Metal organic framework and method for producing the same

Abstract

To provide a cyclodextrin metal-organic framework that can be produced without requiring a prolonged duration or an excessive amount of organic solvents, and has an increased content of pharmacologically active substance, and a method for producing the same.SOLUTION: A cyclodextrin metal-organic framework includes cyclodextrin and alkali metal and is in the form of spherical and hollow fine particles.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a metal-organic framework and a method for producing the same. [Background technology]

[0002] Metal-organic frameworks (MOFs) are known to have a larger specific surface area and higher thermal and chemical stability than conventional porous materials. Furthermore, a variety of structures can be formed by selecting the combination of metal and organic compound depending on the purpose, and therefore MOFs are expected to be applied in a variety of fields, particularly in gas storage and separation, and catalysis.

[0003] Among these, MOFs prepared using cyclodextrin (CD) as an organic molecule (CD-MOF) have attracted attention in the pharmaceutical field due to their low cost, high biodegradability, and high safety. Therefore, there is a demand for cyclodextrin metal-organic frameworks (CD-MOFs) that can encapsulate large amounts of pharmacologically active substances or pharmacologically active substances with large molecular weights, as well as a simple method for their production.

[0004] Known methods for producing cyclodextrin metal organic frameworks include, for example, the vapor diffusion method and the anti-solvent crystallization method (e.g., Non-Patent Documents 1 and 2). However, these methods have problems such as a long production time, low yield, inability to support large amounts of pharmacologically active substances or pharmacologically active substances with high molecular weights, and the use of large amounts of organic solvents that impose a burden on the environment. Therefore, these methods cannot be said to be simple and efficient production methods.

[0005] Furthermore, the cyclodextrin metal organic framework obtained by the conventional production method has a high density, a polyhedral shape derived from a crystalline structure, and a large particle size of about several tens of microns, making it unsuitable for use as a pulmonary formulation. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] J. Ind. Eng. Chem. 2019, 72, 50-66. [Non-patent document 2] Int. J. Chem. Eng. Appl. 2013, 4, 337-341. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention has been made in view of the current state of the prior art described above, and a main object of the present invention is to provide a cyclodextrin metal organic framework and a method for producing the same that do not have the above-mentioned problems. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to achieve the above-mentioned object. As a result, they have found that a desired cyclodextrin metal organic framework can be obtained by spray-drying a solution or suspension containing a cyclodextrin and an alkali metal compound. Based on this finding, the present inventors have conducted further research and have completed the present invention. That is, the present invention includes the following features.

[0009] Item 1. A cyclodextrin metal organic framework comprising a cyclodextrin and an alkali metal, the cyclodextrin metal organic framework being in the form of spherical hollow microparticles.

[0010] Item 2. Median diameter D 50 Item 2. The cyclodextrin metal organic framework according to Item 1, wherein the particle size is 0.001 to 10 μm.

[0011] Item 3. The cyclodextrin metal organic framework according to Item 1 or 2, having an aerodynamic diameter of 0.001 to 10 μm.

[0012] Item 4. The cyclodextrin metal organic framework according to any one of Items 1 to 3, having a fine particle fraction (FPF) of 10% or more.

[0013] Item 5. Micropore volume is 0.00001 to 0.30 cm 3 Item 5. The cyclodextrin metal organic framework according to any one of Items 1 to 4, wherein the cyclodextrin metal organic framework has a molecular weight of 1000 or more.

[0014] Item 6. Specific surface area is 0.01 to 1000 m 2 Item 6. The cyclodextrin metal organic framework according to any one of Items 1 to 5, wherein the cyclodextrin metal organic framework has a molecular weight of 1000 or more.

[0015] Item 7. The cyclodextrin metal organic framework according to any one of Items 1 to 6, which is in a crystalline form.

[0016] Item 8. The cyclodextrin metal organic framework according to any one of Items 1 to 6, which is amorphous.

[0017] Item 9. The cyclodextrin metal organic framework according to any one of Items 1 to 8, which encapsulates a pharmacologically active substance.

[0018] Item 10. The cyclodextrin metal organic framework according to any one of Items 1 to 9, wherein the amount of the pharmacologically active substance encapsulated is 0.01 to 50% by mass, where the total mass of the cyclodextrin and alkali metal in the metal organic framework is 100% by mass.

[0019] Item 11. The cyclodextrin metal organic framework according to any one of Items 1 to 10, which is used for pulmonary administration.

[0020] Item 12. A method for producing a cyclodextrin metal organic framework according to items 1 to 11, (A) mixing a cyclodextrin and an alkali metal compound to a predetermined composition to obtain a precursor aqueous solution or suspension; and (B) A step of spray-drying the precursor aqueous solution or suspension to obtain a dry powder containing the metal-organic framework. A method for producing a cyclodextrin metal organic framework, comprising:

[0021] Item 13. The method for producing a cyclodextrin metal organic framework according to Item 12, wherein the temperature during spray drying in the step (B) is 100 to 200°C.

[0022] Item 14. (C) A step of redispersing the dry powder in an organic solvent to improve the crystallinity of the metal-organic framework. Item 14. The method for producing a cyclodextrin metal organic framework according to Item 12 or 13, further comprising:

[0023] Item 15. The method for producing a cyclodextrin metal organic framework according to any one of Items 12 to 14, wherein the precursor aqueous solution or suspension contains an organic solvent.

[0024] Item 16. The method for producing a cyclodextrin metal organic framework according to Item 14 or 15, wherein the organic solvent is ethanol.

[0025] Item 17. The method for producing a cyclodextrin metal organic framework according to any one of Items 12 to 16, wherein the precursor aqueous solution or suspension further contains a pharmacologically active substance. [Effects of the Invention]

[0026] According to the present invention, it is possible to provide a cyclodextrin metal organic framework which has a low density, a particle size one order of magnitude smaller than conventional ones, and is capable of encapsulating a large amount of a pharmacologically active substance or a high-molecular-weight pharmacologically active substance.

[0027] According to the production method of the present invention, the amount of organic solvents used, which places a burden on the environment, can be reduced compared to conventional methods, and the target cyclodextrin metal organic framework can be provided in a short time and in a high yield. [Brief explanation of the drawings]

[0028] [Figure 1] 1A and 1B are diagrams illustrating a metal organic framework and a method for producing the same according to the present invention. [Figure 2] FIG. 1 is a diagram illustrating a spray drying method carried out in the present invention. [Figure 3] (a) and (b) are scanning electron microscope (SEM) images of the metal-organic frameworks obtained in Examples 1 and 2, respectively. (c) is an SEM image of microparticles obtained by spray-drying γ-cyclodextrin (γ-CD) and levofloxacin (LVFX). [Figure 4] (d) is a powder X-ray diffraction (PXRD) pattern of the metal organic framework (spray drying) and untreated γ-CD obtained in Example 1. (e) is a PXRD pattern of the metal organic framework (spray drying) obtained in Example 2, untreated γ-CD, and untreated LVFX. [Figure 5] (a) to (f) are the adsorption / desorption isotherms and BET specific surface areas of the metal organic frameworks obtained in Comparative Example 1, Comparative Example 3, Example 1, Comparative Example 2, Comparative Example 4, and Example 2, respectively. [Figure 6] (a) and (b) are SEM images of the metal organic frameworks obtained in Comparative Example 4 and Example 2, respectively, and element maps of oxygen, fluorine, and potassium (O, F, and K elements) obtained by energy dispersive X-ray analysis (EDX). [Figure 7] 1 shows the in vitro inhalation characteristics of the metal-organic frameworks obtained in Comparative Example 4 and Example 2. [Figure 8] FIG. 1 is a diagram for schematically explaining the manufacturing method of Examples 3 and 4. [Figure 9] A and B are SEM images of the metal organic frameworks obtained in Examples 3 and 4, respectively. C and D are PXRD patterns of the metal organic frameworks obtained in Examples 3 and 4 (a) after redispersion in ethanol and (b) before redispersion in ethanol, respectively. E and F are the adsorption / desorption isotherms and BET specific surface areas of the metal organic frameworks obtained in Examples 3 and 4, respectively. [Figure 10] 10 is a diagram for schematically explaining the manufacturing method of Example 5. FIG. [Figure 11]A and B are SEM images of the metal organic frameworks obtained in Examples 5 and 6, respectively. C and D are PXRD patterns of the metal organic frameworks obtained by the production methods (a) after the improvement and (b) before the improvement in Examples 5 and 6, respectively. E and F are the adsorption / desorption isotherms and BET specific surface areas of the metal organic frameworks obtained in Examples 5 and 6, respectively. [Figure 12] 1 shows the in vitro inhalation characteristics of the metal-organic frameworks obtained in Examples 2 and 6. [Figure 13] FIG. 1 is a diagram for schematically explaining the manufacturing methods of Comparative Examples 1 and 2 by the vapor diffusion method, which is a conventional technique. [Figure 14] 1(a) and 1(c) are scanning electron microscope (SEM) images of the metal organic frameworks obtained in Comparative Examples 1 and 2, respectively. [Figure 15] FIG. 1 is a diagram for schematically explaining the production methods of Comparative Examples 3 and 4 using a conventional anti-solvent crystallization method. [Figure 16] (b) and (d) are scanning electron microscope (SEM) images of the metal organic frameworks obtained in Comparative Examples 3 and 4, respectively. [Figure 17] (e) is the PXRD pattern of the metal organic framework (vapor diffusion) obtained in Comparative Example 1, the metal organic framework (poor solvent crys.) obtained in Comparative Example 3, and untreated γ-CD. (f) is the PXRD pattern of the metal organic framework (vapor diffusion) obtained in Comparative Example 2, the metal organic framework (poor solvent crys.) obtained in Comparative Example 4, untreated γ-CD, and untreated LVFX. [Figure 18] 1(a) and 1(b) are scanning electron microscope (SEM) images of the metal organic frameworks obtained in Comparative Example 3 and Example 1, respectively, after being intentionally crushed. DETAILED DESCRIPTION OF THE INVENTION

[0029] In this specification, the term "comprise" is a concept that encompasses all of "comprise," "consist essentially of," and "consist only of."

[0030] In this specification, the expression "A to B" indicating a range of values ​​means "greater than or equal to A and less than or equal to B."

[0031] In this specification, the term "metal organic framework" refers to a general term for a substance in which a metal and an organic compound form a three-dimensional structure continuously and with regularity, and which has porosity controlled at the nano level, regardless of whether the substance is in a crystalline or amorphous form.

[0032] In this specification, the term "spherical" refers to a shape that can be recognized as spherical in appearance when observed under a magnified electron microscope.

[0033] In this specification, the term "hollow fine particles" refers to fine particles having a cavity inside the particle.

[0034] 1. Cyclodextrin Metal-Organic Framework The cyclodextrin metal organic framework of the present invention comprises a cyclodextrin and an alkali metal, and is in the form of spherical hollow fine particles.

[0035] The metal organic framework contains a cyclodextrin and an alkali metal in a specific composition ratio, which is preferably about 1:40 to 40:1 in terms of the amount of substance (molar) ratio, more preferably about 1:16 to 16:1, and even more preferably about 1:8 to 8:1.

[0036] As the cyclodextrin, any cyclodextrin widely known in this field or its derivatives can be used.

[0037] The cyclodextrin may be any of α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD). Of these, β-CD and γ-CD are preferred, with γ-CD being more preferred, due to their large pores that can encapsulate pharmacologically active substances.

[0038] The cyclodextrin derivatives include those having a substituent on the hydroxyl group on the glucose constituting the cyclodextrin. Examples of the substituent include an alkyl group having 1 to 10 carbon atoms which may have a hydroxyl group, a sulfonyl group, etc. Examples of the alkyl group having 1 to 10 carbon atoms which may have a hydroxyl group include a methyl group, an ethyl group, and a 2-hydroxypropyl group.

[0039] The cyclodextrin or a derivative thereof (hereinafter, these may be collectively referred to as "cyclodextrin") may form an inclusion complex with a guest molecule. As the guest molecule, a wide variety of known compounds can be used depending on the type of cyclodextrin used. In this case, the metal organic framework can encapsulate the guest molecule, optionally together with a pharmacologically active substance described below, within itself, and the guest molecule can be released upon decomposition of the metal organic framework.

[0040] Examples of alkali metals that can be used in the present invention include lithium, sodium, potassium, rubidium, and cesium. From the viewpoint of safety for the human body, potassium and sodium are preferred, and potassium is more preferred.

[0041] The cyclodextrin metal-organic framework of the present invention has the following properties:

[0042] The metal organic framework has a spherical shape, not a polyhedron. Specifically, the ratio of the tangential diameter in a fixed direction to the diameter of the circle equivalent to the projected area, determined from an image observed by an electron microscope, is usually 0.83 to 1.2.

[0043] The median diameter D of the metal-organic framework 50 is usually 50 μm or less, preferably 0.1 to 10 μm, more preferably 0.3 to 7 μm, and even more preferably 0.5 to 6 μm. 50 is a value measured by a laser diffraction / scattering method.

[0044] The aerodynamic diameter of the metal-organic framework is usually 50 μm or less, preferably 0.1 to 10 μm, more preferably 0.3 to 7 μm, and even more preferably 0.5 to 6 μm. The aerodynamic diameter of the metal-organic framework is a value calculated by the following formula (1).

[0045]

number

[0046] In the formula, D 50 is the median diameter, ρ P is the particle density, ρ * indicates true density.

[0047] The emitted fraction (EF) of the metal-organic framework is usually 70% or more, preferably 75% or more, more preferably 80% or more, and even more preferably 85% or more. The emitted fraction (EF) of the metal-organic framework is a value calculated using an Andersen cascade impactor (ACI) according to the following formula (2):

[0048]

number

[0049] In the formula, total recovered drug indicates the total amount of drug recovered, and emitted dose is the amount of pharmacologically active substance delivered, which indicates the mass of drug released from the capsule.

[0050] The fine particle fraction (FPF) of the metal-organic framework is usually 5% or more, preferably 10% or more, more preferably 20% or more, and even more preferably 25% or more. The fine particle fraction (FPF) of the metal-organic framework is a value calculated using an Andersen cascade impactor (ACI) according to the following formula (3):

[0051]

number

[0052] In the formula, emitted dose is the amount of pharmacologically active substance delivered and indicates the mass of drug released from the capsule, and fine particle dose is the fine particle content and indicates the mass of drug that reaches stage 2 and later stages.

[0053] The micropore volume of the metal organic framework is typically 1.0 cm 3 / g or less, 0.00001 to 0.30 cm 3 / g is preferred, and 0.0001 to 0.20 cm 3 / g is more preferable, and 0.001 to 0.13 cm 3 / g is more preferable. In this specification, "micropore" means a pore having a diameter of 2 nm or less in the metal-organic framework, and "micropore volume" means the total volume of the micropores in the metal-organic framework.

[0054] The total pore volume of the metal organic framework is typically 1.0 cm 3 / g or less, 0.00001 to 0.5 cm 3 / g is preferred, and 0.0001 to 0.40 cm 3 / g is more preferable, and 0.001 to 0.20 cm 3 In this specification, "total pores" means all of the micropores, mesopores, and macropores in the metal organic framework, and "total pore volume" means the sum of the volumes of all pores in the metal organic framework.

[0055] The specific surface area of ​​the metal organic framework is usually 1000 m 2 / g or less, and 0.01 to 750m 2 / g is preferred, and 0.1 to 500m 2 / g is more preferable, and 1 to 300m 2 The specific surface area of ​​the metal organic framework is a value measured by the BET method.

[0056] The bulk density of the metal organic framework is typically 1000 mg / cm 3 or less, 1 to 500 mg / cm 3 is preferred, and 10 to 300 mg / cm 3 More preferably, 100 to 250 mg / cm 3 is more preferable.

[0057] The tap density of the metal-organic framework is typically 1000 mg / cm 3 or less, 1 to 500 mg / cm 3 is preferred, and 10 to 350 mg / cm 3 More preferably, 100 to 300 mg / cm 3 is more preferable.

[0058] The true density of the metal organic framework is typically 2000 mg / cm 3 or less, 10 to 1500 mg / cm 3 is preferred, and 100 to 1450 mg / cm 3 More preferably, 1000 to 1410 mg / cm 3 is more preferable.

[0059] The metal organic framework may be crystalline or amorphous in form, but is preferably crystalline from the viewpoint of the amount of pharmacologically active substance carried and the inhalation properties as a pulmonary preparation.

[0060] When the metal organic framework is in a crystalline form, it has a peak at at least one of 2θ=4°, 7°, and 17° in its powder X-ray diffraction pattern. Alternatively, when the metal organic framework is in a crystalline form, the crystallinity of the metal organic framework is preferably 70% or more, more preferably 80 to 100%, and even more preferably 90 to 100%. Here, the "crystallinity" is determined from the powder X-ray diffraction pattern by the formula: crystallinity=crystalline peak area / (crystalline peak area+amorphous peak area)×100%.

[0061] When the metal organic framework is amorphous, the powder X-ray diffraction pattern has no peak at 2θ=4°, 7°, or 17°. Alternatively, when the metal organic framework is amorphous, the crystallinity of the metal organic framework is preferably less than 30%, more preferably 0 to 20%, and even more preferably 0 to 10%. Here, the "crystallinity" is determined as described above.

[0062] The metal organic framework can encapsulate (support) a pharmacologically active substance (drug). Examples of the pharmacologically active substance include pharmacologically active substances used as antifungal drugs, anti-inflammatory drugs, antihyperlipidemic drugs, antihypertensive drugs, and antianginal drugs. Furthermore, the metal organic framework of the present invention can contain, in addition to the pharmacologically active substance, active ingredients widely used in the fields of cosmetics and food.

[0063] The metal-organic framework can encapsulate (support) both hydrophilic and hydrophobic pharmacologically active substances because the CD-MOF has hydrophilic and hydrophobic pores. Examples of the pharmacologically active substances include hydrophilic pharmacologically active substances such as levofloxacin, ofloxacin, garenosaxin methylate, sitafloxacin, flucytosine, and acetaminophen, and hydrophobic pharmacologically active substances such as ibuprofen, ketoprofen, lansoprazole, ketoconazole, celecoxib, fenofibrate, carvedilol, indomethacin, rifampicin, and budesonide.

[0064] The metal organic framework is a fine particle having a cavity inside the particle, and therefore can encapsulate (support) a pharmacologically active substance with a relatively large molecular weight compared to ordinary metal organic frameworks. Therefore, the molecular weight of the pharmacologically active substance is usually about 2 to 20,000, preferably about 50 to 5,000, more preferably about 100 to 1,000, and even more preferably about 300 to 500.

[0065] In this way, the metal organic framework of the present invention can be used as various preparations, such as pulmonary preparations, oral preparations, transdermal preparations, nasal preparations, etc. Among these, it is preferable to use it as a pulmonary preparation from the viewpoint of low density, spherical fine particles, etc.

[0066] The metal organic framework of the present invention can also be used as a biological imaging probe. In this case, the metal organic framework can encapsulate (support) a wide range of known imaging probes. Examples of the imaging probes include fluorescent organic molecules for optical imaging, metal nanoparticles, quantum dots, positron-emitting nuclides for positron emission tomography (PET), and contrast agents for nuclear magnetic resonance imaging (MRI).

[0067] The content of the pharmacologically active substance in the metal organic framework is preferably 0.01 to 70 mass %, more preferably 0.1 to 60 mass %, and even more preferably 1 to 50 mass %, with the mass of the metal organic framework being 100 mass %.

[0068] In addition to the above components, the metal organic framework may contain appropriate additives, such as surfactants, pH adjusters, and polymers, as long as the additives do not impair the effects of the present invention.

[0069] 2.Method for producing cyclodextrin metal organic framework The method for producing the cyclodextrin metal organic framework of the present invention is carried out by a spray drying method.

[0070] Specifically, the production method of the present invention includes the steps of: (A) mixing a cyclodextrin and an alkali metal compound to a predetermined composition to obtain a precursor aqueous solution or suspension; and (B) A step of spray-drying the precursor aqueous solution or suspension to obtain a dry powder containing the metal-organic framework. Equipped with. (2-1) Process (A) In step (A), cyclodextrin, an alkali metal compound, and water are mixed by a known method to obtain a precursor aqueous solution or suspension.

[0071] The precursor aqueous solution or suspension is obtained by mixing cyclodextrin and an alkali metal compound at a specific content ratio. The content ratio is preferably about 1:40 to 40:1 in terms of the amount of substance (molar) based on the cyclodextrin and the alkali metal contained in the alkali metal compound, more preferably about 1:16 to 16:1, and even more preferably about 1:8 to 8:1. In this case, the metal organic framework of the present invention can contain cyclodextrin and alkali metal at the specific composition ratio.

[0072] As the cyclodextrin, any cyclodextrin widely known in this field or its derivatives can be used.

[0073] The cyclodextrin may be any of α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD). Of these, β-CD and γ-CD are preferred, with γ-CD being more preferred, due to their large pores that can support pharmacologically active substances.

[0074] The cyclodextrin derivatives include those having a substituent on the hydroxyl group on the glucose constituting the cyclodextrin. Examples of the substituent include an alkyl group having 1 to 10 carbon atoms which may have a hydroxyl group, a sulfonyl group, etc. Examples of the alkyl group having 1 to 10 carbon atoms which may have a hydroxyl group include a methyl group, an ethyl group, and a 2-hydroxypropyl group.

[0075] The cyclodextrin or its derivative (hereinafter, these may be collectively referred to as "cyclodextrin") may form an inclusion complex with a guest molecule. As the guest molecule, a wide range of known compounds can be used depending on the type of cyclodextrin used.

[0076] The content of the cyclodextrin in the precursor aqueous solution or suspension is preferably 0.01 to 50 mass%, more preferably 0.1 to 30 mass%, and even more preferably 1 to 10 mass%, from the viewpoint of particle size, where the mass of the precursor aqueous solution or suspension is 100 mass%.

[0077] Examples of the alkali metal compound include hydroxides, carbonates, and hydrogen carbonates of alkali metals such as lithium, sodium, potassium, rubidium, and cesium. From the viewpoint of safety for the human body, potassium hydroxide and sodium hydroxide are preferred, and potassium hydroxide is more preferred.

[0078] The content of the cyclodextrin in the precursor aqueous solution or suspension is preferably 0.01 to 50 mass%, more preferably 0.1 to 30 mass%, and even more preferably 1 to 10 mass%, from the viewpoint of particle size, where the mass of the precursor aqueous solution or suspension is 100 mass%.

[0079] The precursor aqueous solution or suspension may further contain an organic solvent, which improves the crystallinity of the CD-MOF, improves the inhalation properties of the pulmonary formulation, and increases the amount of pharmacologically active substance encapsulated.

[0080] The content of the organic solvent in the precursor aqueous solution or suspension is preferably 0.01 to 100 mass%, more preferably 0.1 to 70 mass%, and even more preferably 1 to 40 mass%, based on 100 mass% of the precursor aqueous solution or suspension.

[0081] As the organic solvent that can be used in the present invention, a wide variety of known polar solvents can be used as long as they do not adversely affect the cyclodextrin metal organic framework. Among them, from the viewpoint of the crystallinity of the metal organic framework, alcohols, ethers, etc. are preferred, alcohols having 1 to 10 carbon atoms such as methanol, ethanol, and propanol are more preferred, and ethanol is even more preferred.

[0082] The precursor aqueous solution or suspension can contain the pharmacologically active substance. In this case, the pharmacologically active substance can be encapsulated in the cyclodextrin metal organic framework obtained by the production method of the present invention. The precursor aqueous solution or suspension will be a precursor aqueous solution if the pharmacologically active substance is a water-soluble pharmacologically active substance, and will be a precursor suspension if the pharmacologically active substance is a poorly water-soluble pharmacologically active substance.

[0083] When the pharmacologically active substance is a poorly water-soluble pharmacologically active substance, it can be appropriately solubilized by widely known methods such as emulsification, formation of amorphous nanoparticles, addition of an amphiphilic polymer compound, etc. Therefore, the metal organic framework of the present invention can also encapsulate a wide range of poorly water-soluble pharmacologically active substances.

[0084] The content of the pharmacologically active substance in the precursor aqueous solution or suspension is preferably 0.01 to 200% by mass, more preferably 0.1 to 100% by mass, and even more preferably 1 to 50% by mass, where the total mass of the cyclodextrin and alkali metal is 100% by mass. In this case, the metal organic framework of the present invention can support the pharmacologically active substance at the above content.

[0085] In addition to the cyclodextrin and alkali metal compound, additives such as surfactants, pH adjusters, and polymers can be added to the precursor aqueous solution or suspension as needed, provided that the effects of the present invention are not impaired.

[0086] The temperature at which the precursor aqueous solution or suspension is prepared is usually 100° C. or lower, preferably 0 to 80° C., more preferably 10 to 60° C., and even more preferably 20 to 40° C. The temperature can be appropriately adjusted by heating or cooling as long as it does not adversely affect the pharmacologically active substance used.

[0087] The viscosity of the precursor aqueous solution or suspension is usually 1000 mPa / s or less, preferably 0.1 to 500 mPa / s, more preferably 1 to 100 mPa / s, and even more preferably 5 to 50 mPa / s.

[0088] The aqueous precursor solution or suspension is usually neutral or alkaline, and the pH of the aqueous precursor solution or suspension is usually preferably about 5-14, more preferably 6-13, and even more preferably 7-12. (2-2) Process (B) In step (B), the aqueous precursor solution or suspension is spray-dried to obtain a dry powder containing the metal organic framework.

[0089] The spray drying of the present invention is carried out using a known spray dryer comprising a gas flow path, a heater, a liquid pump, a sprayer, a drying chamber, a cyclone, a nozzle, a filter, and the like.

[0090] In the production method of the present invention, the inlet temperature during the spray drying is usually 100°C or higher, preferably 100 to 220°C, more preferably 110 to 170°C, and even more preferably 120 to 140°C.

[0091] In the spray drying method, the flow rate of the precursor aqueous solution or suspension is usually 0.1 ml / h or more, preferably 1 to 10 ml / h, more preferably 3 to 7 ml / h, and even more preferably 4 to 6 ml / h.

[0092] In the above spray drying method, the gas flow rate is usually 1 L / h or more, preferably 10 to 3500 L / h, more preferably 100 to 2000 L / h, and even more preferably 400 to 1000 L / h.

[0093] The nozzle that can be used in the spray drying method may be any of a two-fluid nozzle, a three-fluid nozzle, and an ultrasonic nozzle, with a two-fluid nozzle being preferred from the viewpoint of particle size and the like.

[0094] The diameter of the nozzle is usually 0.001 mm or more, preferably 0.001 to 10 mm, more preferably 0.01 to 5 mm, and even more preferably 0.1 to 1 mm.

[0095] In the production method of the present invention, the production time of the metal organic framework is usually less than one day, preferably 10 minutes to 12 hours, more preferably 30 minutes to 6 hours, and even more preferably 1 hour to 3 hours. Here, the "time required to produce the metal organic framework" means the time from the start of step (A) to the end of step (B). (2-3) Process (C) In the production method of the present invention, after the above steps (A) and (B), (C) Optionally, redispersing the dry powder in an organic solvent to adjust the crystallinity of the metal-organic framework. In this case, the crystallinity of the cyclodextrin metal organic framework is improved, the inhalation properties as a pulmonary preparation are improved, and the amount of the pharmacologically active substance encapsulated is also improved.

[0096] As the organic solvent that can be used in step (C), a wide variety of known polar solvents can be used as long as they do not adversely affect the cyclodextrin metal organic framework, as with the above organic solvents. Among them, from the viewpoint of the crystallinity of the metal organic framework, alcohols, ethers, etc. are preferred, alcohols having 1 to 10 carbon atoms such as methanol, ethanol, and propanol are more preferred, and ethanol is even more preferred.

[0097] The amount of the organic solvent used in step (C) is usually 500% by mass or less, preferably 0.01 to 200% by mass, more preferably 0.1 to 100% by mass, and even more preferably 1 to 50% by mass, based on 100% by mass of the dry powder.

[0098] The organic solvent used in step (C) may contain a pharmacologically active substance, in which case the pharmacologically active substance can be encapsulated in the metal organic framework of the present invention. [Example]

[0099] EXAMPLES Hereinafter, examples and comparative examples will be shown to further clarify the features of the present invention, but the present invention is not limited to the following examples.

[0100] [Example 1] Preparation of CD-MOF by spray drying method Metal organic framework fine particles were produced by spray drying a precursor aqueous solution containing potassium hydroxide and γ-CD (Fig. 1). The precursor aqueous solution was prepared by dissolving 200 mM potassium hydroxide and 25 mM γ-CD in 100 mL of water (Fig. 2). The inlet temperature, liquid flow rate, and gas flow rate of the spray drying were 130°C, 5.5 mL, and 473 L / h, respectively. The aspirator was set at approximately 35 m 3 The maximum gas flow rate was set at 1 / h. A two-fluid nozzle with a diameter of 0.7 mm and a mini spray dryer (B-290, Buchi K.K.) were used. Compressed air was used as the drying gas. After preparation, the spray-dried particles were collected for analysis. The yield was 80%.

[0101] [Example 2] Preparation of pharmacologically active substance-loaded CD-MOF by spray drying method The metal organic framework encapsulating levofloxacin (LVFX) was produced by dissolving LVFX (4.0 mg / mL) in the precursor aqueous solution in the same manner as in Example 1. The yield was 90%.

[0102] [Comparative Example 1] Fabrication of CD-MOFs by vapor diffusion method CD-MOF crystals were produced by the conventional vapor diffusion method. In a closed system as shown in Figure 13, excess methanol in an outer bottle was slowly diffused into an aqueous solution (15 mL) containing 8.0 mM potassium hydroxide and 1.0 mM γ-CD in an inner bottle. After 7 days, the cubic crystals adhering to the wall of the inner bottle were collected. After filtration, the collected CD-MOF cubic crystals were placed in a vacuum dryer and dried for 6 hours. These were then subjected to the analysis described below. The yield was 15%.

[0103] Comparative Example 2 Preparation of pharmacologically active substance-loaded CD-MOFs by vapor diffusion method CD-MOF crystals encapsulating levofloxacin (LVFX) were produced in the same manner as in Comparative Example 1, except that LVFX (4.0 mg / mL) was further dissolved in the aqueous solution. The yield was 20%.

[0104] Comparative Example 3 Preparation of CD-MOF by antisolvent crystallization CD-MOF crystals were prepared by the conventional antisolvent crystallization method, specifically by adding an antisolvent to a solution containing the base component. 200 mM potassium hydroxide and 25 mM γ-CD were completely dissolved in water (60 mL) to obtain an aqueous solution. As shown in Figure 15, ethanol (40 mL) was added to the aqueous solution, and the mixture was stirred at 400 rpm for 20 minutes and then placed in a cold water bath at 15 °C for 24 hours, resulting in crystal growth. The CD-MOF crystals at the bottom of the suspension were collected by filtration. The collected CD-MOF crystals were dried in a vacuum dryer for 6 hours and subjected to the analysis described below. The yield was 55%.

[0105] Comparative Example 4 Preparation of pharmacologically active substance-loaded CD-MOF by antisolvent crystallization method CD-MOF crystals encapsulating levofloxacin (LVFX) were produced in the same manner as in Comparative Example 3, except that LVFX (4.0 mg / mL) was further dissolved in the aqueous solution before the addition of ethanol. The yield was 60%.

[0106] The samples obtained in Examples 1 and 2 and Comparative Examples 1 to 4 were evaluated for the following items.

[0107] (Particle size distribution measurement) The powder size was determined by laser diffraction using a Mastersizer particle size analyzer (Spectris, Malvern Panalytical Division). The powder samples were injected into an air jet under a pressure of 0.3 MPa. 50 indicates the median particle diameter. The detection limit for particle size was in the range of 100 to 2000 nm.

[0108] (Scanning electron microscope (SEM) observation) Images of the dried powder were randomly captured using a scanning electron microscope (SEM; MiniscopeTM3030, Hitachi High-Tech). The powder sample was fixed to a metal stub with carbon tape and coated with a thin layer of platinum (E-1045, Hitachi High-Tech) under vacuum conditions. The accelerating voltage during analysis was 15 kV.

[0109] (Powder X-ray Diffraction (PXRD)) The crystallinity of the particles was evaluated using a SmartLab X-ray diffractometer (Rigaku) ​​at 30 kV and 15 mA with a scan rate of 4° / min over a 2θ range of 5–35°. The samples were flattened in the wells of a glass plate.

[0110] (Nitrogen gas adsorption method) Nitrogen adsorption / desorption isotherms were evaluated at 77 K using a BELSORP-max (MicrotracBel). The degassing temperature was 50 °C under vacuum. Brunauer-Emmett-Teller (BET) surface areas were calculated from the adsorption isotherms. To estimate the surface area, adsorption isotherms with P / P0 in the range of 0.05 to 0.3 were applied to the BET equation. Micropore volume was calculated using α s The total pore volume was calculated using the nitrogen adsorption amount at P / P = 0.99.

[0111] (Energy Dispersive X-ray Analysis (EDX)) Elemental maps of the CD-MOF particles were acquired using an EMAX Evolution EDX (Horiba). Energy-dispersive X-ray spectra from each particle were analyzed using a vector-based algorithm to assess the relative abundance of each of the three elements: oxygen (O), fluorine (F), and potassium (K).

[0112] (particle density and aerodynamic diameter) A CD-MOF powder sample (250 mg) was placed in a 5 mL graduated cylinder. The bulk density was calculated from the quotient of the mass and volume of the powder sample. Next, the graduated cylinder filled with the CD-MOF powder sample was gently tapped 100 times until the volume of the powder sample remained constant. The tapped density was calculated from the quotient of the weight and tapped volume of the sample. The true density of the CD-MOF powder sample was determined using a gas pycnometer (AccuPyc1330; Shimadzu Corporation). The bulk density, true density, and D of the CD-MOF powder sample were 50 From this, the theoretical aerodynamic diameter was calculated using the following formula:

[0113]

number

[0114] In the formula, D 50 is the median diameter, ρ P Bulk density, ρ * indicates true density.

[0115] (X-ray photoelectron spectroscopy (XPS)) The surface elemental composition of the powder samples was measured using a JPS-9000MX spectrometer (JEOL) equipped with an MgKα radiation excitation source (10 kV, 10 mA). The pressure in the chamber was 1 × 10 -5 The radiation intensity was less than 100 Pa. Fluorine, potassium, oxygen, and carbon were detected. No radiation damage was observed during data acquisition.

[0116] (High-Performance Liquid Chromatography (HPLC)) Levofloxacin (LVFX) concentration was measured at 40°C using COSMOSIL C 18The absorbance was determined by high-performance liquid chromatography (HPLC; e2695 and 2489; Waters, Milford) equipped with a reversed-phase column (Nacalai Tesque Inc.). The detection wavelength was 295 nm, and the injection volume was 10 μL. The flow rate of the mobile phase, consisting of acetonitrile and 60 mM potassium dihydrogen phosphate (15 / 85, v / v), was maintained at 0.7 mL / min. The absorbance peak appeared approximately 6 minutes after the start of the run. The pharmacologically active substance content in a fixed amount of sample was evaluated.

[0117] (in vitro inhalation properties) The in vitro inhalation performance of CD-MOF particles was evaluated using an Andersen cascade impactor (ACI) (AN-200 system; Tokyo Dylec Corp.), which mimics the human lung. Each sample formulation (10 mg) was inserted into a size 2 hydroxypropyl methylcellulose capsule (Qualicaps). The capsules filled with the sample formulation were placed in a transpulmonary powder inhaler. The collection plate of each stage was immersed in a 2% (v / v) hexane solution of silicone to create a silicone layer to reduce particle rebound. A gentle inhalation rate (28.3 L / min) was set to simulate patients suffering from respiratory disease, and the inhalation time was adjusted to achieve a total airflow of 4 L. The proportion of pharmacologically active substance trapped in each stage was evaluated by HPLC. The inhalation performance of each sample formulation, i.e., the emitted fraction (EF) and fine particle fraction (FPF), were calculated using the following equations (2) and (3).

[0118]

number

[0119]

number

[0120] In the formula, total recovered drug indicates the total amount of drug recovered, emitted dose is the amount of pharmacologically active substance delivered and indicates the mass of drug released from the capsule, and fine particle dose is the fine particle content and indicates the mass of drug that reaches stage 2 and later stages.

[0121] The results of the evaluation of the above items are shown in Tables 1 to 3 and Figures 3 to 7.

[0122] As shown in Figure 3, the metal organic frameworks of Examples 1 and 2 were spherical and hollow microparticles, regardless of the presence or absence of levofloxacin (Figures 3(a) and (b)). The surfaces of the microparticles in Figures 3(a) and (b) were rough, while the surface of the microparticle in Figure 3(c) was smooth. The shells of the microparticles in Figures 3(a) and (b) were more rigid because the metal organic frameworks of the present invention had coordinate bonds between potassium ions and hydroxyl groups.

[0123] Furthermore, as shown in Figure 4, the metal organic frameworks of Examples 1 and 2 did not show sharp diffraction peaks in their powder X-ray diffraction (PXRD) patterns, but showed halo patterns (Figures 4(d) and (e)). This indicated that the cyclodextrin metal organic frameworks of the present invention were amorphous. The morphology was not affected by the presence or absence of levofloxacin.

[0124] In contrast, as shown in Figures 14 and 16, the CD-MOF crystals obtained by conventional techniques (Comparative Examples 1 to 4) have cubic or polyhedral shapes, which are significantly different from spherical microparticles. It is believed that, in both the vapor diffusion method and the antisolvent crystallization method, regularly accumulated cubic crystals were formed by long-term crystal growth. The shape was not affected by the presence or absence of levofloxacin. The results of elemental analysis, described below, revealed that levofloxacin was incorporated into the crystals.

[0125] 17, the CD-MOF crystals of Comparative Examples 1 to 4 have sharp peaks at 2θ=4°, 7°, or 17° in their powder X-ray diffraction (PXRD) patterns. These peaks are not observed in untreated γ-CD and are known to be peaks specific to CD-MOF crystals. Therefore, the morphology of the CD-MOF crystals of Comparative Examples 1 to 4 was clearly crystalline.

[0126] Furthermore, as shown in FIG. 18, the metal-organic framework fine particles of Example 1 were hollow (FIG. 18(b)), whereas the CD-MOF crystal of Comparative Example 3 had no internal cavities and was solid (FIG. 18(a)).

[0127] The properties of each sample are shown in Table 1. The specific surface areas of Examples 1 and 2 are significantly smaller than those of Comparative Examples 1 to 4, and in connection with this, the pore volumes of Examples 1 and 2 are also significantly smaller than those obtained by conventional techniques.

[0128] In addition, with regard to other physical properties, the cyclodextrin metal organic frameworks of Examples 1 and 2 have lower density, smaller particle size, and larger drug encapsulation amounts than those of Comparative Examples 1 to 4. These results demonstrate that the metal organic framework of the present invention is excellent as a pulmonary preparation.

[0129] [Table 1]

[0130] Next, the results of surface elemental analysis by X-ray photoelectron spectroscopy (XPS) are shown in Table 2. Taking into account the results of energy dispersive X-ray analysis (EDX) in Figure 6, it can be said that uniform distribution of oxygen atoms and potassium atoms was confirmed for all samples. The fluorine atoms in Table 2 and Figure 6 are derived from the model drug levofloxacin. Example 2 in Table 2 and Figure 6(b) show that many fluorine atoms are present on the surface of the microparticles. The metal-organic framework of Example 2 can support pharmacologically active substances in sites other than the pores of the CD-MOF crystal, thereby significantly improving the drug loading.

[0131] [Table 2]

[0132] Furthermore, the results of using an Andersen cascade impactor (ACI) to determine the in vitro inhalation characteristics of the metal-organic frameworks obtained in Comparative Example 4 and Example 2 are shown in Figure 7 and Table 3. While most of the CD-MOF crystals of Comparative Example 4 were captured at stage 0 (>11 μm), the metal-organic framework microparticles of Example 2 were able to deliver the drug to deep areas from stage 2 onwards. The metal-organic framework of Example 2 had a fine particle fraction (FPF) of 27.04%, which was equivalent to or higher than that of commercially available powder formulations.

[0133] [Table 3]

[0134] As shown in the following Examples 3 and 4, the crystallinity of each sample obtained in Examples 1 and 2 was improved (FIG. 8).

[0135] [Example 3] Reconstitution of CD-MOF by redispersion in ethanol 0.5 g of the metal-organic framework fine particles obtained in Example 1 was redispersed in 40 mL of ethanol. After 24 hours, it was taken out and dried for 24 hours at 40° C. After drying, the metal-organic framework fine particles were collected for analysis.

[0136] [Example 4] Reconstitution of pharmacologically active substance-loaded CD-MOF by redispersion in ethanol 0.5 g of the metal-organic framework fine particles obtained in Example 2 was redispersed in 40 mL of ethanol. After 24 hours, it was taken out and dried for 24 hours at 40° C. After drying, the metal-organic framework fine particles were collected for analysis.

[0137] The samples obtained in Examples 3 and 4 were analyzed by SEM image observation, powder X-ray diffraction (PXRD), and nitrogen gas adsorption (NGA) methods (Figure 9). The metal-organic framework microparticles of Examples 3 and 4 were spherical hollow microparticles, similar to those of Examples 1 and 2 (Figures 9A and 9B). However, unlike those of Examples 1 and 2, the microparticle surfaces were rough (Figures 9A and 9B). Furthermore, the PXRD patterns of Examples 3 and 4 showed sharp peaks characteristic of CD-MOF crystals (Figures 9C and 9D), and the BET surface areas were nearly four times larger (Figures 9E and 9F). From these changes, it can be concluded that the ethanol redispersion of the metal-organic framework microparticles of Examples 3 and 4 reconstructed the bonds and structures of γ-CD and potassium ions within them, and that the amorphous portions were crystallized into (γ-CD)6 units with pores.

[0138] Based on the results of Examples 3 and 4, the manufacturing methods of Examples 1 and 2 were improved as shown in Examples 5 and 6 below (FIG. 10).

[0139] [Example 5] Preparation of CD-MOFs by an improved spray drying method To improve inhalability, the spray-drying method was modified by changing the composition of the precursor aqueous solvent in the same manner as in Example 1. The precursor aqueous solution contained 35 v / v% ethanol in addition to water. The ethanol was added to the precursor aqueous solution containing 200 mM potassium hydroxide and 25 mM γ-CD immediately before spray-drying. The CD-MOF microparticles after spray-drying were collected for analysis.

[0140] [Example 6] Preparation of pharmacologically active substance-loaded CD-MOFs by an improved spray drying method The metal organic framework encapsulating levofloxacin (LVFX) was produced in the same manner as in Example 5, except that LVFX (4.0 mg / mL) was dissolved in the precursor aqueous solution.

[0141] The samples obtained in Examples 5 and 6 were analyzed by SEM image observation, powder X-ray diffraction (PXRD), and nitrogen gas adsorption (NGA) methods (Fig. 11). The metal-organic framework microparticles of Examples 5 and 6 were spherical hollow microparticles, similar to those of Examples 1 to 4 (Figs. 11A and 11B). However, unlike those of Examples 1 and 2, the microparticle surfaces were rough (Figs. 11A and 11B). Furthermore, the PXRD patterns of Examples 5 and 6 showed sharp peaks characteristic of CD-MOF crystals (Figs. 11C and 11D), and the BET surface areas were several times larger (Figs. 11E and 11F). From these changes, it can be concluded that the metal-organic framework microparticles of Examples 5 and 6 were composed of γ-CD and potassium ions locally forming crystals inside them due to the addition of ethanol before the drying spraying, and that they were composed of a certain proportion of (γ-CD)6 units with pores.

[0142] Furthermore, the results of evaluating various properties of the samples obtained in Examples 5 and 6 are shown in Table 4. Compared with Examples 1 and 2 in Table 1, the metal organic framework fine particles of Examples 5 and 6 have increased specific surface areas and pore volumes, decreased densities, and accordingly, have decreased median diameters D 50 The aerodynamic diameter and in vitro inhalation characteristics were improved (Figure 12). Furthermore, the drug loading was also improved, demonstrating that the formulation is superior in all parameters as a pulmonary formulation.

[0143] [Table 4]

Claims

1. A cyclodextrin metal organic framework comprising a cyclodextrin and an alkali metal, the cyclodextrin metal organic framework being in the form of spherical hollow fine particles, comprising an amorphous metal organic framework, and having a crystallinity of 0% or more and less than 30%.

2. Median diameter D ５０ The cyclodextrin metal organic framework according to claim 1, wherein the particle size is 0.001 to 10 μm.

3. The cyclodextrin metal organic framework according to claim 1, having an aerodynamic diameter of 0.001 to 10 μm.

4. 2. The cyclodextrin metal-organic framework according to claim 1, wherein the fine particle fraction (FPF) is 10% or more.

5. Micropore volume of 0.00001 to 0.30 cm ３ / g.

6. Specific surface area is 0.01 to 300 m ２ / g.

7. The cyclodextrin metal organic framework according to any one of claims 1 to 6, which encapsulates a pharmacologically active substance.

8. The cyclodextrin metal organic framework according to claim 7, which is used for pulmonary administration.

9. A method for producing the cyclodextrin metal organic framework according to claim 1, (A) mixing a cyclodextrin and an alkali metal compound to a predetermined composition to obtain a precursor aqueous solution or suspension; and (B) A step of spray-drying the precursor aqueous solution or suspension to obtain a dry powder containing the metal organic framework. A method for producing a cyclodextrin metal organic framework, comprising:

10. (C) A step of redispersing the dry powder in an organic solvent to improve the crystallinity of the metal-organic framework. The method for producing a cyclodextrin metal-organic framework according to claim 9 , further comprising:

11. The method for producing a cyclodextrin metal-organic framework according to claim 9 , wherein the precursor aqueous solution or suspension contains an organic solvent.

12. The method for producing a cyclodextrin metal organic framework according to claim 10 or 11, wherein the organic solvent is ethanol.

Images