WO2022154463A1

WO2022154463A1 - Metal-organic composite particles and composition comprising metal-organic composite particles

Info

Publication number: WO2022154463A1
Application number: PCT/KR2022/000539
Authority: WO
Inventors: 최경민; 이현신; 강서영
Original assignee: 랩인큐브 주식회사
Priority date: 2021-01-15
Filing date: 2022-01-12
Publication date: 2022-07-21

Abstract

The present invention relates to composite particles which are formed by combination of a metal ion and an organic linker or an organic ligand and have a porous structure capable of supporting a functional material. The composite particles according to the present invention are composite particles formed by combining a metal and an organic material, wherein the composite particles have a structure of which powder X-ray diffraction analysis does not show a peak indicating crystallinity and of which TEM electron diffraction analysis show a ring-shaped diffraction pattern, have a plurality of pores having the size of 1 nm to 10 μm formed thereinside, and include supported active ingredients.

Description

Composition comprising metal-organic composite particles and metal-organic composite particles

The present invention relates to a metal-organic composite particle formed by combining a metal and an organic material.

Nanomaterials that combine molecules to form pores have emerged as a major research field for the past few decades, and are being applied in various fields such as catalysts, adsorption/separation/storage, electronics, health care, semiconductors, food, and detergents.

Nanomaterials having these pores have very high adsorption performance, can control adsorption performance, can create active sites in the backbone, have pore sizes similar to biomolecules, and have excellent ion exchange with most pores ability, and also has insulator, semiconductor and conductor properties.

Among porous materials, a metal organic framework (MOF) is currently receiving the most attention. The metal-organic framework is a porous material in which a metal ion cluster and an organic linker or organic bridging ligands are linked by a coordination bond to form a three-dimensional structure. Since the metal-organic framework has an open pore structure as well as a large surface area, it is possible to move a large amount of molecules or solvents compared to other known porous materials.

However, in the case of metal-organic frameworks, because the pores are very small, it is advantageous for adsorbing or storing monoatomic or molecular gases, but adsorbs substances with a larger size than molecular gases such as drugs, proteins, DNA, RNA, and cells. , difficult to store and release.

One object of the present invention is to provide a metal-organic composite particle that can be used to adsorb, store and release a substance having the same size as a molecular gas to a substance having a size larger than that of a molecular gas, such as drugs, proteins, DNA, RNA, and cells. .

Another object of the present invention is to provide a composition that can be used to slowly release the active material by adhering to or mixing with a variety of objects and having a higher amount of active material than the metal-organic framework.

Another object of the present invention is to provide a composition that can be used for alleviating or removing inflammation by efficiently adsorbing substances such as protein signaling substances that cause inflammation.

A first aspect of the present invention for achieving the above object is a composite particle formed by combining a metal and an organic material, wherein a peak indicating crystallinity is not observed in the powder X-ray diffraction analysis of the composite particle, and the TEM electron In the diffraction analysis, it has a structure in which a ring-shaped diffraction pattern is observed, a plurality of pores having a size of 1 nm to 10 μm are formed inside the composite particle, and it is to provide a metal-organic composite particle including a supported active ingredient. .

A second aspect of the present invention for achieving the other object includes a biodegradable polymer, a composite particle formed by combining a metal and an organic material dispersed in the biodegradable polymer, and an active ingredient supported on the composite particle, , The composite particle has a structure in which a peak indicating crystallinity is not observed in powder X-ray diffraction analysis, and a ring-shaped diffraction pattern is observed in TEM electron diffraction analysis, and the inside of the composite particle has a size of 1 nm to 10 μm It is to provide a composition in which a plurality of pores are formed, and at least a portion of the active ingredient is supported in the plurality of pores.

The metal-organic composite particles according to the present invention can be used to adsorb, store, or release materials of a relatively large size, such as drugs, proteins, DNA, RNA, and cells, from small-sized substances such as molecular gases together, so that the metal-organic framework It can be used for adsorption, storage and release of a variety of substances compared to

The composition according to an embodiment of the present invention exhibits significantly improved active material loading and dispersibility compared to the sustained-release composition using the metal-organic framework powder, and when used in medical or cosmetic fields, treatment, prevention, and cosmetic properties can be improved.

The composition according to an embodiment of the present invention can be used for alleviating or removing inflammation by efficiently adsorbing and removing substances such as protein signaling substances that cause inflammation.

1 is a scanning electron microscope image of the composite particles prepared according to Example 1 of the present invention.

2 is a scanning electron microscope image of the metal-organic composite particles prepared according to Comparative Example 1.

3 is a scanning electron microscope image of the metal-organic composite particles prepared according to Comparative Example 4.

4 is a transmission electron microscope image of the composite particles prepared according to Example 1 of the present invention.

5 is a transmission electron microscope image of the metal-organic composite particles prepared according to Comparative Example 1.

6 shows the results of powder X-ray diffraction analysis of the composite particles prepared according to Example 1.

7 shows the results of powder X-ray diffraction analysis of the composite particles prepared according to Comparative Example 1.

8 shows the results of powder X-ray diffraction analysis of the composite particles prepared according to Comparative Example 4.

9 shows the results of TEM electron diffraction analysis of the composite particles prepared according to Example 1.

10 shows the results of TEM electron diffraction analysis of the composite particles prepared according to Comparative Example 1.

11 shows the results of TEM electron diffraction analysis of the composite particles prepared according to Comparative Example 4.

12 shows the results of low-temperature nitrogen adsorption analysis of the powder of the composite particles prepared according to Example 1.

13 shows the results of low-temperature nitrogen adsorption analysis of the powder of the composite particles prepared according to Comparative Example 1.

14 is a result of comparing the absorption amount of the active material according to the active material concentration of the composite particles prepared in Example 1 and the composite particles prepared in Comparative Example 1.

15 shows the results of measuring the drug release amount of the sustained-release coating agents of Examples 2 and 3, the sustained-release coating agents of Comparative Examples 2 and 3, and PLGA.

16 is a photograph comparing the sustained-release coatings of Examples 2 and 3 coated on a plastic spoon with those coated with PLGA.

17 is a photograph of the sustained-release coating agent of Comparative Examples 2 and 3 coated on a plastic spoon.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.

However, the embodiments of the present invention illustrated below may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

The metal-organic composite particle according to the present invention is a composite particle formed by combining a metal and an organic material, and in the composite particle, a peak indicating crystallinity is not observed in powder X-ray diffraction analysis, and a ring shape in TEM electron diffraction analysis It has a structure in which the diffraction pattern of the composite particle is observed, and a plurality of pores having a size of 1 nm to 10 μm are formed inside the composite particle, and it is characterized in that it contains a supported active ingredient.

That is, in the metal-organic composite particles according to the present invention, unlike the metal-organic framework, a peak enough to confirm crystallinity was not observed in powder X-ray diffraction analysis, whereas a ring-shaped diffraction pattern was observed in TEM electron diffraction analysis. It is observed. That is, it has crystallinity of a fine short range order on an amorphous basis. In addition, a plurality of pores having a size of 1 nm to 10 μm, which are not formed in the metal-organic framework, have a microstructure formed therein.

In the present invention, 'a plurality of pores formed in the interior of the composite particle' is an open type of pores that are depressed from the surface of the composite particle toward the inside, and a closed shape inside the composite particle. It is used in the meaning of including all qigong.

In the metal-organic composite particle, in the low-temperature gas adsorption analysis for the powder of the metal-organic composite particle, the shape of the adsorption/desorption curve may indicate adsorption by a plurality of multi-composite pores increasing at all pressures. Here, 'adsorption by a plurality of multi-composite pores' means adsorption in a form in which adsorption by micropores, mesopores, and macropores all appear.

In the case of metal-organic frameworks, when a low-temperature gas adsorption analysis is performed, the adsorption/desorption curve shows that a large amount of gas is adsorbed at the beginning of the analysis, and then the amount of gas adsorption is slightly increased even if the partial pressure is increased. represents the pattern of In contrast, in the present invention, the metal-organic composite particle exhibits a multi-pore shape showing a rapid increase after a small amount of gas adsorption occurs in the initial stage of low-temperature gas adsorption analysis, and then linearly increases when the partial pressure increases.

In the metal-organic composite particle, the plurality of pores may adsorb one or more selected from molecular gas, drug, protein, DNA, virus, cell, intracellular signal transduction material (eg, protein signal material). it could be

As such, if one or more materials having different sizes can be adsorbed, more diverse properties may be realized during adsorption, storage, and release of materials.

In the metal-organic composite particle, the active ingredient may be, for example, at least one selected from the group consisting of organic acids, drugs, metal ions, oxides, molecular gases, tissue regeneration materials, and the like.

In the metal-organic composite particle, the metal is, for example, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd , Cd, La, W, Os, Ir, Pt, Au, Hg, Sm, Eu, Gd, Tb, Dy, Ho, Al, Ga, In, Ge, Sn, Pb, Li, Na, K, Rb, Cs , Mg, Ca, Sr, and may be at least one element selected from the group consisting of Ba, or an ion thereof.

In the metal-organic composite particle, the organic material is, for example, 4,4'-biphenyldicarboxilic acid, benzene-1,4-dicarboxylic acid (benzene- 1,4-dicarboxylic acid), 9,10-anthracenedicarboxylic acid, biphenyl-3,3,5,5'-tetracarboxylic acid (biphenyl-3,3,5) ,5'-tetracarboxylic acid, biphenyl-3,4',5-tricarboxylic acid, 5-bromoisophthalic acid, 5 -Cyano-1,3-benzenedicarboxylic acid (5-cyano-1,3-benzenedicarboxylic acid), 2,2-diamino-4,4'-stilbenedicarboxylic acid (2,2-diamino -4,4'-stilbenedicarboxylic acid), 2,5-diaminoterephthalic acid (2,5-diaminoterephthalic acid), 1,1,2,2-tetra(4-carboxylphenyl)ethylene (1,1,2, 2-tetra (4-carboxylphenyl) ethylene), 2,5-dihydroxyterephthalic acid (2,5-dihydroxyterephthalic acid), 2,2-dinitro-4,4-stilbenedicarboxylic acid (2,2- dinitro-4,4-stilbenedicarboxylic acid), 5-ethynyl-1,3-benzenedicarboxylic acid (5-ethynyl-1,3-benzenedicarboxylic acid), 2-hydroxyterephthalic acid (2-hydroxyterephthalic acid), 2 ,6-naphthalenedicarboxylic acid (2,6-naphthalenedicarboxylic acid), 1,2,4,5-tetrakis (4-carboxyphenyl) benzene (1,2,4,5-tetrakis (4-carboxyphenyl) benzene ), 4,4,4″-s-triazine-2,4,6-triyl-tribenzoic acid (4,4,4″-s-triazine-2,4,6-triyltribenzoic acid), 1,3 ,5-Tricarboxy Cybenzene (1,3,5-tricarboxybenzene), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (1,4,7,10 -tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), 1,3,5-tris(4-carboxy[1,1'-biphenyl]-4-yl)benzene (1, 3,5-tris(4-carboxy[1,1'-biphenyl]-4-yl)benzene), 1,3,5-tris(4-carboxyphenyl)benzene (1,3,5-tris(4- carboxyphenyl)benzene), 1,3,5-triscarboxyphenylethynylbenzene (1,3,5-triscarboxyphenylethynylbenzene), α-cyclodextrin, β-cyclodextrin, may be at least one selected from the group consisting of γ-cyclodextrin have.

When the metal-organic composite particles have a particle size of less than 0.01 μm or more than 100 μm, the amount of adsorption of the active material may not be sufficient, and thus, it is preferable to have a particle size of 0.01 to 100 μm.

The adsorption, storage and release properties of various substances of the metal-organic composite particles according to the present invention can be used for various purposes.

For example, cosmetics, substances for storing proteins, substances for storing antibacterial agents, additives for food and animal feed, substances for collecting harmful gases such as odor components, fine dust, radiation gas, substances for air purification, substances for collecting moisture, hydrogen or electronic parts Gas storage materials such as process gases, materials for electrode materials for secondary batteries, materials for capacitors, materials for electrolytes in batteries, materials for gas sensors, materials for ion exchangers, pharmaceutical carriers for medical devices, coatings for contact lenses, sustained release animals It can be applied to drugs, sustained-release human drugs, sustained-release preventive drugs, food preservation containers, and deodorants.

In addition, the composition according to the present invention comprises a biodegradable polymer, a composite particle formed by combining a metal and an organic material dispersed in the biodegradable polymer, and an active ingredient supported on the composite particle, wherein the composite particle is a powder In X-ray diffraction analysis, a peak indicating crystallinity is not observed, and in TEM electron diffraction analysis, a ring-shaped diffraction pattern is observed, and a plurality of pores with a size of 1 nm to 10 μm are formed inside the composite particle. and at least a portion of the active ingredient may be supported in the plurality of pores.

Since the composite particles carrying the active ingredient are dispersed in the biodegradable polymer, the composition has a sustained-release property such that the active ingredient supported on the composite particles is gradually released as the biodegradable polymer is decomposed.

In the composite particles included in the composition, when analyzing the low-temperature gas adsorption for the powder of the metal-organic composite particles, the shape of the adsorption/desorption curve may represent the shape of the composite pores increasing at all pressures.

In the composite particles included in the composition, the metal is, for example, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh , Pd, Cd, La, W, Os, Ir, Pt, Au, Hg, Sm, Eu, Gd, Tb, Dy, Ho, Al, Ga, In, Ge, Sn, Pb, Li, Na, K, Rb , Cs, Mg, Ca, Sr, and may be at least one element selected from the group consisting of Ba, or an ion thereof.

In the composite particles included in the composition, the organic material (organic ligand) is, for example, 4,4'-biphenyldicarboxylic acid (4,4'-biphenyldicarboxilic acid), benzene-1,4-dicar benzene-1,4-dicarboxylic acid, 9,10-anthracenedicarboxylic acid, biphenyl-3,3,5,5'-tetracarboxylic acid (biphenyl) -3,3,5,5'-tetracarboxylic acid), biphenyl-3,4',5-tricarboxylic acid (biphenyl-3,4',5-tricarboxylic acid), 5-bromoisophthalic acid (5 -bromoisophthalic acid), 5-cyano-1,3-benzenedicarboxylic acid (5-cyano-1,3-benzenedicarboxylic acid), 2,2-diamino-4,4'-stilbenedicarboxylic acid (2,2-diamino-4,4'-stilbenedicarboxylic acid), 2,5-diaminoterephthalic acid (2,5-diaminoterephthalic acid), 1,1,2,2-tetra (4-carboxylphenyl) ethylene ( 1,1,2,2-tetra(4-carboxylphenyl)ethylene), 2,5-dihydroxyterephthalic acid (2,5-dihydroxyterephthalic acid), 2,2-dinitro-4,4-stilbenedicarboxyl Acid (2,2-dinitro-4,4-stilbenedicarboxylic acid), 5-ethynyl-1,3-benzenedicarboxylic acid (5-ethynyl-1,3-benzenedicarboxylic acid), 2-hydroxyterephthalic acid (2 -hydroxyterephthalic acid), 2,6-naphthalenedicarboxylic acid (2,6-naphthalenedicarboxylic acid), 1,2,4,5-tetrakis (4-carboxyphenyl)benzene (1,2,4,5-tetrakis) (4-carboxyphenyl)benzene), 4,4,4″-s-triazine-2,4,6-triyl-tribenzoic acid (4,4,4″-s-triazine-2,4,6-triyltribenzoic acid) , 1,3,5-tricarboxybenzene (1,3,5-tricarboxybenzene), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), 1,3,5-tris(4-carboxy[1,1'-biphenyl]- 4-yl) benzene (1,3,5-tris (4-carboxy [1,1'-biphenyl] -4-yl) benzene), 1,3,5-tris (4-carboxyphenyl) benzene (1, 3,5-tris(4-carboxyphenyl)benzene), 1,3,5-triscarboxyphenylethynylbenzene (1,3,5-triscarboxyphenylethynylbenzene), α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin It may be at least one selected from the group consisting of.

In the composition, the organic material may preferably include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

The organic material may include crosslinking of other organic molecules in addition to the above three types of cyclodextrins, thereby forming a gap between metals (ions) to form empty regions, that is, pores in the structure, and the size can be adjusted. Among cyclodextrins, when γ-cyclodextrin is used, the space formed is the largest, and thus the ability to capture the active material is the best, so it may be the most preferred example.

In the composition, the biodegradable polymer is, for example, polylactide-glycolide copolymer (PLGA), chitosan (chitosan), polydioxanone (polydioxanone), polylactide- polycaprolactone copolymer (PLA) -PCL), polyglycolide-polycaprolactone copolymer (PGA-PCL), polydioxanone-polycaprolactone copolymer (PDO-PCL), polytrimethylene carbonate (PTMC), polycarbonate (PC), poly Butylene succinate (PBS), polyhydroxybutyrate (PHB), polyhydroalkanoate (PHA), aliphatic polyphosphate ester, aromatic polyester (aromatic polyester) and polyphosphazene (Polyphosphazene) It may be one or more selected from the group consisting of.

In addition, in the present specification, a copolymer is a polymer made by polymerizing two or more different monomers, and each monomer can be independently arranged, alternately arranged in a form, a certain part agglomerated, arbitrarily arranged in a form, one main chain It may be in a form linked to a side chain or in a form crosslinked by a side chain between the main polymer chains. The copolymer may be an alternating copolymer, a random copolymer, a block copolymer, or a graft copolymer, but is not limited thereto.

In addition, the biodegradable copolymer may be a polylactide-glycolide copolymer (PLGA), and the polylactide-glycolide copolymer may have a molar ratio of lactide and glycolide of 0.1:1 to 9:1. The polylactide-glycolide copolymer is coated on the metal-organic framework, so that the release pattern of the active material can be changed, and the release amount and release rate can be controlled according to the composition of the copolymer.

In addition, the biodegradable polymer may be 150 to 300 parts by weight based on 100 parts by weight of the metal-organic composite particles. More specifically, the weight ratio of the polylactide-glycolide copolymer may be 150 to 300 parts by weight based on 100 parts by weight of the metal-organic framework on which the active material is supported. If the weight ratio corresponds to the metal-organic framework may be coated with a biodegradable polymer, and if the weight of the biodegradable polymer is lower than 150, the release amount of the active ingredient may be small due to the uneven surface due to not being sufficiently coated, When the weight part of the biodegradable polymer is greater than 300, the thickness of the polymer coating of the metal-organic framework may be increased, and thus the amount of active ingredient released may be reduced.

In the composition, the active ingredient may be, for example, at least one selected from the group consisting of organic acids, drugs, metal ions, oxides, molecular gases, tissue regeneration materials, and the like.

In the composition, the tissue regeneration material may be at least one selected from the group consisting of protein, DNA, RNA, and stem cells.

The metal-organic composite particles may have an adsorption amount of the active material of 100 mg/g or more, preferably 150 mg/g or more, more preferably 250 mg/g or more, and most preferably 500 mg/g or more.

When the particle size of the composite particles included in the composition is less than 0.01 μm or exceeds 100 μm, the adsorption amount of the active material may not be sufficient, so it is preferably made of 0.01 to 100 μm.

In the composition, a solvent for dissolving the biodegradable polymer may be further included. That is, the composition may be used in a state in which the solvent for dissolving the biodegradable polymer is completely removed, or in a state in which the solvent is partially removed or not removed.

In the composition, the solvent may be one selected from the group consisting of acetonitrile, chloroform, dichloromethane, water, ethyl acetate, acetone, ethanol and methanol, or a mixture thereof.

The composition according to the present invention can be used for various purposes.

For example, the composition may include an implant, stent, artificial bone, artificial joint, catheter or canola, hemostatic clip, vascular access device, peripheral blood vessel, intravenous site, drainage, gastrotrophic tube, airway tube, guide wire , pacemaker, organ regeneration guide tube, dental filler, dental support building resin, dental coating material, indwelling tube, suture, lifting thread, needle, sanitary napkin, tissue adhesion prevention material, contact lens, bone cement, dental use It can be used for sustained release of antibacterial/anti-inflammatory agents of articles that are inserted, attached, or applied to the human body, such as adhesives and medical casts.

The antibacterial/anti-inflammatory agent is not particularly limited as long as it can be supported on the metal-organic composite particles according to the present invention, but may be appropriately selected and used in consideration of the drug properties required for the object to be coated.

For example, minocycline hydrochloride as an antibacterial/anti-inflammatory agent for dental implants (fixtures, abutments, crowns, etc.), dental fillers, resins for building dental supports, or ointments applied after mechanical cleaning of teeth (Minocycline Hydrochloride) and Tetracycline.

When the antibacterial/anti-inflammatory agent is supported on the metal-organic composite particle according to the present invention and used in the form of a sustained-release coating, filler or ointment, due to the increase in the drug loading and the sustained-release effect, for example, antibacterial/anti-inflammatory after implantation. The number of treatments (ie, number of dental visits) can be significantly reduced.

In addition, as the active ingredient, trehalose, rapamycin, perhexiline, amiodarone, niclosamide, which are substances that can be used for promoting autophagy after surgery on implants , rottlerin, torin1, PI103, phenylethylisothiocyanate, dexamethasone, lithium, L-690,330, carbamazepine, sodium valpro Sodium valproate, verapamil, loperamide, nimodipine, nitrendipine, niguldipine, nicardipine, pimozide, Calpastatin, calpeptin, clonidine, rilmenidine, 2',5'-dideoxyadenosine, NF449, minoxidil, penitrem A, spermidine, resveratrol, fluspirilene, trifluoperazine, small-molecule enhancer (SMER) 10, SMER 18, SMER 28 and A substance selected from the group consisting of dorsomorphin may also be used.

Metal-organic composite particles were prepared by the following process.

Cyclodextrin (Cyclodextrin) solution is prepared by putting 0.125 mmol (0.162 g) of cyclodextrin, 1 mmol (0.056 g) of KOH, 2 mL of deionized water (DI) and 2 mL of ethanol (EtOH) in a 10 mL glass bottle. Then, the prepared solution was rapidly dried with hot air at 120° C. to prepare a powder.

Using the metal-organic composite particles prepared in Example 1, an active ingredient-supported sustained-release composition was prepared by the following process.

Ethanol 1 mL, CTAB (cetyltrimethylammonium bromide) 0.022mmol (0.008g), and tetracycline hydrochloride 0.21mmol (0.093g) were put into a 20mL glass bottle, and then supported on the powder prepared according to Example 1. .

After the loading was made, the supernatant was discarded, the residue was washed with isopropyl alcohol, and vacuum dried to prepare drug-supported composite particles.

After dissolving PLGA, a biodegradable polymer, in 1 mL of acetone, it was added to the composite particles subjected to drug loading treatment, and stirred to prepare a coating agent in which the composite particles were homogeneously dispersed.

The coating agent thus prepared contained 0.15 g of PLGA, 1 mL of acetone, and 0.06 g of metal-organic composite particles, and the content of metal-organic composite particles was 6 wt%. The theoretical content of this coating is 87.4 mg _tetracycline /g _total .

After applying the coating agent to the surface of the plastic spoon, by heating in an oven at 60° C. for 3 minutes to substantially remove the solvent contained in the coating agent, a solid coating layer was formed.

The sustained-release composition was prepared in the same manner as in Example 2, except that the coating agent contained 0.15 g of PLGA, 1 mL of acetone, and 0.15 g of metal-organic composite particles, and the content of metal-organic composite particles was 14 wt%. The theoretical content of this coating is 145.7 mg _tetracycline /g _total .

Metal-organic composite particles were prepared by the following process.

In a 10 mL glass bottle, 0.125 mmol (0.162 g) of cyclodextrin, 1 mmol (0.056 g) of KOH, 5 mL of deionized water (DI), and 0.5 mL of ethanol (EtOH) are added to prepare a cyclodextrin solution.

Then, a 10mL glass bottle prepared with the cyclodextrin solution was placed in a 120mL container containing 20mL MeOH, and reacted for 6 hours in an oven maintained at 50°C without a lid to prepare a powder.

Ethanol 1 mL, CTAB (cetyltrimethylammonium bromide) 0.022 mmol (0.008 g), and tetracycline hydrochloride 0.21 mmol (0.093 g) were added to a 20 mL glass bottle, and then loaded onto the powder prepared according to Comparative Example 1. .

By using the metal-organic composite particles prepared in Comparative 1, an active ingredient-supported sustained-release composition was prepared by the following process.

The sustained-release composition was prepared in the same manner as in Comparative Example 2, except that the coating agent contained 0.15 g of PLGA, 1 mL of acetone, and 0.1 g of organic metal composite particles, and the content of the organic metal composite particles was 10% by weight. The theoretical content of this coating is 15 mg _tetracycline /g _total .

Metal-organic composite particles were prepared by the following process.

In a 10 mL glass bottle, 0.125 mmol (0.162 g) of cyclodextrin, 1 mmol (0.056 g) of KOH, 5 mL of deionized water (DI), and 0.5 mL of ethanol (EtOH) are added to prepare a cyclodextrin solution. Then, the prepared solution was rapidly cooled to remove the solvent to prepare composite particles.

Composite particle shape

1 is a scanning electron microscope image of a composite particle prepared according to Example 1 of the present invention, FIG. 2 is a scanning electron microscope image of a metal-organic composite particle prepared according to Comparative Example 1, and FIG. It is a scanning electron microscope image of metal-organic composite particles prepared according to

As can be seen in Figure 1, the metal-organic composite particles prepared according to Example 1 of the present invention are generally spherical particles, particles with one or both sides depressed, donut-shaped particles with a hole in the center, etc. It is mixed, and the surface of each particle has a rough surface.

In contrast, the metal-organic composite particles prepared according to Comparative Example 1 are composed of cube-shaped particles with a smooth surface, as shown in FIG. 2 , and this shape is a typical shape of the metal-organic framework.

On the other hand, the metal-organic composite particles prepared according to Comparative Example 4 had irregular particle shapes and, unlike Comparative Example 1, did not form a smooth surface, and had a shape in which a large number of particles were agglomerated.

4 is a transmission electron microscope image of the composite particles prepared according to Example 1 of the present invention, and FIG. 5 is a transmission electron microscope image of the metal-organic composite particles prepared according to Comparative Example 1.

As can be seen in FIG. 4 , a number of pores are observed inside the composite particles prepared according to Example 1, and the size of these pores varies from a few micrometers to a few nanometers similar to the size of the composite particles. It is observed.

In contrast, as shown in FIG. 5 , pores similar to those of Example 1 were not observed inside the composite particles prepared according to Comparative Example 1.

Crystal Structure of Composite Particles

6 shows the powder X-ray diffraction analysis results of the composite particles prepared according to Example 1, FIG. 7 shows the powder X-ray diffraction analysis results of the composite particles prepared according to Comparative Example 1, and FIG. 8 shows the results of powder X-ray diffraction analysis of the composite particles prepared according to Comparative Example 4.

As can be seen in FIG. 6 , a peak confirming crystallinity could not be observed in the powder X-ray diffraction analysis results of the composite particles prepared according to Example 1.

In contrast, in the case of the composite particles prepared according to Comparative Example 1, as shown in FIG. 7 , a number of peaks indicating strong crystallinity were observed in powder X-ray diffraction analysis.

On the other hand, in the case of the composite particles prepared according to Comparative Example 4, as shown in FIG. 8, as in Example 1, a peak indicating crystallinity could not be observed in the powder X-ray diffraction analysis result.

9 shows the TEM electron diffraction analysis results of the composite particles prepared according to Example 1, FIG. 10 shows the TEM electron diffraction analysis results of the composite particles prepared according to Comparative Example 1, and FIG. 11 is Comparative Example 4 TEM electron diffraction analysis results of the composite particles prepared according to the method are shown.

As can be seen in FIG. 9, the composite particles prepared according to Example 1 showed a ring-type electron diffraction pattern diffracted by fine crystals in the electron diffraction analysis result of a transmission electron microscope. That is, in the composite particles prepared according to Example 1 of the present invention, crystallinity could not be confirmed within the resolution range of the powder X-ray diffraction apparatus, but the crystallinity of the short range order level was not confirmed in TEM. appears to have an organization. As described above, pores of several nm to several μm level are formed inside together with crystallinity that is minutely shown in TEM without being observed in X-ray diffraction, so that the composite particles according to the present invention can be obtained from molecular gas, protein DNA, RNA, It is presumed to have the property of simultaneously adsorbing relatively large-sized substances such as cells.

In contrast, as shown in FIG. 10 , in the composite particles prepared according to Comparative Example 1, a number of electron diffraction points showing clear crystallinity were observed even in electron diffraction analysis of a transmission electron microscope.

On the other hand, as shown in FIG. 11 , in the composite particles prepared according to Comparative Example 4, no crystal diffraction was observed in the electron diffraction analysis results of a transmission electron microscope. That is, the material according to Comparative Example 4 is amorphous.

Low-temperature nitrogen adsorption analysis

12 shows the low-temperature nitrogen adsorption analysis result of the powder of the composite particle prepared according to Example 1, and FIG. 13 shows the low-temperature nitrogen adsorption analysis result of the powder of the composite particle prepared according to Comparative Example 1.

As shown in FIG. 12 , in the case of the composite particles of Example 1, the adsorption/desorption curve shows a tendency to slightly adsorb at the initial stage when the partial pressure of the gas is low, and to increase the adsorption amount as the partial pressure increases. The curve pattern shows a multi-composite pore shape in which microporous, mesoporous, and macroporous are mixed during low-temperature nitrogen adsorption analysis.

On the other hand, in the case of the composite particles of Comparative Example 1, the adsorption/desorption curve shows a "microporous" in which the gas adsorption amount slightly increases even if the partial pressure increases after most of the gas is adsorbed in a state where the partial pressure of the gas is low. " represents the shape.

Evaluation of drug absorption properties

14 shows the activity of the composite particles prepared in Example 1 (indicated as "metal-organic composite particles" in the drawing) and the composite particles prepared by Comparative Example 1 (indicated by "metal-organic frameworks" in the drawings); This is the result of comparing the absorption amount of the active substance according to the substance concentration.

14, when the concentration of the active ingredient was 58 mM, the composite particles of Example 1 absorbed 291 mg/g, and it was confirmed that the metal-organic framework of Comparative Example 1 absorbed 32 mg/g. did. In addition, when the concentration of the active material was 60 mM, the composite particles of Example 1 absorbed 501 mg/g, and the metal-organic framework of Comparative Example 1 absorbed 37 mg/g. In addition, when the concentration of the active material was 63 mM, the metal-organic composite particles of Example 1 absorbed 698 mg/g, and the metal-organic framework of Comparative Example 1 absorbed 37 mg/g.

That is, the drug absorption amount of the metal-organic composite particles prepared according to Example 1 was increased by 9 to 18 times compared to the metal-organic framework prepared according to Comparative Example 1.

Furthermore, in the metal-organic composite particles prepared according to Example 1, the absorption amount of the active material increased as the concentration of the active material increased, but in the case of the metal-organic framework prepared according to Comparative Example 1, the concentration of the active material increased. However, the absorption amount of the active material did not increase any more.

On the other hand, in the case of metal-organic composite particles having an amorphous structure in general, it is known that the drug loading amount (adsorption amount) is lower than that of the crystalline metal-organic framework. did not evaluate

Evaluation of drug sustained-release properties

15, it can be seen that the sustained-release coatings according to Examples 2 and 3 increased the drug release amount by about 17 to 22 times compared to Comparative Examples 2 and 3, and sustained release of the drug for 14 days or more is possible is also confirmed.

That is, the sustained-release compositions prepared according to Examples 2 and 3 of the present invention carry a drug at least 17 times more than the sustained-release compositions of Comparative Examples 2 and 3, and can be released over a longer period of time. It has sustained release properties.

Evaluation of particle dispersibility in coatings

Referring to FIG. 16 , when only PLGA is coated on a spoon of a transparent color, there is no difference in transparency. In contrast, when the sustained-release coating agent according to Examples 2 and 3 of the present invention is immersed in the surface of a transparent plastic spoon and then dried, a pale yellow color appears. The yellow color is due to the composite particles prepared in Example 1 included in the sustained-release coatings of Examples 2 and 3.

As can be seen from the color of the coated spoon, it can be seen that the composite particles of Example 1 dispersed in the sustained-release coating agents of Examples 2 and 3 have very good dispersibility on the surface of PLGA. This means that when the coating agent according to Examples 2 and 3 is coated on the target article, homogeneous medicinal effect can be expected in all coating layers.

17, in the case of the coating agent according to Comparative Examples 2 and 3, a coating layer is formed in a state in which a plurality of particles are aggregated. When the particles are distributed and coated in such a form, there is a problem that an even drug effect cannot be expected throughout the coating layer.

That is, it can be said that the coating agents according to Examples 2 and 3 have significantly improved properties compared to the particles made of the metal-organic framework in terms of dispersibility of the drug-carrying particles.

Claims

Composite particles formed by combining metal and organic matter,

The composite particles have a structure in which a peak indicating crystallinity is not observed in powder X-ray diffraction analysis, and a ring-shaped diffraction pattern is observed in TEM electron diffraction analysis,

A plurality of pores having a size of 1 nm to 10 μm are formed inside the composite particles,

A metal-organic composite particle comprising a supported active ingredient.
The method of claim 1,

When analyzing the low-temperature gas adsorption for the powder of the metal-organic composite particle, the shape of the adsorption/desorption curve indicates an increase at all pressures, the metal-organic composite particle.
The method of claim 1,

The pore of the composite particle will be capable of adsorbing at least one selected from molecular gas, drug, protein, DNA, virus, cell, and intracellular signaling material, the metal-organic composite particle.
The method of claim 1,

The active ingredient is at least one selected from the group consisting of organic acids, drugs, metal ions, oxides, and tissue regeneration materials, metal-organic composite particles.
The method of claim 1,

The metal is Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Cd, La, W, Os, Ir, Pt , Au, Hg, Sm, Eu, Gd, Tb, Dy, Ho, Al, Ga, In, Ge, Sn, Pb, Li, Na, K, Rb, Cs, Mg, Ca, Sr and Ba from the group consisting of One or more selected elements or ions thereof, metal-organic composite particles.
The method of claim 1,

The organic material is, 4,4'-biphenyldicarboxylic acid (4,4'-biphenyldicarboxilic acid), benzene-1,4-dicarboxylic acid (benzene-1,4-dicarboxylic acid), 9,10- Anthracenedicarboxylic acid (9,10-anthracenedicarboxylic acid), biphenyl-3,3,5,5'-tetracarboxylic acid (biphenyl-3,3,5,5'-tetracarboxylic acid), biphenyl-3 ,4',5-tricarboxylic acid (biphenyl-3,4',5-tricarboxylic acid), 5-bromoisophthalic acid (5-bromoisophthalic acid), 5-cyano-1,3-benzenedicarboxyl Acid (5-cyano-1,3-benzenedicarboxylic acid), 2,2-diamino-4,4'-stilbenedicarboxylic acid (2,2-diamino-4,4'-stilbenedicarboxylic acid), 2, 5-diaminoterephthalic acid (2,5-diaminoterephthalic acid), 1,1,2,2-tetra (4-carboxylphenyl) ethylene (1,1,2,2-tetra (4-carboxylphenyl) ethylene), 2 ,5-dihydroxyterephthalic acid (2,5-dihydroxyterephthalic acid), 2,2-dinitro-4,4-stilbenedicarboxylic acid (2,2-dinitro-4,4-stilbenedicarboxylic acid), 5- Ethynyl-1,3-benzenedicarboxylic acid (5-ethynyl-1,3-benzenedicarboxylic acid), 2-hydroxyterephthalic acid (2-hydroxyterephthalic acid), 2,6-naphthalenedicarboxylic acid (2,6) -naphthalenedicarboxylic acid), 1,2,4,5-tetrakis(4-carboxyphenyl)benzene (1,2,4,5-tetrakis(4-carboxyphenyl)benzene), 4,4,4″-s-tri Azine-2,4,6-triyl-tribenzoic acid (4,4,4″-s-triazine-2,4,6-triyltribenzoic acid), 1,3,5-tricarboxybenzene (1,3,5 -tricarboxybenzen e), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (1,4,7,10-tetraazacyclododecane-N,N',N '',N'''-tetraacetic acid), 1,3,5-tris(4-carboxy[1,1'-biphenyl]-4-yl)benzene (1,3,5-tris(4-carboxy [1,1'-biphenyl]-4-yl)benzene), 1,3,5-tris(4-carboxyphenyl)benzene (1,3,5-tris(4-carboxyphenyl)benzene), 1,3, At least one selected from the group consisting of 5-triscarboxyphenylethynylbenzene (1,3,5-triscarboxyphenylethynylbenzene), α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, metal-organic composite particles.
The method of claim 1,

The size of the metal-organic composite particles is 0.1㎛ ~ 100㎛, metal-organic composite particles.
biodegradable polymers,

Composite particles formed by combining a metal and an organic material dispersed in the biodegradable polymer;

Including the active ingredient supported on the composite particles,

The composite particle has a structure in which a peak indicating crystallinity is not observed in powder X-ray diffraction analysis, and a ring-shaped diffraction pattern is observed in TEM electron diffraction analysis, and the inside of the composite particle has a size of 1 nm to 10 μm. A plurality of pores are formed,

At least a portion of the active ingredient is supported in the plurality of pores, the composition.
9. The method of claim 8,

In the case of low-temperature gas adsorption analysis for the powder of the metal-organic composite particle, the composition shows a form in which the form of the adsorption/desorption curve is uniformly increased at all pressures.
9. The method of claim 8,

The metal is Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Cd, La, W, Os, Ir, Pt , Au, Hg, Sm, Eu, Gd, Tb, Dy, Ho, Al, Ga, In, Ge, Sn, Pb, Li, Na, K, Rb, Cs, Mg, Ca, Sr and Ba from the group consisting of at least one element selected or an ion thereof.
9. The method of claim 8,

The organic material is, 4,4'-biphenyldicarboxylic acid (4,4'-biphenyldicarboxilic acid), benzene-1,4-dicarboxylic acid (benzene-1,4-dicarboxylic acid), 9,10- Anthracenedicarboxylic acid (9,10-anthracenedicarboxylic acid), biphenyl-3,3,5,5'-tetracarboxylic acid (biphenyl-3,3,5,5'-tetracarboxylic acid), biphenyl-3 ,4',5-tricarboxylic acid (biphenyl-3,4',5-tricarboxylic acid), 5-bromoisophthalic acid (5-bromoisophthalic acid), 5-cyano-1,3-benzenedicarboxyl Acid (5-cyano-1,3-benzenedicarboxylic acid), 2,2-diamino-4,4'-stilbenedicarboxylic acid (2,2-diamino-4,4'-stilbenedicarboxylic acid), 2, 5-diaminoterephthalic acid (2,5-diaminoterephthalic acid), 1,1,2,2-tetra (4-carboxylphenyl) ethylene (1,1,2,2-tetra (4-carboxylphenyl) ethylene), 2 ,5-dihydroxyterephthalic acid (2,5-dihydroxyterephthalic acid), 2,2-dinitro-4,4-stilbenedicarboxylic acid (2,2-dinitro-4,4-stilbenedicarboxylic acid), 5- Ethynyl-1,3-benzenedicarboxylic acid (5-ethynyl-1,3-benzenedicarboxylic acid), 2-hydroxyterephthalic acid (2-hydroxyterephthalic acid), 2,6-naphthalenedicarboxylic acid (2,6) -naphthalenedicarboxylic acid), 1,2,4,5-tetrakis(4-carboxyphenyl)benzene (1,2,4,5-tetrakis(4-carboxyphenyl)benzene), 4,4,4″-s-tri Azine-2,4,6-triyl-tribenzoic acid (4,4,4″-s-triazine-2,4,6-triyltribenzoic acid), 1,3,5-tricarboxybenzene (1,3,5 -tricarboxybenzen e), 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (1,4,7,10-tetraazacyclododecane-N,N',N '',N'''-tetraacetic acid), 1,3,5-tris(4-carboxy[1,1'-biphenyl]-4-yl)benzene (1,3,5-tris(4-carboxy [1,1'-biphenyl]-4-yl)benzene), 1,3,5-tris(4-carboxyphenyl)benzene (1,3,5-tris(4-carboxyphenyl)benzene), 1,3, One or more selected from the group consisting of 5-triscarboxyphenylethynylbenzene (1,3,5-triscarboxyphenylethynylbenzene), α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, the composition.
9. The method of claim 8,

The organic material is at least one selected from α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, the composition.
9. The method of claim 8,

The biodegradable polymer is polylactide-glycolide copolymer (PLGA), chitosan (chitosan), polydioxanone (polydioxanone), polylactide-polycaprolactone copolymer (PLA-PCL), polyglycolide-poly Caprolactone copolymer (PGA-PCL), polydioxanone-polycaprolactone copolymer (PDO-PCL), polytrimethylene carbonate (PTMC), polycarbonate (PC), polybutylene succinate (PBS), poly At least one selected from the group consisting of hydroxybutylate (PHB), polyhydroalkanoate (PHA), aliphatic polyphosphate ester, aromatic polyester, and polyphosphazene, composition .
9. The method of claim 8,

The biodegradable copolymer is a polylactide-glycolide copolymer (PLGA),

The polylactide-glycolide copolymer has a molar ratio of lactide and glycolide of 0.1: 1 to 9: 1, the composition.
9. The method of claim 8,

A composition comprising 50 to 500 parts by weight of the biodegradable polymer based on 100 parts by weight of the metal-organic composite particles.
9. The method of claim 8,

The active ingredient is at least one selected from the group consisting of organic acids, drugs, metal ions, oxides, and tissue regeneration materials, the composition.
17. The method of claim 16,

The tissue regeneration material is at least one selected from the group consisting of protein, DNA, RNA, stem cells, the composition.
9. The method of claim 8,

The size of the metal-organic composite particles is 0.01㎛ ~ 100㎛, composition.
9. The method of claim 8,

A composition further comprising a solvent for dissolving the biodegradable polymer.
20. The method of claim 19,

The solvent is one selected from the group consisting of acetonitrile, chloroform, dichloromethane, water, ethyl acetate, acetone, ethanol and methanol, or a mixture thereof, the composition.