. Therefore, it is colored when bound and colorless when detached, so that it can be used as an indicator for confirming whether or not the active substance has been released. In addition, in the application of cosmetic foundations, it is possible to produce a color close to human skin by combining an active substance having a diol group. Preferred examples of the molecule having a diol group include catechols such as catechol, methyl catechol, and tertiary butyl catechol; dihydroxycyclobutene; asconolelevic acid; dopamine; alizarin; Ascorbic acid is more preferable. In particular, L-ascorbic acid is also called vitamin C, and is known to have a pharmacological action and an immune enhancing action, as well as a great effect on whitening action and wrinkle prevention. Therefore, by filling L-ascorbic acid as an active substance in the hollow fiber, L-ascorbic acid can be released in response to the irradiation of ultraviolet rays, and as a result, the skin damage that can be caused by ultraviolet rays is reduced. It can be efficiently suppressed by the released L-ascorbic acid.

[0027] According to another preferred embodiment of the present invention, a molecule or particle having a charge can be used as the active substance. The surface of the hollow body, like many oxides and hydroxides, is force thione in acidity and ionic in alkali, so changing the pH changes the surface charge state. Can be made. And if the active substance is charged, an attractive or repulsive force due to the Coulomb force acts between the surface of the hollow body, so by changing the pH so that a repulsive force works between the hollow body and the active substance, The active substance filled inside can be released to the outside.

[0028] 謹

In the present invention, the active substance can be released out of the hollow body by applying some external stimulus to the hollow body filled with the active substance. The external stimulus that can be used in the present invention is not limited as long as it can contribute to the release of the active substance out of the hollow body, and preferably includes light irradiation or pH change.

[0029] According to a preferred embodiment of the present invention, light irradiation accompanied by photoexcitation of a hollow body can be used as an external stimulus. Since the hollow body used in the present invention can have a photocatalytic activity, an acid reduction reaction occurs on the surface by irradiation with ultraviolet rays. By this reaction, the bond (for example, dehydration condensation) between the hollow body and the active substance is decomposed, and the active substance is released to the outside. Preferred light sources for irradiating light include fluorescent lamps, black lights, germicidal lamps, incandescent lamps, low-pressure mercury lamps, high-pressure mercury lamps, xenon lamps, mercury-xenon lamps, halogen lamps, metal halide lamps, LEDs (white, blue , Green, and red), laser light, and sunlight. In addition, in applications such as drug delivery where the active substance is released in the living body, light irradiation into the living body is applied to the outside of the body to transmit light into the body, or from the oral using a light guiding fiber. Irradiate the internal organs or guide light Even if the fiber is inserted directly into the living tissue and irradiated, it may be out of alignment!

[0030] According to another preferred embodiment of the present invention, a change in pH can be used as an external stimulus. Since the surface of the hollow body used in the present invention becomes cationic under acidic conditions and cationic under alkaline conditions, the surface charge state can be changed by changing pH. For example, when a scroll-like layered titanate is used as the hollow body, the pH force at the isoelectric point is .5, so that it is cationic in a pH region lower than this value, and is ionic in a high region. . When the active substance is charged, an attractive or repulsive force due to the Coulomb force acts between the surface of the hollow body, so by changing the pH so that a repulsive force acts between the hollow body and the active substance, The active substance filled inside can be released to the outside. For example, if the active substance is cationic, the active substance can be released by making the surface of the hollow body cationic. On the other hand, if the active substance is char-on, the active substance can be released by making the surface of the hollow body char-on.

[0031] The above-described embodiment using a change in pH as an external stimulus is suitable for a cosmetic application, for example, by releasing an agent having a pharmacological effect in accordance with the pH of the skin that changes due to sweating or proliferation of various bacteria. It is possible to exert a cosmetic effect appropriately according to the skin condition. This embodiment is also suitable for pharmaceutical use. For example, effective gastric treatment can be achieved by releasing a gastric drug in response to a change in pH caused by contact with gastric acid. At this time, the charged active substance may be a substance in which a drug is supported on a particulate substance having a size smaller than the inner diameter of the hollow body.

[0032] Modification molecule

According to a preferred embodiment of the present invention, a modifying molecule immobilized on at least one of the inner wall and the outer wall of the hollow body can be further provided according to the use environment and the type of active substance. The substance that modifies the inner wall and the outer wall may be the same substance or a different substance. This modifying molecule has a linker part and a main chain part, and a part of the linker is bound to the surface of the hollow body. By binding the modifying molecule to the outer wall of the hollow body, it is possible to enhance the dispersibility in the use environment or to function as an active target for malignant tissues such as cancer cells. On the other hand, it is possible to pack the active substance with high density by binding the modifying molecule with high affinity to the active substance to the inner wall. It becomes ability. In addition, by binding the modifying molecule to the inner wall of the hollow body, the interaction between the active substance and the hollow body changes, so that the release rate of the active substance can be increased or decreased.

[0033] According to a more preferred embodiment of the present invention, the linker force of the modifying molecule and the surface of the hollow body are selected from a group force consisting of a covalent bond, a hydrogen bond, an ionic bond, and a coordination bond. It is preferable to be fixed by one bond because of its high thermal and chemical stability. The bond of the modifying molecule may be formed so as to cover a part of the surface of the hollow body, or may be formed so as to cover all of the surface.

[0034] Preferred examples of the linker part of the modifying molecule include, for example, diketones such as carboxyl group, phosphate group, sulfonate group, hydroxyl group, amino group, pyridine, and acetylethylacetone, and ethylene such as polyethylene dallicol. These include oxides, siloxanes, and combinations thereof. These functional groups have high bonding strength with the hollow body.

[0035] When the material of the present invention is used by being dispersed in water, preferred examples of the main chain portion of the modifying molecule include polymers such as polycation and polyion, more preferably polyethyleneimine, Examples thereof include polyethylene glycol, polyallylamine, polyallylalkylamine, polyacrylic acid, polyethylene glycol and the like, and copolymers thereof.

[0036] When the material of the present invention is used dispersed in an organic solvent or floated in water, a modifying molecule having a hydrophobic structure in the main chain is used in order to make the outer wall of the hollow body hydrophobic. It is preferable. Preferable examples of the modifying molecule having a hydrophobic structure in the main chain part include substances containing an alkyl chain, fluorine resin, and an aromatic molecule, and more preferably a long-chain silane coupling agent or Alkylamine is mentioned. These modifying molecules can be easily and firmly bound to the surface of the hollow body. In particular, when a silane coupling agent is used, condensation occurs during dehydration between the functional group of the hydrophilic portion modified with silane and the hollow fiber, and strong bonds are formed by covalent bonds. In addition, the silane coupling agent is stable and difficult to be decomposed by the photocatalytic activity of the hollow body.

[0037] When the material of the present invention is used for in vivo cells or medical applications, the main chain portion of the modifying molecule can function as active targeting of the substance to be decomposed. For example, raw In order to decompose malignant tissues such as cancer in the body, it is easy to incorporate the hollow body into the cells by selecting the main chain portion with high affinity with the cells. Examples of the main chain part having high affinity with cells include polyethylene glycol, chitin, chitosan and the like. According to a preferred embodiment of the present invention, active targeting of a substance to be decomposed by using a protein that can specifically bind to a malignant substance in a living body as a main chain part or a main chain part of a modifying molecule is used. Can function effectively. Examples of such proteins include antibodies, ligands, receptors, polypeptides, oligopeptides, and amino acids. Further, according to another preferred embodiment of the present invention, a nucleic acid is used as a main chain part of the modifying molecule or a substance to be bound to the main chain part. High selective adsorption ability can be exhibited.

[0038] When the material of the present invention is used as a cosmetic, it is preferable to use an amphiphilic molecule as the main chain of the modifying molecule in order to prevent water and sweat. Since these amphiphilic molecules have a high affinity for water and oil, they adhere well to the skin and do not sweat well. Preferred amphiphilic molecules are molecules comprising both hydrophilic and hydrophobic groups. Preferable examples of the hydrophilic group of the amphiphilic molecule include diketone such as carboxyl group, phosphate group, sulfone group, hydroxyl group, amino group, pyridine, and acetylacetone, and ethylene oxide such as polyethylene glycol. Can be mentioned. Preferred examples of the hydrophobic group of the amphiphilic molecule include alkyl, fluorinated resin, and aromatic molecules. According to a preferred embodiment of the present invention, the photocatalytic activity of the outer wall portion in contact with the skin can be suppressed by modifying the outer wall of the hollow body with a modifying molecule having a hardly decomposable main chain portion, and the photocatalytic reaction can be suppressed. Therefore, damage to the skin due to the generated active oxygen can be suppressed. Preferred examples of the modifying molecule having a hardly decomposable main chain include silane coupling agents and alkylamines.

[0039] In the material of the present invention, the binding of the modifying molecule to the hollow body may be performed by any method, but can be easily performed by immersing the hollow body in a solvent containing the modifying molecule. At this time, in order to promote bonding, heat treatment or chemical treatment using acid, alkali or the like may be performed. Depending on the molecular length of the modified molecule, this The modifying molecule can be attached to both the inner and outer walls of the body, or only to the outer wall.

[0040] When a long-chain modifying molecule is bonded to both the inner and outer walls of the hollow fiber, it is preferable to design the molecular length (R) of the modifying molecule to be twice (2R) smaller than the inner diameter of the hollow fiber. Yes. In general, the modifying molecules are polar and, like many surfactants, can form micelles in hollow fibers. Inside the hollow fiber, the hydrophilic portion of the modifying molecule is immobilized on the hollow fiber side, and the hydrophobic portion is oriented toward the center of the hollow fiber to form a so-called “rod-like micelle”. Since the diameter of this rod-like micelle is equivalent to twice the length (R) of the modifying molecule (2R), in order to form micelles on the inner wall, the value of 2R must be smaller than the inner diameter of the hollow fiber. I hope. By setting the inner diameter in this way, the modifying molecule can be bonded to the inside of the hollow fiber. For example, when the inner diameter of the hollow fiber is 3.5 nm, the 2R of the modifying molecule is designed to be smaller than 3.5 nm.

[0041] On the other hand, when the modifying molecule is bonded only to the outer wall of the hollow fiber, the molecular length of the modifying molecule is

Two times (2R) of (R) is designed to be larger than the inner diameter of the hollow fiber. For example, when the inner diameter force of the hollow fiber is ¾.5 nm, the 2R of the modifying molecule is designed to be larger than 3.5 nm. If the length (2R) of the modification molecule corresponding to the size of the micelle is larger than the inner diameter of the hollow fiber, it will be difficult to form micelles on the inner wall, and the modification molecule will bind only to the outer wall. To do.

[0042] As a method of bonding the modifying molecule only to the inner wall of the hollow fiber, the modifying molecule is bonded to both the inner wall and the outer wall by the above-described method, and then chemical treatment such as acid or alkali treatment or argon sputtering is performed. It is possible to remove only the modifying molecules bound to the outer wall by plasma etching.

[0043] Other methods for bonding the modifying molecule to the hollow body include dry coating methods such as CVD, PVD, vacuum deposition, laser ablation, ion plating, and sputtering.

[0044] The presence or absence of a chemical bond between the hollow body and the modifying molecule can be confirmed by instrumental analysis such as FT-IR or NMR. For example, when the modifying molecule is alkylamine, the presence or absence of a chemical bond can be determined by measuring the NH stretching vibration of free amine ions and amine ions adsorbed on the hollow fiber by FT-IR. In other words, NH stretching vibration force observed in the vicinity of 3300 cm-l with free amine ions. Shift to the side. The presence or absence of chemical bonds can also be confirmed by measuring the stretching vibration of the OH group of the hollow fiber. In other words, when the modifying molecule is chemically bonded to the OH group of the hollow fiber, the signal of the OH group force that was originally adsorbed in the hollow fiber disappears. The presence or absence of chemical bonds between the hollow fiber and the modifying molecule can be confirmed.

[0045] Usage

The hollow body filled with the active substance according to the present invention can be used as it is, but depending on the application, it can be dispersed in a dispersion medium such as water, organic solvent and oil or fat, or supported on a base material. It can be preferably used by making it.

[0046] According to a preferred embodiment of the present invention, it is preferable that an aqueous amine solution is used as a dispersion medium, and protons are added to the inside or the surface of the titanium-containing compound constituting the hollow body. Thereby, the electrical neutrality of the hollow body that maintains the electrical neutrality and serves as the driving force for aggregation can be reduced, and the material of the present invention can be dispersed in the dispersion medium with high dispersibility. Therefore, it is possible to further promote the release of the active substance outside the hollow body by external stimulation.

[0047] This dispersion can be easily obtained by bringing the hollow body into contact with an aqueous acid solution and then dispersing or adding it to an aqueous amine solution. That is, the hollow body is stabilized by the addition of protons to the inside and the surface by contact with the acid aqueous solution, and is highly dispersed by the aqueous amine solution.

[0048] The hollow body to which protons are added exhibits stronger ionic properties than conventional acid titanium, and preferably has a pH of 3-6 at the isoelectric point, more preferably pH 5-6. It is. A hollow body to which such a peptone is added is superior in dispersibility in the neutral region as compared with a conventional acidic titanium colloid having a pH of 6-7 at the isoelectric point. Examples of usable acids that are preferably used by contacting the hollow body with an acid aqueous solution as a method for adding protons to the hollow body include nitric acid, hydrochloric acid, sulfuric acid, perchloric acid, hydrofluoric acid, and bromic acid. , Iodic acid, nitrous acid, acetic acid, and oxalic acid. The temperature at which the hollow body is brought into contact with the aqueous acid solution is preferably 0-100 ° C, more preferably 10-50 ° C. The amount of proton addition to the hollow body can be analyzed by infrared spectroscopy (IR), temperature programmed desorption (TDS), or CHN coder. example For example, when the hydrogen concentration in the hollow body obtained by analysis with a CHN coder is 3% or more, it is higher than about 1%, which is the amount of hydrogen contained in the conventional anatase type titanium oxide, It can be considered that protons are added at a hydrogen concentration of 1.5% or more.

[0049] Preferable examples of amine compounds that can be used in the dispersion medium in the present invention include (i) a quaternary amine compound represented by the following formula:

[Chemical 1]

[Wherein, Rl, R2, R3, and R4 are each independently a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, or an aryl group having 1 to 18 carbon atoms]; (ii) A tertiary amine compound represented by the following formula:

[Chemical 2]

[Wherein, Rl, R2 and R3 are each independently a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, or an aryl group having 1 to 18 carbon atoms]; (iii) A polyamine compound having a plurality of amine sites, for example, a diamine compound represented by the following formula:

[Chemical 3]

[0052] [wherein n is an integer of 1 to 10]; and (iv) a high number of amine amines may be present in the molecule, such as a polymer amine such as polydiallyldimethylamine (PDDA), polyethylene Min (PEI) and polyallylamine (PAA). [0053] pH of the hollow dispersion in the present invention is not limited, it is possible to ensure a stable dispersion over a wide _P H region. When an alkaline dispersion is used, the concentration of the amine compound in the solution is preferably 0.001-10M, more preferably 0.01-2M. A neutral dispersion can also be used. That is, unlike conventional photocatalytic materials (eg titanium oxide) where the isoelectric point is usually around pH 7, the preferred isoelectric point of the hollow body with protons is in the weakly acidic region of PH3-6. This hollow body can be dispersed even in the neutral region. Furthermore, acidic dispersions can also be used. This is because the more preferable isoelectric point of the hollow body is pH 5-6, and if the pH of the solution is set to 1 to 5, electrostatic repulsion between the hollow bodies occurs and the dispersion can be suitably dispersed. .

[0054] According to a preferred embodiment of the present invention, the dispersion of the present invention may further comprise a binder component, so that it may be a coating agent for application to a substrate. As the binder, a substance having a siloxane bond or fluorine resin emulsion can be preferably used.

[0055] According to a preferred embodiment of the present invention, the solid concentration in the dispersion or coating agent of the present invention is preferably 10% or less. Within this range, the dispersion is highly stable and stable for a long time at room temperature without causing precipitation.

Example

[0056] Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited to these examples.

[0057] Example 1: Fabrication of hollow fiber

Titanium oxide powder (trade name F6, Showa Denko Co., Ltd.) (0.64 g) was placed in 80 ml of 10M aqueous sodium hydroxide solution and stirred with a glass rod for 1 minute to obtain a white suspension. This white suspension was placed in a 100 ml fluorocoagulant container, and this fluorocoagulant container was further placed in a stainless steel container. This stainless steel container was put in a drier and kept at 110 ° C for 20 hours. After completion of the reaction, the stainless steel container was naturally allowed to cool to room temperature, and a solution containing a white precipitate was collected.

[0058] The following washing step was performed on the solution containing the white precipitate. First, the supernatant was removed from the above solution using a dropper. 100 ml of 0.1 M aqueous hydrochloric acid solution was added to the remaining white precipitate. Small portions were added. After all the aqueous hydrochloric acid solution was added, the solution was allowed to stand at room temperature (20 ° C) for 3 hours to remove the supernatant. This washing process was performed three times in total, and it was confirmed that the supernatant liquid had a pH of 7 or less. After these neutralization operations, the remaining white precipitate was washed twice with distilled water to obtain a white powder. This obtained powder is used as # 1 sample.

The white powder was observed at a magnification of 150,000 times using a scanning transmission electron microscope (Hitachi, Ltd., STEM S-5200). As a result, it was confirmed that the obtained white powder was an aggregate of hollow fibers, and the center of each fiber had a hollow structure with a diameter of 3.5 nm.

[0060] Further, the crystal structure of the white powder was analyzed using XRD (manufactured by Mac'Science, MXP-18). As a result, it was found that the crystal structure of the white powder was a titanic acid structure.

[0061] Further, the white powder was analyzed using a specific surface area Z pore distribution measuring device (Asap 2000, manufactured by Micromeritics). As a result, with respect to the pore size distribution, a steep peak corresponding to the inner diameter of 3.5 mm of the hollow fiber was observed, and the specific surface area was 78 m ² / g.

[0062] Example 2: Medium Fabrication of thin film carrying fiber

The powder of sample # 1 obtained in Example 1 was added to 64 ml of 2M nitric acid aqueous solution and stirred with a magnetic stirrer at room temperature for 15 hours to obtain a translucent solution. This translucent solution was subjected to centrifugal separation at 5000 rpm for 30 minutes with a centrifuge (Sakuma Seisakusho Co., Ltd., M200-IVD) to obtain a white gel with added protons. This white gel was added to a 0.1 M aqueous solution of sodium tetrabutylammonium hydroxide and stirred at room temperature for 24 hours using a magnetic stirrer to obtain a translucent solution. To this solution was further added lOOmmol hydrochloric acid to adjust the pH to ¾. 5 to obtain an aqueous solution in which hollow fibers were dispersed.

On the other hand, quartz glass (Toshiba Glass, T-4040) was prepared as a base material. The substrate was immersed in hot concentrated sulfuric acid to remove organic substances adhering to the substrate surface, and then washed with pure water. This substrate was immersed in a 0.25 wt% aqueous solution of polyethyleneimine (Wako Pure Chemical Industries, average molecular weight: 10000) for 10 minutes, and then washed with pure water.

[0064] The substrate thus cleaned was immersed in a solution containing hollow fibers for 10 minutes and washed with pure water. This substrate was further immersed in a 2 wt% aqueous solution of poly (diaryldimethyldimethylammonium chloride) (PDDA: Aldrich, average molecular weight: 100000-200000) for 10 minutes and washed with pure water. It was. Thereafter, immersion and washing in a solution containing hollow fibers and an aqueous PDDA solution were repeated to produce a thin film having five hollow fiber layers.

[0065] The resulting thin film was irradiated with ultraviolet rays to decompose and remove the cationic polymer between the layers. This UV irradiation was carried out for 24 hours using a 200 W mercury-xenon lamp (LA-210UV, manufactured by Hayashi Watch Industry). When the cross section of the obtained thin film was observed with a scanning electron microscope (Hitachi, S-4100), the film thickness was 50 °.

[0066] Example 3: Measuring zeta potential of hollow fiber

The zeta potential of the hollow fiber at various pH values was measured using an electrophoretic light scattering photometer (model name: ELS-6000, manufactured by Otsuka Electronics Co., Ltd.). The sample solution used for this measurement was lmg of the aqueous solution in which the hollow fiber prepared in Example 2 was dispersed, dropped into 200 g of 10 mmol / L sodium chloride aqueous solution, and then 10 mmol / L hydrochloric acid and sodium hydroxide. It was prepared by adjusting the pH using

[0067] The results were as shown in FIG. The pH at which zeta potential force ^ is the isoelectric point.

As a result, the pH at the isoelectric point of the hollow fiber of the present invention was 5.5.

[0068] Example 4: Release of an active substance (methylene blue) by hatching of DH

The thin film (1.5 cm × 2.5 cm) obtained in Example 2 was immersed in an ImM methylene blue aqueous solution at room temperature for 15 hours and then dried in the dark. This thin film adsorbed with methylene blue was immersed in 5 mL of water adjusted to pH 1.0 and 6.0 in the dark, and the concentration change of methylene blue in water (change in absorbance at 660 nm) was measured using a spectrophotometer ( It was measured using Shimadzu Corporation, UV-3150). The pH was adjusted using hydrochloric acid. Water at pH 6.0 was obtained without adding HC1, and water at pH 1.0 was obtained by adding HC1.

[0069] The results were as shown in FIG. As shown in Figure 2, it can be seen that the methylene blue release rate is faster than the low ρΗ (ρΗ: 1.0). Therefore, when methylene blue is used as an active substance, the release rate is dependent on pH.

[0070] Example 5: Release of active substance (ibuprofen) by DH change

The thin film obtained in Example 2 (1.5 cm × 2.5 cm) was immersed in a 0.1 wt% ibuprofen aqueous solution at room temperature for 15 hours and then dried in the dark. The thin film adsorbed with ibuprofen was added to 5 mL of p H1.0 Submerged in water adjusted to 6.0 and 14.0, and measured concentration change of ibuprofen in water (change in absorbance at 220 nm) using a spectrophotometer (Shimadzu Corporation, UV-3150) did. The pH is adjusted using sodium hydroxide and hydrochloric acid, pH 14.0 water is added with NaOH, pH 6.0 water is not added with NaOH and HC1, pH 1.0 The water was obtained by adding HC1.

[0071] The results were as shown in FIG. As shown in Figure 3, it can be seen that for ibuprofen, the release rate is faster at higher pH. Therefore, when ibuprofen is used as the active substance, the release rate is pH-dependent.

[0072] Example 6: Release of active substances (binaphthalene diol and ascorbic acid) by light irradiation

The thin film (1.5 cm × 2.5 cm) obtained in Example 2 was immersed in 0.1M binaphthalenediol and ascorbic acid aqueous solution at 60 ° C. for 24 hours. This thin film was immersed in 5 mL of pure water in the dark, and the concentration changes of binaphthalenediol and ascorbic acid in the water were measured using a spectrophotometer (Shimadzu Corporation, UV-3150).

At this time, the absorbance at a wavelength of 276 was measured in order to evaluate the concentration of binaphthalene diol, and the absorbance at a wavelength of 264 nm was measured in order to evaluate the concentration of ascorbic acid. After a predetermined time in the dark, the thin film was irradiated with ultraviolet rays using a 20W black light (Toshiba). At this time, irradiation was performed so that the illuminance of ultraviolet rays was 500 μW / cm 2 as measured by an ultraviolet illuminance meter (Topcon, UVR-2).

[0074] The change in the concentration of ascorbic acid before and after UV irradiation was as shown in FIG. 4, and the change in the concentration of binaphtharangeol was as shown in FIG. As shown in Figs. 4 and 5, it can be seen that the concentrations of ascorbic acid and pinaphthalene diol increased as a result of UV irradiation. Therefore, when a molecule having a diol group is used as an active substance, it can be said that release is accelerated by light irradiation.

[0075] Example 7: Immobilization of a modified molecule (alkylamine)

The powdered # 1 sample obtained in Example 1 was added to five alkylamine ion aqueous solutions having different molecular lengths. The five types of alkylamines include ethylamine (carbon chain C = 2), hexylamine (C = 6), octylamine (C = 8), decylamine (C = 10), and dodecylamine (C = 12). The concentration of alkylamine in the aqueous solution should be 0.2 mM. It was. To each of these five aqueous solutions, # 1 sample O.lg was added and stirred with a stirrer in the dark at room temperature.

[0076] In order to measure the amount of alkylamine immobilized on the sample surface, the concentration of various alkylamine ions remaining in the aqueous solution was measured using a single electrophoresis system (HP 3DCE, HEWLETT PACKARD). did. At this time, the time for binding the alkylamine to the sample surface at a certain place was set to 2 hours.

[0077] The relationship between the double value (2R) of the molecular length of the amine ion and the amount of fixed ions was as shown in FIG. The length of the alkylamine molecule was calculated using density fonctional theory (DFT) (Accelyl, Dmol3). As shown in Fig. 6, in the region where 2R is smaller than 3 nm, the amount of fixed ions increased with the length of alkylamine.Therefore, when the molecular length of alkylamine increases, the dipole of the molecule increases and the adsorption increases. It can be seen that the force increases. On the other hand, if the length of alkylamine is longer than 3.0 nm, the amount of anchorage decreases, so if the value of 2R is equal to the inner diameter of the hollow fiber, the diffusion of alkylamine into the hollow fiber is suppressed. I understand that In other words, it was suggested that when the value of 2R is larger than the inner diameter of the hollow fiber, alkylamine is fixed only on the outer wall.

[0078] Example 8: Oka straitization of modifier molecule (silane coupling agent)

The powdery # 1 sample obtained in Example 1 was put into an lw% octadecyltriethoxysilane (AMAX, SIO6642.0) solution dissolved in toluene and reacted at 60 ° C. The obtained reacted sample was put into water and photographed. For comparison, the unprocessed hollow fiber (# D was also photographed in the same way.

It was as shown in 7. As shown in Fig. 7, it can be seen that the hollow fiber modified with the silane coupling agent floats in water. This is because twice the molecular length (R) of the modifying molecule silane coupling agent (R) is longer than the inner diameter (r) of the hollow fiber, so the silane coupling agent is fixed on the outer wall of the hollow fiber. As a result, it is thought that particles float on the water surface due to the hydrophobic outer wall.

[0079] Example 9: Verification of chemical bond between modifying molecule and hollow fiber

The FT-IR was installed in the # 1 sample (untreated hollow fiber) obtained in Example 1 and the hollow fiber modified with alkylamine in Example 6 and modified with decylamine. Nicholet, 710). For comparison, FT-IR was measured in the same manner for molecularly free decylamine not adsorbed on the hollow fiber. At this time, as a pretreatment for removing the physically adsorbed water, each sample was heat-treated at 150 ° C. in a vacuum.

[0080] The measurement results were as shown in FIG. As shown in Figure 8, the free decylamine has NH stretching vibrations observed at 3219 cm " ¹ , 1649 cm- ^{1 The} NH stretching vibration is lower in hollow fibers modified with decylamine. 3219 cm " ¹ , 1607 cm on the side—this was observed as a broader peak shifted. This shift may have been induced as a result of hydrogen bonding between the modified amino terminal amino group and the hollow fiber. The results in Fig. 8 also show that the peak of chemisorbed water (3660 cm " ¹ ) present in the untreated hollow fiber (# 1 sample) disappeared by binding the modifying molecule. From this, it is considered that the amino group at the end of the modifying molecule is bonded to the hydroxyl group of the hollow fiber by a hydrogen bond!

[0081] Example 10: Medium fiber coloring by Oka qualification

The # 1 sample powder obtained in Example 1 was immersed in 0.1M binaphthalenediol and ascorbic acid aqueous solution at 60 ° C. for 24 hours to obtain a hollow fiber powder in which the active substance was immobilized. The powder was collected, washed with ethanol, and dried.

When the obtained powder was photographed, the photograph shown in FIG. 9 was obtained. When the reflectance of the powder was measured by a diffuse reflection method using a spectrophotometer (Shimadzu Corporation, UV-3150), the results shown in Fig. 10 were obtained. As shown in FIG. 10, it can be seen that hollow fibers are colored when binaphthalenediol having a diol group and ascorbic acid are immobilized on hollow fibers. In other words, the band gap of the hollow fiber itself is about 3.4 eV, so it does not absorb visible light, but it can be seen that absorption occurs in the visible light region of 400+ or more by binding molecules with diol groups to the hollow fiber. In addition, although binaphthalenediol and ascorbic acid are colorless and transparent in the molecular form and do not absorb visible light, these active substances are colored in the visible light region by fixing to the hollow fiber. . From this, it is considered that the diol group of these molecules is dehydrated and polycondensed with the hydroxyl group of the hollow fiber.

[0083] Example 11: Immobilization of modifying molecule (silane coupling agent) The substrate on which the hollow fiber thin film obtained in Example 2 was formed was immersed in an ethanol solution in which the silane coupling agent was dissolved at 60 ° C for 40 hours, and the silane coupling agent was subjected to dehydration polycondensation. # Reacted to 1 sample. As silane coupling agents, hexyltriethoxysilane (AMAX, SIH6167.5) and octadecyltriethoxysilane (AMAX, SIO6642.0) were used. The concentration of each silane coupling agent in the ethanol solution was 2 wt%. After the reaction, the substrate on which the thin film was formed was washed with ethanol and dried. A sample obtained using hexyltriethoxysilane as a silane coupling agent was designated as # 2, and a sample obtained using octadecyltriethoxysilane was designated as # 3.

[0084] The obtained thin film was subjected to a methylene blue staining test. Samples # 2 and # 3 were immersed in an O.lmol / L methylene blue aqueous solution for 2 hours and dried, and then the change in absorbance of the thin film was measured with a spectrophotometer (Shimadzu Corporation, UV-3150). For comparison, the same measurement as described above was performed for an untreated air fiber.

[0085] The results were as shown in FIG. As shown in Fig. 11, the untreated hollow fiber surface showed the highest adsorption capacity. This is probably because the methylene blue molecule is sufficiently smaller than the inner diameter (3.5 mm) of the hollow fiber, so it adsorbs not only to the outside of the hollow fiber but also to the inside.

[0086] On the other hand, in Samples # 2 and # 3 that had undergone silane coupling treatment, the amount of adsorption decreased compared to untreated hollow fiber, because the sample surface became hydrophobic. It may be a thing. In particular, in the case of sample # 2 using a silane coupling agent (hexyltriethoxysilane) in which the alkyl group has 6 carbon atoms, the adsorption ability of methylene blue is low, but this is because the silane coupling agent is outside the hollow fiber. It is thought that it was because it was fixed on both the inside and the inside. In addition, in the case of sample # 3 using a silane coupling agent (octadecyltriethoxysilane) having 18 carbon atoms in the alkyl group, the adsorption ability of methylene blue is higher than that of sample # 2. This is probably because the molecules of the silane coupling agent are larger than the inner diameter of the hollow fiber, so that they are not fixed on the inner wall of the hollow fiber but only on the outer side. In other words, when octadecyltriethoxysilane is used, the inner wall is exposed to the surface of the hollow fiber, so that it acts as an adsorption capacity site for methyl blue, and hexyltriethoxysilane is used. It is thought that the adsorption capacity of methylene blue may increase.

Claims

The scope of the claims

[I] At least one type of hollow body selected from the group force consisting of titanium oxide, titanium hydroxide, and titanate filled with an active substance is prepared,

A method for controlling the release of an active substance, comprising:

[2] The method according to claim 1, wherein filling the hollow body with the active substance is performed by immersing the hollow body in a solution containing the active substance.

[3] The method according to claim 1 or 2, wherein the hollow body is a hollow fiber.

4. The method according to claim 3, wherein the hollow fiber has an inner diameter of 3-8.

[5] The method according to any one of claims 3 and 4, wherein the hollow fiber also has a roll-like layered titanate force.

[6] The method according to any one of [1] to [15], wherein the external stimulation is performed by light irradiation accompanied by photoexcitation of a hollow body.

[7] The active substance is a substance that can be bonded to the inner wall of the hollow body by dehydration condensation.

The method according to any one of 1 to 6.

[8] The method according to any one of claims 1 to 7, wherein the active substance is a substance having a hydroxyl group.

[9] The method according to any one of claims 1 to 8, wherein the active substance is a substance having a diol group.

10. The method according to any one of claims 1 to 9, wherein the active substance is ascorbic acid.

[II] The method according to any one of claims 1 to 10, which is performed by changing the external stimulation force ¾H.

12. The method according to claim 11, wherein the agent is a charged molecule or particle.

[13] The hollow body further includes a modifying molecule immobilized on at least one surface of the inner wall and the outer wall, the modifying molecule having a linker part and a main chain part, and the linker part Is coupled to the surface of the hollow fiber. The method according to one item.

14. The method according to claim 13, wherein the hollow body is dispersed in an aqueous amine solution, and protons are added to the inside and Z or the surface of the hollow body.

[15] Titanium oxide, titanium hydroxide, and a group force including titanate force, and at least one kind of hollow body selected and an active substance filled in the hollow body. Release material for active substances.

16. The material according to claim 15, wherein the hollow body is a hollow fiber.

17. The material according to claim 16, wherein the hollow fiber has an inner diameter of 3-8 nm.

18. The material according to claim 16 or 17, wherein the hollow fiber also has a scroll-like layered titanate force.

[19] The active substance is a substance that can be bonded to the inner wall of the hollow body by dehydration condensation.

The material according to any one of 15-18.

[20] The material according to any one of claims 15 to 19, wherein the active substance is a substance having a hydroxyl group.

[21] The material according to any one of claims 15 to 20, wherein the active substance is a substance having a diol group.

[22] The material according to any one of claims 15 to 21, wherein the active substance is ascorbic acid.

23. The material according to claim 15-22, wherein the active substance is a charged molecule or particle.

[24] The hollow body further includes a modifying molecule immobilized on at least one surface of the inner wall and the outer wall, the modifying molecule having a linker part and a main chain part, and the linker part 24. A material according to any one of claims 15 to 23, wherein is attached to the surface of the hollow fiber.

[25] The material according to any one of [15] to [24], wherein the material is dispersed in an aqueous amine solution, and a proton is added to the inside and Z or the surface of the hollow body.

[26] The material of any one of claims 15-25, wherein the agent is a drug, thereby functioning as a drug delivery material.

[27] The material according to any one of claims 14 to 26, wherein the active substance is a cosmetic and thereby functions as a cosmetic.

[28] A material according to any one of claims 15-27, used in a method according to any one of claims 1-14.

[29] Use of the material according to any one of claims 15 to 27 for releasing the active substance out of the hollow body according to an external stimulus.