Solid cyclosporin a and dispersion composition comprising the same

Abstract

To satisfy a need for a technology capable of achieving improved solubility even when the amount of surfactant used is reduced or minimized compared to existing technologies.SOLUTION: Provided is a dispersion composition comprising: a dispersion medium; and particles comprising a target substance, wherein the dispersion composition comprises at least one type of surfactant having a threshold micelle concentration or more, the dispersion composition does not comprise a solubilizer, and the target substance is cyclosporin A, satisfying the S-parameter>1 defined above.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a solid phase of cyclosporin A having improved dispersibility and a dispersion composition having improved dispersibility obtained by dispersing the same. [Background technology]

[0002] In the pharmaceutical technology field, preparing aqueous solutions is one of the most important challenges. Water is the most common solvent and is the most commonly used solvent for drug dosage forms as a drinkable liquid. However, many drugs exhibit strong non-polarity and therefore have poor solubility in water, a polar solvent. Thus, despite their excellent therapeutic efficacy, poorly soluble drugs with poor solubility cannot be formulated into clinically useful pharmaceutical dosage forms.

[0003] A well-known technique to address this issue is micellar solubilization, which uses surfactants to solubilize poorly soluble drugs. Surfactants are substances that possess both hydrophilic and hydrophobic groups within a single molecule and distribute primarily at the interface between a target substance (e.g., a drug) and a dispersant (e.g., water) to aid in the dispersion of the target substance or stabilize the dispersion state. Micellar solubilization involves selectively distributing a poorly soluble target substance in a dispersant into nanometer-sized micelles formed by the self-assembly of surfactants contained in the dispersant at a concentration exceeding a specific threshold micelle concentration, thereby allowing the target substance to be incorporated into the dispersant at a high concentration exceeding its saturation solubility. Summary of the Invention [Problem to be solved by the invention]

[0004] In pharmaceutical technology, bioavailability is a concept that indicates the amount and rate at which a drug is delivered from the site of administration to the target site of action in the body where it exerts its therapeutic effect. If bioavailability is low, even if a drug has high therapeutic efficacy outside the body, the actual amount delivered to the organs in the body where it must act will be small, resulting in a low or negligible therapeutic effect inside the body. Bioavailability can be understood as the flux (FLUX) through biological barriers in the body, such as the cornea, skin, blood-brain barrier, and blood-retina barrier (see Equation 8 below).

[0005] [Formula 8] Flow rate (FLUX) = solubility x permeability

[0006] Equation 8 shows that solubility and permeability must be balanced to increase flux. According to the Biopharmaceutics Classification System, 70% of all drugs belong to Class II, which has high permeability and low solubility, and 20% belong to Class IV, which has low permeability and low solubility. (Reintjes, T., Solubility enhancement with BASF Pharma polymers: Solubilizer Compendium. BASF, (2021) pp. 9-10.)

[0007] When micellar solubilization technology is applied to polar dispersion media such as water, the outer surface of a drug surrounded by a surfactant becomes more hydrophilic than when the drug is present independently. However, because most physiological barriers in the body contain phospholipids or hydrophobic layers, pharmaceutical compositions formulated using micellar solubilization technology generally have low permeability through biological barriers. For this reason, micellar solubilization technology has the limitation of making it difficult to obtain pharmaceutical compositions with improved bioavailability that result in improved therapeutic efficacy, as improved solubility and increased permeability are trade-offs. Furthermore, surfactants often cause environmental pollution, toxicity, or side effects in the body, making it necessary to minimize their usage.

[0008] Therefore, there is a great need and commercial value for a technology that can achieve improved solubility while minimizing or reducing the amount of surfactant used compared to existing technologies. By reducing the amount of surfactant required compared to existing technologies, such a technology can improve permeability compared to existing technologies, thereby improving bioavailability and therapeutic efficacy, while also minimizing environmental pollution and internal toxicity / side effects.

[0009] The objects of the present invention are not limited to the objects mentioned above, and other objects and advantages of the present invention not mentioned above can be understood from the following description and will become more clearly understood from the embodiments of the present invention. Furthermore, it can be easily seen that the objects and advantages of the present invention can be realized by the means and combinations thereof set forth in the claims.

[0010] Cyclosporines are immunosuppressants with a non-polar cyclic structure consisting of 11 amino acids, and include cyclosporines A, B, C, D, and G. In immune lymphocytes, cyclosporines block the activity of calcineurin, thereby suppressing the production of immune cytokines that ultimately trigger immune responses. In addition to treating several immune disorders, cyclosporines are known to be effective in restoring the destruction and dysfunction of the lacrimal gland caused by keratoconjunctivitis sicca or dry eye syndrome (US patent 4,839,342).

[0011] However, cyclosporine's large molecular weight and hydrophobic properties make it difficult to achieve its therapeutic effect in ocular tissues. In particular, cyclosporine is an insoluble substance, making it difficult to expect improved solubility in aqueous or water-soluble media (US Patent 5,051,402). To address this drawback, numerous attempts have been made to solubilize cyclosporine in pharmaceutical compositions for the treatment of dry eye. For example, the previously known cyclosporine formulations Restasis, Cequa, and Ikervis, developed by Allergan, Sun Pharma, and Santen, contain surfactants such as polysorbate 80, hydrogenated castor oil, and poloxamer, respectively (US Patent 2014020662 A1p, 2014005785 A1p, EP2049079B1). However, a large amount of surfactants can cause side effects such as environmental pollution and internal toxicity.

[0012] Additionally, the Restasis and Ikervis cyclosporine formulations are manufactured with solutions containing castor oil and MCT oil (Medium Chain Triglycerides), respectively. However, ocular compositions containing oil can cause side effects such as blurred vision and eye irritation when instilled into the eyes.

[0013] To minimize these side effects and improve bioavailability, it is necessary to minimize the content of surfactants and oils such as castor oil. Thus, there remains a need to develop a cyclosporine dosage form that uses less surfactant than known techniques but has improved solubility in polar dispersion media. [Means for solving the problem]

[0014] In one embodiment of the present invention, a dispersion composition is provided that includes a dispersion medium and particles containing a target substance, the dispersion composition comprises at least one surfactant having a threshold micelle concentration or higher; the dispersion composition does not include a solubilizer; The target substance is cyclosporin A, When the dispersion composition contains one surfactant, the S-parameter of Equation 3 calculated by Equation 1 and Equation 2 satisfies S-parameter>1; When the dispersion composition contains at least two surfactants having a micelle concentration above the threshold, the S obtained by the following Equation 4 for each surfactant type is surf(i) and calculate the sum of these using the following formula 5: surf The value of S is calculated as follows: surf The S-parameter of Equation 3 obtained by applying the value to Equation 1 satisfies S-parameter>1. <Formula 1> S micelle =S w +S surf In the above formula 1, S wis the concentration corresponding to the saturated solubility of the target substance in the dispersion medium, and S surf is calculated by the following formula 2. <Formula 2> S surf =k(C surf -CMC) In Equation 2, k is the molar solubilization capacity, which is defined as the number of moles of the target substance that can be dispersed in the dispersion medium by one surfactant having a micelle concentration equal to or greater than 1 mole, and C surf is the molar concentration of the surfactant component in the composition, and CMC is the threshold micelle molar concentration of the surfactant in the composition. <Formula 3> S-parameters = S tot / S micelle In the above formula 3, S tot is the total molar content of the target substance contained in the dispersion composition. <Formula 4> S surf(i) =k surf(i) (C surf(i) -CMC surf(i) ) In the above formula 4, k surf(i) is the molar solubilization capacity defined as the number of moles of the target substance that can be dispersed in the dispersion medium by any one of the surfactant components at a micelle concentration equal to or greater than 1 mole, and C surf(i) is the concentration of any one of the surfactant components above the threshold micelle concentration, and CMC surf(i) is the threshold micelle concentration of any one surfactant component having a threshold micelle concentration or higher in the dispersion medium.

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[0015] In another embodiment of the present invention, there is provided a solid phase cyclosporin A that can be used as the target substance. That is, the dispersion composition is obtained by using the solid phase cyclosporin A as the target substance. [Effects of the Invention]

[0016] In the field of dispersion compositions such as drugs and cosmetics, stably dispersing a high content of active ingredients is an important challenge for facilitating the absorption of the active ingredients. Therefore, the dispersion composition can be innovatively applied to various industrial fields that require high content and dispersion stability. For example, when the dispersion composition embodied in the present invention contains a poorly soluble drug, it can expand the use of drugs that could not be used previously and minimize the side effects of additives such as surfactants, thereby achieving a breakthrough in disease treatment.

[0017] The dispersion composition embodied in the present invention has a lower surfactant content than conventional techniques, improving not only the solubility but also the permeability of the target substance, resulting in improved bioavailability and superior therapeutic efficacy. Furthermore, by reducing the surfactant content compared to conventional techniques, it is possible to reduce or prevent problems caused by surfactants, such as environmental pollution and internal toxicity / side effects. For example, Polyoxyl 35 castor oil (Kolliphor EL or Cremophor EL), which is commonly used as a surfactant in pharmaceutical compositions, is highly toxic. Furthermore, the surfactant Polysorbate 80 (Polysorbate 80 or Tween 80) is used to prepare dispersions of cyclosporine A, but this has the disadvantage of causing severe eye irritation. The dispersion composition of the present invention maintains a stable dispersion state despite its low surfactant content, thereby reducing or avoiding the side effects of toxic surfactants. As another example, cosmetic products made with the dispersion composition embodied in the present invention have a minimized content of additives such as surfactants, improving application and penetration, thereby improving cosmetic effects.

[0018] The specific effects of the present invention will be described together with the above-mentioned effects while explaining the specific matters for carrying out the invention below. DETAILED DESCRIPTION OF THE INVENTION

[0019] <Terminology> First, definitions / descriptions of key terms used in the description of the present invention.

[0020] The "target ingredient" refers to a substance to be dispersed in the dispersion composition to be embodied. It can be a pharmacologically active ingredient for pharmaceutical use or an active ingredient effective in improving skin aesthetics for cosmetic use, and can be a variety of substances depending on the intended use. For example, pharmacologically active ingredients of the present invention include, but are not limited to, tyrosine kinase inhibitors such as sunitinib, axitinib, and pazopanib, cyclosporine, niclosamide, adenosine, deoxycholic acid, paclitaxel, or pharmaceutically acceptable salts or derivatives thereof. The target ingredient can be a single substance or a mixture of two or more target ingredients. The dispersion composition according to one embodiment of the present invention is commercially valuable when the target substance is a substance that is poorly soluble in a dispersion medium. Examples of such poorly soluble substances include drugs, which may be classified as pi (practically insoluble), vss (very slightly soluble), ss (slightly soluble), sps (sparingly soluble), etc. in the United States Pharmacopeia (USP) Solubility Criteria.(O. Wolk, et al., Drug Design, Development and Therapy, 8 (2014) pp. 1563-1575) Examples of drugs among the target substances include, but are not limited to, drugs that are insoluble or poorly soluble in water, such as paclitaxel, deoxycholic acid, cyclosporine, minoxidil, finasteride, latanoprost, miconazole, prednisolone, fluorometholone, or prostaglandin analogs, as well as pharmaceutically acceptable salts or derivatives of such drugs, or combinations thereof. The target substance may be a nutritional ingredient that is poorly soluble in water, such as curcumin, or an active substance with cosmetic effects, and may be a variety of substances depending on the use and purpose of the dispersion composition.

[0021] A "medium with a plurality of surfaces" is a medium composed of porous materials, non-porous materials, or a mixture thereof, and containing intraparticle pores, interparticle pores, or a mixture thereof. That is, the voids within the medium may be intraparticle pores or interparticle pores. For example, if the medium is a porous material containing pores within the material, the voids within the medium may be intraparticle pores contained within the porous material. For example, if the medium is formed as an aggregate or conglomerate (e.g., secondary particles, powder, or packed bed) formed by the accumulation or accumulation of non-porous particles, the voids within the medium are interparticle pores. For example, if the polyhedron is formed as an aggregate or conglomerate (such as a secondary particle, powder, or packed bed) of mixed porous and non-porous particles, the voids within the polyhedron are intra-particle voids or inter-particle voids. In other words, the polyhedron can be an aggregate or conglomerate composed of various types of porous materials or any porous or non-porous particles.

[0022] The average void size of the polyhedron may be about 1 nm to about 1 μm. For example, the average void size of the polyhedron may be about 1 nm to about 100 nm. For example, the average void size of the polyhedron may be about 1 nm to about 50 nm. For example, the average void size of the polyhedron may be about 1 nm to about 30 nm. Using polyhedrons with void sizes within these ranges can help form particles with a predetermined target size. The porosity of the polyhedron is about 5 to about 97% (v / v). For example, the porosity of the polyhedron is about 20 to about 60% (v / v). For example, when the polyhedron is an aerogel, the porosity is about 90 to about 97% (v / v).

[0023] For example, the polyhedron may be silica gel, silica xerogel, mesoporous silica, fumed silica, mesoporous alumina, mesoporous metal oxides, mesoporous materials, charcoal, activated carbon, aerogel, zeolite, molecular sieves, metal-organic frameworks, organic / inorganic hybrid porous materials, etc., and may be natural, synthetic, or biological materials, crystalline or amorphous, and are not limited by composition, material, structure, synthesis / manufacturing method, etc. The pores within the polyhedron may vary in shape, size, production method, arrangement structure (regular or irregular), etc. The polyhedron may be in the form of particles of any size and shape, secondary particles of a plurality of particles, powder of any size and shape, packed bed of particles, solid foam, membrane, or sheet, but is not limited to these forms. The polyhedron may be composed of a single material or may contain at least two or more materials, or may be a mixture of these materials.

[0024] In other words, as long as the size, shape, and porosity of the intra- or inter-particle voids, or the predetermined surface area and physicochemical properties of the surface, of the polyhedron are suitable for use in the method and composition of the present invention, there are no limitations on the material, phase, crystalline or amorphous nature of the polyhedron, composition, size, shape, morphology, formation method or assembly method, void arrangement structure, whether the voids of the polyhedron are intra- or inter-particle voids, or whether the polyhedron is a porous or non-porous material.

[0025] The "solvent for preparing a mixture" is a solvent capable of dissolving the target substance at the intended content, and can be selected taking into consideration solvent properties such as saturation solubility and polarity to dissolve the target substance at the desired content. The target substance can be dissolved at a higher content in the solvent for preparing a mixture than in the dispersant. For example, the solubility of the target substance in the solvent for preparing a mixture is greater than that in the dispersant. For example, the solvent for preparing a mixture can include organic solvents such as water, alcohol (e.g., methanol, ethanol), acetone, acetic acid, acetonitrile, ethyl acetate, methylene chloride, chloroform, and dimethyl sulfoxide (DMSO), and sugars such as polyethylene glycol (PEG), mannitol, and sorbitol, and can include combinations of two or more of these, but is not limited to these. The solvent for preparing a mixture can be compatible or incompatible with the dispersant. The solvent for preparing the mixture may be miscible, immiscible, or partially miscible with the dispersion medium. The solvent for preparing the mixture may be a hydrophilic substance, a hydrophobic substance, or an amphipathic substance. The solvent for preparing the mixture may be polar, non-polar, or amphipathic. The solvent for preparing the mixture may be a volatile compound. When the solvent for preparing the mixture is finally removed to prepare the dispersion composition, if the solvent for preparing the mixture is a volatile compound, it has the advantage of being easily removed. The solvent for preparing the mixture may be a compound with a lower boiling point than the dispersion medium. When the solvent for preparing the mixture is finally removed to prepare the dispersion composition, if the solvent for preparing the mixture is a compound with a lower boiling point than the dispersion medium, it has the advantage of being easily removed by distillation, which is a separation process.

[0026] The "mixture" refers to a solution obtained by mixing the target substance with the solvent for preparing the mixture, in which the target substance is dissolved in the solvent for preparing the mixture. For example, the mixture may contain the target substance in a content of about 0.01% (w / v) to about 50% (w / v). Specifically, the mixture (A) may contain the target substance in a content of about 0.1% (w / v) to about 10% (w / v). The content of the target substance in the mixture may be determined in consideration of the solubility of the target substance in the solvent for preparing the mixture, and the type of solvent for preparing the mixture may be selected accordingly.

[0027] The term "process fluid" refers to a fluid used together with the mixture during contact with the multi-surfaced bodies to facilitate contact, increase productivity, or control the residence time of the mixture within the multi-surfaced bodies. The process fluid is selected based on viscosity and surface tension to control the contact ease, productivity, or residence time of the mixture. The type of process fluid can also be selected based on the solubility of the target substance and miscibility with the solvent used to prepare the mixture, so as to prevent precipitation or solidification of the target substance during contact between the mixture and the multi-surfaced bodies. The process fluid may be the same as or different from the solvent used to prepare the mixture, or may be a mixture of the solvent used to prepare the mixture with another fluid.

[0028] The "dispersion medium" corresponds to the continuous phase among the components of the dispersion composition, and various substances can be used depending on the application. For example, in the case of a pharmaceutical composition, it can be water, saline solution, or buffered aqueous solution. In the dispersion composition of the present invention, the content of the target substance can exceed the saturation solubility in the dispersion medium.

[0029] The dispersion medium may be a polar or hydrophilic solvent. For example, the polar or hydrophilic solvent may be water, methanol, ethanol, glycerol, polyol, etc. For example, the dispersion medium may be water, and the target substance may be a water-insoluble substance such as paclitaxel, deoxycholic acid, cyclosporine, latanoprost, miconazole, or curcumin. The dispersion medium may be a non-polar or hydrophobic solvent. For example, the non-polar or hydrophobic solvent may be a hydrocarbon, silicone oil, ethyl acetate, acetone, tetrahydrofuran (THF), etc. For example, the dispersion medium may be hexane, and the target substance may be a hexane-insoluble substance such as a saccharide or glucose. The dispersion medium may also be an amphiphilic solvent. The dispersion medium may be a polar or non-polar solvent to which an amphiphilic solvent is added. The type and composition of the dispersion medium may be selected in consideration of the solubility of the target substance therein, differences in physicochemical properties, and the intended use of the dispersion composition, and may be used alone or in combination of two or more. For example, the dispersion medium may be an organic solvent.

[0030] A "particle" is defined as an association of multiple molecules having any composition, shape, size, or structure, and corresponds to the dispersed phase, which is the discrete phase in a dispersion composition. In the present invention, the particles in the dispersion composition may further contain auxiliary agents and additive materials in addition to the target substance.

[0031] A "dispersion composition" is a composition in which particles containing the target substance are dispersed in a continuous dispersion medium as a discontinuous phase distinct from the dispersion medium. The dispersion composition is distinct from a single-phase solution in which the target substance is dissolved in a solvent as a solute, because the particles are dispersed in the dispersion medium as a discrete phase distinct from the dispersion medium, forming an interface or interphase boundary between the particles and the dispersion medium. The dispersion composition may further contain additives or supplements to adjust the physical properties and quality required for the intended use or administration route, such as viscosity, osmotic pressure, pH, ionic strength, surface tension, color, taste, and fragrance.

[0032] A "surfactant" is a surface-active, amphiphilic substance that possesses both a hydrophilic head and a hydrophobic tail in its molecule and reduces surface and interfacial tension in a dispersion medium. It is a substance that can aid in the dispersion of a target substance or stabilize the dispersion state by distributing primarily at the interface between the target substance and the dispersion medium when added in small amounts to a dispersion composition. Surfactants are also called emulsifiers or detergents depending on the application and industry. Surfactants can be monomers, oligomers, or polymers and can have various molecular weights. Surfactants can be cationic, anionic, nonionic, or zwitterionic, and their ionic state can change depending on the pH. Furthermore, the surfactant may be a natural substance, a synthetic substance, or a biological material, and may be used as a mixture of a plurality of substances, but is not limited thereto.

[0033] "Critical Micelle Concentration (CMC)" refers to the concentration at which a surfactant added to a dispersion medium self-assembles to form colloidal particles (1 nm-1 μm) (hereafter referred to as micelles). When the surfactant is below the CMC, the solubility of a target substance in the dispersion medium is determined by the saturated solubility of the target substance. The saturated solubility of a specific target substance in a specific dispersion medium is determined by conditions including the type, composition, phase, and content of the target substance, the type and composition of the dispersion medium, temperature, and pressure. For example, the saturated solubility of the target substance in the dispersion medium is listed in widely known databases such as "The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals" and PubChem: Open Chemistry Database at the National Institutes of Health (NIH)." However, it is well known that when the concentration of a surfactant added to a dispersion medium exceeds the threshold micelle concentration, the solubility increases in proportion to the amount of micelles ("micelle solubilization" or "micellar solubilization") (M.J. Rosen & J.T. Kunjappu, "Surfactants and Interfacial Phenomena," Fourth Edition, 2012, Wiley). For example, the threshold micelle concentrations of various surfactants are listed in M.J. Rosen & J.T. Kunjappu, "Surfactants and Interfacial Phenomena," 4th Edition, Wiley (2012), pp. 141-143, p. 155.

[0034] The "molar solubilization capacity (κ)" is defined by the following Equation 9 as the number of moles of a target substance solubilized in the dispersion medium per mole of surfactant exceeding the threshold micelle concentration (CMC), and is usually less than 1. In Equation 9, S w is the molar saturation solubility, which is the characteristic value of the target substance in the dispersion medium, and S tot is the total molar content of the target substance contained in the dispersion composition, and C surf indicates the total molar content of surfactant contained in the dispersion composition (Rangel-Yagui CO, Pessoa A Jr, Tavares LC. J Pharm Pharm Sci. 20058(2):147-65). When plotting the target substance content (y-axis) versus surfactant content (x-axis) on a graph, if there is no surfactant or the content is below CMC, the target substance content is at saturated solubility or cannot significantly exceed saturated solubility. Once the surfactant exceeds its CMC, the target substance content increases linearly in proportion to the surfactant content (solubilization by micelles or micellar solubilization). The molar solubilization capacity (κ) corresponds to the slope of the linear section of the graph and is an index of the amount of target substance that can be solubilized per unit amount of surfactant. A surfactant with a high molar solubilization capacity (κ) has a high solubilization efficiency. The molar solubilization capacity (κ) is a physical property that has a specific value depending on the surfactant, the target substance, and the dispersion medium.

[0035]

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[0036] A "solubilizer" is a substance distinct from the target substance and dispersion medium. It is added to a dispersion composition containing the target substance in a smaller amount than the dispersion medium to increase the content of the target substance beyond its saturation solubility in the dispersion medium. Examples of solubilizers include, but are not limited to, cyclodextrins, liposomes, oils, liquid, solid, or nanostructured lipids, metallic, organic, or inorganic nanoparticles, porous media, water-soluble polymers, and antibodies, as well as combinations of two or more of these. The target substance can be incorporated into the dispersion medium at a content exceeding its saturation solubility through various physicochemical mechanisms in conjunction with the solubilizer. These physicochemical mechanisms include, but are not limited to, complexation, inclusion, encapsulation, conjugation, adsorption, absorption, dissolution, etc. Surfactants have surface activity (a physical property that reduces the surface / interfacial tension of a dispersion medium) and exhibit a characteristic concentration value called the threshold micelle concentration in the dispersion medium. When their concentration in the dispersion medium exceeds the threshold micelle concentration, they self-assemble to form micelles. The formation of micelles changes the physicochemical properties (osmotic pressure, turbidity, diffusion coefficient, surface tension, electrical conductivity, etc.) from those before the formation of the micelles, and target substances are selectively distributed in the formed micelles. Therefore, their mechanism and physical properties are clearly distinguishable from other solubilizers, and in this invention, they are treated as separate substances and referred to as solubilizers.

[0037] In this specification, unless otherwise stated, terminology follows the definitions and recommendations of the International Union of Pure and Applied Chemistry (IUPAC).

[0038] Hereinafter, embodiments of the present invention will be described in detail, but they are presented as examples and do not limit the present invention, which is defined by the scope of the claims that follow.

[0039] The dispersion composition according to one embodiment of the present invention is a dispersion composition that contains the maximum amount of hydroxybenzoates (S micelle The present invention provides a dispersion composition containing a target substance stably dispersed in a dispersion medium in an amount exceeding the maximum amount (S micelle ) It was not possible to stably disperse the target substance in the dispersion medium at a content higher than this.

[0040] In one embodiment of the present invention, a separated solid-phase target substance is obtained by removing the solvent and process fluids used to prepare the mixture.

[0041] In the dispersion composition according to one embodiment of the present invention, the target substance is cyclosporin A.

[0042] In one embodiment of the present invention, the separated solid phase target substance is mixed with a separately prepared dispersion medium, surfactant, and necessary additives to form a dispersion composition in which the separated solid phase target substance is dispersed in the dispersion medium, and the dispersion composition is a dispersion composition in which the maximum amount (S micelle ) and the target substance is stably dispersed in the dispersion medium.

[0043] One embodiment of the present invention provides a dispersion composition that has a high target substance content (i.e., improved solubilization efficiency) while reducing the surfactant content below that required by existing micellar solubilization techniques.

[0044] One embodiment of the present invention provides a dispersion composition containing a target substance in an amount exceeding that which can be solubilized by existing micelle solubilization techniques.

[0045] One embodiment of the present invention provides a pharmaceutical composition with improved bioavailability or therapeutic efficacy by reducing the surfactant content below that required by existing micelle solubilization techniques.

[0046] The present invention is not limited to drugs, but can be equally applied to fields that increase solubility or bioavailability in the body. For example, in the cosmetics field, many substances with excellent cosmetic effects have poor solubility, and various additives are added to the final formulation. The cosmetic products made in this way have an opaque formulation, poor aesthetics, and a poor feel on the skin. Furthermore, excessive additives can clog pores, hindering the easy absorption of active substances. Thus, the present invention is not limited to a specific target substance, a specific dispersion medium, or a specific efficacy / function.

[0047] When a dispersion composition contains one surfactant at a concentration exceeding the threshold micelle concentration, the maximum content of the target substance that can be solubilized using existing micelle solubilization technology is calculated by the following equations 1 and 2: micelle It is determined by the value.

[0048] <Formula 1> S micelle =S w +S surf In the above formula 1, S w is the concentration corresponding to the saturated solubility of the target substance in the dispersion medium, and S surf is calculated by the following formula 2.

[0049] <Formula 2> S surf =k(C surf -CMC) In Equation 2, k is the molar solubilization capacity (κ) of the surfactant and target substance measured in the dispersion medium, and C surfis the molar concentration of the surfactant component added to the composition, and CMC is the threshold micelle molar concentration of a given surfactant known to be present in the dispersion medium. surf can therefore be calculated using the measured and known physical properties (κ, CMC) of the target substance, surfactant, and dispersion medium.

[0050] The S-parameter is the total content (S tot ) is the maximum content of the target substance that can be solubilized using existing micellar solubilization technology (S micelle ) and is calculated using Equation 3.

[0051] <Formula 3> S-parameters = S tot / S micelle

[0052] When the dispersion composition embodied in the present invention contains one surfactant in an amount exceeding the threshold micelle concentration, the content of the target substance that can be stably contained in the dispersion composition (S tot ) is the above S micelle (Equation 1 and 2) exceeds the value. That is, the S-parameter of a dispersion composition including one surfactant embodied in the present invention exceeds 1. For example, the S-parameter value of a dispersion composition embodied in the present invention may be 1.05 or more, 1.06 or more, 1.1 or more, 1.2 or more, 1.5 or more, 2 or more, or 3 or more.

[0053] In a dispersion composition according to an embodiment of the present invention that can be prepared by a method described below, the S-parameter is embodied as a value exceeding 1. Also, in a dispersion composition prepared using a solid-phase target substance (which may be powder, for example) according to an embodiment of the present invention that will be described below, the S-parameter is embodied as a value exceeding 1.

[0054] S micelleis a value calculated using experimentally measured physical properties of the target substance, surfactant, and dispersion medium, so the content of the target substance in the dispersion composition realized by the existing micelle solubilization technology is S micelle Therefore, the S-parameter of dispersion compositions realized by existing micellar solubilization technology is 1 or less. However, as described above, the S-parameter of the dispersion composition realized by the present invention exceeds 1, so the present invention can realize a dispersion composition containing a higher content of a target substance, exceeding the limit of solubilization by existing micellar solubilization technology. Expressed in terms of surfactants, this means that the present invention can realize a dispersion composition containing a specific target substance content even when using a smaller amount of surfactant than is required to solubilize the specific target substance content by existing micellar solubilization technology.

[0055] As mentioned above, in existing micellar solubilization technology, the surfactant can solubilize the target substance at the maximum amount (S micelle ) It is natural from the definition of the concept that the S-parameter cannot exceed 1 for dispersion compositions formulated with surfactants using existing micellar solubilization technology, since the target substance cannot be stably dispersed in the dispersion medium at a content higher than 1.

[0056] However, when the S-parameters are experimentally measured for a dispersion composition prepared by using existing micellar solubilization technology and containing a surfactant, measurement errors can result in the S-parameters being measured / calculated to a value exceeding 1. The present invention is not intended to include cases where the S-parameters are measured / calculated to a value exceeding 1 due to experimental or measurement errors for dispersion compositions prepared by using existing micellar solubilization technology and containing a surfactant.

[0057] On the other hand, when two or more surfactant components having a micelle concentration above the threshold are present, the S obtained by the following Equation 4 for each of these surfactant components is surf(i) Calculate the sum of these using the following formula 5: surf Get the value.

[0058] <Formula 4> S surf(i) =k surf(i) (C surf(i) -CMC surf(i) ) In the above formula 4, k surf(i) is the known molar solubilization capacity (κ) of any one surfactant and target substance measured in the dispersion medium, and C surf(i) is the concentration of any one of the surfactant components above the threshold micelle concentration, and CMC surf(i) is the known threshold micelle concentration measured in the dispersion medium of any one of the surfactant components having a threshold micelle concentration or higher.

[0059]

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[0060] It is known that the sum rule is effectively applied to cyclosporine A, which was used as the target substance in the examples of the present invention, and non-ionic surfactants based on PEG (polyoxyethylene glycol) (Feng et al., J. Pharmaceutical Sciences, Vol. 107(8), 2018, 2079-2090). Examples of non-ionic surfactants based on PEG (polyoxyethylene glycol) include polysorbates (e.g., Tween 20, 40, 60, 80, etc.), polyethoxylated castor oils (e.g., Polyoxyl 35 castor oil, Kolliphor EL or Cremophor EL, Marlowet 40, Emulgin RO40, etc.), polyethoxylated hydrogenated castor oils (e.g., Cremophor RH40, etc.), polyethoxylated fatty alcohols (e.g., Brij 30, Brij 35, etc.), polyethoxylated fatty acids (e.g., Myrj 52, Myrj 59, etc.), polyethoxylated hydroxy fatty acids (e.g., Kolliphor HS 15, Solutol HS 15, etc.), vitamin E TPGS (Vitamin E Examples of suitable poloxamers include, but are not limited to, TPGS, Vitamin E Tocopheryl Polyethylene Glycol Succinate, and poloxamers (e.g., Poloxamer 407, Lutrol F127, Poloxamer 188, Lutrol F68, etc.).Furthermore, the rule of sum between the PEG (polyoxyethylene glycol)-based nonionic surfactants is known to be effective not only for cyclosporin A used in the examples of the present invention, but also for various pharmacologically active substances with different chemical structures and physicochemical properties, such as progesterone, ritonavir, and butylparaben (Feng et al., J. Pharmaceutical Sciences, Vol. 107(8), 2018, 2079-2090). In other words, the maximum amount (S) of a target substance that can be solubilized using micellar solubilization technology is known. micelle ) can be calculated using experimentally measured and known physical properties (κ, CMC, etc.) for the surfactant, target substance, and dispersion medium used, and the content of the target substance that can be contained in an existing composition in which the target substance is solubilized using micellar solubilization technology can be calculated using the above S micelle cannot be exceeded.

[0061] When an existing dispersion composition realized by micellar solubilization technology contains two or more surfactants exceeding the threshold micelle concentration, the maximum content of the target substance that can be solubilized by the two or more surfactants is S obtained through Equations 1, 4, and 5. micelle It is determined by the value.

[0062] When the dispersion composition embodied in the present invention contains two or more surfactants in an amount exceeding the threshold micelle concentration, the content of the target substance that can be stably contained in the dispersion composition is S micelle (Equations 1, 4, and 5) exceed the value. That is, the S-parameter of a dispersion composition including two or more surfactants embodied in the present invention exceeds 1. For example, the S-parameter value of a dispersion composition embodied in the present invention may be 1.05 or more, 1.06 or more, 1.1 or more, 1.2 or more, 1.5 or more, 2 or more, or 3 or more.

[0063] S micelleis a value calculated using experimentally measured physical properties of the target substance, surfactant, and dispersion medium, so the content of the target substance in the dispersion composition realized by the existing micelle solubilization technology is S micelle Therefore, the S-parameter of dispersion compositions embodied by existing micellar solubilization technology is 1 or less. However, because the S-parameter of the dispersion composition embodied in the present invention exceeds 1, the present invention can embody dispersion compositions containing higher amounts of target substances, exceeding the limit of solubilization by existing micellar solubilization technology. That is, when the dispersion composition of the present invention contains two or more surfactants, the S-parameter of the dispersion composition embodied in the present invention can exceed 1, regardless of the type or total number of surfactants used or the type of target substance. Expressed in terms of surfactants, this means that the present invention can embody dispersion compositions containing a specific target substance content even when using a smaller amount of surfactant than is required to solubilize the specific target substance content using existing micellar solubilization technology.

[0064] As mentioned above, in existing micellar solubilization technology, the surfactant can solubilize the target substance at the maximum amount (S micelle ) It is natural from the definition of the concept that the S-parameter cannot exceed 1 for dispersion compositions formulated with surfactants using existing micellar solubilization technology, since the target substance cannot be stably dispersed in the dispersion medium at a content higher than 1.

[0065] However, when the S-parameters are experimentally measured for a dispersion composition prepared by using existing micellar solubilization technology and containing a surfactant, measurement errors can result in the S-parameters being measured / calculated to a value exceeding 1. The present invention is not intended to include cases where the S-parameters are measured / calculated to a value exceeding 1 due to experimental or measurement errors for dispersion compositions prepared by using existing micellar solubilization technology and containing a surfactant.

[0066] As described above, the present invention can realize dispersion compositions containing higher amounts of target substances than can be solubilized using existing micellar solubilization techniques. This is believed to be due to the physicochemical interactions (described below) induced / promoted / induced by contacting the mixture with the polyhedrons in the process of the present invention, which induce / promote / cause the molecular clustering, arrangement, and morphology of target substance molecules in the mixture in a specific direction / form, thereby changing the surface properties of the target substance in the subsequently formed solid phase. Several theories and explanations are possible, including that the interaction between the surface properties of the target substance and the added surfactant changes compared to previous methods, resulting in the formation of micelles with altered size or physical properties, a difference in the partition coefficient of the target substance between the micelle and the dispersion medium compared to previous methods, or the operation of a new mechanism different from the micellar solubilization mechanism. While the above theories and explanations have scientific basis and logical validity, it is not intended that the realization of the results of the present invention is limited to these theories and explanations alone. Other mechanisms that have not yet been elucidated may be operating, or a third mechanism may be operating in combination with the above-mentioned theories and explanations. Regardless of the specific molecular unit mechanism, the present invention can realize a dispersion composition containing a higher content of target substance than can be solubilized using existing micellar solubilization technology, and this can be confirmed by comparing the coefficients with existing dispersion compositions using the above-mentioned S-parameter analysis.

[0067] In one embodiment of the present invention, a dispersion composition is provided that includes a dispersion medium and particles containing a target substance, the dispersion composition comprises at least one surfactant having a threshold micelle concentration or higher; the dispersion composition does not include a solubilizer; The target substance is cyclosporin A, When the dispersion composition contains one surfactant, the S-parameter of Equation 3 calculated by Equation 1 and Equation 2 satisfies S-parameter>1; When the dispersion composition contains at least two surfactants having a micelle concentration equal to or higher than the threshold concentration, the S obtained by the following Equation 4 for each surfactant is surf(i) Calculate the sum of these using the following formula 5: surf The value of S is calculated as follows: surf The S-parameter of Equation 3 obtained by applying the value to Equation 1 satisfies S-parameter>1. <Formula 1> S micelle =S w +S surf In the above formula 1, S w is the concentration corresponding to the saturated solubility of the target substance in the dispersion medium, and S surf is calculated by the following formula 2. <Formula 2> S surf =k(C surf -CMC) In Equation 2, k is the molar solubilization capacity, which is defined as the number of moles of the target substance that can be dispersed in the dispersion medium by one surfactant having a micelle concentration equal to or greater than 1 mole, and C surf is the molar concentration of the surfactant component in said composition, and CMC is the threshold micelle molar concentration of the surfactant in said composition. <Formula 3> S-parameters = S tot / S micelle In the above formula 3, S tot is the total molar content of the target substance contained in the dispersion composition. <Formula 4> S surf(i) =k surf(i) (C surf(i) -CMC surf(i) ) In the above formula 4, k surf(i) is the molar solubilization capacity defined as the number of moles of the target substance that can be dispersed in the dispersion medium by any one of the surfactant components at a micelle concentration equal to or greater than 1 mole, and Csurf(i) is the concentration of any one of the surfactant components above the threshold micelle concentration, and CMC surf(i) is the threshold micelle concentration of any one surfactant component having a threshold micelle concentration or higher in the dispersion medium.

number

[0068] When the dispersion composition contains two or more surfactants having a micelle concentration equal to or higher than the threshold concentration, the types of surfactants may be selected such that the total amount of the target substance that can be dispersed is equal to the sum of the amounts of the target substance that can be dispersed by each type of surfactant.

[0069] The dispersion composition may contain the target substance in an amount exceeding the amount corresponding to the saturation solubility in the dispersion medium.

[0070] The particles, which are the dispersed phase of the dispersion composition of the present invention, can contain one or more target substances. When the particles contain multiple target substances, the phrase "the content of the target substances exceeds the content corresponding to the saturated solubility of the target substances in the dispersion medium" means that at least one of the multiple substances is contained in an amount exceeding the content corresponding to the saturated solubility in the dispersion medium. In addition to the target substances, the particles can further contain additives.

[0071] The particles may be crystalline, amorphous, or a mixture of these. In one embodiment, the target substance is a drug, and the particles are amorphous or crystalline. The particles may be single-component or multi-component. The particles may be single-phase or multi-phase.

[0072] In the dispersion composition embodied in the present invention, the number average diameter of particles containing the target substance is about 100 nm or less.

[0073] In one embodiment, the number average diameter may be about 80 nm or less.

[0074] In one embodiment, the number average diameter may be about 50 nm or less.

[0075] In one embodiment, the number average diameter may be about 1 nm to about 20 nm.

[0076] In one embodiment, the number average diameter may be about 1 nm to about 10 nm.

[0077] In one embodiment, the number average diameter may be about 1 nm to about 5 nm.

[0078] The dispersion composition is transparent. If the particle size is small and does not aggregate or settle, the transmittance of the dispersion composition is maintained at a high level. If the particles are formed in nanometer sizes, the dispersion composition is transparent and has high transmittance. The transmittance can be measured by transmittance or turbidity at specific wavelengths, and transparency can be confirmed by visual inspection.

[0079] The dispersion composition exhibits excellent dispersion stability. The dispersion composition is stably dispersed even when the target substance is contained in an amount exceeding the saturation solubility in the dispersion medium. For example, the stability of the dispersion composition can be confirmed by visually observing whether transparency is maintained or no precipitation occurs over time. Alternatively, dispersion stability can be confirmed by measuring particle size-sensitive properties such as transmittance or turbidity obtained by optical measurement, or particle size (Z-avg or mean particle diameter) measured by dynamic light scattering (DLS) over time, and observing the rate of change over time.

[0080] Dispersion stability can also be measured by the change in the content of the target substance over time. If particles settle due to aggregation, the content measured by high performance liquid chromatography (HPLC) after filtering will decrease over time. Therefore, dispersion stability can be confirmed by investigating whether the HPLC content measured after filtering remains the same as immediately after the composition is made over time.

[0081] For example, the dispersion composition can stably maintain a dispersed state in which the particles have a number average diameter of 100 nm or less for about 24 hours or more.

[0082] In another example, the dispersion composition can stably maintain a dispersed state in which the particles have a number average diameter of 100 nm or less for about one week or more.

[0083] In another example, the dispersion composition can stably maintain a dispersed state in which the particles have a number average diameter of 100 nm or less for about one month or more.

[0084] In another example, the dispersion composition can stably maintain a dispersed state in which the particles have a number average diameter of 100 nm or less for about 3 months or more.

[0085] In another example, the dispersion composition can stably maintain a dispersed state in which the particles have a number average diameter of 100 nm or less for about 12 months or more.

[0086] In one embodiment of the present invention, a solid phase material is provided by removing the dispersion medium from the dispersion composition.

[0087] In one embodiment of the present invention, the solid phase material is used as the target substance to obtain the dispersion composition.

[0088] In one embodiment of the present invention, there is provided a solid phase of cyclosporin A obtained by removing the dispersion medium from the dispersion composition.

[0089] In one embodiment of the present invention, the solid phase cyclosporin A is used as the target substance to obtain the dispersion composition.

[0090] In another embodiment of the present invention, a solid phase material that can be used as the target substance is provided, that is, the dispersion composition is obtained by using the solid phase material as the target substance.

[0091] In one embodiment, the target substance is cyclosporin A and the solid phase substance is solid phase cyclosporin A.

[0092] The solid phase material is solubilized in the maximum amount (S micelle) and can be stably dispersed in the dispersion medium. As described above, the resulting dispersion composition satisfies the S-parameter of Equation 3 > 1, and the detailed explanation is the same as that for the dispersion composition described above. This is presumably because the physicochemical interactions described below, which are induced / promoted / induced by contacting the mixture with the polyhedron in the process of the present invention, induce / promote / induce the molecular clustering, arrangement, and morphological formation of the target substance molecules in the mixture in a specific direction / form, thereby changing the surface properties of the target substance in the solid phase that is subsequently formed.

[0093] The solid phase material may be a powder.

[0094] The dispersion composition according to one embodiment of the present invention has a lower surfactant content than that of conventional techniques, improving not only the solubility but also the permeability of the target substance, resulting in improved bioavailability and superior therapeutic efficacy. Furthermore, by lowering the surfactant content compared to conventional techniques, it is possible to reduce or prevent problems caused by surfactants, such as environmental pollution and internal toxicity / side effects. For example, Polyoxyl 35 castor oil (Kolliphor EL or Cremophor EL), which is commonly used as a surfactant in pharmaceutical compositions, is highly toxic. Furthermore, the surfactant polysorbate 80 (Polysorbate 80 or Tween 80) is used to prepare dispersions of cyclosporine A, but this has the disadvantage of causing severe eye irritation. The dispersion composition according to one embodiment of the present invention maintains a stable dispersion state despite its low surfactant content, thereby reducing or avoiding the side effects of toxic surfactants. For another example, a cosmetic product prepared using a dispersion composition according to an embodiment of the present invention may have improved spreadability and penetration, thereby improving cosmetic effects, as the content of additives such as surfactants is minimized.

[0095] The dispersion composition or solid phase substance (or solid phase target substance) can be prepared by the preparation method described below.

[0096] The method may include the steps of: preparing a mixture by mixing a target substance with a solvent for preparing a mixture; preparing a polyhedron; and contacting the mixture with the polyhedron.

[0097] In one embodiment of the present invention, when a mixture containing a target substance is brought into contact with a polyhedron, physicochemical interactions such as shear, spatial confinement effect, and surface effects can be induced, promoted, or caused between the mixture and the intraparticle pores, interparticle pores, or surfaces inside / outside the pores of the polyhedron and the intraparticle pores.

[0098] The mixture is subjected to high shear rates as it passes through the nanometer or micrometer-sized particles of the polysurface or between the interparticle voids. Under such high shear rates, specific molecular clustering, arrangement, alignment, or conformation of target molecules can be induced / promoted / caused within the mixture.

[0099] When the mixture comes into contact with the polyhedron, the target molecules become spatially confined within the voids (inside or between particles) of several tens of nanometers contained in the polyhedron (confinement effect), which can induce / promote / cause specific molecular clustering, arrangement / alignment, or conformation of the target molecules within the mixture.

[0100] When a liquid mixture comes into contact with the surface inside / outside the pores of the polyhedron, the surface properties of the polyhedron (e.g., polarity, hydrophilicity, or type of surface functional group) can induce / promote / cause specific molecular clustering, arrangement, or morphology of target molecules within the liquid mixture.

[0101] The time during which the mixed liquid contacts the polyhedron and remains in the polyhedron (residence time) changes the time during which the mixed liquid undergoes the above-mentioned physicochemical interaction with the polyhedron, and this can easily induce / promote / cause specific molecular clustering, arrangement, or morphological formation of the target substance molecules within the mixed liquid.

[0102] It is believed that the physicochemical interactions induced / promoted / caused by contacting the mixed solution with the polyhedron in the process of the present invention induce / promote / cause molecular clustering, arrangement, or morphology of target substance molecules in a specific direction / form within the mixed solution, thereby changing the surface characteristics of the subsequently formed solid-phase target substance or particles containing the target substance to be more compatible with the dispersant. For example, when attempting to disperse a target substance that is poorly soluble in water in water, the process of the present invention induces / promotes / causes molecular clustering, arrangement, or morphology of the target substance in a specific form within the mixed solution, changing the surface characteristics of the subsequently formed target substance particles to be more compatible with water, the dispersant, improving dispersibility in water, and thereby resulting in a reduction in the amount of surfactant required for solubilization.

[0103] The step of contacting the mixed liquid with the polyhedron is a process of inducing / promoting / inducing the various physicochemical interactions, and may include a step of continuously passing the mixed liquid through the polyhedron and then collecting it, or contacting or mixing the passed mixed liquid with a dispersion medium. If necessary, a process fluid may be passed through the polyhedron sequentially or in parallel with the mixed liquid. In another embodiment, the step includes a step of impregnating the mixed liquid into the voids in the polyhedron, and then contacting the polyhedron containing the liquid mixed liquid with the dispersion medium (which may be by various methods, such as simple mixing), thereby releasing the mixed liquid into the dispersion medium.

[0104] In one embodiment, the mixture and the process fluid are passed sequentially or in parallel through a packed bed or a multi-surface membrane or sheet made of a porous or non-porous material, and then collected directly to obtain a flow-through. The solvent used to prepare the mixture and the process fluid are then completely removed from the flow-through by freeze-drying, atmospheric / reduced / vacuum drying, or distillation to obtain a solid target substance (or the solid substance described above). The separated solid target substance (or solid substance) may be in the form of a powder. The resulting solid target substance (or solid substance) may be mixed with a dispersion medium (e.g., water), one or more surfactants, and additives (e.g., osmolality adjusters, thickeners, pH buffers, etc.) depending on the purpose and application of the final composition to obtain a desired dispersion composition. In particular, the target substance may be poorly soluble in the dispersion medium, and the target substance may be supersaturated and dispersed in the dispersion medium. In the above example, when the mixed solution is allowed to flow through the polysurface, the pressure (pressure difference between the inlet and outlet) and temperature can be adjusted as needed during the process to control the residence time or the degree / strength of the physicochemical interaction.

[0105] In the process of the present invention, when a mixed solution is passed through and contacted with the polyhedron, very little of the target substance remains in the polyhedron; therefore, most (more than 95%) of the target substance leaves the polyhedron. The purpose of the process of the present invention is to impart physicochemical interactions to the target substance molecules while contacting the mixed solution with the polyhedron, and not to induce, promote, or cause a thermodynamic phase transition, such as solidification, crystallization, or amorphization, or precipitation, of the target substance within the polyhedron (which may be within the voids). If the target substance undergoes a phase transition, such as solidification or precipitation, and remains within the polyhedron, it will be difficult to achieve the results of the present invention (solid-phase target substance (or solid-phase material) or dispersion composition) and the effects and efficacy of the present invention. Therefore, it is important to adjust / control the process conditions (e.g., residence time, flow rate, etc.) so that the target substance does not remain within the polyhedron.

[0106] In the process according to the present invention, when the mixed solution is passed through the multi-surface material and contacted with the multi-surface material, the residence time (t ret ) is calculated using the following equation 7. In equation 7, q is the Darcy flux, which is the fluid volume passing through the unit cross-sectional area of the polysurface per unit time, and L is the dimension of the polysurface in the direction in which the fluid passes through the polysurface (if the polysurface is a packed bed, this corresponds to the height of the packed bed).

[0107] <Formula 7> t ret =L / q

[0108] In the process of the present invention, to induce / promote / induce specific molecular clustering, alignment, or morphogenesis of target molecules, the advection rate, which causes ordering, must be dominant over the diffusion rate, which causes randomization. Expressed in terms of residence time, this is undesirable because too long a residence time provides sufficient time for diffusion, making it difficult to form specific molecular clustering, alignment, or morphogenesis. On the other hand, too high a flow rate and too short a residence time can result in turbulent flow, which also hinders the formation of specific molecular clustering, alignment, or morphogenesis of target molecules. Therefore, when embodying the present invention by passing a mixture through a polyhedron, there is an appropriate range for the residence time, and it is appropriate to adjust the residence time to be more than about 30 seconds and less than about 390 seconds. Meanwhile, according to Equation 7, the residence time is proportional to the height (L) of the packed bed. Therefore, setting the height (L) of the packed bed, or more precisely, the aspect ratio (height / diameter) of the packed bed, to be greater than about 0.01 and less than about 1 helps to obtain the appropriate residence time.

[0109] The surface properties of the solid target substance (or solid-phase material) obtained by removing all of the solvents and process fluids used to prepare the mixture from the penetrating liquid are presumably changed to have a greater affinity with the dispersion medium due to the formation of molecular clusters, arrangements, or morphologies of the target substance molecules that are changed by the physicochemical interactions that occur as the mixture passes through the polysurface. Therefore, the solid target substance (or solid-phase material) according to one embodiment of the present invention can be solubilized in a dispersion medium containing a surfactant using existing micellar solubilization technology to a maximum amount (S micelle) can be stably dispersed at a higher content. When the target substance is mixed with a dispersion medium, one or more surfactants, and necessary additives to form a dispersion composition, it is believed that the surface properties of particles containing the target substance change to be more compatible with the dispersion medium, improving dispersibility in the dispersion medium, thereby reducing the amount of surfactant required for solubilization. Furthermore, the solid-phase target substance (or solid-phase substance) obtained by removing the dispersion medium from the dispersion composition maintains the surface properties of the particles even when dispersed again in a dispersion medium, similarly improving dispersibility in the dispersion medium, thereby reducing the amount of surfactant required for solubilization.

[0110] In one embodiment of the present invention, the step of contacting the mixed solution with the polyhedron as described above is referred to as a unit operation. In one embodiment of the present invention, the unit operation can be performed once to prepare a dispersion composition in which particles containing the target substance (or the substance) are dispersed. In one embodiment of the present invention, the unit operation can be repeated several times under the same process conditions to prepare a dispersion composition in which particles containing the target substance (or the substance) are dispersed. In one embodiment of the present invention, the unit operation can be performed several times while changing / adjusting the process conditions for each unit operation to obtain a dispersion composition in which particles containing the target substance (or the substance) are dispersed. In this case, the process conditions for each unit operation can be changed / adjusted individually or gradually.

[0111] In one embodiment of the present invention, the solvent for preparing the mixture and the process fluid are completely removed from the permeate by freeze-drying, atmospheric pressure / reduced pressure / vacuum drying, distillation, etc., to obtain a solid-phase target substance (or solid-phase substance). The solid-phase target substance is then mixed with a dispersant, one or more surfactants, and various additives (osmolality regulators, thickeners, pH buffers, etc.) depending on the purpose and use of the final composition to obtain a desired final dispersion composition. In another embodiment, the permeate is mixed with a dispersant and one or more surfactants, and then the solvent for preparing the mixture and the process fluid are preferentially separated / removed, and then necessary additives are added to obtain a desired final dispersion composition. Methods for selectively separating / removing only the solvent for preparing the mixture and the process fluid include methods using separation technologies such as distillation. For example, if the boiling point of the solvent or process fluid for preparing the mixture is lower than that of the dispersion medium, the solvent or process fluid can be selectively separated / removed by heating at a temperature equal to or higher than the boiling point of the solvent or process fluid but lower than the boiling point of the dispersion medium. In addition, the solvent or process fluid for preparing the mixture can be selectively separated / removed using various separation technologies that utilize the difference in physicochemical properties between the solvent or process fluid for preparing the mixture and the dispersion medium.

[0112] The dispersion composition may contain a small amount of the solvent or process fluid used to prepare the mixture that has not been partially removed. The amount of the solvent or process fluid used to prepare the mixture may be determined depending on the intended use. For example, when preparing a composition as a drug, the amount may be determined depending on the toxicity of the solvent or process fluid used to prepare the mixture. For example, if the solvent or process fluid used to prepare the mixture is ethanol, the dispersion composition may contain less than about 0.5% (w / w) of ethanol (United States Pharmacopoeia <467> Residual Solvents, December1, 2020).

[0113] The method for preparing the dispersion composition may further include a step of separating and removing the polyhedrons. The polyhedrons may be separated, for example, by filtration using a filter, or by various other separation methods such as, but not limited to, physical removal, centrifugation, flocculation, precipitation, and electrostatic attraction. The method for preparing the dispersion composition may further include a step of selectively removing or adding a certain amount of the dispersion medium of the dispersion composition to determine or adjust the final content / concentration of the target substance.

[0114] In one embodiment of the present invention, preparing a mixture by mixing the target substance with a solvent for preparing a mixture; Preparing a polysurface body; contacting the mixture with the polyhedron; and a step of separating the target substance from the mixture to obtain a solid-phase target substance; and a method for producing a solid-phase target substance (or a solid-phase substance).

[0115] In one embodiment of the present invention, preparing a mixture by mixing the target substance with a solvent for preparing a mixture; providing a multi-surface body in the form of a packed bed or a membrane or sheet; flowing the mixture and optionally the process fluid through the multi-surface body; collecting the mixed liquid that has passed through the multi-surface body and optionally the used process fluid; and The present invention provides a method for producing a solid-phase target substance (or a solid-phase substance), which includes the step of removing the solvent and process fluid used to produce the mixture from the collected permeate.

[0116] In one embodiment of the present invention, preparing a mixture by mixing the target substance with a solvent for preparing a mixture; providing a multi-surface body in the form of a packed bed or a membrane or sheet; flowing the mixture and optionally the process fluid through the multi-surface body; collecting the mixed liquid that has passed through the multi-surface body and optionally the used process fluid; Removing the solvent and process fluid from the collected permeate to obtain a solid-phase target substance; and The present invention provides a method for preparing a dispersion composition in which particles, which are a dispersed phase containing a target substance, are dispersed, the method comprising the steps of: mixing a dispersion medium, one or more surfactants, and / or necessary additives with the target substance in the solid phase;

[0117] The dispersion composition according to one embodiment of the present invention may be a dispersion composition prepared by obtaining the solid-phase target substance (or solid-phase substance) and then mixing the solid-phase target substance (or solid-phase substance) with a dispersant, one or more surfactants and / or necessary additives, as described above.

[0118] In one embodiment of the present invention, preparing a mixture by mixing the target substance with a solvent for preparing a mixture; providing a multi-surface body in the form of a packed bed or a membrane or sheet; flowing the mixture and optionally the process fluid through the multi-surface body; collecting the mixed liquid that has passed through the multi-surface body and optionally the used process fluid; mixing a dispersion medium and one or more surfactants with the collected permeate; and The present invention provides a method for preparing a dispersion composition in which particles, which are a dispersed phase containing a target substance, are dispersed, the method comprising the step of preferentially removing a solvent or process fluid for preparing the mixture from the mixture.

[0119] In one embodiment of the present invention, a pharmaceutical product for animals or humans containing the solid phase substance (or solid phase target substance) is provided. In one embodiment of the present invention, a cosmetic product containing the solid phase substance (or solid phase target substance) is provided. In one embodiment of the present invention, a food or beverage containing the solid phase substance (or solid phase target substance) is provided.

[0120] In one embodiment of the present invention, there is provided a pharmaceutical product for animals or humans comprising the dispersion composition. In one embodiment of the present invention, there is provided a cosmetic product comprising the dispersion composition. In one embodiment of the present invention, there is provided a food or beverage comprising the dispersion composition.

[0121] Examples of the present invention and comparative examples are described below. The following examples are examples of the present invention, and the present invention is not limited to the following examples. [Example]

[0122] The units used to express content / concentration in this specification, including the examples, are explained below. % (w / v): The percentage of the mass (g) of the target substance to the volume (mL) of the total system. For example, mass (g) of the target substance / volume (mL) of the dispersion composition x 100 or mass (g) of the solute / volume (mL) of the solution x 100 % (w / w) = percentage of the mass of the target substance to the mass of the whole system. For example, mass of target substance / mass of dispersion composition x 100 or mass of target substance / mass of mixture x 100 %(v / v) = percentage of the volume of the substance to be measured to the volume of the entire system, e.g., volume of process fluid / volume of solution x 100.

[0123] Examples 1-1 to 1-4: CsA powder preparation Ethanol (95% v / v ethanol) was prepared as a solvent for preparing the mixture. 5 g of the target substance, cyclosporine A (99.1% purity, TEVA, lot no. 7414004320, hereafter referred to as CsA), was dissolved in 995 g of the 95% v / v ethanol by stirring at 500 rpm for 30 minutes using a magnetic bar and a magnetic stirrer, resulting in a 0.5% w / w CsA mixture. A Buchner funnel (90 mm inner diameter) was placed in a 250 mL Erlenmeyer flask, and a 1 μm paper filter was placed in the funnel and wetted with 95% v / v ethanol. The suction pump was operated at a pressure difference of 0.8 bar, allowing the paper filter (1 μm) to adhere to the bottom of the Buchner funnel. Ten grams of mesoporous silica powder (ABC Nanotech, XL-100) was weighed into a 250 mL beaker. 100 g of 95% v / v ethanol was added to the beaker containing the mesoporous silica. The mixture was thoroughly mixed with the ethanol using a spoonful, thoroughly wetting the mesoporous silica. The mesoporous silica supported in 95% v / v ethanol was slowly poured into a Büchner funnel containing a paper filter, maintaining a pressure difference of 0.8 bar with a suction pump. A packed bed of mesoporous silica measuring 8 mm in height and 90 mm in diameter was formed at the bottom of the Büchner funnel (diameter 90 mm, packed bed height 8 mm, aspect ratio (height / diameter) 0.09). When about 1 cm of supernatant liquid remained on the mesoporous silica packed bed, the suction pump was stopped and the filter filtrate collected in the Erlenmeyer flask was discarded. The 250 mL Erlenmeyer flask was then replaced with a 3000 mL Erlenmeyer flask. A 1 μm paper filter was placed on top of the mesoporous silica packed bed formed in the Büchner funnel, and 1000 g of the previously prepared 0.5% w / w CsA mixture was poured into the Büchner funnel several times.95% v / v ethanol was prepared as the process fluid, similar to the solvent used to prepare the mixture. 500 g of this process fluid was poured into a Buchner funnel, and the mixture and process fluid were passed through the mesoporous silica packed bed at an average volumetric flow rate of 13.76 mL / min for a total of 145 minutes. The collected mixture was then collected in a 3000 mL Erlenmeyer flask. Therefore, the Darcy flux, calculated by dividing the average volumetric flow rate by the cross-sectional area of the packed bed (diameter 90 mm), was 0.216 cm / min. The residence time of the mixture in the mesoporous silica packed bed, calculated using Equation 7, was 222 seconds (L = 0.8 cm, q = 0.216 cm / min). The collected flowthrough was filtered through a 0.45 μm membrane filter. The mixture was then concentrated for 4 hours using a rotary vacuum concentrator (Eyela, OSB-2200) at 25°C, 150 rpm, and 20 mbar. The concentrate was then dried under reduced pressure in a vacuum oven for 12 hours. The solvent and process fluids used in preparing the mixture were then completely removed, yielding 4.84 g of CsA powder. The yield was calculated as 96.8% by dividing the amount of solid CsA obtained through this process (4.84 g) by the amount of CsA introduced into the process (5 g). This indicates that most of the CsA (over 95%) passed through the mesoporous silica packed bed. This process is referred to as Example 1-1. Similar processes using different average volumetric flow rates and residence times are referred to as Examples 1-2, 1-3, and 1-4. The main process conditions for each example are listed in Table 1.

[0124] [Table 1]

[0125] Examples 2-1 to 2-3: CsA aqueous dispersion composition Kolliphor EL (manufactured by BASF, lot no. 55573988Q0), polysorbate 80 (Tween 80, manufactured by Croda, lot no. 45971), and the CsA powder prepared in Example 1-1 were sequentially added to a 10 mL transparent vial in the amounts listed in Table 2 and thoroughly mixed by stirring at 300 rpm for 12 hours at room temperature. 5 mL of purified water was first added to the CsA / Kolliphor EL / Tween 80 mixture while stirring, and the mixture was thoroughly mixed by stirring at 600 rpm for 30 minutes. Further purified water was then added to bring the total volume to 200 mL, and a CsA aqueous phase dispersion composition was finally prepared in which CsA particles were dispersed in the continuous phase water according to the composition listed in Table 2.

[0126] [Table 2]

[0127] As a control group for comparing / contrasting differences from existing prior art, a commercial CsA powder (manufacturer: TEVA, lot no. 7414004320) was used instead of the CsA powder embodied in Example 1-1. Each component was added in the same amount as in the CsA aqueous dispersion compositions of Examples 2-1, 2-2, and 2-3 according to Table 2 to prepare a CsA aqueous dispersion composition prepared with the commercial CsA powder (hereinafter referred to as Comparative Groups 2-1, 2-2, and 2-3). Immediately after preparation, precipitation was observed in all Comparative Groups 2-1, 2-2, and 2-3 prepared with the commercial CsA powder, and the compositions appeared translucent or opaque, indicating that a dispersion composition was not realized. In contrast, the CsA aqueous dispersion compositions of the same composition prepared in Examples 2-1, 2-2, and 2-3 did not exhibit precipitation after preparation, and all appeared transparent, indicating that a dispersion composition was realized.

[0128] The CsA aqueous phase dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 and Comparative Groups 2-1, 2-2, and 2-3 were filtered through a 0.22 μm PES (Polyethersulfone) filter to obtain filter filtrates. The filter filtrates were analyzed by HPLC under the following conditions to measure the CsA content / concentration, which are shown in Table 3. The content in the filter filtrates corresponds to the amount of CsA stably dispersed in water, excluding the amount of CsA precipitated during or immediately after preparation. Therefore, the CsA content / concentration shown in Table 3 corresponds to the actual content / concentration of CsA stably dispersed in the CsA aqueous phase dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 and Comparative Groups 2-1, 2-2, and 2-3.

[0129] Equipment: Agilent 1260 Infinity II Column: Hypersil ODF (4.6 x 250 mm, 3 μm) Column temperature: 50℃ Flow rate: 1mL / min Detector: ultraviolet absorption photometer (measurement wavelength: 210 nm) Injection volume: 40μL

[0130] As can be seen from Table 3 below, the actual CsA contents in the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 were all within ±5% of the nominal content of 0.02% w / v in Table 2. On the other hand, the actual CsA contents in the CsA aqueous dispersion compositions prepared in Comparative Groups 2-1, 2-2, and 2-3 were all less than the nominal content of 0.02% w / v, indicating that no dispersion compositions containing 0.02% w / v CsA were obtained.

[0131] [Table 3]

[0132] <S-parameter evaluation of CsA aqueous dispersion composition> The physical properties of CsA required for calculating the S-parameters of the CsA aqueous dispersion composition, the physical properties of the surfactants used, Tween 80 and Kolliphor EL, and the molar solubilization capacity of these surfactants for CsA (Feng et al., J. Pharmaceutical Sciences, Vol. 107(8), 2018, 2079-2090) are listed in Table 4.

[0133] [Table 4]

[0134] The physical properties in Table 4, the surfactant content in Table 2, and the actual CsA content in Table 3 were substituted into Equations 1, 3, 4, and 5 to calculate the S-parameters of the CsA aqueous phase dispersion compositions embodied in Examples 2-1, 2-2, and 2-3. Table 5 shows each step and the final results. (Since the molar solubilization capacity is the ratio of the number of moles of CsA to the number of moles of surfactant used, when calculating Equation 4, the surfactant % w / v composition is converted to the number of moles using the molecular weight of the surfactant and substituted. Also, since the calculated value is the number of moles of CsA, it is converted again to CsA % w / v using the molecular weight of CsA to calculate the S-parameter.) surf The contents / compositions in Tables 5 and 6 are the % w / v obtained through this conversion process.

[0135] [Table 5]

[0136] Similarly, the physical properties in Table 4, the surfactant content in Table 2, and the actual CsA content in Table 3 were substituted into Equations 1, 3, 4, and 5 to calculate the S-parameters of the CsA aqueous phase dispersion compositions embodied in Comparative Groups 2-1, 2-2, and 2-3, and each process and the final results are shown in Table 6.

[0137] [Table 6]

[0138] As can be seen from Table 5, the S-parameters of the CsA dispersion compositions embodied in Examples 2-1, 2-2, and 2-3 were 1.12, 1.18, and 1.17, respectively, all exceeding 1. This indicates that the CsA in the CsA dispersion compositions embodied in Examples 2-1, 2-2, and 2-3 is within the existing limit (S micelle ) amount by 12%, 18%, and 17%, respectively. On the other hand, as can be seen from Table 6, the S-parameters of the dispersion compositions of comparative groups 2-1, 2-2, and 2-3, which were realized by conventional techniques, were all less than 1. In other words, even when the same amount of surfactant and CsA were added and formulated, the S-parameters of the dispersion compositions of conventional techniques were micelle It can be seen that if the amount of CsA exceeds 0.02%, it will precipitate, and the target CsA will not be contained in the dispersion composition. Therefore, by using the present invention, it is possible to disperse a high content of CsA that cannot be realized by existing known technologies. In terms of surfactant, this means that a smaller amount of surfactant is required than in known technologies to disperse the same CsA content (0.02%).

[0139] Experimental Example 1-1: Dispersion stability of CsA aqueous dispersion composition: Visual inspection To confirm the stability of the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3, they were stored at 25±2°C and 60±5% relative humidity for 2-4 weeks after preparation. Visual inspection was performed to determine whether precipitation occurred or whether the transparency changed over time. The results of the visual inspection are shown in Table 7. As shown in Table 7, the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 maintained their transparency without precipitation for 2-4 weeks. This indicates that the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 did not exhibit CsA precipitation or aggregation during this period, and CsA was stably dispersed in water.

[0140] [Table 7]

[0141] Experimental Example 1-2: Dispersion stability of CsA aqueous dispersion composition: HPLC content To confirm the stability of the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3, they were stored at 25±2°C and 60±5% relative humidity for 2-4 weeks after preparation, and the CsA content over time was measured by HPLC. Immediately after preparation, and at 1 week, 2 weeks, and 4 weeks after preparation, the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 were filtered through a 0.22 μm PES (Polyethersulfone) filter, and the filtrate was analyzed by HPLC under the following conditions to determine the rate of change in CsA content over time (the HPLC content immediately after preparation was set to 100%, and the rate of change in content over time was calculated). The results are shown in Table 8.

[0142] Equipment: Agilent 1260 Infinity II Column: Hypersil ODF (4.6 x 250 mm, 3 μm) Column temperature: 50℃ Flow rate: 1mL / min Detector: ultraviolet absorption photometer (measurement wavelength: 210 nm) Injection volume: 40μL

[0143] [Table 8]

[0144] As can be seen from Table 8, the CsA content of the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 remained at the same level immediately after preparation even after 2 to 4 weeks. This indicates that the CsA in the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 remained stably dispersed without precipitation during this period.

[0145] Example 2-4: CsA aqueous dispersion composition Ethanol (95:5 by volume) containing ethanol and water (hereafter referred to as 95% v / v ethanol) was prepared as the solvent for preparing the mixture. 0.06 g of the target substance, cyclosporine A (99.1% purity, manufactured by TEVA, lot no. 7414004320, hereafter referred to as CsA), was dissolved in 29.94 g of the 95% v / v ethanol by stirring at 500 rpm using a magnetic bar and magnetic stirrer for 30 minutes, resulting in a 0.2% w / w CsA mixture. A Buchner funnel (90 mm inner diameter) was placed in a 250 mL Erlenmeyer flask, and a 1 μm paper filter was placed in the funnel and wetted with 95% v / v ethanol. The paper filter (1 μm) was then attached to the bottom of the Buchner funnel by operating a suction pump at a pressure difference of 0.8 bar. 10 g of mesoporous silica powder (ABC Nanotech, XL-100) was weighed and placed in a 250 mL beaker. 100 g of 95% v / v ethanol was added to the beaker containing the mesoporous silica. The mixture was thoroughly mixed with a spoon to thoroughly wet the mesoporous silica. The 95% v / v ethanol-supported mesoporous silica was slowly poured into a Buchner funnel containing a paper filter, maintaining a pressure difference of 0.8 bar with a suction pump. A packed bed of mesoporous silica measuring 8 mm in height and 90 mm in diameter was formed at the bottom of the Buchner funnel (diameter 90 mm, packed bed height 8 mm, aspect ratio (height / diameter) 0.09). When about 1 cm of supernatant liquid remained on the mesoporous silica packed bed, the suction pump was stopped, and the filtrate collected in an Erlenmeyer flask after passing through a paper filter was discarded. The 250 mL Erlenmeyer flask was then replaced with a new 250 mL Erlenmeyer flask. A 1 μm paper filter was placed on top of the mesoporous silica packed bed formed in the Buchner funnel, and 30 g of the previously prepared 0.2% w / w CsA mixture was poured into the Buchner funnel several times. 95% v / v ethanol was prepared as the process fluid, similar to the solvent used to prepare the mixture. 120 g of ethanol was mixed with 80 g of purified water, and 200 g of the mixture was poured into the Buchner funnel.205 g of the flowthrough collected through the mesoporous Silica was filtered using a 0.45 μm membrane filter.

[0146] A 250 mL concentration flask was prepared with a magnetic bar inserted. 10 g of the resulting solution was taken and mixed with 10 g of 95% v / v ethanol, along with 6 mg each of polysorbate 80 (Tween 80, manufactured by TCI, XHLAA-GM) and Polyoxyl-35 Castor oil (manufactured by ACROS, lot no. A0403500). The mixture was then mixed thoroughly using a magnetic stirrer for 10 minutes. After 10 minutes, 40 mL of purified water was added to the 250 mL concentration flask and stirred at 500 rpm for 30 minutes. The resulting mixture was then selectively removed from the ethanol and partially distilled off the purified water using a rotary vacuum concentrator (Eyela, OSB-2200) at 25°C, 150 rpm, and 20 mbar for 2 hours and 20 minutes, yielding 15.8 mL of a CsA aqueous dispersion composition. The resulting solution was filtered through a 0.45 μm syringe filter (manufactured by FUTECS, PVDF) and a 0.22 μm filter (manufactured by FUTECS, PTFE) to obtain a filter filtrate. The filter filtrate was analyzed by HPLC under the following conditions to determine the CsA content / concentration, which is shown in Table 9.

[0147] HPLC equipment: Waters Model name: e2695 Column: RP C18 (250 x 4.6 mm) average particle size 5 μm Column temperature: 65℃ Flow rate: 1mL / min Detector: UV spectrophotometer (measurement wavelength 204 nm) Injection volume: 10μL

[0148] Example 2-5: CsA aqueous dispersion composition Ethanol (95:5 by volume) containing ethanol and water (hereafter referred to as 95% v / v ethanol) was prepared as the solvent for preparing the mixture. 0.06 g of the target substance, cyclosporine A (99.1% purity, manufactured by TEVA, lot no. 7414004320, hereafter referred to as CsA), was dissolved in 29.94 g of the 95% v / v ethanol by stirring at 500 rpm using a magnetic bar stirrer for 30 minutes, resulting in a 0.2% w / w CsA mixture. A Buchner funnel (90 mm inner diameter) was placed in a 250 mL Erlenmeyer flask, and a 1 μm paper filter was placed in the funnel and wetted with 95% v / v ethanol. The suction pump was operated at a pressure difference of 0.8 bar, allowing the paper filter (1 μm) to adhere to the bottom of the Buchner funnel. 10 g of mesoporous silica powder (ABC Nanotech, XL-100) was weighed and placed in a 250 mL beaker. 100 g of 95% v / v ethanol was added to the beaker containing the mesoporous silica. The mixture was thoroughly mixed with a spoon to thoroughly wet the mesoporous silica. The 95% v / v ethanol-supported mesoporous silica was slowly poured into a Büchner funnel containing a paper filter, maintaining a pressure difference of 0.8 bar with a suction pump. A packed bed of mesoporous silica measuring 8 mm in height and 90 mm in diameter was formed at the bottom of the Büchner funnel (diameter 90 mm, packed bed height 8 mm, aspect ratio (height / diameter) 0.09). When about 1 cm of supernatant liquid remained on the mesoporous silica packed bed, the suction pump was stopped, and the filtrate that had passed through the paper filter and collected in the Erlenmeyer flask was discarded. The 250 mL Erlenmeyer flask was then replaced with a new 250 mL Erlenmeyer flask. A 1 μm paper filter was placed on top of the mesoporous silica packed bed formed in the Buchner funnel, and 30 g of the previously prepared 0.2% w / w CsA mixture was poured into the Buchner funnel several times. 95% v / v ethanol was prepared as the process fluid, similar to the solvent used to prepare the mixture. 120 g of ethanol was mixed with 80 g of purified water, and 200 g of the mixture was poured into the Buchner funnel.205 g of the flowthrough collected through the mesoporous Silica was filtered using a 0.45 μm membrane filter.

[0149] A 250 mL concentration flask was prepared, and a magnetic bar was inserted to separate 10 g of the resulting solution. 10 g of 95% v / v ethanol was added to 3 mg of polysorbate 80 (Tween 80, manufactured by TCI, XHLAA-GM) and 9 mg of Polyoxyl-35 Castor oil (manufactured by ACROS, lot no. A0403500). The mixture was then mixed thoroughly using a magnetic stirrer for 10 minutes. After 10 minutes, 40 mL of purified water was added to the 250 mL concentration flask and stirred at 500 rpm for 30 minutes. The resulting mixture was then selectively removed from the ethanol and partially distilled off from the purified water using a rotary vacuum concentrator (Eyela, OSB-2200) at 25°C, 150 rpm, and 20 mbar for 1 hour and 20 minutes, yielding 15.6 mL of a CsA aqueous dispersion composition. The resulting solution was filtered through a 0.45 μm syringe filter (manufactured by FUTECS, PVDF) and a 0.22 μm filter (manufactured by FUTECS, PTFE) to obtain a filter filtrate. The filter filtrate was analyzed by HPLC under the following conditions to determine the CsA content / concentration, which is shown in Table 9.

[0150] HPLC equipment: Waters Model: e2695 Column: RP C18 (250 x 4.6 mm) average particle size 5 μm Column temperature: 65℃ Flow rate: 1mL / min Detector: UV spectrophotometer (measurement wavelength 204 nm) Injection volume: 10μL

[0151] The final compositions of the CsA aqueous phase dispersion compositions of Examples 2-4 and 2-5 are shown in Table 9.

[0152] [Table 9]

[0153] The physical properties in Table 4 and the surfactant content and actual CsA content in Table 9 were substituted into Equations 1, 3, 4, and 5 to calculate the S-parameters of the CsA aqueous phase dispersion compositions embodied in Examples 2-4 and 2-5, and Table 10 lists each step and the final results. (Since the molar solubilization capacity is the ratio of the number of moles of CsA to the number of moles of surfactant used, when calculating Equation 4, the surfactant % w / v composition is converted to the number of moles using the molecular weight of the surfactant and substituted. Furthermore, since the calculated value is the number of moles of CsA, this is again converted to CsA % w / v using the molecular weight of CsA to obtain Ssurf. The contents / compositions in Table 10 are all % w / v obtained through these conversion processes.)

[0154] [Table 10]

[0155] As seen in Table 10, the S-parameters of the CsA aqueous phase dispersion compositions embodied in Examples 2-4 and 2-5 were 1.90 and 2.19, respectively, both exceeding 1. This indicates that the CsA in the CsA aqueous phase dispersion compositions embodied in Examples 2-4 and 2-5 can be solubilized within the existing limit (S micelle ) by 90% and 119%, respectively.

[0156] Although the present invention has been described above, it is obvious that the present invention is not limited to the embodiments disclosed herein, and that various modifications can be made by those skilled in the art within the scope of the technical concept of the present invention. At the same time, even if the effects of the configurations of the present invention are not clearly described while describing the embodiments of the present invention, it is natural that the effects that can be predicted by the corresponding configurations should also be recognized.

Claims

1. A dispersion composition comprising a dispersion medium; and particles containing a target substance, the dispersion composition comprises at least one surfactant having a threshold micelle concentration or higher; the dispersion composition does not include a solubilizer; The target substance is cyclosporin A, When the dispersion composition contains one surfactant, the S-parameter of Equation 3 calculated by Equation 1 and Equation 2 satisfies S-parameter>1; When the dispersion composition contains at least two surfactants having a micelle concentration equal to or higher than the threshold concentration, the S obtained by the following Equation 4 for each surfactant is ｓｕｒｆ（ｉ） and calculate the sum of these using the following formula 5: ｓｕｒｆ The value is obtained by calculating S ｓｕｒｆ The S-parameter of Equation 3 obtained by applying the value to Equation 1 satisfies S-parameter>1. Dispersion composition. <Formula 1> S ｍｉｃｅｌｌｅ =S ｗ +S ｓｕｒｆ In the above formula 1, S ｗ is the concentration corresponding to the saturated solubility of the target substance in the dispersion medium, and S ｓｕｒｆ is calculated by the following formula 2. <Formula 2> S ｓｕｒｆ =k(C ｓｕｒｆ ‐CMC) In Equation 2, k is the molar solubilization capacity defined as the number of moles of the target substance that can be dispersed in the dispersion medium by one surfactant having a micelle concentration equal to or greater than 1 mole, and C ｓｕｒｆ is the molar concentration of the surfactant component in said composition, and CMC is the threshold micelle molar concentration of the surfactant in said composition. <Formula 3> S-parameter = S ｔｏｔ / S ｍｉｃｅｌｌｅ In the above formula 3, S ｔｏｔ is the total molar content of the target substance contained in the dispersion composition. <Formula 4> S ｓｕｒｆ（ｉ） =k ｓｕｒｆ（ｉ） (C ｓｕｒｆ（ｉ） ‐CMC ｓｕｒｆ（ｉ） ) In the above formula 4, k ｓｕｒｆ（ｉ） is the molar solubilization capacity defined as the number of moles of the target substance that can be dispersed in the dispersion medium by any one of the surfactant components at a threshold micelle concentration of 1 mole or more, and C ｓｕｒｆ（ｉ） is a concentration of any one of the surfactant components equal to or greater than the threshold micelle concentration, and CMC ｓｕｒｆ（ｉ） is the threshold micelle concentration of any one surfactant component having a threshold micelle concentration or higher in the dispersion medium. [Equation 1] In Equation 5, m is the total number of types of surfactant components having a micelle concentration equal to or greater than the threshold concentration.

2. The dispersion composition of claim 1, wherein the dispersion composition contains the cyclosporin A in an amount exceeding the amount corresponding to the saturation solubility of the cyclosporin A in the dispersion medium.

3. 2. The dispersion composition according to claim 1, wherein when the dispersion composition contains two or more surfactants having a micelle concentration above the threshold, the types of surfactants are selected so that the total amount of cyclosporine A that can be dispersed is equal to the sum of the amounts of cyclosporine A that can be dispersed by each type of surfactant.

4. 2. The dispersion composition of claim 1, wherein the particles have a number average diameter of 100 nm or less.

5. 2. The dispersion composition of claim 1, wherein the particles have a number average diameter of 50 nm or less.

6. A veterinary or human pharmaceutical comprising the dispersion composition of claim 1.

7. A cosmetic product comprising the dispersion composition of claim 1.

8. A food or beverage comprising the dispersion composition of claim 1.

9. As solid phase cyclosporin A, The dispersion composition according to claim 1 is obtained by applying the cyclosporin A as the target substance according to claim 1. Solid phase cyclosporin A.

10. A veterinary or human pharmaceutical product comprising the solid phase cyclosporin A of claim 9.

11. A cosmetic product comprising the solid phase cyclosporin A of claim 9.

12. A food or beverage containing the solid phase cyclosporin A of claim 9.

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