JP2007061559A - New complex and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a honeycomb porous body with a drug, metallic nanoparticulates and/or a coloring matter, which can also be used as a carrier for drug delivery. <P>SOLUTION: The honeycomb porous body with the drug, the metallic nanoparticulates and/or the coloring matter, which is composed of a water-insoluble polymer, is useful as the carrier for the sustained release of the drug and a drug delivery system, particularly, because the honeycomb porous body retains particulates composed of a polymer supporting the drug, the metallic nanoparticulates and/or the coloring matter. Particularly, since the drug is released by making the porous body retain the drug-supporting particulates, a release pattern can be more finely and freely controlled. Additionally, a scaffold for cell expansion can be provided. Since the drug required for the expansion or differentiation induction of cells is released from the scaffold, the honeycomb porous body is extremely useful for a field of regenerative medicine. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention holds a honeycomb-shaped porous body having a drug, metal nanoparticles and / or a dye, particularly fine particles having a uniform particle size carrying a drug and the like, which are suitable for sustained release of the drug in vivo. The present invention relates to a honeycomb-shaped porous body, a drug delivery carrier, and a method for producing the same.

  As a technique for administering drugs such as low molecular weight organic compounds, nucleic acids such as DNA, peptides or proteins having a molecular weight of tens of thousands or more to living bodies, these drugs are not administered as they are or as simple mixtures with pharmaceutical carriers. A so-called drug delivery system (DDS) is known, in which the drug is carried or contained in a carrier having liposomes or other various forms to adjust the strength or duration of the drug, and is actively researched. It continues to be.

  One of the important points in the development of DDS is to improve the accuracy of targeting technology that selectively delivers drugs to disease sites such as cancer tissue, lymphoma, pneumonia, hepatitis, nephritis, vascular endothelial injury sites, etc. is there. Targeting technology that works only at the necessary site not only for the purpose of increasing the healing effect of the drug on the disease but also for the purpose of suppressing the side effects of the drug that may occur at the site unrelated to the disease Improvement of accuracy is recognized as an important issue.

  In addition, for the treatment of diseases that require continuous administration of a certain amount of drug, especially for the treatment of diseases that require continuous supply of a low volume of drug, the amount of drug released per unit time can be set arbitrarily. The development of sustained release technology that controls and maintains the release for a desired time is also an important point for the development of DDS.

  In the field of DDS, hitherto, research has been mainly conducted to apply membrane carrier particles such as liposomes, emulsions, and lipid microspheres. This is due to the fact that it is a technique that does not depend on the solubility of the drug to be administered, and that targeting can be carried out by loading a specific antibody or the like against a characteristic substance present in the disease site on the particle.

  However, all DDS technologies based on particles administer free particles in a liquid to a living body. In principle, it is difficult to keep particles in one place. It is also a disadvantageous technology to achieve the important issues of DDS. Further, in the field of regenerative medicine performed through the control, proliferation, differentiation or function control of stem cells by administration of cytokines or chemokines, as a result, particulate DDS such as liposomes does not give a good effect.

  An object of the present invention is to develop a new DDS technique, particularly a DDS technique suitable for regenerative medicine in which cell proliferation is promoted and treated.

  The present invention provides a regenerative treatment in which a honeycomb-like porous body has a drug or the like, in particular, a drug delivery carrier, particularly a regenerative treatment that needs to induce or promote cell proliferation or differentiation by holding fine particles carrying the drug. Was found to be able to provide a drug delivery carrier that can be used in Japan, and completed the following invention.

1) A honeycomb-like porous body made of a water-insoluble polymer having a drug, metal nanoparticles and / or a dye.

2) A honeycomb formed of a water-insoluble polymer as described in 1) having a drug, metal nanoparticles and / or a dye by holding fine particles made of a polymer carrying a drug, metal nanoparticles and / or a dye. Porous body.

3) A honeycomb-shaped porous body made of a water-insoluble polymer as described in 2), wherein fine particles made of a polymer carrying a drug, metal nano-particles and / or a dye are held in the pores of the honeycomb-shaped porous body. .

4) The water-insoluble polymer according to 2), wherein a part or all of the fine particles made of a polymer supporting a drug, metal nano-particles and / or a dye are embedded and held in a honeycomb porous body. Honeycomb porous body made of

5) A honeycomb-like porous body made of the water-insoluble polymer according to any one of 2) to 4), wherein the fine particles have a particle size of 0.01 μm to 50 μm.

6) A carrier for drug delivery, which is a honeycomb-like porous body made of a water-insoluble polymer having a drug.

7) The carrier for drug delivery according to 6), which is a honeycomb-like porous body made of a water-insoluble polymer having a drug by holding fine particles made of a polymer carrying the drug.

8) The carrier for drug delivery according to 7), which is a honeycomb-like porous body made of a water-insoluble polymer holding fine particles made of a polymer carrying a drug in the pores of the honeycomb-like porous body.

9) The honeycomb-shaped porous body composed of a water-insoluble polymer in which all or part of the fine particles composed of the polymer carrying the drug are embedded and held in the honeycomb-shaped porous body. Carrier for drug delivery.

10) The carrier for drug delivery according to any one of 7) to 9), wherein the particle diameter of the fine particles is 0.01 μm to 50 μm.

11) The carrier for drug delivery according to any one of 6) to 10), which is a carrier for inducing or promoting cell proliferation or differentiation.

  Since the honeycomb-like porous body of the present invention can be composed of various biocompatible materials and biodegradable polymers, it can effectively release the drug and is useful as a carrier for a drug delivery system. is there. In particular, the release pattern can be controlled more finely by holding the drug-carrying fine particles and releasing the drug.

  In addition, the honeycomb-shaped porous body having the drug of the present invention can provide a so-called scaffold (scaffold) in cell proliferation, and can release a drug necessary for cell proliferation or differentiation induction from the scaffold. Thus, it can be used as a carrier for drug delivery that is extremely useful in the field of regenerative medicine.

  The present invention holds a honeycomb-like porous body having a drug, metal nano-particles and / or a dye (hereinafter referred to as a drug), in particular, a fine particle composed of a polymer supporting a drug or the like (hereinafter referred to as a drug-supported fine particle). By doing so, it is a honeycomb-like porous body having a drug or the like.

  A honeycomb-like porous body (also referred to as a honeycomb structure or a honeycomb sheet) constituting the present invention is a porous thin film made of a polymer (polymer) and has minute pores oriented in the vertical direction of the film. It means that (including the depression) is provided in a honeycomb shape (in a honeycomb shape) in the plane direction of the film. The holes may penetrate the membrane in the longitudinal direction, or may communicate with surrounding holes existing in the planar direction. The honeycomb-shaped porous body having a drug or the like is a honeycomb containing a drug or the like in a polymer portion (hereinafter referred to as a trunk) constituting the honeycomb-shaped porous body or in pores of the honeycomb-shaped porous body. Refers to a porous material. In addition, the honeycomb-shaped porous body having a drug or the like by holding the drug-supported fine particles refers to a substance in which the drug-supported fine particles and the honeycomb-shaped porous body are physically integrated. One example of such physical integration is a state in which fine particles such as drugs are filled in the pores of the honeycomb-shaped porous body (for example, the state shown in FIG. 14). In addition, a case in which all or part of the drug-carrying fine particles are embedded in the trunk of the honeycomb-shaped porous body (for example, the state shown in FIG. 15) is also an example of physical integration. 14 and FIG. 15 may coexist.

  The honeycomb porous body usable in the present invention has a thickness of 0.01 μm to 100 μm, preferably 0.1 μm to 50 μm, more preferably 1 μm to 20 μm, and a pore diameter of 0.01 μm to 100 μm, preferably The thickness is desirably 0.1 μm to 50 μm, more preferably 1 μm to 20 μm.

  A honeycomb-like porous body having such structural features can be manufactured according to various known methods. For example, photolithography and soft lithography (Whiteside et al., Angew. Chem. Int. Ed., 1998, 37, 550-575), phase separation of block copolymers (Albrecht et al., Macromolecules) 2002, 35, pp. 8106-8110), a method for producing a two-dimensional and three-dimensional periodic structure by accumulating submicron colloidal particles (Gu et al., Langmuir, Vol. 17) And a method for producing an inverse opal structure using this as a template (Carso et al., Langmuir, 1999, Vol. 15, pages 8276-8281).

  Also, the methods described in JP-A-8-311231, JP-A-2001-157475, JP-A-2002-347107, or JP-A-2002-335949, which are greatly different from these methods and the manufacturing principle, can be used. . In these methods, water droplets are condensed on the surface of the polymer non-aqueous organic solvent solution, and a honeycomb-shaped porous body is prepared using the water droplets as a template. It is advantageous compared to the law. This will be described in more detail below.

  In this method, a water-incompatible organic solvent solution of a water-insoluble polymer obtained by dissolving a water-insoluble polymer in a water-incompatible organic solvent, particularly a water-incompatible organic solvent having a surface tension γL of 50 dyn / cm or less, The surface of the substrate satisfying the relationship of γS−γLS> γL when the surface tension of the surface is γS and the surface tension γL of the water-incompatible organic solvent to be applied and the surface tension γLS between the substrate and the solvent It is preferable to evaporate the water-incompatible organic solvent solution of the water-insoluble polymer applied to the substrate in the presence of 30% or more of air.

  The water-incompatible organic solvent here has a surface tension of 50 dyn / cm or less and water-incompatibility that can hold water droplets condensed on the solution surface, and 0 to 150 ° C. under atmospheric pressure. , Preferably an organic solvent having a boiling point of 10-50 ° C. For example, halogenated hydrocarbons such as carbon tetrachloride, dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate and butyl acetate, water-insoluble ketones such as methyl isobutyl ketone, Examples thereof include carbon sulfide.

  The water-insoluble polymer is not particularly limited as long as it is insoluble in water and soluble in the above-mentioned water-incompatible organic solvent, or can be dissolved in a water-incompatible organic solvent in the presence of an appropriate surfactant. There is no restriction | limiting, It can select and use suitably.

  Examples thereof include biodegradable polymers such as polylactic acid and polyhydroxybutyric acid, aliphatic polycarbonates, amphiphilic polymers, photofunctional polymers, and electronic functional polymers.

In particular, it is preferable to use a biocompatible non-biodegradable polymer or a biodegradable polymer as the water-insoluble polymer for preparing a honeycomb-shaped porous body having a drug. Preferred biocompatible biodegradable polymers include fatty acid polyesters such as poly (lactides), poly (glycolide) s, poly (lactide-co-glycolide) s, poly (lactic acid) s, poly (glycolic acid) s Poly (lactic acid-co-glycolic acid) s, polycaprolactones, polycarbonates, polyesteramides, polyanhydrides, poly (amino acids), polyorthoesters, polyacetals, polycyanoacrylates, polyetheresters, Mention may be made of poly (dioxanone) s, poly (alkylene alkylates), copolymers of polyethylene glycol and polyorthoesters, biodegradable polyurethane mixtures or copolymers thereof. Preferable examples include polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, poly (lactic acid-glycolic acid) copolymer, and the like. Biopolymers such as collagen, gelatin, amylose, amylopectin, chitosan, mannan, cyclodextrin, pectin or carrageenan can also be used.

  Preferred biocompatible non-biodegradable polymers include polyethylene oxide, polyvinyl alcohol, styrene-maleic anhydride alternating copolymer, divinyl ether-maleic anhydride alternating copolymer, ethylene-vinyl acetate polymer and acyl substituted acetic acid. Conjugated diene polymers such as cellulose and polybutadiene, styrene polymers such as polystyrene, other non-degradable polyurethanes, polysulfones, poly (meth) acrylates, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulfonate polyolefins And non-biodegradable polymers selected from the group consisting of these, mixtures thereof and copolymers thereof.

  Non-biodegradable polymer is used when sustained release of drug from honeycomb porous material needs to be sustained for a long time in vivo, and biodegradable when drug needs to be released in a shorter time It is preferable to prepare a honeycomb-shaped porous body using each polymer. In addition, for example, polyε caprolactone, poly (lactide), and poly (lactide-co-glycolide) increase the biodegradation rate in this order. Therefore, the controlled release speed of the drug can be controlled by selecting a water-insoluble polymer. it can.

  Examples of specific combinations of the water-incompatible organic solvent and the water-insoluble polymer include, for example, polyalkyl methacrylates such as polystyrene, polycarbonate, polysulfone, polyethersulfone, polyalkylsiloxane, and polymethyl methacrylate, or polymethyl methacrylate. For a polymer selected from the group consisting of alkyl acrylate, polybutadiene, polyisoprene, poly-N-vinylcarbazole, polylactic acid, poly-ε-caprolactone, polyalkylacrylamide, and copolymers thereof, carbon tetrachloride, A combination of organic solvents such as dichloromethane, chloroform, benzene, toluene, xylene, carbon disulfide can be used. For polymers selected from the group consisting of acrylates, methacrylates and copolymers thereof having a fluorinated alkyl side chain, fluorocarbon solvents such as AK-225 (Asahi Glass Co., Ltd.), trifluorobenzene, etc. The use of fluoroethers also gives good results. Among these, it can be appropriately selected and used in consideration of solubility in the water-insoluble polymer specifically used.

  Further, when manufacturing a honeycomb-shaped porous body using a fluorine-based polymer in which hydrogen in a side chain of polyacrylate or methacrylate having a fluorinated alkyl side chain is substituted with fluorine, a fluorine-based organic solvent (AK- 225) also gives good results.

  When the water-insoluble polymer is dissolved in the water-incompatible organic solvent, it is preferable to use 0.1 g / L to 10 g / L of the water-insoluble polymer in the same solvent. Here, the concentration of the water-insoluble polymer in the solution can be appropriately determined according to the characteristics and physical properties required for the honeycomb-shaped porous body and the water-incompatible organic solvent to be used.

  Further, the substrate to which the water-incompatible organic solvent solution of the water-insoluble polymer is applied includes the surface tension γS of the substrate surface and the surface tension γL of the water-incompatible organic solvent to be applied, and between the substrate and the solvent. It is desirable to select and use a substrate that satisfies the relationship of γS−γLS> γL with the surface tension γLS. This is because the wettability of the water-incompatible organic solvent solution of the water-insoluble polymer solution to the water-incompatible organic solvent of the substrate itself can affect the thickness of the liquid film formed on the substrate. is there. The substrate preferably has a high affinity for the water-incompatible organic solvent solution of the water-insoluble polymer to be applied. Specifically, a substrate having a surface exhibiting a surface tension that can be expressed by the above formula using the surface tension γL of the water-incompatible organic solvent as an index may be used. Preferable examples of such a substrate include a glass plate, a silicon plate, or a metal plate.

  It is also possible to use a substrate whose surface has been processed to increase the affinity with a water-incompatible organic solvent solution. Such improvement of the wettability of the substrate surface can be achieved by a method known per se, such as silane coupling treatment or thiol for glass or metal substrates, depending on the water-incompatible organic solvent used with the substrate. A monomolecular film forming method using a compound can be used.

  For example, when using a hydrophobic organic solvent such as chloroform as a water-incompatible organic solvent, it is possible to use a sufficiently cleaned Si substrate or a glass substrate whose surface is modified with an alkylsilane coupling agent or the like. preferable. When using a fluorine-based solvent, it is preferable to use a Teflon (registered trademark) substrate or a glass substrate modified with a fluorinated alkylsilane coupling agent or the like.

  The liquid film thickness when a water-incompatible organic solvent solution of a water-insoluble polymer is applied to a substrate to form a liquid film of the solution is 200 μm or less, preferably 100 μm, more preferably 30 μm or less. desirable. In addition, as a method of applying a water-incompatible organic solvent solution of a water-insoluble polymer to the substrate, in addition to the method of dropping the same solution on the substrate, there can be mentioned bar coating, dip coating, spin coating method, etc. Either batch type or continuous type can be used.

  The honeycomb-shaped porous body having a drug or the like of the present invention is obtained by further dissolving or suspending a drug or the like in a water-incompatible organic solvent solution of a water-insoluble polymer in the method for manufacturing a honeycomb-shaped porous body described above. It can be prepared by using one.

  There are no particular restrictions on the type of drug as long as it is a drug for diagnosis and / or treatment. Examples of therapeutic agents include anticancer agents, antibiotics, anti-inflammatory agents, steroid agents, enzyme agents, enzyme inhibitors, antioxidants, lipid challenge inhibitors, hormone agents, angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, Vascular endothelial cell proliferation or inhibitor, smooth muscle cell proliferation / migration inhibitor, platelet aggregation inhibitor, chemical mediator release inhibitor, aldose reductase inhibitor, mesangial cell proliferation inhibitor, lipoxygenase inhibitor, immunosuppressant , Immunostimulants, antiviral agents, anticoagulants, vasodilators, Maillard reaction inhibitors, amyloidosis inhibitors, NOS inhibitors, AGEs inhibitors, biological materials or radical scavengers. In addition, glycosaminoglycans or derivatives thereof, oligosaccharides, polysaccharides or derivatives thereof, proteins, peptide nucleic acids, polynucleotides or analogs thereof can be used.

  Examples of drugs that can be used for diagnosis include X-ray contrast agents, radioisotope-labeled nuclear medicine diagnostic agents, diagnostic agents for nuclear magnetic resonance diagnosis, and the like.

  Examples of the dye include fluorescent dyes such as pyrene and perylene; photofunctional dyes such as azobenzene; other octadecyl rhodamine B; There are no particular restrictions on the type.

  Metal nanoparticles are fine particles containing metal with a particle size of approximately 100 nm or less, and are characterized by a quantum size effect and an increase in the ratio of the number of surface atoms, changes in optical properties, a decrease in melting point, high catalytic properties, and high magnetic properties. In many cases, it exhibits useful properties such as properties that are not found in bulk metals. By having such metal nanoparticles, it is possible to provide functional materials useful in various fields such as electronic materials, optical materials, phosphor materials, magnetic materials, and pharmaceuticals. Examples of metal nanoparticles usable in the present invention include nanoparticles composed of gold, silver, iron, nickel, copper, cobalt, platinum, and the like.

  The amount of the water-insoluble polymer such as a drug added to the water-incompatible organic solvent solution can be appropriately set according to the purpose and, for example, the type and amount of the drug required for treatment or diagnosis if the drug is used. However, it is generally prepared within the range of 0.05 to 80% by weight, preferably 0.1 to 60% by weight, more preferably 0.1 to 40% by weight, more preferably 1 to 10% by weight per solution weight. That's fine.

  Further, in addition to or instead of adding a drug or the like to a water-incompatible organic solvent solution of a water-insoluble polymer, a drug-supported fine particle is separately prepared, and this is described above as a honeycomb-like porous body. By holding the particles, a honeycomb-like porous body having a drug or the like can be prepared by holding the drug or the like supported fine particles. Hereinafter, the drug-supported fine particles will be described in more detail.

  The drug-carrying fine particles are particulate substances composed of a substantially spherical polymer having a particle size of 0.01 μm to 50 μm, preferably 0.02 μm to 30 μm, more preferably 0.03 μm to 10 μm, It refers to those carrying a drug, a dye and / or metal nanoparticles. Here, the term “supported” means a form in which a drug or the like is encapsulated or encapsulated in a particulate substance made of a polymer, or is taken in between molecules of the polymer. For example, a form in which a drug or the like is enclosed or enclosed in a closed space formed of a polymer, a form in which a molecule such as a drug exists between polymer molecules, or a form in which these are combined may be used.

  Such drug-carrying fine particles, for example, disclosed in JP-A-6-79168, in a reprecipitation method comprising dropping a solution containing a material that constitutes fine particles into a vigorously stirred poor solvent, It can be produced by dissolving a desired drug or the like in the dropping solution.

  Another method that does not have problems such as difficulty in controlling the particle size in the above-described method and extremely vigorous stirring required when preparing fine particles having a small particle size is disclosed in JP-A-2004-67883. In a method for preparing fine particles by adding a poor solvent of the material compatible with the good solvent to the polymer solution dissolved in the good solvent to reduce the concentration of the polymer, Drug-supported fine particles can also be prepared by dissolving the. Hereinafter, a method based on the method disclosed in Japanese Patent Application Laid-Open No. 2004-67883, which is preferable as a method for producing drug-supported fine particles, will be further described.

  Specific examples of the polymer constituting the drug-supported fine particles include general-purpose polymers (polystyrene-maleic anhydride copolymer, polystyrene, etc.), photofunctional materials (dye-supported polyion complex, dye-containing polystyrene, cyanine dye, EL material) Etc.), electronic functional materials (such as polyhexylthiophene which is a conductive polymer), biofunctional materials (such as biodegradable polymers such as poly (ε-caprolactone) or polyhydroxybutyrate (PHB), collagen, etc. ), Nucleic acid polymers (RNA, DNA, etc.), fluorine-containing copolymers, and the like.

  In particular, it is preferable to use a biocompatible non-biodegradable polymer or a biodegradable polymer as a polymer that forms fine particles carrying a drug. Preferred biocompatible biodegradable polymers include fatty acid polyesters such as poly (lactides), poly (glycolide) s, poly (lactide-co-glycolide) s, poly (lactic acid) s, poly (glycolic acid) s Poly (lactic acid-co-glycolic acid) s, polycaprolactones, polycarbonates, polyesteramides, polyanhydrides, poly (amino acids), polyorthoesters, polyacetals, polycyanoacrylates, polyetheresters, Mention may be made of poly (dioxanone) s, poly (alkylene alkylates), copolymers of polyethylene glycol and polyorthoesters, biodegradable polyurethane mixtures or copolymers thereof. Preferable examples include polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, poly (lactic acid-glycolic acid) copolymer, and the like. Biopolymers such as collagen, gelatin, amylose, amylopectin, chitosan, mannan, cyclodextrin, pectin or carrageenan can also be used.

  Preferred biocompatible non-biodegradable polymers include polyethylene oxide, polyvinyl alcohol, styrene-maleic anhydride alternating copolymer, divinyl ether-maleic anhydride alternating copolymer, ethylene-vinyl acetate polymer and acyl substituted acetic acid. Conjugated diene polymers such as cellulose and polybutadiene, styrene polymers such as polystyrene, other non-degradable polyurethanes, polysulfones, poly (meth) acrylates, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole), chlorosulfonate polyolefins And non-biodegradable polymers selected from the group consisting of these, mixtures thereof and copolymers thereof.

  Use a non-biodegradable polymer when it is necessary to maintain the sustained release effect of the drug from fine particles in the body for a long period of time, and use a biodegradable polymer when it is necessary to release the drug in a shorter time. If used, it is preferable to prepare fine particles each carrying a drug using fine particles. In addition, for example, polyε caprolactone, poly (lactide), and poly (lactide-co-glycolide) increase the biodegradation rate in this order. You can also.

  The concentration at which the above polymer is dissolved in a good solvent is not particularly limited as long as it is equal to or lower than the saturation concentration of the polymer to be used with respect to the good solvent. However, the concentration is preferably about 1/100 of the saturation concentration to the saturation concentration. .

  The good solvent and the poor solvent used in the present method are compatible with each other, but have different solvent powers for the polymer to be used. The solvent having a high / strong solvent power is a low / weak or weak solvent. A solvent that has almost no dissolving power is appropriately selected and used as a poor solvent. Specifically, as a standard for solubility, a solvent having a solubility parameter difference of 2.5 or more with respect to a polymer to be used may be selected as a poor solvent, and a solvent having a solubility less than 2.5 may be selected as a good solvent. Therefore, both the good solvent and the poor solvent need to be appropriately selected and used in consideration of the solubility of the polymer used in both solvents. Further, it is desirable that the good solvent and the poor solvent are mixed well, that is, the good solvent and the poor solvent that are within 15 differences in solubility parameter difference between the two solvents with respect to the polymer to be used are selected and combined.

  Furthermore, since it is necessary to evaporate and remove the good solvent after adding the poor solvent to the good solvent solution of the polymer, the selection of the good solvent and the poor solvent requires that each boiling point be one of the conditions. Specifically, solvents having a boiling point of the poor solvent equal to or higher than that of the good solvent are selected and combined.

  Specific examples of the solvent include water, alcohols, ketones, esters, aromatics, halogen compounds, etc., and among these, each polymer used has the properties described above. A good solvent and a poor solvent may be selected. Specifically, it is only necessary to collect or confirm solubility difference data of various polymers used in various solvents, compatibility data between solvents, boiling points, and the like, and select an appropriate solvent.

Specific examples of combinations of polymer, good solvent, poor solvent and final dispersion solvent are shown in Table 1 below.

In the table, PMSA is the chemical formula (1), polyion complex 1 is the chemical formula (2), octadecyl RhoB is the chemical formula (3), NK2622 is the chemical formula (4), and poly A, U, C + parents. The medium substance is a compound represented by the chemical formula (5).

  In order to carry a drug or the like on fine particles, the drug or the like is dissolved or suspended in the above-mentioned good solvent, and a poor solvent may be added thereto.

  The drug that can be carried on the microparticles is not particularly limited as long as it is a drug for diagnosis and / or treatment. Examples of therapeutic agents include anticancer agents, antibiotics, anti-inflammatory agents, steroid agents, enzyme agents, enzyme inhibitors, antioxidants, lipid challenge inhibitors, hormone agents, angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, Vascular endothelial cell proliferation or inhibitor, smooth muscle cell proliferation / migration inhibitor, platelet aggregation inhibitor, chemical mediator release inhibitor, aldose reductase inhibitor, mesangial cell proliferation inhibitor, lipoxygenase inhibitor, immunosuppressant , Immunostimulants, antiviral agents, anticoagulants, vasodilators, Maillard reaction inhibitors, amyloidosis inhibitors, NOS inhibitors, AGEs inhibitors, biological materials or radical scavengers. In addition, glycosaminoglycans or derivatives thereof, oligosaccharides, polysaccharides or derivatives thereof, proteins, peptide nucleic acids, polynucleotides or analogs thereof can be used.

  Examples of drugs that can be used for diagnosis include X-ray contrast agents, radioisotope-labeled nuclear medicine diagnostic agents, diagnostic agents for nuclear magnetic resonance diagnosis, and the like.

  Examples of the dye include fluorescent dyes such as pyrene and perylene; photofunctional dyes such as azobenzene; other octadecyl rhodamine B; There are no particular restrictions on the type.

  Metal nanoparticles are fine particles containing metal with a particle size of approximately 100 nm or less, and are characterized by a quantum size effect and an increase in the ratio of the number of surface atoms, changes in optical properties, a decrease in melting point, high catalytic properties, and high magnetic properties. In many cases, it exhibits useful properties such as properties that are not found in bulk metals. By incorporating such metal nanoparticles into fine particles, a honeycomb-like porous body useful in various fields such as electronic materials, optical materials, phosphor materials, magnetic materials, and pharmaceuticals can be provided. Examples of metal nanoparticles usable in the present invention include nanoparticles composed of gold, silver, iron, nickel, copper, cobalt, platinum, and the like.

  The use amount of the drug or the like may be appropriately set according to the purpose and, for example, the type and amount of the drug required for treatment or diagnosis if it is a drug. What is necessary is just to prepare in 80 weight%, Preferably it is 0.1-60 weight%, More preferably, it is 0.1-40 weight%, More preferably, it may prepare in the range of 1-10 weight%. As shown in the examples described later, the particle size of the fine particles can be changed according to the amount of the drug supported.

  Moreover, the combination of a polymer, a drug, etc. can also be combined based on each physical property. For example, when simvastatin is selected as a drug and dissolved in THF, poly (lactic acid-glycolic acid) may be selected as a polymer. In addition, when paclitaxel is selected as a drug and dissolved in chloroform, polyε caprolactone may be selected as a polymer.

  The rate of addition of the poor solvent to the good solvent solution is not particularly limited, and may be added in accordance with a normal experimental operation. Depending on the concentration of the organic or inorganic material, it is desirable to take a time of (liquid volume) × 10 / min or more. Further, the temperature at which the fine particles of the present invention are produced may be determined in consideration of the boiling point of the solvent to be used, but it can be carried out at an arbitrary temperature of about 0 to 90 ° C., preferably at room temperature. be able to.

  Further, the amount of the poor solvent added to the good solvent solution can be appropriately selected in consideration of the type of polymer, the type of good solvent and the poor solvent, or the particle size of the fine particles to be produced, Generally, the amount of the poor solvent that is 0.5 to 10 times the amount of the good solvent solution of the polymer can be added.

  The particle size of the fine particles can also be controlled by adjusting the concentration of the polymer in the good solvent solution and the amount of the poor solvent to be added (ratio to the amount of the good solvent). By carrying out uniformly, fine particles having a narrow particle size distribution can be produced.

After mixing the good solvent and the poor solvent in this way, the fine particles supported by the drug can be recovered by removing the good solvent. At that time, the good solvent is rapidly evaporated and removed under reduced pressure. It is possible to produce drug-supported fine particles having a smaller particle size and an ordered particle size distribution. The degree of decompression may be 10 −3 Pa to 10 kPa, preferably 10 Pa to 1 kPa. This is a condition that can be reproduced using, for example, a rotary evaporator, a decompression pump, or other general decompression equipment. Accordingly, there is no particular need for large-scale equipment for maintaining the ultra-vacuum state, and it can be easily prepared at the laboratory level and at the industrial production level.

  Moreover, when evaporating and removing the good solvent under such reduced pressure, it is desirable to finish within 3 hours at the longest from the start of the reduced pressure. Specifically, it is desirable to evaporate and remove the good solvent at a rate of 0.01% by volume or more per second for a total volume of 100% of the good solvent to be removed by evaporation. If the total volume of the good solvent is relatively small, the evaporative removal can be ended substantially instantaneously. In addition, when the total volume of the good solvent is large and it is practically difficult to evaporate and remove it within one hour, the solution after addition of the poor solvent is fractionated into an appropriate amount. The solvent may be removed for each fraction.

  When the good solvent is removed by evaporation under reduced pressure, the particle size of the fine particles is further reduced by about 10 to 50%, compared with the case where the good solvent is not removed. In addition, the standard deviation of the particle size distribution of the fine particles is also reduced by about 10%, and drug-supported fine particles having a more uniform particle size can be produced.

  The above-mentioned methods can be applied to problems reported in conventional methods such as drug bulk disruption, emulsion polymerization, or polymer micelle method, such as large energy loss, large particle size distribution, and contamination with surfactants. Inevitable problems can be solved and the limits of applicable drugs can be removed.

  When the drug is supported on fine particles, a surfactant or an emulsifier may be added as an optional component to a good solvent for the purpose of controlling the sustained release of the drug, and other additives such as a stabilizer or an aggregation stabilizer may be added. A form may also be included. Stabilizers are added to maintain the efficacy of the drug's biologically active agent during the production, storage, and drug release periods of the drug-loaded microparticles.

  The honeycomb-like porous body having the drug or the like of the present invention can be prepared by holding the above-described fine particles carrying a medicine or the like on the honeycomb-like porous body described above by the method described below.

  For example, after adding a suspension of fine particles carrying drugs and the like to a honeycomb porous body sandwiched between glass plates, sliding the glass in parallel and evaporating the solvent from the meniscus, as shown in FIG. A honeycomb-like porous body made of a water-insoluble polymer in which fine particles made of a polymer carrying a drug or the like are held in the pores of the honeycomb-like porous body can be prepared.

In such a method, it is preferable that the honeycomb-shaped porous body is immersed in an appropriate alkaline solution for about 10 to 30 minutes before being sandwiched between glass plates, and further dried after washing. By this treatment, it is possible to improve the filling rate of the loaded fine particles such as drugs into the pores of the honeycomb-shaped porous body. As the alkaline solution, an alkali metal hydroxide (for example, NaOH, KOH) solution of about 0.1 to 1 N or an alkaline earth metal hydroxide (Ca (OH) ₂ , Mg (OH) ₂ ) solution is used. That's fine. Needless to say, the sliding of the glass plate must be performed so as not to damage the honeycomb-like porous body, but the sliding speed is preferably about 1 to 5 μm / second.

  Further, by softening the honeycomb-like porous body by heating, a part or all of the fine particles made of a polymer carrying a drug or the like as shown in FIG. 15 are embedded in the honeycomb-like porous body. A honeycomb-like porous body made of the retained water-insoluble polymer can be prepared. For example, after dropping a suspension of supported particles such as a drug on a honeycomb-shaped porous body placed on a glass plate, the polymer constituting the honeycomb-shaped porous body is heated at a temperature at which the polymer is softened. All or part of the supported fine particles can be embedded in the softened honeycomb porous body. In addition, the honeycomb porous body can be pressed and embedded from above the drug-carrying fine particles arranged on the substrate in advance.

  In such a method, it is desirable to hydrophilize the glass plate in advance by ozone treatment. This operation facilitates embedding the drug-supported fine particles in the softened honeycomb porous body. The heating may be performed until the solvent in which the drug-supported fine particles are suspended evaporates.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples.

  Poly (ε-caprolactone) (PCL): Amphiphilic polyacrylamide copolymer (Cap) = 10: 1 was dissolved in a chloroform solution to a concentration of 2 mg / ml. Cap is a compound represented by the following structural formula.

In this solution, simvastatin (SV) or pyrene was further dissolved to 5 wt% with respect to the total amount of the solution. 5 ml of this solution is cast into a petri dish with a diameter of 9.3 cm under a relative humidity of 80%, and the solvent is evaporated under normal pressure to obtain a honeycomb-like porous body having SV (PCL-SV) and a honeycomb-like porous body having pyrene (PCL-pyrene) was prepared. FIG. 1 (PCL-SV) and FIG. 2 (PCL-pyrene) show electron micrographs of each honeycomb-like porous body.

  Further, except that poly (L-lactide) (Poly (L-lactide), PLLA) was used instead of PCL, the same operation as described above was carried out to obtain a honeycomb-shaped porous body having SV (PLLA-SV) and pyrene. A honeycomb-like porous body (PLLA-pyrene) having the above was prepared. 3 (PLLA-SV) and FIG. 4 (PLLA-pyrene) show electron micrographs of the respective honeycomb-like porous bodies.

  Furthermore, the confocal microscope observation was performed about PLLA-pyrene, and the slice image (FIG. 5) only of the surface of PLLA-pyrene and the superimposition image (FIG. 6) from the surface to the bottom were obtained.

  From the confocal micrograph of PLLA-pyrene, it can be seen that pyrene exists throughout the honeycomb porous body.

  A honeycomb-like porous body holding fine particles carrying simvastatin (SV) was prepared.

1) Preparation of honeycomb-like porous material Poly (ε-caprolactone) (poly (ε-caprolactone), PCL): Amphiphilic polyacrylamide copolymer (Cap) = 10: 1 dissolved to 2 mg / ml 4 ml of the resulting chloroform solution was cast into a petri dish having a diameter of 9.3 cm under a relative humidity of 80%, and the solvent was evaporated under normal pressure to produce a honeycomb-like porous body having an apparent size of 90 mm × 90 mm. The honeycomb porous body had a pore diameter of 4 μm as a result of observation by an electron microscope (FIG. 7).

2) Preparation of fine particles carrying SV
THF was selected as a good solvent, and poly (L-glycolide-lactide, PGLA), which is a copolymer of glycolide: lactide = 50: 50, was adjusted to a concentration of 1.0 mg / ml. Simvastatin (SV), a hyperlipidemic agent, is dissolved in 100 wt% of PGLA to 5 wt%, 10 wt%, and 15 wt%, respectively, and three types of PGLA-SV / THF solutions are prepared. did.

  MilliQ water was added dropwise to each solution at a speed of 1.0 ml / min so that the volume ratio of each solution to MilliQ water was 1: 1 (5 ml: 5 ml) to obtain three types of mixed solutions. The mixed solution was set on a rotary evaporator and evaporated at 210 mmHg for 16 minutes and 30 seconds and further at 70 mmHg for 2 minutes and 30 seconds to obtain three types of fine particles (hereinafter referred to as SV5, SV10, and SV15, respectively).

  When the average particle diameter of each fine particle was measured using an electrophoretic light scattering photometer, SV5 was 291.7 ± 23.5 nm, SV10 was 292.7 ± 10.2 nm, and SV15 was 193.7 ± 7.7 nm (N = 3). The SEM image of each fine particle was a monodispersed spherical fine particle, and SV crystals were hardly seen in the fine particle. 8 (SV5), FIG. 9 (SV10), and FIG. 10 (SV15) are photographs obtained by observing each fine particle with an electron microscope.

  Furthermore, when each fine particle was dried and measured using NMR, the charts shown in FIG. 11 (SV5), FIG. 12 (SV10), and FIG. 13 (SV15) were observed. Based on the molecular weight of SV 418.57, the molecular weight of PGLA (1 unit) 130.098 and the peak integrated value, SV5 corresponds to 2.7 wt% of the dissolved 5 wt% in SV5, and 5.7 wt of 10 wt% dissolved in SV10. SV corresponding to% and SV15 corresponding to 12.5 wt% of the dissolved 15 wt% were supported on SV15, respectively.

3) Preparation of honeycomb porous body in which fine particles supporting SV were held in pores The honeycomb porous body prepared in 1) was immersed in 1N NaOH aqueous solution for 30 minutes, then washed with MilliQ water and dried. The dried honeycomb porous body was sandwiched between two slide glasses, and 0.1 ml of the 0.1 wt% suspension of SV5 prepared in 2) was added to the honeycomb porous body sandwiched between the slide glasses. After moving the two glass slides at 5 mm / sec several times until the solvent of the suspension was completely evaporated, the honeycomb-like porous material was recovered from the glass slides.

  When this honeycomb-shaped porous body was observed with an electron microscope, it was confirmed that the honeycomb-shaped porous body had a structure in which SV5 was held in the pores as shown in FIG.

  A honeycomb-like porous material prepared by the same method as in Example 2 1) was placed on a round cover glass having a diameter of 15 mm, and a 0.1 wt% suspension of SV5 prepared in Example 2 2) was placed thereon. After 0.1 ml was dropped, the whole cover glass was heated at 50 ° C. for 1 to 9 hours. FIG. 15 shows an electron micrograph of the honeycomb-shaped porous body after heating for 1 hour, and FIG. 16 shows an electron micrograph of the honeycomb-shaped porous body after 9 hours of heating.

  As shown in FIG. 15 or FIG. 16, the honeycomb-shaped porous body prepared by this method has a structure in which all or part of the fine particles carrying SV are embedded and held in the trunk. Was confirmed.

  The PGLA used in 2) of Example 2 was replaced with an equal amount of poly (DL-lactide) (poly (DL-lactide), PDDLA), and the SV was 5 wt% with respect to the weight of 100 wt% of PDDLA. Except for dissolving and preparing one kind of PDDLA-SV / THF solution, the same operation as in 2) of Example 2 was performed to prepare fine particles (PDDLA-SV5) composed of PDDLA carrying SV.

  Two 18 mm × 18 mm cover glasses were subjected to ozone treatment using an eye graphics UV-ozone cleaning apparatus. A honeycomb-like porous material prepared by the same method as in 1) of Example 2 was placed on an ozone-treated cover glass, and 0.1 ml of a 0.1 wt% suspension of PDDLA-SV5 was added dropwise thereto. A cover glass that has been further treated with ozone is applied from above, and the whole cover glass is heated at 50 ° C. for 7 minutes, and then the upper cover glass that has been covered is peeled off and further heated for 2 hours. The body was recovered. An electron micrograph of this honeycomb porous body is shown in FIG.

  As shown in FIG. 17, it was confirmed that the honeycomb porous body had a structure in which all or part of the fine particles carrying SV were embedded and held in the trunk.

  Two 18 mm × 18 mm cover glasses were subjected to ozone treatment using an eye graphics UV-ozone cleaning apparatus. On one cover glass, 0.1 ml of a 0.1 wt% suspension of PDDLA-SV5 prepared in Example 4 was dropped and dried. Place the honeycomb-like porous material prepared in 1) of Example 2 on another cover glass, place the dried cover glass with fine particles upside down on the cover glass, and cover the two covers at 50 ° C. The whole glass was heated for 1 hour. After heating, the two cover glasses were peeled off to recover the honeycomb-like porous body. An electron micrograph of this honeycomb porous body is shown in FIG.

  As shown in FIG. 18, it was confirmed that the honeycomb porous body had a structure in which all or part of the fine particles carrying SV were embedded and held in the trunk.

  A honeycomb-like porous body having fine particles supporting gold nano-particles was prepared.

1) gold (Au) and stirred to dissolve nanoparticles Preparation NaAuCl 4 · 2H ₂ O _(Wako Pure Chemical Industries, Ltd. / EP, 273.4mg of molecular weight 397.80) and (0.687 mmol) in MilliQ water 25 mL, yellow Solution A was obtained. A dispersion B was obtained by adding 1.4529 g (2.66 mmol) of tetraoctylammonium bromide (Aldrich / GR, molecular weight 546.82) to 80 mL of toluene and applying ultrasonic waves thereto.

After the dispersion B was added to the solution A and stirred, an orange-brown toluene phase and a transparent aqueous phase were separated. The toluene phase was separated by decantation, to which 480.0 mg (2.37 mmol) of 1-dodecanethiol (1-dodecanethiol, Wako Pure Chemical Industries, Ltd./GR, molecular weight 202.40) was added, and the solution C was stirred. Obtained. A solution D was obtained by dissolving 392.2 mg (10.4 mmol) of NaBH ₄ (molecular weight 37.83) in 25 mL of MilliQ water. Solution C was added to solution D, and vigorous stirring was continued at room temperature for 4 hours. After stopping stirring, the mixture was allowed to stand for a while, and the separated toluene phase (black) was collected. Thereafter, the solvent was evaporated by a rotary evaporator.

Acetone was added and dispersed by applying ultrasonic waves, and the by-product was filtered under reduced pressure through a glass filter (52X). This operation was repeated twice, and the resulting black lump was dried under reduced pressure at room temperature to obtain gold nanoparticles 2) Gold nanoparticles supported on polymer particles 1) Gold nanoparticles obtained by the method of 1) were carried out. A microparticle carrying gold nanoparticles was prepared in the same manner as in 2) of Example 1, except that it was dissolved in a chloroform solution of PLLA at a concentration of 0.1 mg / mL instead of SV in 2) of Example 1.

3) Preparation of composite The same operation as in 3) of Example 1 was performed to obtain a honeycomb-like porous body holding fine particles carrying gold nanoparticles in the pores.

3 is an electron micrograph of a honeycomb porous body (PCL-SV) of the present invention having SV. 2 is an electron micrograph of a honeycomb porous body (PCL-pyrene) of the present invention having pyrene. 3 is an electron micrograph of a honeycomb porous body (PLLA-SV) of the present invention having SV. It is an electron micrograph of the honeycomb-like porous body of the present invention (PLLA-pyrene) having pyrene. It is a confocal microscope picture (surface) of PLLA-pyrene. It is a confocal microscope picture (superposition image) of PLLA-pyrene. 3 is an electron micrograph of a honeycomb-like porous body of Example 2). 4 is an electron micrograph showing fine particles SV5 obtained in 2) of Example 2. 4 is an electron micrograph showing fine particles SV10 obtained in 2) of Example 2. 4 is an electron micrograph showing fine particles SV15 obtained in 2) of Example 2. The NMR observation chart of fine particle SV5 obtained in 2) of Example 2 is shown. An NMR observation chart of the fine particle SV10 obtained in 2) of Example 2 is shown. The NMR observation chart of fine particle SV15 obtained in 2) of Example 2 is shown. 4 is an electron micrograph of a honeycomb porous body having fine particles obtained in 3) of Example 2. FIG. 4 is an electron micrograph of a honeycomb-like porous body (with heating for 1 hour) having fine particles obtained in Example 3. FIG. 4 is an electron micrograph of a honeycomb-shaped porous body (heating for 9 hours) having fine particles obtained in Example 3. FIG. 4 is an electron micrograph of a honeycomb-shaped porous body having fine particles obtained in Example 4. FIG. 4 is an electron micrograph of a honeycomb porous body having fine particles obtained in Example 5. FIG.

Claims (11)

  A honeycomb-like porous body comprising a water-insoluble polymer having a drug, metal nanoparticles and / or a dye.   The honeycomb-shaped porous material comprising a water-insoluble polymer according to claim 1, wherein the porous material comprises the drug, the metal nanoparticle, and / or the dye by holding the drug, the metal nanoparticle, and / or the fine particle comprising the polymer carrying the dye. Body.   The honeycomb-shaped porous body made of a water-insoluble polymer according to claim 2, wherein fine particles made of a polymer carrying a drug, metal nano-particles and / or a pigment are held in the pores of the honeycomb-shaped porous body.   3. From the water-insoluble polymer according to claim 2, wherein a part or all of the fine particles comprising a polymer carrying a drug, metal nanoparticles and / or a dye are embedded and held in a honeycomb porous body. A honeycomb-like porous body.   The honeycomb-shaped porous body made of a water-insoluble polymer according to any one of claims 2 to 4, wherein the fine particles have a particle size of 0.01 to 50 µm.   A carrier for drug delivery, which is a honeycomb-like porous body made of a water-insoluble polymer having a drug.   The carrier for drug delivery according to claim 6, which is a honeycomb-like porous body made of a water-insoluble polymer having a drug by holding fine particles made of a polymer carrying the drug.   The carrier for drug delivery according to claim 7, which is a honeycomb-like porous body made of a water-insoluble polymer in which fine particles made of a polymer carrying a drug are held in pores of the honeycomb-like porous body.   The honeycomb-shaped porous body made of a water-insoluble polymer in which all or part of fine particles made of a polymer carrying a drug are embedded and held in the honeycomb-shaped porous body. Drug delivery carrier.   The carrier for drug delivery according to any one of claims 7 to 9, wherein the particle size of the fine particles is 0.01 µm to 50 µm. The carrier for drug delivery according to any one of claims 6 to 10, which is a carrier for inducing or promoting cell proliferation or differentiation.