JP2006104081A - Drug delivery material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a drug delivery material capable of controllably releasing an active substance, having high biocompatibility, and having high dispersibility. <P>SOLUTION: This drug delivery material contains at least one kind of hollow fiber of a material selected from titanium oxide, titanium hydroxide, a titanic acid salt, and amorphous titanium oxide, wherein the active substance is filled into the inside of the hollow fiber, so that the active substance is released from the hollow fiber to the outside by external stimulation. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  It relates to a material capable of sustained release of a medicinal active substance. The present invention relates to a drug delivery material capable of controlling the release of an active substance (controlled release).

  Drug delivery has been developed as a new concept of drug treatment that brings about certain therapeutic effects, expansion of applicable diseases, reduction of side effects, improvement of usability, and the like. In particular, control of drug release in vivo (controlled release) has attracted attention as a technique that can reduce side effects and achieve a large therapeutic effect. A drug delivery material that can release a drug gradually or can be controlled and released makes it possible to maintain a medicinal effect for a long time, and an effective treatment is possible even with a small amount of drug administration. Moreover, since the concentration of the medicinal component is not excessively increased in the body or blood, side effects can be suppressed.

  As drug delivery materials, sustained release of drugs using polymeric micelles has been proposed. The drug is supported on the hydrophilic part, which is the central part of the micelle formed by the association of molecules, but lacks thermal and chemical stability, and there are restrictions on the concentration required to produce micelles (for example, Non-Patent Document 1).

On the other hand, hollow particles of inorganic compounds are highly expected as carriers for filling drugs because of their thermal and chemical stability. As a drug delivery material for inorganic compounds, a system using mesoporous silica has been proposed (see, for example, Patent Document 1). Mesoporous silica has a plurality of holes having specific pore diameters, and can carry molecules that can enter the holes. However, since mesoporous silica is a substance having a skeleton of SiO ₂ , the surface shows strong solid acidity and poor biocompatibility. In addition, since the particle size of mesoporous silica is at least several hundred microns, it is difficult to disperse in body fluids or blood.

On the other hand, titanium-based oxides have high biocompatibility and are suitable as drug delivery materials for drugs, cosmetics, foods and the like. Conventionally, it has been difficult to synthesize titanium oxides with specific pore diameters due to unstable starting materials. However, in recent years, hollow fibers of titanium oxide or titanic acid hollow fibers by hydrothermal synthesis have been used. Synthesis has been reported (see, for example, Patent Document 2 and Non-Patent Document 2).
JP 2002-173319 A Japanese Patent Laid-Open No. 10-152323 A. Harada, K. Kataoka, Science, 283, 65 (1999) LM Peng et al., Adv. Mater. 14, 1208 (2002)

  Provided is a drug delivery material capable of controlled release of an active substance, highly biocompatible and highly dispersible.

  A drug delivery material comprising at least one hollow fiber selected from titanium oxide, titanium hydroxide, titanate, and amorphous titanium oxide, wherein the hollow fiber is filled with an active substance, The drug delivery material is characterized in that the active substance is released to the outside of the hollow fiber by an external stimulus.

  The drug delivery material of the present invention has high dispersibility and biocompatibility, and can control the release of a medicinal substance by external stimulation.

The hollow fiber drug delivery material according to the present invention is at least one selected from titanium oxide, titanium hydroxide, titanate, and amorphous titanium oxide. All of these materials are known as highly dispersible, non-toxic and highly biocompatible materials. When the hollow fiber drug delivery material according to the present invention is titanium oxide, a rutile type, anatase type, brookite type, and TiO ₂ (B) can be preferably used. When the hollow fiber drug delivery material according to the present invention is titanate, polyvalent titanic acid containing protons such as trititanic acid, tetratitanic acid, pentatitanic acid, hexatitanic acid, heptitanic acid, octatitanic acid, etc. Alternatively, it may be a polyvalent titanate such as potassium titanate, calcium titanate, cesium titanate, sodium titanate, magnesium titanate, aluminum titanate, strontium titanate or barium titanate.

The inner diameter (r) of the hollow fiber according to the present invention is in the range of 3 nm to 8 nm. An active substance smaller than this size can be encapsulated inside the hollow fiber.
The inner diameter of the hollow fiber may be observed directly using a transmission electron microscope (TEM), or the pore diameter distribution may be measured by the BET method.

  The hollow fiber drug delivery material of the present invention is filled with an active substance. The active substance can be released to the outside by an external stimulus such as light or pH change. When the active substance is encapsulated in the hollow fiber, the active substance has a sustained release property that gradually releases, and the release (controlled release) can be controlled by an external stimulus. Further, when the active substance is encapsulated in the hollow fiber, the chemical effect of the active substance can be prevented by the masking effect of the hollow fiber.

  When filling an anticancer agent as an active substance, for example, fluorouracil, gemcitabine, methotrexate, cyclophosphamide, daunorubicin hydrochloride, adriamycin, idarubicin hydrochloride, bleomycin, mitomycin, actinomycin, vincristine, cisplatin, carboplatin, etoposide, nedaplatin, At least one drug selected from paclitaxel, docetaxel, irinotecan hydrochloride and the like can be used.

  When an antibacterial agent is used as the active substance, for example, at least one drug selected from a penicillin series, a macrolide series, a new quinolone series, a tetracycline series, and the like can be used.

  When a virus therapeutic agent is used as the active substance, for example, at least one drug selected from lamivudine, nelfinavir, indinavir, saquinavir, interferon / amantadine / acyclovir and the like can be preferably used.

  When a hormonal disease therapeutic agent is used as the active substance, drugs such as neuprorelin, buserelin, goserelin, triptorelin, nafarelin can be preferably used. Moreover, you may use analgesics, such as ibuprofen, as an active substance. In order to treat complex diseases, a plurality of drugs may be encapsulated inside the hollow fiber.

  The drug delivery material of the present invention may be taken orally, or may be injected into a blood vessel or instilled. Moreover, you may inject directly into a cell tissue.

  As an external stimulus for releasing the active substance to the outside, light irradiation with excitation of the hollow fiber can be suitably used. More preferably, the active substance is bonded to the inner wall of the hollow fiber by dehydration polycondensation. Since the hollow fiber according to the present invention has photocatalytic activity, oxidation and reduction reactions occur on the surface when irradiated with ultraviolet rays. These reactions can break the bond between the hollow fiber and the active substance and release the active substance to the outside. Examples of the light source for performing the light irradiation include a fluorescent lamp, a black light, a sterilization lamp, an incandescent lamp, a low pressure mercury lamp, a high pressure mercury lamp, a xenon lamp, a mercury-xenon lamp, a halogen lamp, a metal halide lamp, and an LED (white, Blue, green, red), laser light, sunlight, etc. can be suitably used. The irradiation of light may be applied from outside the body, or irradiation to the internal organs from the oral cavity using a light guide fiber, or the light guide fiber may be directly inserted into a living tissue.

  As the active substance bonded to the inner wall of the hollow fiber by dehydration polycondensation, a molecule having a hydroxyl group is preferably used. The hydroxyl group of the active substance reacts with the hydroxyl group of the hollow fiber and undergoes dehydration condensation. Since this bond is relatively weak, it is broken by light irradiation accompanied by excitation of the hollow fiber, and the hydroxyl group of the active substance is released to the outside in a regenerated form, and the active substance itself is not easily decomposed.

  In a further preferred embodiment of the present invention, a molecule having a diol group is used as an agent bonded to the inner wall of the hollow fiber by dehydration condensation. These molecules are colorless and transparent in a free state, but are colored by the interface state when both of the two hydroxyl groups contained in the diol group are dehydrated and condensed with the hollow fiber. In other words, it is colored when bound and colorless when detached, so that it can be used as an indicator for confirming whether the active substance has been released.

  As the molecule having a diol group, for example, catechols such as catechol, methyl catechol, and tertiary butyl catechol, dihydroxycyclobutene diene, ascorbic acid, dopamine, alizarin, and binaphthalenediol can be preferably used.

  As another aspect of the external stimulus according to the present invention, the agent can be released to the outside by changing the pH. As with many oxides and hydroxides, the surface of the hollow fiber is cationic when acidic and anionic when alkaline. That is, the surface charge can be changed by changing the pH. For example, in the case of a roll-shaped layered titanic acid as a hollow fiber, the pH at the isoelectric point is 5.5, so that it is cationic in a pH region lower than this value and anionic in a high region. When the active substance is charged, an attractive force or a repulsive force acts on the surface of the hollow fiber due to the Coulomb force. If a repulsive force is exerted between the hollow fiber and the active substance, the active substance filled inside can be discharged to the outside. For example, if the active substance is cationic, the active substance can be released by making the surface of the hollow fiber cationic. On the other hand, if the active substance is anionic, the active substance can be released by making the surface of the hollow fiber anionic. For example, when used as a stomach medicine, a medicine that releases in response to stomach acid can be selected.

  The charged active substance may have a drug supported on a particulate substance. At this time, a particulate material having a size smaller than the inner diameter of the hollow fiber is used.

  In a particularly preferred embodiment, the hollow fiber drug delivery material of the present invention is composed of a scroll-like layered titanic acid. The scroll-like layered titanic acid has a uniform pore diameter, a large specific surface area, non-toxicity and high biocompatibility. The scroll-like layered titanic acid can be synthesized in large quantities at low cost. In order to improve crystallinity and to improve thermal chemical stability, heat treatment may be performed. The heat treatment temperature is preferably 50 ° C to 600 ° C.

  In the drug delivery material of the present invention, a modifying molecule may be immobilized on at least one of the inner wall and the outer wall of the hollow fiber according to the use environment and the type of active substance. When the modifying molecule is bonded to both the inner wall and the outer wall, the modifying molecule may be the same or different between the inner wall and the outer wall. Preferably, the modifying molecule has a linker portion and a main chain portion, and the linker portion and the surface of the hollow fiber are bonded. By binding the modifying molecule to the outer wall of the hollow fiber, it functions as an active target for malignant tissue such as cancer cells, or by increasing dispersibility in the use environment. On the other hand, by binding a modifying molecule having a high affinity for the active substance to the inner wall, it becomes possible to pack the active substance with a high density and to control the release rate of the active substance. In other words, the modification to the outer wall expresses harmony with the environment of use and the function of active targeting, and the modification to the inner wall enables high-density filling of the active substance and control of the release rate. In a preferred embodiment of the present invention, the linker portion of the modifying molecule and the surface of the hollow fiber are immobilized with at least one bond selected from the group consisting of a covalent bond, a hydrogen bond, an ionic bond, and a coordination bond. . Thermal and chemical stability is higher than that of immobilization by simple physical adsorption. The binding of the modifying molecule may be part or all of the surface of the hollow fiber. Examples of the linker portion of the modifying molecule according to the present invention include groups consisting of, for example, diketone such as carboxyxyl group, phosphate group, sulfone group, hydroxyl group, amino group, pyridine, acetylacetone, ethylene oxide such as polyethylene glycol, and siloxane. At least one functional group selected from more can be used. The bonding force between these functional groups and the hollow fiber is high.

  Below, the preferable aspect of the principal chain part of the said modification molecule is described. For example, in order to enhance the dispersibility of the drug delivery material of the present invention in body fluids or blood, a polymer such as polycation or polyanion can be used as the main chain portion of the modifying molecule. As the polymer, at least one polymer selected from polyethyleneimine, polyethylene glycol, polyallylamine, polyallylalkylammonium, polyacrylic acid, polyethylene glycol and the like, or a copolymer of these polymers can be used. .

  On the other hand, the main chain portion of the modifying molecule can function as active targeting of the degradation target substance. For example, in order to decompose malignant tissue such as cancer in a living body, when a main chain portion having high affinity with a cell is selected, the hollow fiber can be easily taken into the cell. Examples of the main chain portion having high affinity with cells include polyethylene glycol, chitin, chitosan and the like.

  In order to make active targeting of a substance to be decomposed function, even if a protein capable of specifically binding to a malignant substance in a living body is immobilized as the main chain part or the main chain part of the modifying molecule, I do not care. As the protein, at least one selected from an antibody, a ligand, a receptor, a polypeptide, an oligopeptide, and an amino acid can be used. Growth factors such as epidermal growth factor, transforming growth factor, platelet-derived growth factor, bone morphogenetic factor, nerve growth factor, and other factors that specifically bind between the protein and malignant substances in the body Besides these, hormones and ligands such as interferon, interleukin, colony stimulating factor, tumor necrosis factor, erythropoietin, Fas antigen, activin and the like can be mentioned.

  As another embodiment for causing active targeting of a substance to be decomposed, a nucleic acid can be used as a main chain part of the modifying molecule or a substance bonded to the main chain part. Depending on the nucleotide sequence of the nucleic acid, high selective adsorption ability to in vivo pathogenic genes and pathogenic substances is exhibited.

  On the other hand, when the modifying molecule is bonded to the inner wall of the hollow fiber, the interaction between the active substance and the hollow fiber changes, so that the sustained release rate can be increased or decreased. When a large amount of a hydrophobic drug is included, it is preferable that the main chain portion of the modifying molecule is hydrophobic. As the hydrophobic main chain portion, for example, a substance containing an alkyl, a fluororesin, or an aromatic molecule can be selected. More preferably, a silane coupling agent or an alkylamine is used as the modifying molecule. These modifying molecules can be easily and firmly bound to the surface of the hollow fiber. When a silane coupling agent is used, condensation occurs during dehydration between the functional group in the hydrophilic portion modified with silane and the hollow fiber, and the covalent bond strongly bonds.

As a method for binding the modifying molecule to the hollow fiber, for example, the modifying molecule can be immobilized on the surface of the hollow fiber by immersing the hollow fiber in a solvent containing the modifying molecule. In order to promote bonding, heat treatment or chemical treatment such as acid or alkali may be performed. At this time, depending on the molecular length of the modifying molecule, it is possible to bind to both the inner wall portion and the outer wall portion or only to the outer wall portion. When immobilizing a long-chain modifying molecule on both the inner wall and the outer wall, twice the molecular length (R) (2R) of the modifying molecule is designed to be smaller than the inner diameter of the hollow fiber. In general, the modifying molecules are polar, and like many surfactants, they can form micelles in hollow fibers. Inside the hollow fiber, the hydrophilic portion of the modifying molecule is fixed to 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 corresponds to twice (2R) the length (R) of the modifying molecule, it is desirable that the value of 2R is smaller than the inner diameter of the hollow fiber in order to form micelles on the inner wall. . 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, 2R of the modifying molecule is designed to be smaller than 3.5 nm.
On the other hand, when the modifying molecule is bound only to the outer wall of the hollow fiber, the molecular length (R) of the modifying molecule is designed to be twice (2R) larger than the inner diameter of the hollow fiber. For example, when the inner diameter of the hollow fiber is 3.5 nm, 2R of the modifying molecule is designed to be larger than 3.5 nm. When the length (2R) of the modifying molecule corresponding to the size of the molecule at the time of micelle formation is larger than the inner diameter of the hollow fiber, it becomes difficult to form micelles on the inner wall, and the modifying molecule binds only to the outer wall.

  As a method of bonding the modifying molecule only to the inner wall of the hollow fiber according to the present invention, after the modifying molecule is bonded to both the inner wall and the outer wall, chemical treatment such as acid or alkali treatment or plasma etching such as argon sputtering is performed. Only the modifying molecule bound to the outer wall can be removed.

  Further, as another method for bonding the modifying molecule to the hollow fiber, for example, at least one dry coating method selected from CVD, PVD, vacuum deposition, laser ablation, ion plating, sputtering, etc. may be used. .

In order to verify whether the hollow fiber according to the present invention and the modifying molecule are chemically bonded, instrumental analysis such as FT-IR and NMR can be suitably used. For example, when the modifying molecule is an alkylamine, it can be determined whether or not chemical bonding has occurred by measuring the NH stretching vibration of free amine ions and amine ions adsorbed on the hollow fiber by FT-IR. NH stretching vibration observed in the vicinity of 3300 cm ^{−1 with} free amine ions shifts to the lower wavenumber side when chemically bonded to the hollow fiber. Further, the stretching vibration of the OH group of the hollow fiber may be observed as an index of chemical bonding. When the modifying molecule is chemically bonded to the OH group of the hollow fiber, the signal from the chemisorbed OH group originally present in the hollow fiber disappears.

  In the drug delivery material of the present invention, an opening / closing mechanism such as a molecular door may be provided at both ends of the opening of the hollow fiber in order to precisely control the sustained release rate of the active substance. As a material for the door, quantum dots such as gold fine particles, CdS, and CdSe may be used, and photoisomer materials such as azobenzene, spiropyran, and coumarin may be used. When the photoisomer is used, the opening / closing of the molecular door can be controlled by the wavelength of light irradiation. Further, the substance corresponding to the door may be removed by chemical treatment to release the contained active substance.

In order to make the drug delivery material of the present invention visible or to increase the solid acidity of the surface to enhance the binding with the modifying molecule, an anion other than oxygen is substituted at the oxygen position of the hollow fiber, or other than oxygen between the lattices. An anion other than oxygen may be arranged at the grain boundary part. In order to promote charge separation during light irradiation of the sustained-release material of the present invention, the hollow fiber may be supported with a metal such as Pt, Pd, Ag, Cu, Au, Ni. By carrying the metal, photoexcited electron-hole pairs are efficiently separated, and hydrophilization activity and oxidative degradation activity increase. In particular, when Ag or Cu is supported, it also exhibits antibacterial properties.

  In order to improve the recoverability of the molecular carrier, the molecular carrier may be combined with a magnetic material such as iron oxide. By combining the magnetic material, for example, the molecular carrier inserted into the living body can be recovered by magnetic force.

  Surprisingly, the drug delivery material of the present invention can control and release the agent filled inside by stimulation such as light irradiation or pH change. The material of the present invention can be widely applied in medical applications.

EXAMPLES Next, although an Example demonstrates this invention concretely, it is not restrict | limited to these Examples at all.
1. Preparation of sample 1-1. Preparation of hollow fiber 0.64 g of titanium oxide powder (trade name F6, Showa Denko KK) was put into 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 fluororesin container, and the fluororesin container was 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 allowed to cool naturally to room temperature, and a solution containing a white precipitate was collected. As a washing step, the supernatant was first removed from the solution containing the white precipitate with a dropper. To the remaining white precipitate, 100 ml of 0.1 M hydrochloric acid aqueous solution was added little by little. After the entire amount of aqueous hydrochloric acid was added, the mixture was allowed to stand at room temperature (20 ° C.) for 3 hours. After standing, the supernatant was removed. This washing step 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. When this white powder was observed with a scanning transmission electron microscope (Hitachi, Ltd., STEM S-5200), at a magnification of 150,000 times, the white powder obtained by this method was an aggregate of hollow fibers. It was confirmed that the center of the fiber had a hollow structure with a diameter of 3.5 nm. Moreover, when the crystal structure was analyzed with XRD (manufactured by Mac Science, MXP-18), it was found to be a titanic acid structure. Furthermore, when analyzed using a specific surface area / pore distribution measuring apparatus (Asap 2000, manufactured by Micromeritics), a sharp peak corresponding to the inner diameter of the hollow fiber of 3.5 nm was observed for the pore size distribution. The surface area was 78 m ² / g. Let the powder obtained here be a # 1 sample.

1-2. Production of thin film carrying hollow fiber The powder of sample # 1 produced by the method described in 1-1 was added to 64 ml of 2M nitric acid aqueous solution and stirred with a magnetic stirrer at room temperature for 15 hours. After stirring, the obtained translucent solution was centrifuged at 5000 rpm for 30 minutes with a centrifuge (Sakuma Seisakusho M200-IVD) to obtain a white gel added with protons. Furthermore, this white gel was added to an aqueous solution of 0.1 M tetrabutylammonium hydroxide and stirred with a magnetic stirrer at room temperature for 24 hours to obtain a translucent solution. Further, 100 mmol of hydrochloric acid was added to this solution to adjust the pH to 9.5, and an aqueous solution in which hollow fibers were dispersed was prepared. Quartz glass (Toshiba glass, T-4040) was used as a base material, and after removing organic substances adhering to the surface in hot concentrated sulfuric acid, the substrate was 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. Further, it was immersed in the solution containing the hollow fiber for 10 minutes and washed with pure water. Further, this substrate was immersed in a 2 wt% aqueous solution of poly (diallyldimethylammonium chloride) (PDDA: Aldrich, average molecular weight: 100000-200000) for 10 minutes and washed with pure water. Thereafter, immersion and washing in a solution containing a hollow fiber and an aqueous PDDA solution were repeated to produce a thin film having five hollow fiber layers. In either case, the hollow fiber is exposed on the outermost surface. The interlayer cationic polymer was removed from the resulting thin film by ultraviolet irradiation. UV irradiation was performed using a 200 W mercury-xenon lamp (LA-210UV, manufactured by Hayashi Watch Industry) for 24 hours. When the cross section of the obtained thin film was observed with a scanning electron microscope (Hitachi, S-4100), the film thickness was 50 nm.

2. Measurement of zeta potential of hollow fiber The zeta potential of the hollow fiber at various pH values was measured by an electrophoretic light scattering photometer (model name: ELS-6000, manufactured by Otsuka Electronics Co., Ltd.). 1 mg of the aqueous solution in which the hollow fiber was dispersed prepared in 1-2 was dropped into 200 g of a 10 mmol / L sodium chloride aqueous solution, and 10 mmol / L hydrochloric acid and sodium hydroxide were used for pH adjustment.
The results are shown in FIG. The pH at which the zeta potential is 0 is the isoelectric point. As a result, the pH at the isoelectric point of the hollow fiber of the present invention was 5.5.

3. Release of active substance (methylene blue) by pH The thin film (1.5 cm × 2.5 cm) obtained in 1-2 was immersed in a 1 mM aqueous solution of methylene blue at room temperature for 15 hours and then dried in the dark. Thereafter, the thin film adsorbed with methylene blue was immersed in 5 mL of water adjusted to each pH in the dark, and the concentration change of methylene blue in water (change in absorbance at 660 nm) was measured with a spectrophotometer (Shimadzu Corporation, UV-3150). ). The pH was adjusted with hydrochloric acid to 6.0 (no HCl added) and 1.0 (HC1 added).
The results are shown in FIG. As a result, the release rate of methylene blue was faster at lower pH (pH: 1.0). When the pH is 1.0, the surface of the hollow fiber becomes cationic. It became clear that methylene blue became cationic when dissolved in water, and the release was accelerated by repulsion between cations.

4). Release of active substance (ibuprofen) by pH The thin film (1.5 cm × 2.5 cm) obtained in 1-2 was immersed in a 0.1 wt% ibuprofen aqueous solution at room temperature for 15 hours and then dried in the dark. After this, the thin film adsorbed with ibuprofen was immersed in 5 mL of water adjusted to each pH in the dark, and the concentration change of ibuprofen in water (change in absorbance at 220 nm) was measured using a spectrophotometer (Shimadzu Corporation, UV-3150). ). The pH was adjusted with sodium hydroxide and hydrochloric acid to 14.0 (NaOH addition), 6.0 (no HCI addition), and 1.0 (HCI addition).
The results are shown in FIG. As a result, the release rate of ibuprofen was higher at higher pH. When it becomes alkaline, the hollow fiber becomes anionic. It became clear that ibuprofen became anionic when dissolved in water, and the release was promoted by repulsion between the anions.

5. Release of active substances (binaphthalene diol, ascorbic acid) by light irradiation The thin film (1.5 cm x 2.5 cm) obtained in 1-2 was immersed in 0.1 M binaphthalene diol and ascorbic acid aqueous solution at 60 ° C for 24 hours. . Thereafter, these thin films were 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 nm was observed as the concentration of binaphthalene diol, and the absorbance at a wavelength of 264 nm was measured as the concentration of ascorbic acid. After a predetermined time in the dark, 20 W black light (Toshiba) was used for ultraviolet irradiation. The ultraviolet illuminance was irradiated using an ultraviolet illuminometer (Topcon, UVR-2) so as to be 500 μW / cm 2.
The concentration change of ascorbic acid before and after UV irradiation is shown in FIG. 4, and the concentration change of binaphthalenediol is shown in FIG. As a result, it became clear that the concentrations of ascorbic acid and binaphthalene diol were increased by irradiation with ultraviolet rays. From the above results, it was revealed that molecules having a diol group can be released by light irradiation.

6). Immobilization of modifying molecule (alkylamine) The powdery # 1 sample was added to an aqueous alkylamine ion solution of various molecular lengths. Alkylamines were classified into five types: ethylamine (carbon chain C = 2), hexylamine (C = 6), octylamine (C = 8), decylamine (C = 10), and dodecylamine (C = 12). The concentration of each of the various alkylamines was 0.2 mM, and 0.1 g of sample # 1 was added to a 50 mL aqueous solution and stirred with a stirrer in the dark at room temperature. In order to measure the amount immobilized on the surface, the concentration of various alkylamine ions remaining in the aqueous solution was measured using a capillary electrophoresis system (HP 3DCE, HEWLETT PACKARD). The binding time in the dark was 2 hours.
FIG. 6 shows the relationship between the double value (2R) of the molecular length of the amine ion and the amount immobilized. The molecular length of the alkylamine was calculated using density functional theory (DFT) (Accelyl, Dmol3). As a result, in the region where 2R was smaller than 3 nm, the amount of immobilization increased according to the length of the alkylamine. As the molecular length of the alkylamine increases, the dipole of the molecule increases and the adsorption power increases. On the other hand, it was found that the amount of immobilization decreases when the length of the alkylamine is longer than 3.0 nm. When the value of 2R is equal to the inner diameter of the hollow fiber, diffusion of alkylamine into the hollow fiber is suppressed. It was suggested that when the value of 2R is larger than the inner diameter of the hollow fiber, the alkylamine is immobilized only on the outer wall.

7). Immobilization of modifier molecule (silane coupling agent) A powdery # 1 sample was put into an octadecyltriethoxysilane (Amax, SIO6642.0) solution dissolved in toluene. The concentration of octadecyltriethoxysilane was 1 w%, the reaction temperature, and the reaction time were 60 ° C. × overnight. FIG. 7 shows a photograph when this sample is put into water. An untreated hollow fiber (# 1) is also shown. As a result, it was clear that the hollow fiber modified with the silane coupling agent floated on water. The silane coupling agent is immobilized on the outer wall of the hollow fiber because twice the molecular length (R) of the silane coupling agent as a modifying molecule (2R) is longer than the inner diameter (r) of the hollow fiber. Since the outer wall becomes hydrophobic, the particles float on the water surface. Naturally, when the molecular length (2R) of the silane coupling agent, which is a modifying molecule, is 2 times shorter (2R) than the inner diameter (r) of the hollow fiber, the modifying molecule is immobilized on both the inner and outer walls of the hollow fiber. Therefore, it floats on water like the # 8 sample. When a modified molecule having a hydrophobic main chain is immobilized on the inner wall, a large amount of hydrophobic agent can be filled from the hydrophobic interaction. Further, it is considered that the release rate of the active substance can be controlled by the hydrophobic strength of the modifying molecule.

8). 4. Verification of chemical bond between modifying molecule and hollow fiber # 1 sample (untreated hollow fiber) and 5. The FT-IR of the hollow fiber modified with decylamine produced during the modification of alkylamine was measured using an apparatus (Nicholet, 710). For comparison, the molecular free decylamine not adsorbed on the hollow fiber was also measured. As a pretreatment for removing physically adsorbed water, a heat treatment at 150 ° C. was performed in vacuum. The results are shown in FIG. As a result, when NH stretching vibration (3219 cm ^-1 , 1649 cm ^-1 ) observed in free decylamine is adsorbed to the hollow fiber, it shifts to the lower wavenumber side (3219 cm ^-1 , 1607 cm ^-1 ), and the peak is Broadened. This shift is induced as a result of hydrogen bonding between the amino group at the end of the modified molecule and the hollow fiber. Furthermore, the peak of chemisorbed water (3660 cm ⁻¹ ) present in the untreated hollow fiber (# 1 sample) disappeared by binding the modifying molecule. These results suggest 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.

  The drug delivery material of the present invention enables sustained release of the active substance and controlled release. A highly biodispersible and highly dispersible drug delivery material can be provided.

The figure which shows the zeta potential of the drug delivery material of this invention The figure which shows the methylene blue release characteristic of the drug delivery material which concerns on this invention The figure which shows the ibuprofen release characteristic of the drug delivery material which concerns on this invention The figure which shows the ascorbic acid release characteristic of the drug delivery material which concerns on this invention The figure which shows the binaphthalene diol release characteristic of the drug delivery material which concerns on this invention The figure which shows the fixed quantity of the modification molecule | numerator (alkylamine) based on this invention Photograph of drug delivery material on which modifying molecule (silane coupling agent) according to the present invention is immobilized The figure which shows FT-IR of the drug delivery material which fix | immobilized the modification molecule | numerator (alkylamine) based on this invention

Claims (11)

A drug delivery material comprising at least one hollow fiber selected from titanium oxide, titanium hydroxide, titanate, and amorphous titanium oxide, wherein the hollow fiber is filled with an active substance, A drug delivery material, wherein the active substance is released to the outside of the hollow fiber by an external stimulus. The drug delivery material according to claim 1, wherein an inner diameter (r) of the hollow fiber is in a range of 3 nm to 8 nm. The drug delivery material according to claim 1 or 2, wherein the size of the active substance is smaller than the inner diameter (r) of the hollow fiber. The drug delivery material according to claim 1, wherein the external stimulus is light irradiation accompanied by excitation of a hollow fiber. 6. The drug delivery material according to claim 1, wherein the active substance is bonded to the inner wall of the hollow fiber by dehydration condensation. The drug delivery material according to claim 1, wherein the active substance has a hydroxyl group. The drug delivery material according to claim 1, wherein the active substance has a diol group. The drug delivery material according to any one of claims 1 to 3, wherein the external stimulus is a change in pH. The drug delivery material according to claim 8, wherein the active substance is a molecule or particle having a charge. The drug delivery material according to claim 1, wherein the hollow fiber is a scroll-like layered titanic acid. A modifying molecule is immobilized on the surface of at least one of the inner wall and the outer wall of the hollow fiber. The modifying molecule has a linker part and a main chain part, and the linker part and the surface of the hollow fiber are bonded to each other. The drug delivery material according to claim 1, wherein the drug delivery material is a drug delivery material.

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