Nanomolecular aggregates composed of organic substances, inorganic substances, or salts thereof, and methods for producing the same.

Abstract

The present invention relates to a molecular association derived from a pharmacologically active ingredient, which is produced by applying shear stress to a solution containing the pharmacologically active ingredient.

Description

【Technical Field】 【0001】 The present invention relates to nano-molecular aggregates composed of organic / inorganic substances or their salts, and more particularly to structures of pharmacologically active ingredients having excellent solubility and permeability to lipid membranes, which are produced by applying shear stress to organic substances, inorganic substances or their salts. 【Background Art】 【0002】 Generally, it is known that in order to effectively deliver a drug, a pharmacologically active ingredient in the form of an organic / inorganic substance or its salt, i.e., a so-called active ingredient, to a target position in the human body, the following two conditions must be satisfied. 【0003】 First, the aqueous solubility of the active ingredient must be ensured. Since all fluids in the human body are water-based solutions or dispersions, in order for the drug to be transmitted to move in the body, sufficient solubility in water and a dispersion phase in water must be ensured. 【0004】 In addition, the permeability of the active ingredient to a hydrophobic membrane must be ensured. Since cells in the human body are surrounded by a hydrophobic membrane such as a phospholipid membrane, in order to pass through it, the surface properties of drug molecules or drug structures must be hydrophobic or the size must be very small enough to penetrate the cell membrane. 【0005】 As a conventional method for such a drug to permeate the cell membrane in a molecular state, an encapsulation method in which the drug is enclosed in the form of an emulsion or suspension in microspheres utilizing a surfactant / polymer structure as a third substance has been widely used. 【0006】 However, such drug encapsulation methods have limitations, including the difficulty of the encapsulation process, which can result in low encapsulation yields. Furthermore, there are problems such as the removal of surfactants and polymer components surrounding the drug in order to release it, or the need for the drug to pass through these components. Additionally, since the surfaces of cells and tissues that require permeability are mostly composed of lipophilic phospholipid components, there is a problem that drug absorption is inefficient when the drug is hydrophilic. 【0007】 To address the problems with such drug encapsulation methods, many researchers have utilized a third substance and leveraged physicochemical bonding, as mentioned earlier, rather than relying on the structure of the molecule itself. 【0008】 To disperse or dissolve drug molecules in water, methods can be employed such as giving the drug molecules polarity to induce polar interactions with water molecules, or by covalently or ionically bonding (complexing) molecules that are very compatible with water, such as PEG, to part of the molecular structure. 【0009】 However, this method has drawbacks: it requires the cumbersome process of altering the drug's molecular structure, leading to increased costs due to the manufacturing process; and because the altered molecular structure differs structurally from the original, it reverts to its original molecular state after absorption in the body, thus failing to exhibit the intended drug effect. Consequently, there are limitations in maintaining the drug's original efficacy because the drug molecule cannot maintain multiple aggregated states without chemical structural changes. Furthermore, conventional drug structures reaching several hundred nanometers in size were difficult to penetrate skin gaps with a size of 80 nm. 【0010】 Therefore, various methods for producing such drugs have been studied. In particular, methods for producing drugs on a nanometer scale include top-down techniques such as high-pressure homogenization, milling, and piston-gap homogenizers, and bottom-up techniques such as precipitation and self-assembly. 【0011】 The top-down method (downward process) is a technology that reduces particle size through methods such as grinding to produce micrometer-sized particles, but it has disadvantages such as increased costs, the risk of contamination, and product damage due to repeated grinding. On the other hand, the bottom-up method (upward process), in contrast to the top-down method, is a technology that grows structures to nanometer size at the atomic and molecular level, and it has been presented as a solution to overcome the limitations of the conventional top-down method, which reduces the size to nanometer size in a bulk state. However, at the current level of technology, it is difficult to directly obtain the economic advantages of atomic and molecular level technology. Furthermore, although the conventional method of crystal growth has the advantage of low cost and a simple manufacturing process, it can only produce crystalline products, and there is a problem that excessive crystal growth and their aggregation require the addition of other compounds such as surfactants. [Prior art documents] [Patent Documents] 【0012】 [Patent Document 1] Korean Published Patent No. 2011-0053775 [Overview of the project] [Problems that the invention aims to solve] 【0013】 Therefore, in order to solve the aforementioned problems, the inventors of the present invention confirmed that when drug molecules, which are pharmacologically active ingredients, are dissolved in a solvent and then brought very close to each other, the polar groups within the molecules behave as if they were a single entity. 【0014】 Furthermore, we confirmed that when polar groups interact with each other due to the proximity of molecules, the drug molecules as a whole become hydrophobic. This reduces the size of the structure to which such drug molecules are bound, lowering the surface tension and thus increasing the degree of dispersion. 【0015】 Through this process, we confirmed that it is possible to manufacture small particles at the molecular level using a bottom-up method rather than a top-down method, while producing amorphous, nano-sized drug structures rather than crystalline forms. 【0016】 Furthermore, we confirmed that structures with novel properties can be created by combining molecules through various methods that bring molecules closer together, such as manufacturing molecular structures using voids in powders and bringing molecules closer together using flexible rolls, thus completing the present invention. 【0017】 Therefore, the object of the present invention is to provide a structure of a pharmacologically active ingredient and an apparatus capable of producing such a structure, which has a hydrophobic surface and increased permeability to a phospholipid membrane, by producing a new structure utilizing polar interactions or hydrogen bonds of molecules without changing the chemical structure of the pharmacologically active ingredient molecule. [Means for solving the problem] 【0018】 In order to achieve the above object, the present invention provides a molecular aggregate in which an organic or inorganic substance is physically bonded. When the molecular aggregate is formed with a composition containing water, the molecular aggregate has an aggregated structure in the composition, the average particle size of the molecular aggregate is 50 nm or less, and when comparing the solubility A of the pharmacologically active ingredient in water with the dispersibility B of the molecular aggregate in water, the value of dispersibility B / solubility A is 1.2 or more, and a nano molecular aggregate is provided. 【Advantages of the Invention】 【0019】 The present invention does not have the trouble of changing the molecular structure of organic substances, inorganic substances or salts thereof such as pharmacologically active ingredients. By producing a molecular aggregate with a new structure that utilizes polar interactions or hydrogen bonds, the surface of the structure can be made hydrophobic, and not only can the permeability to the phospholipid membrane be increased, but since the original molecule and the structure itself are the same, the effect of the originally intended drug can be shown as it is, and there are advantages that the manufacturing method is simple and the manufacturing cost can be saved. 【0020】 Due to such advantages, the molecular aggregate of the present invention can be used in various pharmaceutical compositions. 【Brief Description of the Drawings】 【0021】 [Figure 1] It is a schematic diagram of an apparatus for producing a molecular aggregate according to an embodiment of the present invention. [Figure 2] It is a schematic diagram of an apparatus for producing a molecular aggregate according to another embodiment of the present invention. [Figure 3] It is a graph showing the result of measuring NOESY, which is a two-dimensional NOE (Nuclear Overhauser Effect) spectrum, for a pharmacologically active ingredient according to an embodiment of the present invention. [Figure 4] It is a graph showing the result of measuring NOESY, which is a two-dimensional NOE spectrum, for a molecular aggregate of a pharmacologically active ingredient according to an embodiment of the present invention. [Figure 5] A graph showing the XRD measurement results of a molecular aggregate according to another embodiment of the present invention. [Figure 6] A graph showing the DSC measurement results of a molecular aggregate according to another embodiment of the present invention. [Figure 7] A TEM photograph of a molecular aggregate according to another embodiment of the present invention. [Figure 8] A 3D hologram photograph showing the permeation performance of the phospholipid membrane of a structure according to another embodiment of the present invention. 【Mode for Carrying Out the Invention】 【0022】 In the present invention, while producing molecular-level small particles by a bottom-up method instead of a top-down method, a molecular aggregate having a structure of an amorphous nano-sized drug rather than a crystalline form is produced without changing the chemical structure of an organic substance, an inorganic substance or a salt thereof. By producing a molecular aggregate having a new structure utilizing polar interactions or hydrogen bonds, the surface of the molecular aggregate has hydrophobicity, and a molecular aggregate of an organic substance, an inorganic substance or a salt thereof with an increased permeability to a phospholipid membrane is presented. 【0023】 This will be described in more detail below. 【0024】 Apparatus for producing a molecular aggregate of an organic substance, an inorganic substance or a salt thereof The apparatus for producing a molecular aggregate of an organic substance, an inorganic substance or a salt thereof referred to in this specification is characterized in that after a solution containing an organic substance, an inorganic substance or a salt thereof is introduced into the apparatus, a shear stress is applied to the solution containing an organic substance, an inorganic substance or a salt thereof to produce a molecular aggregate of an organic substance, an inorganic substance or a salt thereof. 【0025】 Methods for producing drugs at the nanometer scale included top-down techniques such as high-pressure homogenization, milling, and piston-gap homogenizers, as well as bottom-up techniques such as precipitation and self-assembly. 【0026】 The top-down manufacturing method is a technique that reduces particle size through methods such as grinding to produce micrometer-sized particles, but it has disadvantages such as increased costs, the risk of contamination, and product damage due to repeated grinding. 【0027】 On the other hand, bottom-up manufacturing techniques such as precipitation have the advantage of being low-cost and having a simple manufacturing process through crystal growth, but they have the problem that they can only produce crystalline products, and excessive crystal growth and their aggregation require the addition of other compounds such as surfactants. 【0028】 Furthermore, in order to effectively deliver pharmacologically active ingredients, which are in the form of organic, inorganic, or salts thereof, to targets within the human body, the solubility in water and permeability to hydrophobic membranes of these organic, inorganic, or salt substances must be ensured. Conventional methods for such drugs to permeate cell membranes in molecular form have often involved giving the drug polarity to induce polar interactions with water molecules, or forming a complex with water-friendly molecules such as PEG via covalent or ionic bonds in part of the molecular structure. 【0029】 However, this method has the drawback of requiring the alteration of the drug's molecular structure, and because the altered molecular structure is structurally different from the original molecule, it has the limitation that after being absorbed into the body, it may revert to its original molecular state, thus failing to exhibit the intended drug effect. 【0030】 To solve the aforementioned problems, the inventors have confirmed that when drug molecules, in the form of organic, inorganic, or salts thereof, are dissolved in a solvent and then brought very close together, the polar groups within the molecules interact to form molecular aggregates, which then behave like a single entity. 【0031】 Through this process, we confirmed that when polar groups interact with each other due to the proximity of molecules, the overall structure becomes hydrophobic. This reduces the size of the structure to which such drug molecules are bound, lowering the surface tension and thus increasing the degree of dispersion. 【0032】 We have completed the present invention by confirming that molecular aggregates with novel properties can be created by bringing molecules closer together through various methods that reduce the distance between molecules, such as manufacturing molecular structures using voids in powders and bringing molecules closer together using flexible rolls. 【0033】 In other words, the present invention is for producing small particles at the molecular level using a bottom-up method rather than a top-down method, while producing amorphous, nano-sized drug structures rather than crystalline ones. 【0034】 First, the present invention provides an apparatus for producing molecular aggregates of organic substances, inorganic substances, or salts thereof by introducing a solution containing organic substances, inorganic substances, or salts thereof into the apparatus and then applying shear stress to the solution containing organic substances, inorganic substances, or salts thereof. The apparatus for producing molecular aggregates of organic substances, inorganic substances, or salts thereof can be used without special limitations as long as it is capable of producing the molecular aggregates of organic substances, inorganic substances, or salts thereof of the present invention by applying shear stress to a solution containing organic substances, inorganic substances, or salts thereof. Preferably, an apparatus that uses a roll mill process or a ball mill process to apply shear stress can be used. 【0035】 When preparing a solution containing the aforementioned organic or inorganic substances or salts thereof, it may also be prepared using an oil phase. In this case, the solvent used for preparation in the oil phase may be one or more of the following: oils derived from grain extracts such as castor oil, MCT oil, soybean oil, and peanut oil, or oils derived from herbal extracts exhibiting pharmacological effects such as ginseng, camellia, green tea, and angelica tree. 【0036】 Furthermore, in the present invention, the organic substances, inorganic substances, or salts thereof can be used as pharmacologically active ingredients, and these can be used without any special limitations as long as they are pharmaceutically useful substances or substances that have medical effects. Examples include cyclosporine A, paclitaxel, docetaxel, declusin, meloxicam, itraconazole, celecoxib, capecitabine, travoprost, isoflavones, diclofenac sodium, tyrosine kinase inhibitors such as sunitinib, pazopanib, axitinib, regorafenib, trametinib, ginsenoside Rg1, tacrolimus, alendronate, latanoprost, bimatoprost, atorvastatin calcium, rosuvastatin calcium, entecavir, amphotericin B, omega-3, and deodorant. Various cholic acids such as xycholic acid and ursodeoxycholic acid, and their sodium or potassium salts; steroids such as prednisolone, which are substituted with fluorine or hydrogen; aromatic oils such as eucalyptus oil, lavender oil, lemon oil, sandalwood oil, rosemary oil, chamomile oil, cinnamon oil, and orange oil; alpha-bisabolol, vitamin A (retinol), vitamin E, tocopheryl acetate, vitamin D, vitamin F, or derivatives thereof; and combinations thereof may be used. 【0037】 As one specific example of a device that applies shear stress in this manner, Figure 1 shows a schematic diagram illustrating a device for producing molecular aggregates of organic substances, inorganic substances, or salts thereof according to one embodiment of the present invention. 【0038】 As shown in Figure 1, an apparatus for producing molecular aggregates of organic substances, inorganic substances, or salts thereof according to one embodiment of the present invention may be equipped with a plurality of rolls so as to be able to apply shear stress to a solution containing organic substances, inorganic substances, or salts thereof. In this case, the plurality of rolls may be two opposing rolls, or one or more additional rolls may be included. 【0039】 Specifically, a solution containing the aforementioned organic matter, inorganic matter, or salts thereof (shown as PTX Sol. in Figure 1 as an example) can be introduced between two opposing rolls in the apparatus (roll A and roll B in Figure 1). By rotating the two opposing rolls, shear stress is applied to the organic matter, inorganic matter, or salts contained in the solution, thereby producing molecular aggregates of the organic matter, inorganic matter, or salts thereof according to the present invention. 【0040】 In an apparatus for producing molecular aggregates of organic substances, inorganic substances, or salts thereof according to one embodiment of the present invention, the distance between the two opposing rolls may be set to 0.5 to 1000 μm. The distance between the two opposing rolls may be set to, for example, 0.5 μm or more, 1 μm or more, 2 μm or more, 3 μm or more, 4 μm or more, 5 μm or more, 10 μm or more, 1000 μm or less, 900 μm or less, 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, 100 μm or less, and preferably to 10 to 100 μm. If the distance between the two opposing rolls is less than 0.5 μm, the discharge amount between the rolls is very small, which is a problem for production speed, and if it is greater than 1000 μm, the shear stress and compressive stress are very small, which is a problem for particle formation. 【0041】 As mentioned above, when the solution is passed between the rollers, excessive force is applied between molecules, resulting in a bottom-up particle structure where particles aggregate between molecules, rather than a top-down grinding process. 【0042】 Furthermore, in order to more efficiently transfer shear stress to organic substances, inorganic substances, or salts thereof contained in the solution, the apparatus for producing molecular aggregates according to one embodiment of the present invention can be configured such that the two opposing rolls rotate at different speeds. In this case, one of the two opposing rolls can be configured to rotate at a speed of 50 to 250 rpm, and the other at a speed of 200 to 500 rpm. Alternatively, the two opposing rolls can be rotated in a ratio of 1:1.5 to 1:5. 【0043】 Furthermore, in an apparatus for producing molecular aggregates according to one embodiment of the present invention, the rotation directions of the two opposing rolls may be set to co-current directions having the same rotation direction, or they may be set to counter-current directions having different rotation directions. 【0044】 Furthermore, the apparatus for producing molecular aggregates according to one embodiment of the present invention can repeatedly apply shear stress and compressive stress to the contents that have been dispensed once, several times. 【0045】 Furthermore, the present invention provides an apparatus for producing molecular aggregates by introducing a solution containing organic matter, inorganic matter, or salts thereof into the apparatus in a first-sided direction, introducing another solution in a second-sided direction opposite to the first-sided direction, and then applying shear stress. The apparatus for producing molecular aggregates of the present invention can also be used without special limitations as long as it can produce molecular aggregates of the present invention by applying shear stress to a solution containing organic matter, inorganic matter, or salts thereof, but preferably one that uses a roll mill process or a ball mill process to apply shear stress can be used. 【0046】 In the present invention, the pharmacologically active ingredient can be the same as that mentioned above. 【0047】 In the present invention, the water-soluble compound can be one or more selected from the group consisting of citric acid, carbonic acid, lactic acid, acetic acid, phosphoric acid, ascorbic acid, malic acid, tartaric acid, glutaric acid, succinic acid, maleic acid, fumaric acid, malonic acid, HCl, H2SO4, NaH2PO4, NaHCO3, KHCO3, Na2CO3, K2CO3, Na3PO4, K3PO4, NaH2PO4, NH4OH, sodium acetate (NaOAc), KOH, NaOH, and Ca(OH)2. 【0048】 As a specific example of a device that applies shear stress in this way, Figure 2 shows a schematic diagram illustrating a device for producing molecular aggregates according to one embodiment of the present invention. 【0049】 As shown in Figure 2, the apparatus for producing molecular aggregates according to one embodiment of the present invention may be equipped with multiple rolls so as to be able to apply shear stress to a solution containing organic matter, inorganic matter, or salts thereof. In this case, the multiple rolls may be two opposing rolls (roll A, roll B), or one or more additional rolls (roll C) may be included as shown in Figure 2. 【0050】 Specifically, a solution containing the organic, inorganic, or salt thereof (shown as PTX Sol. in Figure 2 as an example) can be introduced to the first roll side, and a solution containing the water-soluble compound (shown as Sucrose Sol. in Figure 2 as an example) can be introduced to the second roll side facing the first roll. 【0051】 In this manner, when two opposing rolls rotate over solutions containing organic substances, inorganic substances, or salts thereof, and a solution containing a water-soluble compound, which are fed into the two rolls in opposite directions, shear stress is applied to the organic substances, inorganic substances, or salts thereof and the water-soluble compound contained in these solutions, thereby enabling the production of molecular aggregates of organic substances, inorganic substances, or salts thereof according to the present invention. 【0052】 In an apparatus for producing molecular aggregates according to one embodiment of the present invention, the distance between the two opposing rolls may be set to 0.5 to 1000 μm. The distance between the two opposing rolls may be set to, for example, 0.5 μm or more, 1 μm or more, 2 μm or more, 3 μm or more, 4 μm or more, 5 μm or more, 1000 μm or less, 900 μm or less, 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, and preferably to 5 to 500 μm. 【0053】 If the distance between the two opposing rolls is less than 0.5 μm, the discharge volume between the rolls is very small, resulting in production speed problems. If it is greater than 1000 μm, the shear stress and compressive stress are very small, resulting in problems with particle formation. 【0054】 Furthermore, in order to more efficiently transfer shear stress to organic matter, inorganic matter, or salts thereof contained in the solution, the two opposing rolls can be made to rotate at different speeds. In this case, one of the two opposing rolls can be used with a rotation speed of 50 to 150 rpm and the other with a rotation speed of 200 to 500 rpm. Alternatively, the two opposing rolls can be rotated in a ratio of 1:1.5 to 1:5. 【0055】 Furthermore, in an apparatus for producing molecular aggregates according to one embodiment of the present invention, the rotation directions of the two opposing rolls may be set to co-current directions having the same rotation direction, or they may be set to counter-current directions having different rotation directions. 【0056】 Furthermore, the apparatus for producing molecular aggregates according to one embodiment of the present invention can repeatedly apply shear stress and compressive stress to the contents that have been dispensed once, several times. 【0057】 In the present invention, the apparatus for producing the molecular aggregate may be further equipped with a third roll that applies shear stress again to the solution passing between the first and second rolls. The third roll can apply shear stress in relation to the second roll, and the distance between the opposing second and third rolls may be set to 0.5 to 1000 μm. The distance between the two opposing rolls may be set to, for example, 0.5 μm or more, 1 μm or more, 2 μm or more, 3 μm or more, 4 μm or more, 5 μm or more, 1000 μm or less, 900 μm or less, 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, and preferably to 5 to 500 μm. If the distance between the second and third rolls is less than 0.5 μm, the discharge volume between the rolls is very small, which is a problem for production speed, and if it is greater than 1000 μm, the shear stress and compressive stress are very small, which is a problem for easy particle formation. 【0058】 Furthermore, in order to transmit shear stress more efficiently, the second and third rolls can be made to rotate at different speeds. In this case, one of the second and third rolls can be rotated at a speed of 200 to 500 rpm, and the other at a speed of 600 to 1200 rpm. Alternatively, the rotation speeds of the second and third rolls can be made to be in a ratio of 1:1.5 to 1:5. 【0059】 In the present invention, the apparatus for producing the molecular aggregate is not limited to the method described above, and can be freely modified as long as it is an apparatus capable of applying shear stress to organic matter, inorganic matter, or salts thereof. 【0060】 Molecular aggregates of organic substances, inorganic substances, or salts thereof The inventors have confirmed that when drug molecules, which are pharmacologically active ingredients, are dissolved in a solvent and then brought very close together, the polar groups within the molecules interact to form molecular aggregates, which then behave like a single entity. 【0061】 Through this process, we confirmed that when polar groups interact with each other due to the proximity of molecules, the overall structure becomes hydrophobic. This reduces the size of the molecular aggregate to which such drug molecules are bound, lowering the surface tension and thus increasing the degree of dispersion. 【0062】 We have completed the present invention by confirming that molecular assemblies with novel properties can be created by bringing molecules closer together through various methods that reduce the distance between molecules, such as manufacturing molecular assemblies by utilizing the voids in powders and bringing molecules closer together using flexible rolls. 【0063】 Therefore, the molecular aggregates produced by the apparatus referred to herein have the following characteristics: 【0064】 First, the nanomolecular aggregate according to the present invention is produced by applying shear stress to a solution containing an organic substance, an inorganic substance, or a salt thereof which is a precursor of the molecular aggregate, thereby bringing the intermolecular distances of the organic substance, the inorganic substance, or a salt thereof very close together. As a result, the dispersion of the molecular aggregate and the solubility of the organic substance, the inorganic substance, or a salt thereof which is a precursor of the molecular aggregate have different characteristics from each other. 【0065】 It is a well-known fact that the solubility of a substance in water and a solvent occurs through a process called solvation, and that it always has the same value when the temperature and pressure are the same; this is usually referred to as a thermodynamic property. 【0066】 The molecular aggregates provided in this invention are found to be substances that differ in various physicochemical aspects, such as surface polarity and size, from organic substances, inorganic substances, or their salts themselves (i.e., precursors of molecular aggregates). It can be predicted that the changes caused by the formation of such molecular aggregates will result in changes in physical properties, such as thermodynamic properties and solubility. 【0067】 As a result, the molecular aggregate of the present invention is characterized in that, when comparing the solubility A in water of the organic, inorganic, or salt thereof precursor of the molecular aggregate with the dispersion B of the molecular aggregate in water, the value of dispersion B / solubility A exceeds 1. Here, a value of dispersion B / solubility A of 1 or more means that the dispersion of the molecular aggregate of the present invention increases compared to the solubility of the organic, inorganic, or salt thereof precursor of the molecular aggregate of the present invention. 【0068】 In this invention, dispersion in the degree of dispersion means that aggregates of several or more molecules do not precipitate due to gravity and that the number of molecules does not continuously increase due to surface interactions with the dispersion medium, and the degree of dispersion measures the degree of such dispersion. Solubility means the maximum amount of solute that can maintain a state of being reduced to molecular size in a particular solution. The degree of dispersion or solubility is determined based on the case when the material is in powder form in the same volume of solution at the same temperature. 【0069】 In the present invention, there are no particular restrictions on the method for measuring solubility and dispersion, as long as it is a method used in the industry, but preferably it can be measured using the HPLC method. This means a method in which a supersaturated solution is prepared by adding an excess amount of solute to a solvent, the liquid phase is separated by a filter after being allowed to stand at a predetermined temperature for a sufficient amount of time, and then the solubility and dispersion are measured by measuring the mass of pharmacologically active components such as organic substances, inorganic substances or salts thereof, or molecular aggregates of the present invention that are dissolved in the liquid phase. As a specific example, after preparing a supersaturated solution, it can be allowed to stand for a sufficient amount of time at 25°C, the liquid phase can be separated by a filter, and then the mass of pharmacologically active components such as organic substances, inorganic substances or salts thereof, or molecular aggregates of the present invention that are dissolved in the liquid phase can be measured. 【0070】 In the present invention, the dispersibility B / solubility A value may vary depending on the type of pharmacologically active ingredient, such as organic substances, inorganic substances, or salts thereof, for example, greater than 1.0, 1.2 or more, 1.4 or more, 1.5 or more, 1.7 or more, 1.8 or more, 1.85 or more, 2.0 or more, 2.5 or more, 3.0 or more, 4.0 or more, 5.0 or more, 6.0 or more, 7.0 or more, 8.0 or more, 9.0 or more, 10 or more, 11 or more. It may be 12 or older, 13 or older, 14 or older, 15 or older, 16 or older, 17 or older, 18 or older, 19 or older, 20 or older, 21 or older, 22 or older, 23 or older, 24 or older, 25 or older, 26 or older, 27 or older, 28 or older, 29 or older, 30 or older, 31 or older, 40 or older, 50 or older, 60 or older, 70 or older, 80 or older, 90 or older, or 100 or older, and there is no special restriction on the upper limit, but it may be 1000 or less. 【0071】 Specifically, if the pharmacologically active ingredient is adenosine, the dispersibility B / solubility A value may be 1.5 or higher, 1.7 or higher, or 1.8 or higher. 【0072】 Furthermore, if the pharmacologically active ingredient is cyclosporine A, the dispersibility B / solubility A value may be 2.0 or higher, 2.5 or higher, or 3.0 or higher. 【0073】 Furthermore, if the pharmacologically active ingredient is niclosamide, the dispersion B / solubility A value may be 15 or higher, 18 or higher, or 20 or higher. 【0074】 Furthermore, if the pharmacologically active ingredient is DCF-DA, the dispersion B / solubility A value may be 25 or higher, 28 or higher, or 31 or higher. 【0075】 Furthermore, if the pharmacologically active ingredient is efinaconazole, the dispersibility B / solubility A value may be 2.0 or higher, 2.5 or higher, or 3.0 or higher. 【0076】 Furthermore, if the pharmacologically active ingredient is tacrolimus, the dispersion B / solubility A value may be greater than 1.0, 1.2 or greater, 1.4 or greater, or 1.5 or greater. 【0077】 Furthermore, the nanomolecular aggregate according to the present invention has the following characteristics. 【0078】 First, the nanomolecular aggregates according to the present invention are produced by applying shear stress to a solution containing organic, inorganic, or salts thereof, which are precursors to the molecular aggregates, thereby bringing the intermolecular distances of the organic, inorganic, or salts thereof very close together. This process results in nanoparticle-sized aggregates that possess amorphous characteristics. In other words, by applying shear stress between molecules of the same structure, these molecules are physically bonded together to form nano-sized amorphous molecular aggregates. 【0079】 Furthermore, the molecular aggregate and the chromatographic measurements of the organic, inorganic, or salt thereof precursors of the molecular aggregate are the same, while the spectroscopy measurements of the molecular aggregate and the pharmacologically active component precursors of the molecular aggregate are different. 【0080】 Common methods for determining the structure of a substance include various instrumental analyses such as elemental analysis, FT-IR, NMR, UV spectroscopy, X-ray, and DSC (differential scanning calorimeter). Among these, NMR and FT-IR are the most effective methods for analyzing chemical structure, that is, the atoms that make up a molecule and their connections. X-ray and DSC are typically used to investigate secondary structures, such as the crystalline structure formed by molecules. In addition, scanning electron microscopes and transmission electron microscopes are sometimes used to analyze the fine structure. 【0081】 Among the methods mentioned, NMR allows us to know the electronic environment of atomic nuclei, which is determined by the electronic structure of a molecule. The results of this invention relate to a method for producing a certain compound and its physical structure, and NMR provides very useful information as a way to check for chemical mutations during the formation of the physical structure. If there is no creation or annihilation of chemical bonds, the compound and its physical structure will basically have similar NMR spectra. Of course, in order to know how close the compounds are to form molecular aggregates, we roughly measured the intermolecular distances of compounds that are usually located at a distance of 0.5 nm using NOE (Nuclear Overhauster Effect) and two-dimensional NOESY spectra. 【0082】 Furthermore, according to one embodiment of the nanomolecular aggregate according to the present invention, the molecular aggregate may have an intermolecular distance of 10 Å or less. The intermolecular distance means measuring the average distance of these molecules with respect to the molecules that make up the molecular aggregate, and can be measured, for example, using NOE in NMR. NOE (Nuclear Overhauster Effect) is the phenomenon in which the intensity of nearby hydrogens increases when one hydrogen is excited using a pulse, and this is inversely proportional to the sixth power of the internuclear distance of hydrogens. Therefore, even if it is a hydrogen within a molecule, if the distance is far, it does not contribute to the increase in peak intensity due to NOE. However, when molecules are very close together, NOE is detected when the distance between intermolecular hydrogens becomes closer than the distance between hydrogens within the molecule, which means that the distance between molecules is very close. It is generally known that NOE is observed when the distance is closer than 1 nm. 【0083】 In this invention as well, the intermolecular distance between the NaDC (sodium deoxycholate) compound and the molecular aggregate obtained in this invention is very small, as observed through two-dimensional NOESY NMR, and the angstrom (10) is very small. -10 We confirmed that the data was collected on a scale of approximately m. 【0084】 Figures 3 and 4 show the NOESY, a two-dimensional NOE spectrum, for the NaDC molecule and its molecular aggregate, respectively. The areas marked with * and ** in Figures 3 and 4 represent the same location. In Figure 3, no off-diagonal peaks appear in the regions marked with * and ** for the NaDC molecule itself, whereas in Figure 4, off-diagonal peaks appear in the regions marked with * and ** for the NaDC molecular aggregate. This indicates that in pure NaDC, the distance between the two nuclei was far, but when the molecular aggregate is formed, the distance between the two nuclei decreases. Through this, it can be seen that when a molecular aggregate is formed, the distance between molecules becomes very small. Generally, the distance required for two hydrogen atoms to exhibit NOE is known to be approximately 6 Å (angstroms), so it can be seen that the intermolecular distances forming the molecular aggregate of the present invention are also within the range of approximately 6 Å (angstroms). 【0085】 In summary, the reason why peaks that were too far away to appear in the molecules themselves appear in the nanomolecular aggregates provided by this invention is due to a change in the physical positions of the organic, inorganic, or salt molecules bound to the nanomolecular aggregate. In other words, it means that the distance between molecules within the molecular aggregate is very small. 【0086】 As mentioned above, the position of the peak in the NMR spectrum represents the frequency of rotational motion of the atomic nucleus within a molecule composed of atomic bonds, depending on the magnitude of the magnetic field applied to it. The magnitude of the magnetic field applied to the atomic nucleus varies depending on the properties of surrounding active groups that push or pull electrons. Consequently, as the strength of the magnetic field applied to the nucleus increases, the peak shifts to a higher frequency. Conversely, if there are many electrons around the nucleus and the strength of the magnetic field felt by the nucleus decreases, the rotational motion frequency of the nucleus decreases in the lower direction. When molecular aggregates are physically formed, the density of the electron cloud of the atomic nucleus changes depending on the distance between strongly interacting molecules. Another method is that nuclei near a phenyl ring (C6H5-), where a ring current is formed under a magnetic field, will experience a local change in the magnitude of the magnetic field due to the ring current, which changes the rotational speed of the nucleus. Furthermore, even in cases where the electron density is high due to a double bond, such as C=O, the position of the peak can shift to the up field or down field because the strength of the magnetic field changes depending on the relative position of the surrounding nuclei to C=O. 【0087】 In the case of molecular aggregates produced by the present invention, they can be physically bound together by intermolecular interactions and consist substantially of organic or inorganic materials, without the need for separate binders or additives. 【0088】 Judging from these points, when comparing the NMR values ​​measured for the molecular aggregate produced by the present invention with those of the organic or inorganic precursor of the nanomolecular aggregate, the position of some peaks in the NMR spectrum changes. This indicates that there is no change in the chemical structure between the nanomolecular aggregate and the organic or inorganic precursor, but rather a change in the physical structure. Specifically, when comparing the NMR values ​​measured for the nanomolecular aggregate and the organic or inorganic precursor of the nanomolecular aggregate, if the peak shift is 0.005 ppm or more based on 1H NMR, they can be judged to be different. 【0089】 On the other hand, in the case of FT-IR, the density of electrons constituting the molecular bonds is unevenly distributed, and it is known that changes in the peak often appear when the dipole moment changes as the molecule moves. It is known that the peaks in the spectrum are excited by various molecular motions such as stretching and bending. Polarity in molecular bonds occurs when they are formed by heteroatoms, and changes in the peak often appear. For example, ether bonds (CO), which are primary bonds, and carbonyl bonds (C=O), which are secondary bonds, between carbon and oxygen show stretching bands when exposed to infrared lasers. Similarly, in the case of carbon and hydrogen, stretching bands also appear because they are bonds between different molecules. In the case of stretching, it can be explained by a model in which two masses are connected by a spring, and when the energy that excites the spring's motion is supplied by infrared light, a peak appears in the spectrum. 【0090】 Even when multiple carbon atoms are linked together, such as in benzene where six atoms are bonded, various bending peaks appear, including in-plane vibrations and out-of-plane vibrations. In particular, in the case of bending motion, various types of molecular motion can be observed by FT-IR spectroscopy. For example, rocking (movement from side to side), scissorsing (movement like scissors), wagging (swaying back and forth in a plane), and twisting / torsion (repeated twisting motion) can occur. 【0091】 Molecules with strong polarity can interact through hydrogen bonding, polar interactions, or π-π stacking, and these interactions cause changes in the position and intensity of peaks in the FT-IR spectrum. Therefore, even the same molecular bond can exhibit changes in peak position and intensity depending on the surrounding environment. In other words, if the FT-IR spectra are the same, it indicates that they are the same molecule. Especially at 400 cm⁻¹ -1 ~700 cm -1 The area between these points is called the fingerprint zone, and if the peaks are the same within this zone, they are considered to be the same compound. 【0092】 The present invention aims to form compounds into molecular aggregates, which are physical aggregates. When compounds are formed into molecular aggregates in this way, the intermolecular distances within the aggregate are very close, within approximately 10 Å or 5 Å. When intramolecular bonds are excited by infrared light, the compound bonds within the molecular aggregate undergo molecular motion such as stretching and bending. At this time, it has been found that in the molecular aggregates of the present invention, various changes occur, such as the appearance or disappearance of peaks that were not present in the original compound spectrum, changes in the position of peaks, and decreases or increases in peak intensity, due to compounds present at a very close distance to the original compound. 【0093】 In other words, if one or more peaks are generated or disappear based on the results measured by the FT-IR, it can be determined that they are different. 【0094】 When comparing the FT-IR measurements of the nanomolecular aggregate produced by the present invention with those of an organic or inorganic precursor of the nanomolecular aggregate, one or more peaks appear or disappear in the FT-IR spectrum. This indicates that there is no change in the chemical structure between the nanomolecular aggregate and its organic or inorganic precursor, but a change in the physical structure occurs. Furthermore, when comparing the FT-IR measurements of the nanomolecular aggregate and its organic or inorganic precursor, the position of one or more peaks changes at 5 cm. -1 If the above changes occur, it can be determined that the result is different. In other words, the conversion of a compound into a molecular aggregate is due to a physical action, and no new chemical bonds are formed or existing chemical bonds are destroyed. Therefore, such a change in the spectrum can be well explained as the fact that a new molecular aggregate with a novel structure, unlike anything in the past, has been created in this invention. 【0095】 However, the nanomolecular aggregates produced by the present invention and the organic or inorganic precursors of the nanomolecular aggregates have the same chemical structure as previously mentioned. This can be seen by performing chromatographic analysis on the nanomolecular aggregates and the organic or inorganic precursors of the nanomolecular aggregates and observing that the measured values ​​are the same. The chromatographic measurements may also be results obtained by HPLC (high-performance liquid chromatography), and it is observed that the organic or inorganic products provided by the present invention and the molecular aggregates exhibit peaks at approximately the same position and have a retention time of approximately 10% (i.e., within ±5%). Generally, when the same column, mobile phase, and stationary phase are used, peaks that appear within 10% of the time can be judged to be the same substance. 【0096】 Thus, because the nanomolecular aggregate and the organic or inorganic precursor of the nanomolecular aggregate have different physical structures, the peaks of the two target substances in the NMR spectrum are generally similar, or some peaks can be altered. On FT-IR, various forms of changes may be observed, such as the generation and disappearance of peaks, and changes in peak intensity. Furthermore, because the nanomolecular aggregate and the organic or inorganic precursor of the nanomolecular aggregate have the same chemical structure, the chromatographic measurements may be identical. 【0097】 In the present invention, there are no particular limitations on the NMR measurement of the nanomolecular aggregate and the organic or inorganic precursor of the nanomolecular aggregate, but as an example, it can be measured using a Bruker 400 MHz Avance. 【0098】 In the present invention, there are no particular limitations on the FT-IR measurement of the nanomolecular aggregate and the organic or inorganic precursor of the nanomolecular aggregate, but as an example, it can be measured using a Bruker Alpha 2 ATR. 【0099】 Next, the drug molecule-derived or other molecular aggregate according to the present invention is a precursor of the nanomolecular aggregate, characterized in that shear stress is applied to a solution containing an organic or inorganic salt to produce a nanomolecular aggregate having a structure in which the organic or inorganic salt is physically bonded. 【0100】 The molecular aggregate produced in this manner is a molecular aggregate to which a pharmacologically active ingredient and a water-soluble compound are bound, characterized in that the chromatographic measurement values ​​of the organic or inorganic salt that is a precursor of the nanomolecular aggregate and the molecular aggregate to which the organic or inorganic salt is bound are the same, and the spectroscopic measurement values ​​of the organic or inorganic salt that is a precursor of the nanomolecular aggregate and the molecular aggregate to which the organic or inorganic salt is bound are different. 【0101】 In the aforementioned nanomolecular aggregate, the chromatographic and spectroscopic measurements are the same as those mentioned earlier. 【0102】 Similarly, without the need for separate binders or additives, molecules can be physically bound together by intermolecular interactions and consist essentially of organic or inorganic salts. 【0103】 In the present invention, the salt of the organic or inorganic substance can be one used as a pharmacologically active ingredient, and the salts of the organic or inorganic substances mentioned above can be used. 【0104】 As mentioned earlier, the organic or inorganic salt that is a precursor of the nanomolecular aggregate and the molecular aggregate formed by the physical bonding of the organic or inorganic salt have different physical structures. Therefore, in the NMR spectrum, the peaks of the two target substances are generally similar, although some can be altered. On FT-IR, various forms of changes may be observed, such as the generation and disappearance of peaks and changes in peak intensity. 【0105】 For example, when comparing the NMR values ​​measured for an organic or inorganic salt that is a precursor of the nanomolecular aggregate with those of a molecular aggregate to which the organic or inorganic salt is bound, if the peak position changes, it can be determined that they are different. Specifically, when comparing the NMR values ​​measured for an organic or inorganic salt that is a precursor of the nanomolecular aggregate with those of a molecular aggregate to which the organic or inorganic salt is bound, if the peak shift is 0.005 ppm or more on a 1H NMR basis, it can be determined that they are different. 【0106】 Furthermore, when comparing the FT-IR measurements of an organic or inorganic salt that is a precursor of the nanomolecular aggregate with those of a molecular aggregate to which the organic or inorganic salt is bonded, if one or more peaks appear or disappear, they can be determined to be different. Specifically, when comparing the FT-IR measurements of an organic or inorganic salt that is a precursor of the nanomolecular aggregate with those of a molecular aggregate to which the organic or inorganic salt is bonded, if one or more peaks appear or disappear, they can be determined to be different. -1 If the above changes occur, they can be considered different. 【0107】 Furthermore, since the organic or inorganic salt that is a precursor of the nanomolecular aggregate and the molecular aggregate to which the organic or inorganic salt is bonded have the same chemical structure, the chromatographic measurements may be the same. Specifically, if the HPLC measurement results of the organic or inorganic salt that is a precursor of the nanomolecular aggregate and the molecular aggregate to which the organic or inorganic salt is bonded have a retention time of 10% or less, they can be considered to be the same. 【0108】 Furthermore, the nanomolecular aggregates according to the present invention may have very small particle sizes, with an average particle size of 50 nm or less, preferably 30 nm or less, more preferably 20 nm or less, very preferably 15 nm or less, and most preferably 10 nm or less or 5 nm or less. The average particle size can be measured through diffraction experiments, preferably using Small Angle Neutron Scattering (SANS). Alternatively, an image can be measured using Transmission Electron Microscopy. If the average particle size of the nanomolecular aggregate exceeds 50 nm, there is a problem of reduced dispersibility, transparency, and transmittance. There is no particular lower limit to the average particle size of the nanomolecular aggregate, but those of approximately 1 nm or more can be used. 【0109】 The manufacturing method of the present invention will be described in more detail below through examples of the present invention. It goes without saying that the present invention is not limited to these examples. 【0110】 Examples Equipment used 3 roll mill 【0111】 [Table 1] 【0112】 manufacturing [Example 1] A 0.2% adenosine solution was prepared by dissolving 1 g of adenosine (adenosine, Aldrich) in 99 mL of ethanol. As shown in Figure 1, a roll mill consisting of two rolls, roll A and roll B, was prepared, and the prepared adenosine aqueous solution was introduced between roll A and roll B at an input rate of 50 ml / min. The rotation speed of roll A was adjusted to 100 rpm and the rotation speed of roll B to 300 rpm, and the distance between roll A and roll B was set to 10 μm. After mixing the solution of ethanol-adenosine molecular aggregates obtained between the rolls with distilled water, the ethanol was removed using a vacuum dryer to obtain a clear aqueous adenosine dispersion. 【0113】 The obtained aqueous solution was frozen at -50°C, and then the water was removed by running it through a freeze-dryer at a temperature and pressure of 0.1 bar and -70°C for 48 hours to obtain a powder of adenosine molecule aggregates. 【0114】 [Comparative Example 1] Excluding the case where an adenosine solution was prepared and the rolling process for producing the molecular aggregate was not carried out, adenosine powder was obtained through the same process as in Example 1. 【0115】 [Example 2] Except for the use of cyclosporine A (cyclosporine A, TEVA) instead of adenosine, the powder of cyclosporine A molecular aggregates was obtained in the same manner as in Example 1. 【0116】 [Comparative Example 2] Excluding the case where a cyclosporine A solution was prepared and the rolling process for producing the molecular aggregate was not carried out, cyclosporine A powder was obtained through the same process as in Example 2. 【0117】 [Example 3] The yellow powder of the niclosamide molecular aggregate was obtained using the same method as in Example 1, excluding the use of niclosamide (Sigma-Aldrich) instead of adenosine. 【0118】 [Comparative Example 3] Excluding the case where a niclosamide solution was prepared and the rolling process for producing the molecular aggregate was not carried out, niclosamide powder was obtained through the same process as in Example 3. 【0119】 [Example 4] 19.8 mg of DCF-DA (2',7'-Dichlorofluorescin diacetate, Sigma-Aldrich) was dissolved in 10 mL of water to prepare an aqueous solution of DCF-DA with a concentration of approximately 0.2%. As shown in Figure 1, a roll mill consisting of two rolls, roll A and roll B, was prepared, and the prepared DCF-DA solution was introduced between roll A and roll B at an input rate of 50 ml / min. The rotation speed of roll A was adjusted to 100 rpm, the rotation speed of roll B to 300 rpm, and the distance between roll A and roll B was set to 10 μm. 【0120】 The obtained aqueous solution was frozen at -50°C, and then the water was removed by running it through a freeze-dryer at a temperature and pressure of 0.1 bar and -70°C for 48 hours to obtain a DCF-DA molecular aggregate powder. 【0121】 [Comparative Example 4] Excluding the case where an aqueous solution was prepared with DCF-DA and the rolling process for producing the molecular aggregate was not carried out, the DCF-DA powder was obtained through the same process as in Example 4. 【0122】 [Example 5] In Example 1, the use of efinaconazole (Sigma-Aldrich) instead of adenosine was excluded, and a white powder of efinaconazole molecular aggregates was obtained using the same method as in Example 1. 【0123】 [Comparative Example 5] Excluding the case where an efinaconazole ethanol solution was prepared and the rolling process for producing the molecular aggregate was not carried out, a white powder of efinaconazole was obtained by following the same procedure as in Example 5. 【0124】 [Example 6] A white powder of tacrolimus molecular aggregates was obtained using the same method as in Example 1, excluding the use of tacrolimus (Sigma-Aldrich) instead of adenosine. 【0125】 [Comparative Example 6] Excluding the case where the solution was prepared and the rolling process for producing the molecular aggregate was not carried out, a white powder of tacrolimus was obtained by following the same procedure as in Example 6. 【0126】 Experimental Example 1: Comparison of XRD structures of Example 2 and Comparative Example 2 Figure 5 shows a comparison of the XRD measurement results of the molecular aggregate of Example 2 of the present invention, manufactured using cyclosporine A, and cyclosporine A itself in Comparative Example 2. As can be seen from the comparison of the graphs, when the peaks that appear due to the holder (SUS material) that grips the specimen (peaks that appear similarly on the right side of the graph) are excluded, it can be seen that, unlike the API (cyclosporine A) in Comparative Example 2 before the process, which exists in a crystal form (sharp peak on the left), the molecular aggregate of Example 2 of the present invention after the process changed to an amorphous form (amorphous peak on the left) due to a change in its physical structure. 【0127】 In the case of amorphous crystalline structures like the molecular aggregates of the present invention, the peaks may change due to changes in the size of the reticles inside, but this also only involves a change from one conventional crystal form to another, and does not involve a change to an amorphous form as in the present invention. 【0128】 Therefore, as can be seen from Figure 5, the molecular aggregate of the present invention did not change into a solvent form, but rather its physical structure itself changed into an amorphous form. 【0129】 Experimental Example 2: Comparison of DSC measurement experiments in Example 2 and Comparative Example 2 To clearly demonstrate that the molecular aggregate of this application is not a crystalline (sorbated) product, the applicant of this application conducted the following DSC measurement experiment. 【0130】 Specifically, Figure 6 shows a comparison of the DSC measurement results of the molecular aggregate of Example 2 of the present invention, which was produced using cyclosporine A as the API, and Comparative Example 2, which is cyclosporine A itself. If the molecular aggregate produced through the process of the present invention were a solvent, a peak should appear on the DSC graph indicating that the solvent (the solvent used in the present invention is water or ethanol) is evaporating near its boiling point (approximately 100°C for water and 60°C for ethanol). However, no such peak appears in the DSC measurement results data shown in Figure 6. Therefore, it is clear that the difference in the spectroscopic measurements of the molecular aggregate of the present application and the pharmacologically active component, which is a precursor of the nanomolecular aggregate, is not due to changes caused by sorbation, but rather to changes in the physical structure. 【0131】 Experimental Example 3: Confirmation of Particle Photographs in the Example The applicant of this application took a TEM image of the molecular aggregate of Example 2, which was prepared using cyclosporine A as the API, in order to confirm that the molecular aggregate of this application has a structure in which it is a molecular aggregate of APIs. First, a TEM image of the molecular aggregate of Example 2, which was prepared using cyclosporine A as the API, was taken and is shown in Figure 7. Unlike cyclosporine A itself, which is poorly soluble in water and cannot be confirmed by TEM, as can be confirmed in the TEM image in Figure 7, the molecular aggregate according to the present invention can be confirmed to have a structure in which multiple APIs are physically bonded together. 【0132】 Therefore, it is clear that the molecular aggregate according to the present invention is a molecular aggregate structure in which multiple APIs are physically bonded together. 【0133】 Experimental Example 4: Comparison of Solubility Performance of Examples and Comparative Examples The dispersion of the molecular aggregates (B) prepared in Examples 1-6 was compared with the solubility of the pharmacologically active substances themselves (A) prepared in Comparative Examples 1-6. Each sample was stirred at 25°C for 10 hours and filtered through a 0.2 micron filter. The solubility of the comparative examples was determined by peak integration using the concentration obtained by HPLC (Waters e2695) to determine the amount in which the API dissolved or the molecular aggregates dispersed in the examples. 【0134】 [Table 2] 【0135】 As mentioned above, it has been found that the dispersibility of pharmacologically active substances in solvents and water is greatly improved compared to the pharmacologically active substances themselves. This will not only be a very important feature when formulating drugs in the future, but will also be a great advantage in enhancing their efficacy. 【0136】 Experimental Example 5: Comparison of Cell Permeability Performance of Example 4 and Comparative Example 4 The cell permeability performance of the DCF-DA molecular aggregate in powder form produced in Example 4 and the DCF-DA itself from Comparative Example 4 was compared. Suspension cells (MV-4-11 human macrophage) were grown to fill a dish to approximately 50%. The DCF-DA from Comparative Example 4 was dissolved in ethanol, and the DCF-DA molecular aggregate from Example 4 was dissolved in distilled water at the same concentration of 0.005% for 30 minutes. After that, the cells were washed with PBS (phosphate buffer solution) to remove extracellular DCF-DA and stop diffusion-induced cell ingestion. After stabilizing the cells with an additional 30 minutes of culture, they were treated with 0.03% hydrogen peroxide (H2O2), and the DCF exhibiting intracellular fluorescence was imaged as a 3D hologram and fluorescence using a 3D microscope (Tomocube HT-2H), which is shown in Figure 8. The experimental results confirmed that the DCF-DA molecular aggregate treatment in Example 4, shown in Figures 8C and 8D, exhibited much stronger fluorescence than the DCF-DA treatment treatment in Comparative Example 4, shown in Figures 8A and 8B. Therefore, it was confirmed that the molecular aggregate produced by the present invention has much higher phospholipid membrane permeability.

Claims

[Claim 1] A molecular aggregate in which organic or inorganic substances are physically bound together, When the molecular aggregate is formed with a composition containing water, the molecular aggregate in the composition has an aggregated structure. The average particle size of the molecular aggregate is 50 nm or less. The molecular aggregate is produced by applying shear stress to a solution containing the organic or inorganic substance. The aforementioned organic or inorganic substance is one or more selected from the group consisting of adenosine, cyclosporine A, niclosamide, DCF-DA, efinaconazole, and tacrolimus. The solubility A of the aforementioned organic or inorganic substance in water, When comparing the degree of dispersion B of the molecular aggregates in water, It is characterized by having a dispersion B / solubility A value of 1.2 or higher at 25℃. Nanomolecular aggregates. [Claim 2] The nanomolecular aggregate according to claim 1, characterized in that the nanomolecular aggregate is amorphous. [Claim 3] The nanomolecular aggregate according to claim 1, characterized in that the distance between molecules is 10 Å or less. [Claim 4] When the aforementioned organic or inorganic substance is adenosine The nanomolecular aggregate according to claim 1, characterized in that the dispersion B / solubility A value is 1.5 or greater. [Claim 5] When the aforementioned organic or inorganic substance is cyclosporine A The nanomolecular aggregate according to claim 1, characterized in that the dispersion B / solubility A value is 2.0 or greater. [Claim 6] When the aforementioned organic or inorganic substance is niclosamide The nanomolecular aggregate according to claim 1, characterized in that the dispersion B / solubility A value is 15 or more. [Claim 7] When the aforementioned organic or inorganic substance is DCF-DA The nanomolecular aggregate according to claim 1, characterized in that the dispersion B / solubility A value is 25 or more. [Claim 8] When the aforementioned organic or inorganic substance is efinaconazole The nanomolecular aggregate according to claim 1, characterized in that the dispersion B / solubility A value is 2.0 or greater. [Claim 9] When the aforementioned organic or inorganic substance is tacrolimus The nanomolecular aggregate according to claim 1, characterized in that the dispersion B / solubility A value is 1.2 or greater. [Claim 10] The nanomolecular aggregate according to claim 1, characterized in that the molecular aggregate is made of organic or inorganic material.

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