Solid cyclosporin a and dispersions comprising the same

Abstract

The present invention provides a dispersion composition comprising: a dispersion medium; and particles comprising a target substance. The dispersion composition comprises at least one surfactant at a concentration above the critical micelle concentration, and does not comprise a solubilizer. The target substance is cyclosporin A, and satisfies the previously defined S-parameter > 1.

Description

Technical Field

[0001] The present invention relates to a solid cyclosporine A with improved dispersibility and a dispersion composition obtained by dispersing the solid cyclosporine A, the dispersion composition exhibiting improved dispersibility. Background Technology

[0002] In the field of pharmaceutical technology, the preparation of aqueous solutions is a crucial task. Water is the most common solvent and liquid phase used for drinking and is the most frequently used solvent in pharmaceutical formulations. However, many drugs are strongly nonpolar, and therefore have insufficient solubility in water, a polar solvent. Thus, even drugs with excellent therapeutic effects may be insoluble or poorly soluble, posing a problem in their inability to be formulated into clinically useful pharmaceutical preparations.

[0003] As a representative known technique for addressing these problems, micellar solubilization technology exists, which uses surfactants to dissolve poorly soluble drugs. Surfactants are substances that possess both hydrophilic and hydrophobic properties within a single molecule. They are generally defined as substances that, by being primarily distributed at the interface between the target substance (e.g., a drug) and the dispersion medium (e.g., water), help disperse the target substance or stabilize its dispersion, or perform these functions. Micellar solubilization technology is a technique that selectively distributes poorly soluble target substances in the dispersion medium into nano-sized micelles, thereby containing the target substance in the dispersion medium at a high concentration exceeding saturation solubility. These nano-sized micelles are formed through the self-assembly of surfactants contained in the dispersion medium at concentrations exceeding a specific concentration (critical micelle concentration). Summary of the Invention

[0004] Technical issues

[0005] In pharmaceutical technology, bioavailability is a concept representing the amount and rate at which a drug is delivered from the site of administration to the site of action in which it exerts its therapeutic effect. If bioavailability is low, even if the drug has high efficacy in vitro, the actual amount delivered to the organ in the body where it should exert its effect is low, thus the in vivo efficacy remains at a low or insignificant level. Bioavailability can be understood as the flux across biological barriers in the body (e.g., cornea, skin, blood-brain barrier, and blood-retinal barrier) (see Equation 8 below).

[0006] [Equation 8]

[0007] Flux = Solubility Permeability

[0008] This shows that solubility and permeability must be highly balanced in order to increase throughput. 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).

[0009] When micellar solubilization is applied to polar dispersion media (such as water), the drug's outer surface, surrounded by a surfactant, becomes hydrophilic compared to its free-floating state. However, since most physiological barriers in vivo include phospholipid or hydrophobic layers, the permeability of drug compositions achieved through micellar solubilization is typically reduced. For this reason, micellar solubilization presents a trade-off between improved solubility and increased permeability, thus limiting the acquisition of drug compositions with bioavailability improvements that translate into therapeutic efficacy. Furthermore, most surfactants pose problems such as environmental pollution or toxicity and side effects in vivo, necessitating the minimization of surfactant dosage.

[0010] Therefore, it can be said that technologies that can improve solubility even with lower or minimized amounts of surfactant compared to existing technologies are of great necessity and commercial value. Compared to existing technologies, these technologies can improve permeability with less surfactant than required by existing technologies, resulting in improved bioavailability or therapeutic efficacy, and can also minimize environmental pollution or in vivo toxicity / side effects.

[0011] The purpose of this invention is not limited to the objectives described above. Other objectives and advantages of this invention not mentioned above can be understood through the following description and through embodiments of the invention. It will also be readily understood that the objectives and advantages of this invention can be achieved by means set forth in the claims and combinations thereof.

[0012] Cyclosporins are immunosuppressive drugs with 11 nonpolar cyclic amino acid structures, including cyclosporin A, B, C, D, and G. In immune lymphocytes, cyclosporins block the activity of calcineurin, thereby inhibiting the production of immune cytokines that ultimately lead to an immune response. In addition to various immune diseases, cyclosporins are known to effectively restore / repair lacrimal gland collapse and dysfunction in keratoconjunctivitis sicca or dry eye syndrome (US Patent 4,839,342).

[0013] However, due to its large molecular weight and hydrophobicity, cyclosporine is difficult to achieve therapeutic effects in ocular tissues. In particular, because cyclosporine is an insoluble substance, it is difficult to expect improved solubility in aqueous solutions or aqueous media (US Patent 5051402). To overcome these drawbacks, numerous attempts have been made to dissolve cyclosporine in pharmaceutical compositions used to treat dry eye syndrome. For example, 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 (US Patents 2014020662A1p, 2014005785A1p, EP2049079B1). However, large amounts of surfactants can cause side effects, leading to environmental pollution and in vivo toxicity.

[0014] In addition, although the cyclosporine preparations Restasis and Ikervis are formulated as solutions containing castor oil and MCT oil (medium-chain triglycerides), respectively, oil-containing ophthalmic compositions can cause side effects such as blurred vision and eye irritation when instilled into the eyes.

[0015] To minimize these side effects and improve bioavailability, it is necessary to minimize the content of surfactants or oils (such as castor oil). Therefore, there is still a need to develop a cyclosporine formulation that uses less surfactant than existing technologies but has improved solubility in polar dispersion media.

[0016] Technical solution

[0017] In one embodiment of the invention, a dispersion composition is provided comprising a dispersion medium and particles comprising a target substance.

[0018] The dispersion composition comprises at least one surfactant with a critical micelle concentration above a certain level.

[0019] The dispersion composition does not contain a solubilizer.

[0020] The target substance is cyclosporine A.

[0021] If the dispersion composition contains at least one surfactant, then the S-parameter of Equation 3, calculated from Equations 1 and 2, satisfies S-parameter > 1, and

[0022] If the dispersion composition contains at least two surfactants with a critical micelle concentration of 4 or higher, then S is calculated for each surfactant using the following Equation 4. surf(i) Then, these S are obtained from the following equation 5. surf(i)The sum of S surf The value, and by calculating S surf The S-parameter of Equation 3 obtained by applying the value to Equation 1 above satisfies S-parameter > 1.

[0023] Equation 1

[0024] S 胶束 = S w + S surf

[0025] Among them, S w S is the concentration corresponding to the saturation solubility of the target substance in the dispersion medium. surf The calculation is performed using Equation 2 below.

[0026] Equation 2

[0027] S surf = k(C surf - CMC)

[0028] Where k is the molar solubilizing capacity, defined as the number of moles of the target substance that a surfactant can disperse in the dispersion medium at a critical micelle concentration of 1 mole or higher, and C surf It is the molar concentration of the surfactant component in the composition, and CMC is the critical micelle molar concentration of the surfactant in the composition.

[0029] Equation 3

[0030] S-parameter = S tot / S 胶束

[0031] Among them, S tot It is the total molar content of the target substance contained in the dispersion composition.

[0032] Equation 4

[0033] S surf(i) = k surf(i) (C surf(i) - CMC surf(i) )

[0034] Where, k surf(i) Molar solubilizing ability is defined as the number of moles of the target substance that can be dispersed in the dispersion medium by any surfactant component with a critical micelle concentration of 1 mole or higher. surf(i) It is the concentration of any surfactant component above the critical micelle concentration, and CMC surf(i) It is the critical micelle concentration of any surfactant component in the dispersion medium that is above the critical micelle concentration.

[0035] Equation 5

[0036]

[0037] Where m is the total number of surfactant components above the critical micelle concentration.

[0038] In another embodiment of the invention, a solid cyclosporine A is provided that can be used as a target substance. In other words, the dispersion composition is obtained by applying this solid cyclosporine A as the target substance.

[0039] Beneficial effects

[0040] In the field of dispersion compositions, such as pharmaceuticals, the stable dispersion of high concentrations of active substances is an important task for their easy absorption. Therefore, this dispersion composition can be creatively applied to various industrial fields requiring high concentrations and dispersion stability. For example, if the dispersion composition of the present invention contains poorly soluble pharmaceutical drugs, it is possible to expand the availability of previously unavailable drugs and minimize the side effects of additives (e.g., surfactants), thereby achieving significant progress in disease treatment.

[0041] The dispersion composition of the present invention has a lower surfactant content than that of the prior art, and not only improves the solubility of the target substance but also improves its permeability, thereby resulting in improved bioavailability and superior therapeutic efficacy. Furthermore, compared to the prior art, by reducing the surfactant content, it has the effect of reducing or preventing problems such as environmental pollution or in vivo toxicity / side effects caused by surfactants. For example, polyoxyethylene 35 castor oil (Kolliphor EL or Cremophor EL), which is mainly used as a surfactant in pharmaceutical compositions, is highly toxic. Moreover, even in the preparation of dispersions of cyclosporine A, the surfactant polysorbate 80 (polysorbate 80 or Tween 80) is used, which has the disadvantage of severely irritating the eyes. The dispersion composition of the present invention can reduce or avoid the side effects of toxic surfactants because of its low surfactant content and stable dispersion.

[0042] In addition to the effects described above, the specific effects of the present invention will also be described when explaining the specific details of implementing the present invention. Detailed Implementation

[0043] <Terminology Definition>

[0044] First, the definitions / descriptions of the core terms used in this invention specification are as follows.

[0045] The term "target substance" refers to a substance to be dispersed in a dispersion composition to be implemented, which can be an active pharmaceutical substance for pharmaceutical use, or a variety of pharmaceutical substances depending on the use. For example, the pharmacologically active pharmaceutical substance in this invention can be, but is 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 substance can be a single pharmaceutical substance or a mixture of two or more target substances. The dispersion composition of one embodiment of this invention has commercial value when the target substance is a poorly soluble pharmaceutical substance in the dispersion medium. Examples of poorly soluble pharmaceutical substances may include substances classified as pi (practically insoluble), vss (very slightly soluble), ss (slightly soluble), and sps (slightly soluble) 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 that are target substances may 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, fluocinolone, or prostaglandin analogs, or pharmaceutically acceptable salts of these drugs or derivatives of these drugs, or combinations thereof. Furthermore, target substances may be nutritional components or poorly soluble active substances with cosmetic effects, such as curcumin, and may be a variety of substances depending on the use or purpose of the dispersing composition.

[0046] The term "medium with multiple surfaces" refers to a medium composed of porous or non-porous materials or mixtures thereof, and containing intraparticle pores or interparticle pores or mixtures thereof. In other words, the pores in a medium with multiple surfaces can be intraparticle pores or interparticle pores. If the medium with multiple surfaces is, for example, a porous material containing pores within the material itself, then the pores in the medium with multiple surfaces can be intraparticle pores contained within the porous material. For example, if the medium with multiple surfaces is formed as an aggregate or agglomerate (secondary particles, powder, or packed bed, etc.) formed by agglomerating or stacking non-porous particles, then the pores in the medium with multiple surfaces can be interparticle pores. For example, if the medium with multiple surfaces is formed as an aggregate or agglomerate (secondary particles, powder, or packed bed, etc.) formed by mixing porous and non-porous particles and agglomerating or stacking them, then the pores in the medium with multiple surfaces can be intraparticle pores or interparticle pores. In other words, a medium with multiple surfaces can be an aggregate or agglomerate composed of various porous materials or arbitrary porous or non-porous particles.

[0047] The average size of a medium having multiple surface pores can be from about 1 nm to about 1 μm. For example, the average size of a medium having multiple surface pores can be from about 1 nm to about 100 nm. For example, the average size of a medium having multiple surface pores can be from about 1 nm to about 50 nm. For example, the average size of a medium having multiple surface pores can be from about 1 nm to about 30 nm. By using a medium having multiple surfaces with pore sizes within the above range, it is helpful to form particles with predetermined desired sizes. The porosity of a medium having multiple surfaces can be from about 5% to about 97% (v / v). For example, the porosity of a medium having multiple surfaces can be from about 20% to about 60% (v / v). For example, when the medium having multiple surfaces is an aerogel, the porosity can be from about 90% to about 97% (v / v).

[0048] For example, a medium with multiple surfaces can be silica gel, silica dry gel, mesoporous silica, fumed silica, mesoporous alumina, mesoporous metal oxides, mesoporous materials, charcoal, activated carbon, aerogel, zeolite, molecular sieve, metal-organic framework, or organic / inorganic mixed porous materials. It can be a natural, synthetic, or biomaterial, and can be crystalline or amorphous, without limitations on composition, material, structure, synthesis / manufacturing method, etc. The pores in a medium with multiple surfaces can have various shapes, sizes, formation methods, and arrangement structures (regular or irregular). The pores in a medium with multiple surfaces can be in the form of particles of arbitrary size and shape, secondary particles containing aggregated particles, powders composed of particles of arbitrary size and shape, filled beds formed by stacking particles, solid foams, or films or sheets, but are not limited to these forms. Furthermore, a medium with multiple surfaces can include not only a single material but also at least two or more materials, or mixtures thereof.

[0049] In other words, if the size, shape, porosity, predetermined surface area, or surface physicochemical properties of the pores within or between particles are suitable for use with the methods and compositions of the present invention, then the medium having multiple surfaces is not limited in terms of material, phase, crystalline or amorphous state, composition, size, shape, form, method of formation or aggregation, and void arrangement structure, or is not limited to whether the pores of the medium having multiple surfaces are intraparticle pores or interparticle pores, and whether the medium having multiple surfaces is a porous material or a non-porous material.

[0050] The term "solvent for preparing a mixture" refers to a solvent capable of dissolving a target substance in a desired concentration. The solvent is selected considering its physical properties, such as saturated solubility or polarity, to dissolve the target substance at the target concentration. The target substance may dissolve in the solvent for preparing the mixture at a higher concentration than it does in the dispersion medium. For example, the target substance may have a higher solubility in the solvent than in the dispersion medium. For example, the solvent for preparing the mixture may include water, organic solvents such as alcohols (methanol, ethanol, etc.), acetone, acetonitrile, ethyl acetate, dichloromethane, chloroform, and dimethyl sulfoxide (DMSO), sugars such as polyethylene glycol (PEG), mannitol, and sorbitol, and may include combinations of two or more of these, but is not limited to these. The solvent for preparing the mixture may be friendly or unfriendly to the dispersion medium. 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, hydrophobic, or amphiphilic material. The solvent used to prepare the mixture can be polar, nonpolar, or amphiphilic. The solvent used to prepare the mixture can be a volatile compound. When preparing a dispersion composition by ultimately removing the solvent used to prepare the mixture, if the solvent used to prepare the mixture is a volatile compound, there is an advantage that the solvent used to prepare the mixture is easily removed. The solvent used to prepare the mixture can be a compound with a boiling point lower than that of the dispersion medium. When preparing a dispersion composition by ultimately removing the solvent used to prepare the mixture, if the solvent used to prepare the mixture is a compound with a boiling point lower than that of the dispersion medium, there is an advantage that the solvent used to prepare the mixture is easily removed by distillation as one of the separation processes.

[0051] The term "mixture" refers to a solution obtained by mixing a target substance with a solvent used to prepare the mixture, thereby dissolving the target substance in the solvent. For example, a mixture may contain from about 0.01% (w / v) to about 50% (w / v) of the target substance. Specifically, mixture (A) may contain from about 0.1% (w / v) to about 10% (w / v) of the target substance. The content of the target substance in the mixture can be determined by taking into account the solubility of the target substance in the solvent used to prepare the mixture; therefore, the type of solvent used to prepare the mixture can be selected.

[0052] The term "process fluid" refers to a fluid used with a mixture when in contact with a medium having multiple surfaces. The purpose is to facilitate contact, improve productivity, or control the residence time of the mixture in the medium with multiple surfaces. The process fluid is selected considering viscosity or surface tension to adjust the ease of contact, productivity, or residence time of the mixture. The type of process fluid can be selected by appropriately considering the solubility of the target substance or its miscibility with the solvent used to prepare the mixture, so that the target substance does not precipitate or solidify during contact between the mixture and the medium with multiple surfaces. The process fluid may be the same as or different from the solvent used to prepare the mixture, or it may be a mixture of fluids different from the solvent used to prepare the mixture.

[0053] The term "dispersion medium" corresponds to the continuous phase in a dispersion composition, and various substances can be used depending on the application. For example, if used in a pharmaceutical composition, the dispersion medium can be water, a salt solution, or a buffered aqueous solution. In the dispersion compositions of the present invention, the content of the target substance can exceed its saturation solubility in the dispersion medium.

[0054] The dispersion medium can be a polar or hydrophilic solvent. For example, a polar or hydrophilic solvent can be water, methanol, ethanol, glycerol, or a polyol. For example, the dispersion medium can be water, and the target substance can be water-insoluble paclitaxel, deoxycholic acid, cyclosporine, latanoprost, miconazole, curcumin, etc. The dispersion medium can also be a nonpolar or hydrophobic solvent. For example, a nonpolar or hydrophobic solvent can be hydrocarbons, silicone oil, ethyl acetate, acetone, tetrahydrofuran (THF), etc. For example, the dispersion medium can be hexane, and the target substance can be hexane-insoluble sugars, glucose, etc. Furthermore, the dispersion medium can be an amphiphilic solvent. Additionally, the dispersion medium can be a polar or nonpolar solvent in which an amphiphilic solvent has been added. The type or composition of the dispersion medium can be selected based on the solubility of the target substance therein, differences in physicochemical properties, the application of the dispersion composition, etc., and one or more mixtures can be used. For example, the dispersion medium can be an organic solvent.

[0055] The term "particle" is defined as an assembly of multiple molecules having any composition, shape, size, or structure, and corresponds to a dispersed phase (the discrete phase in a dispersed composition). In this invention, in addition to the target substance, the particles in the dispersed composition may also contain adjuvants or additives.

[0056] The term "dispersion composition" refers to a composition in which particles containing a target substance are dispersed in a dispersion medium in a continuous phase, in a discrete phase different from the dispersion medium. The dispersion composition is distinct from a single-phase solution in which the target substance is dissolved as a solute in the solvent, because the particles containing the target substance are dispersed in the dispersion medium in a phase different from the dispersion medium, while an interface (or phase interface) is formed between the particles and the dispersion medium. The dispersion composition may additionally contain additives or adjuvants to adjust the desired physical properties and quality, such as viscosity, osmotic pressure, pH, ionic strength, surface tension, color, taste, and aroma, according to the intended use or route of administration.

[0057] The term "surfactant" refers to a surface-active and amphiphilic material that has a hydrophilic head and a hydrophobic tail in its molecular structure, and reduces the surface tension or interfacial tension in a dispersion medium. It generally refers to a material added to a dispersion composition in a smaller amount than the dispersion medium and that helps disperse the target substance or stabilize the dispersion state by being predominantly distributed at the interface between the target substance and the dispersion medium, or a substance that performs these functions. Depending on its application or industry, surfactants are also called emulsifiers or detergents. Surfactants can be monomers, oligomers, or polymers, and can have different molecular weights. Furthermore, surfactants can be cationic, anionic, nonionic, or zwitterionic, and their ionic state can be altered by pH. Additionally, surfactants can be natural, synthetic, or biological materials, and mixtures of various materials can be used, but are not limited to these.

[0058] The term "critical micelle concentration (CMC)" refers to the concentration at which a surfactant added to a dispersion medium self-assembles into particles with a colloidal size (1 nm-1 μm) (hereinafter collectively referred to as micelles). If the surfactant concentration is below the critical micelle concentration, the solubility of the target substance in the dispersion medium is the saturation solubility of the target substance (saturation solubility is a specific value determined by factors including the type, composition, phase and content of the target substance, the type and composition of the dispersion medium, and temperature and pressure conditions. For example, saturation solubility of target substances in dispersion media is described in the Merck Index Encyclopedia of Chemicals, Pharmaceuticals & Biologicals or PubChem: the Open Chemistry Database of the National Institutes of Health (NIH), a well-known database). However, it is well known that if the concentration of surfactant added to the dispersion medium exceeds the critical micelle concentration, the behavior (micelle solubilization, solubilization by micelles, or micelle solubilization) increases proportionally to the amount of micelles (MJ Rosen, JT Kunjappu, Surfactants and Interfacial Phenomena, 4th ed.). For example, the critical micelle concentration values ​​for various surfactants are listed in the reference MJ Rosen & JT Kunjappu, Surfactants and Interfacial Phenomena, 4th Edition, Wiley (2012), pp. 141-143, 155.

[0059] The term "molar solubilizing capacity (κ)" is the number of moles of target substance dissolved in a dispersion medium per mole of surfactant exceeding the critical micelle concentration (CMC), defined by Equation 9 below, and its value is typically less than 1. In Equation 9 below, S w S is the molar saturated solubility, a unique value of the target substance in the dispersion medium. tot C represents the total molar content of the target substance contained in the dispersion composition. surfThe total molar content of surfactants contained in the dispersion composition is represented (Rangel-Yagui CO, Pessoa A Jr, Tavares LC., J Pharm Pharm Sci. 2005 8(2):147-65). When the content of the target substance (y-axis) is measured and plotted according to the surfactant content (x-axis), if there is no surfactant or its content is less than the CMC, the content of the target substance is saturated solubility or does not deviate significantly from saturated solubility. When the surfactant begins to exceed the CMC, the content of the target substance shows a linear increase in proportion to the surfactant content (micelle solubilization, solubilization by micelles, or micellar solubilization). Molar solubilization capacity (κ) corresponds to the slope of the straight line in the above figure and is an indicator of the amount of target substance that a unit amount of surfactant can solubilize, and a surfactant with a high molar solubilization capacity (κ) means a high solubilization efficiency. Molar solubilization capacity (κ) corresponds to a physical property that has a specific value depending on the surfactant, the target substance, and the dispersion medium.

[0060] [Equation 9]

[0061]

[0062] The term "solvent" generally refers to a substance added to a dispersion composition in a smaller amount than the dispersion medium in which the target substance is dispersed, and is used to increase the content of the target substance to a level exceeding its saturation solubility in the dispersion medium. The sovent is distinct from both the target substance and the dispersion medium. Sovents can be, for example, cyclodextrins, liposomes, oils, liquid, solid, or nanostructured lipids, metal / organic / inorganic nanoparticles, porous media, water-soluble polymers, antibodies, etc., and may include combinations of two or more of these, but are not limited thereto. Through soventing and various physicochemical mechanisms, the target substance can be contained in an amount exceeding its saturation solubility in the dispersion medium. These physicochemical mechanisms include, but are not limited to, complexation, inclusion, encapsulation, binding, adsorption, absorption, dissolution, etc. Surfactants possess surface activity (the physical property of reducing the surface / interfacial tension of the dispersion medium) and exhibit a characteristic concentration in the dispersion medium called the critical micelle concentration. When the concentration exceeds the critical micelle concentration in the dispersion medium, the surfactant self-assembles to form micelles. As micelles form, the physicochemical properties (osmotic pressure, turbidity, diffusion coefficient, surface tension, conductivity, etc.) become different from those before micelle formation. The target substance is selectively distributed in the formed micelles. Therefore, surfactants are significantly different from other solubilizers in terms of mechanism or physical properties, and in this invention, they are considered as substances separate from solubilizers and are mentioned separately from solubilizers.

[0063] In this specification, unless otherwise stated, the terminology follows the definitions and recommendations of the International Union of Pure and Applied Chemistry (IUPAC).

[0064] The embodiments of the present invention will now be described in detail. However, these embodiments are presented by way of example, and the present invention is not limited thereto, and is limited only by the scope of the claims described below.

[0065] One embodiment of the present invention provides a dispersion composition comprising a target substance stably dispersed in a dispersion medium, the target substance exceeding a maximum amount (S) that can be solubilized by micellar solubilization techniques. 胶束 Using existing micellar solubilization techniques, it is impossible to dissolve more than the maximum amount (S) of the target substance. 胶束 The content of ) is used to stably disperse the target substance in the dispersion medium.

[0066] In one embodiment of the invention, the invention provides a product of a separated solid target substance obtained by removing the solvent used to prepare the mixture and process fluid.

[0067] In a dispersion composition according to one embodiment of the present invention, the target substance is cyclosporine A.

[0068] In one embodiment of the invention, the dispersion composition is one in which the separated solid target substance is dispersed in a dispersion medium by mixing the product of the separated solid target substance with a separately prepared dispersion medium, a surfactant, and necessary additives, and the dispersion composition is a dispersion composition containing a target substance stably dispersed in the dispersion medium, the target substance exceeding the maximum amount (S) that can be solubilized by micellar solubilization technology. 胶束 ).

[0069] One embodiment of the present invention provides a dispersion composition having a high content of the target substance (i.e., increased solubilization efficiency) while reducing the content of surfactant to a lower amount than required in existing micellar solubilization techniques.

[0070] 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 micellar solubilization techniques.

[0071] One embodiment of the present invention provides a pharmaceutical composition with improved bioavailability or therapeutic efficacy by reducing the surfactant content to a level lower than required in existing micellar solubilization techniques.

[0072] This invention is not limited to pharmaceuticals, but can also be applied to increasing in vivo solubility or bioavailability. Therefore, this invention is not limited to specific target substances, specific dispersion media, or specific effects / functions.

[0073] When the dispersion composition contains a surfactant exceeding the critical micelle concentration, the maximum amount of the target substance that can be solubilized by existing micelle solubilization techniques is determined by S obtained through equations 1 and 2 below. 胶束 The value is determined.

[0074] Equation 1

[0075] S 胶束 = S w + S surf

[0076] Among them, S w S is the concentration corresponding to the saturation solubility of the target substance in the dispersion medium. surf Calculate using Equation 2 below.

[0077] Equation 2

[0078] S surf = k(C surf - CMC)

[0079] Where k is the known molar solubilizing power (κ) measured in the dispersion medium of the surfactant and the target substance, and C surf S is the molar concentration of the surfactant component in the composition, while CMC is the critical micelle molar concentration of a known surfactant in the dispersion medium. Therefore, S can be calculated using the known and measured physical properties (κ, CMC) of the target substance, surfactant, and dispersion medium. surf .

[0080] As calculated by Equation 3 below, the S-parameter is the total content (Si) of the target substance contained in the dispersion composition of one embodiment of the present invention. tot Divide by the maximum content (S) of the target substance that can be solubilized using existing micellar solubilization techniques. 胶束 The value obtained is ).

[0081] Equation 3

[0082] S-parameter = S tot / S 胶束

[0083] When the dispersion composition achieved by the present invention contains a surfactant exceeding the critical micelle concentration, the content (S) of the target substance contained in the dispersion composition can be stably maintained. tot (Exceeding S) 胶束The value of the S-parameter (Equations 1 and 2). In other words, the S-parameter of the dispersion composition containing a surfactant achieved by the present invention is greater than 1. For example, in the dispersion composition achieved by the present invention, the S-parameter value can 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.

[0084] In a dispersion composition prepared by the method described below according to one embodiment of the present invention, the S-parameter is implemented with a value greater than 1. Furthermore, in a dispersion composition prepared according to the embodiments of the present invention below using a solid target substance (e.g., which may be a powder), the S-parameter is implemented with a value greater than 1.

[0085] Due to S 胶束 This value is calculated using experimentally measured physical properties of the target substance, surfactant, and dispersion medium. The content of the target substance in the dispersion composition achieved through existing micellar solubilization techniques must not exceed S. 胶束 Therefore, the S-parameter of the dispersion composition achieved by existing micellar solubilization techniques is no greater than 1. However, as mentioned above, since the dispersion composition achieved by the present invention has an S-parameter greater than 1, the present invention can achieve dispersion compositions containing a higher content of the target substance, exceeding the solubility limit of existing micellar solubilization techniques. In terms of surfactants, this means that even when using a smaller amount of surfactant than is required to dissolve a specific content of the target substance by existing micellar solubilization techniques, the present invention can achieve dispersion compositions containing the aforementioned specific content of the target substance.

[0086] As mentioned above, in existing micellar solubilization techniques, surfactants cannot be used in quantities exceeding the maximum amount (S) that can dissolve the target substance. 胶束 The content of surfactants will stably disperse the target substance in the dispersion medium. Therefore, the S-parameter of the dispersion composition prepared by incorporating surfactants through existing micellar solubilization technology cannot be greater than 1, which is natural by definition.

[0087] However, when experimentally measuring the S-parameter of a dispersion composition prepared by incorporating a surfactant using existing micellar solubilization techniques, the S-parameter may be measured / calculated as a value greater than 1 due to measurement errors. This invention is not intended to include the case of dispersion compositions prepared by incorporating a surfactant using existing micellar solubilization techniques, where the obtained S-parameter value is greater than 1 due to experimental or measurement errors.

[0088] On the other hand, when there are two or more surfactant components exceeding the critical micelle concentration, if S is calculated for each surfactant using the following Equation 4... surf(i) Then, S, which is their sum, can be obtained from the following equation 5.surf value.

[0089] Equation 4

[0090] S surf(i) = k surf(i) (C surf(i) - CMC surf(i) )

[0091] Where, k surf(i) It is the known molar solubilizing power (κ) of any surfactant and target substance in the dispersion medium, C. surf(i) It is the concentration of any surfactant component exceeding the critical micelle concentration, CMC. surf(i) It is the critical micelle concentration, which is the known critical micelle concentration measured in the dispersion medium for any surfactant component exceeding the critical micelle concentration.

[0092] Equation 5

[0093]

[0094] Where m is the total number of surfactant components exceeding the critical micelle concentration. If the summation rule of the solubilizing power of the surfactants used is followed (i.e., the amount of the target substance solubilized by multiple surfactants is equal to the simple sum of the amounts solubilized by each surfactant), then Equation 5 above applies whether the multiple surfactants form pure micelles or mixed micelles in the dispersion medium.

[0095] It is known that in examples of the present invention, the above addition rule is effectively applied between polyoxyethylene glycol (PEG) nonionic surfactants for cyclosporine A, which is used as the target substance (Feng et al., J. PharmaceuticalSciences, Vol. 107(8), 2018, 2079-2090). Examples of polyethylene glycol (PEG) nonionic surfactants include, but are not limited to, polysorbates (e.g., Tween 20, 40, 60, 80, etc.), polyethoxylated castor oil (e.g., Kolliphor EL as polyoxyethylene 35 castor oil, or Cremophor EL, Marlowet 40, Emulgin RO 40, etc.), polyethoxylated hydrogenated castor oil (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 tocopherol polyethylene glycol succinate), and poloxamer (e.g., Poloxamer 407, Lutrol F127, Poloxamer 188, Lutrol F68, etc.). Furthermore, the known addition rule between PEG (polyoxyethylene glycol) nonionic surfactants is effective not only for cyclosporine A used in the embodiments of this invention, but also for various active pharmaceutical 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 physical properties (κ, CMC, etc.) of the surfactants, target substances, and dispersion media used can be obtained through experimental measurements, and the maximum amount (S) of the target substance that can be solubilized by micellar solubilization technology can be calculated using the known properties of the substance (κ, CMC, etc.). 胶束 Furthermore, the content of the target substance that can be contained in existing compositions obtained by solubilizing the target substance through micellar solubilization technology cannot exceed the above-mentioned S. 胶束 .

[0096] If an existing dispersion composition achieved using micellar solubilization technology contains two or more surfactants exceeding the critical micelle concentration, the maximum content of the target substance that can be solubilized by two or more surfactants is determined by S obtained through equations 1, 4, and 5. 胶束 The value is determined.

[0097] If the dispersion composition achieved by the present invention contains two or more surfactants exceeding the critical micelle concentration, the content of the target substance stably contained in the dispersion composition can exceed S. 胶束 (Equations 1, 4, and 5) values. In other words, the S-parameter of the dispersion composition containing two or more surfactants achieved by the present invention is greater than 1. For example, in the dispersion composition achieved by the present invention, the S-parameter value can 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.

[0098] Due to S 胶束 This value is calculated using experimentally measured physical properties of the target substance, surfactant, and dispersion medium. The content of the target substance in the dispersion composition achieved through existing micellar solubilization techniques must not exceed S. 胶束 Therefore, the S-parameter of dispersion compositions achieved by existing micellar solubilization techniques is less than 1. However, since the S-parameter of the dispersion compositions achieved by the present invention is greater than 1, the present invention can achieve dispersion compositions containing a higher content of the target substance, exceeding the solubility limit of existing micellar solubilization techniques. In other words, when the dispersion composition of the present invention contains two or more surfactants, the S-parameter of the dispersion composition achieved by the present invention may be greater than 1, regardless of the type or total number of surfactants used or the type of target substance. Regarding surfactants, this means that even when using a smaller amount of surfactant than required to dissolve a specific amount of the target substance by existing micellar solubilization techniques, the present invention can achieve dispersion compositions containing the aforementioned specific amount of the target substance.

[0099] As mentioned above, in existing micellar solubilization techniques, surfactants cannot be used in quantities exceeding the maximum amount (S) that can dissolve the target substance. 胶束 The content of surfactants will stably disperse the target substance in the dispersion medium. Therefore, the S-parameter of the dispersion composition prepared by incorporating surfactants through existing micellar solubilization technology cannot be greater than 1, which is natural by definition.

[0100] However, when experimentally measuring the S-parameter of a dispersion composition prepared by incorporating a surfactant using existing micellar solubilization techniques, the S-parameter may be measured / calculated as a value greater than 1 due to measurement errors. This invention is not intended to include the case of dispersion compositions prepared by incorporating a surfactant using existing micellar solubilization techniques, where the obtained S-parameter value is greater than 1 due to experimental or measurement errors.

[0101] As described above, the present invention can achieve dispersion compositions containing higher concentrations of the target substance than the solubilization limits of existing micellar solubilization techniques. This is presumably because, in the method of the present invention, when the mixture comes into contact with a medium having multiple surfaces, the molecular aggregation or alignment or conformation of the target substance molecules in the mixture in a specific direction / shape is induced / promoted / caused by the following physicochemical interactions, resulting in a change in the surface properties of the solid target substance, which will be described later. Based on various theories and explanations, this may be due to a change in the interaction between the altered surface properties of the target substance and the added surfactant compared to existing methods, forming micelles with different sizes or physical properties than the original micelles, or the partition coefficient between the target substance and the dispersion medium becoming different from existing known techniques, or a new mechanism different from the micellar solubilization mechanism taking effect. The foregoing theories and explanations have a scientific basis and logical validity, but the realization of the results of the present invention is not limited to situations where only the foregoing theories or explanations are possible. In addition to the foregoing theories or explanations, other unidentified mechanisms may be operated, or a third mechanism may be operated in combination. Regardless of the specific molecular unit mechanism, the present invention can achieve dispersion compositions containing a higher content of the target substance than the solubility limit of existing micellar solubilization techniques, and this can be confirmed by numerical comparison with existing dispersion compositions through the above-mentioned S-parameter analysis.

[0102] In one embodiment of the invention, a dispersion composition is provided comprising a dispersion medium and particles comprising a target substance.

[0103] The dispersion composition comprises at least one surfactant with a critical micelle concentration above a certain level.

[0104] The dispersion composition does not contain a solubilizer.

[0105] The target substance is cyclosporine A.

[0106] If the dispersion composition contains at least one surfactant, then the S-parameter of Equation 3, calculated from Equations 1 and 2, satisfies S-parameter > 1, and

[0107] If the dispersion composition contains at least two surfactants with a critical micelle concentration of 1 or higher, then for each surfactant, S is calculated using the following Equation 4. surf(i) Then, these S's are obtained from the following equation 5. surf(i) The sum as S surf The value, and by calculating S surf The S-parameter of Equation 3 obtained by applying the value to Equation 1 above satisfies S-parameter>1.

[0108] Equation 1

[0109] S 胶束 = S w + S surf

[0110] Among them, S w S is the concentration corresponding to the saturation solubility of the target substance in the dispersion medium. surf The calculation is performed using Equation 2 below.

[0111] Equation 2

[0112] S surf = k(C surf - CMC)

[0113] Where k is the molar solubilizing capacity, defined as the number of moles of the target substance that a surfactant can disperse in the dispersion medium at a critical micelle concentration of 1 mole or higher, and C surf It is the molar concentration of the surfactant component in the composition, and CMC is the critical micelle molar concentration of the surfactant in the composition.

[0114] Equation 3

[0115] S-parameter = S tot / S 胶束

[0116] Among them, S tot It is the total molar content of the target substance contained in the dispersion composition.

[0117] Equation 4

[0118] S surf(i) = k surf(i) (C surf(i) - CMC surf(i) )

[0119] Where, k surf(i) Molar solubilizing ability is defined as the number of moles of a target substance that can be dispersed in a dispersion medium by a surfactant component at any critical micelle concentration of 1 mole or higher. surf(i) It is the concentration of any surfactant component above the critical micelle concentration, and CMC surf(i) It is the critical micelle concentration of any surfactant component in the dispersion medium that is above the critical micelle concentration.

[0120] Equation 5

[0121]

[0122] Where m is the total number of surfactant components above the critical micelle concentration.

[0123] When the dispersion composition contains two or more surfactants with a critical micelle concentration of more than two, the types of surfactants can be selected such that the total content of the target substance that can be dispersed corresponds to the sum of the content of the target substance that each surfactant can disperse.

[0124] The amount of the target substance contained in the dispersion composition may exceed the amount corresponding to its saturation solubility in the dispersion medium.

[0125] The dispersed phase particles in the dispersion composition of the present invention may contain one or more target substances. If the particles contain multiple target substances, the statement "the content of the target substance exceeds the content corresponding to the saturated solubility of the target substance in the dispersion medium" means that the content of at least one of the multiple substances exceeds the content corresponding to the saturated solubility in the dispersion medium. In addition, besides the target substances, the particles may also contain additives.

[0126] The particles can be crystalline, amorphous, or a mixture thereof. In one embodiment, the target substance is a drug, and the particles are amorphous or crystalline. The particles can be single-component or multi-component. The particles can be single-phase or multi-phase.

[0127] The dispersion composition achieved by the present invention contains particles of the target substance with a number average diameter of less than about 100 nm.

[0128] In one embodiment, the number-average diameter can be less than about 80 nm.

[0129] In one embodiment, the number-average diameter can be less than about 50 nm.

[0130] In one embodiment, the number-average diameter can be from about 1 nm to about 20 nm.

[0131] In one embodiment, the number-average diameter can be from about 1 nm to about 10 nm.

[0132] In one embodiment, the number-average diameter can be from about 1 nm to about 5 nm.

[0133] The dispersion composition is transparent. If the particle size is small and there is no agglomeration or sedimentation, the permeability of the dispersion composition remains at a high level. Because the particles are formed at nanometer unit sizes, the dispersion composition forms transparently and has high permeability. Permeability can be measured as permeability or turbidity at a specific wavelength, and it can also be confirmed by visual inspection.

[0134] This dispersion composition exhibits excellent dispersion stability. The dispersion composition disperses stably while containing an amount of the target substance exceeding its saturation solubility in the dispersion medium. For example, the stability of the dispersion composition can be confirmed by visually observing that the transparency remains unchanged over time or that no precipitation occurs. As another example, dispersion stability can be confirmed by measuring the rate of change over time of physical properties sensitive to particle size (e.g., permeability or turbidity obtained by optical measurements, or particle size (Z-avg or average particle diameter) measured by dynamic light scattering (DLS)).

[0135] Furthermore, dispersion stability can also be measured by the change in the content of the target substance over time. If particles precipitate due to reasons such as agglomeration, the content measured by high-performance liquid chromatography (HPLC) (measured after filtration) will decrease over time. Therefore, dispersion stability can be confirmed by checking whether the content measured by HPLC after filtration remains at the value it was when the composition was first produced.

[0136] For example, the dispersion composition can stably remain dispersed for more than 24 hours, wherein the number average diameter of the particles is less than 100 nm.

[0137] In another example, the dispersion composition can remain stably dispersed for more than one week, wherein the number average diameter of the particles is less than 100 nm.

[0138] In another example, the dispersion composition can remain stably dispersed for more than one month, wherein the number average diameter of the particles is less than 100 nm.

[0139] In another example, the dispersion composition can remain stably dispersed for more than 3 months, wherein the number average diameter of the particles is less than 100 nm.

[0140] In another example, the dispersion composition can remain stably dispersed for more than 12 months, wherein the number average diameter of the particles is less than 100 nm.

[0141] In one embodiment of the invention, the invention provides a solid substance obtained by removing the dispersion medium from a dispersion composition.

[0142] In one embodiment of the present invention, the above-described dispersion composition can be obtained by using the above-described solid substance as the target substance.

[0143] In one embodiment of the invention, the invention provides solid cyclosporine A obtained by removing the dispersion medium from the dispersion composition.

[0144] In one embodiment of the present invention, the above-described dispersion composition can be obtained by using solid cyclosporine A as the target substance.

[0145] In another embodiment of the invention, the invention provides a solid substance that can be used as the target substance. In other words, the above-described dispersion composition is obtained by applying the solid substance as the target substance.

[0146] In one embodiment, the target substance is cyclosporine A, and the solid substance is solid cyclosporine A.

[0147] Solid substances can exceed the maximum amount that can be solubilized by micellar solubilization technology (S 胶束 The dispersion is stably dispersed in the dispersion medium. In the dispersion composition thus obtained, as described above, the S-parameter of Equation 3 satisfies S-parameter > 1, and the details are the same as those described for the aforementioned dispersion composition. It is presumed that this is because, in the method of the present invention, when the mixture comes into contact with a medium having multiple surfaces, the molecular aggregation or arrangement or conformation of the target substance molecules in the mixture in a specific direction / shape is induced / promoted / caused by the following physicochemical interactions, and then the surface properties of the solid target substance formed are changed.

[0148] Solid substances can be powders.

[0149] The dispersion composition of one embodiment of the present invention has a lower surfactant content than that of the prior art, and not only improves the solubility of the target substance but also improves its permeability, thereby resulting in improved bioavailability and superior therapeutic efficacy. Furthermore, compared to the prior art, by reducing the surfactant content, it has the effect of reducing or preventing problems such as environmental pollution or in vivo toxicity / side effects caused by surfactants. For example, polyoxyethylene 35 castor oil (Kolliphor EL or Cremophor EL), which is mainly used as a surfactant in pharmaceutical compositions, is highly toxic. Moreover, even in the preparation of dispersions of cyclosporine A, the surfactant polysorbate 80 (polysorbate 80 or Tween 80) is used, which has the disadvantage of severely irritating the eyes. The dispersion composition of one embodiment of the present invention can reduce or avoid the side effects of toxic surfactants because the surfactant content is low and a stable dispersion is maintained.

[0150] The dispersion composition or solid substance (or solid target substance) can be prepared by the following preparation method.

[0151] The preparation method may include the following steps: preparing a mixture by mixing a target substance and a solvent for preparing the mixture; preparing a medium having multiple surfaces; and contacting the mixture with the medium having multiple surfaces.

[0152] In one embodiment of the invention, during the step of contacting a mixture containing the target substance with a medium having multiple surfaces, physicochemical interactions, such as shearing, confinement effects, and surface effects, can be induced / promoted / caused between the pores or inter-pores of the medium having multiple surfaces and the mixture.

[0153] The mixture undergoes high shear rates as it passes through the intrapores or interpores of nano- or micro-sized particles in a medium with multiple surfaces. Under these high shear rate conditions, certain types of molecular aggregation, alignment, or uniformity of the target substance molecules in the mixture can be induced / promoted / caused.

[0154] During the contact between the mixture and a medium with multiple surfaces, if the molecules of the target substance are spatially confined within pores (intraparticle or interparticle) of tens of nanometers or smaller contained in the medium with multiple surfaces (confinement effect), it can induce / promote / cause specific forms of molecular aggregation or arrangement / alignment or uniformity of the target substance molecules in the mixture.

[0155] When the mixture comes into contact with the internal / external surfaces of a medium having multiple surfaces, it can induce / promote / cause specific forms of molecular aggregation or arrangement / alignment or uniformity of the target substance molecules in the mixture, depending on the surface characteristics of the medium having multiple surfaces (e.g., polarity, hydrophilicity, or the type of surface functional groups).

[0156] When a mixture comes into contact with a medium having multiple surfaces, the duration of the physicochemical interaction between the mixture and the medium having multiple surfaces varies depending on the residence time in the medium having multiple surfaces, thereby easily inducing / promoting / causing specific forms of molecular aggregation or arrangement / alignment or uniformity of molecules of the target substance in the mixture.

[0157] In the method of the present invention, it is presumed that due to the physicochemical interactions induced / promoted / induced when the mixture comes into contact with a medium having multiple surfaces, the molecular aggregation or alignment / consistency of the target substance molecules in a specific direction / shape is induced / promoted / induced, and the surface properties of the resulting solid target substance or particles containing the target substance are then altered to be more favorable to the dispersion medium. For example, it is presumed that when a target substance that is poorly soluble in water is dispersed in water, if the method of the present invention is implemented, a specific form of molecular aggregation or alignment / consistency of the target substance in the mixture will be induced / promoted / induced, and the surface properties of the resulting target substance particles will then be altered to be more favorable to water as the dispersion medium, thus improving the dispersibility to water and resulting in a reduction in the amount of surfactant required for solubilization.

[0158] The step of contacting the mixture with a medium having multiple surfaces is a process of inducing / promoting / causing the various physicochemical interactions described above, and includes continuously passing the mixture through (flowing through) the medium having multiple surfaces, and then collecting the passed mixture or contacting or mixing it with a dispersion medium. In this step, if desired, process fluids may flow sequentially or parallel to the medium having multiple surfaces along with the mixture. In another embodiment, after impregnating the mixture into the pores of the medium having multiple surfaces, the step includes contacting the medium containing the liquid phase with the dispersion medium (which can be in various ways, such as simple mixing) to release the mixture into the dispersion medium.

[0159] In one embodiment, an effluent is obtained by passing the mixture and process fluid sequentially or in parallel through a medium having multiple surfaces and collecting them directly. The medium is in the form of a packed bed, membrane, or sheet composed of porous or non-porous materials. All solvents used to prepare the mixture and process fluid are removed from the effluent by freeze-drying, atmospheric / reduced pressure / vacuum drying, or distillation to obtain a solid target substance (or the aforementioned solid substance). The separated solid target substance (or solid substance) may be a powder. Depending on the purpose and use of the final composition, a desired dispersion composition can be obtained by mixing the obtained solid target substance (or solid substance), a dispersion medium (e.g., water), one or more surfactants and additives (osmotic pressure regulators, thickeners, pH buffers, etc.). In particular, the target substance may be poorly soluble in the dispersion medium, and the target substance may be supersaturated and thus dispersed in the dispersion medium. In the above examples, when the mixture flows through a medium having multiple surfaces, the residence time or the degree / intensity of physicochemical interactions can be adjusted, if desired, by adjusting the pressure (pressure difference between the inlet and outlet) or temperature during the process.

[0160] In the method of this invention, when the mixture comes into contact with a medium having multiple surfaces, the amount of the target substance retained in the medium is very small, so most (over 95%) of the target substance leaves the medium. The purpose of the method of this invention is to apply physicochemical interactions to the molecules of the target substance while contacting the mixture with the medium having multiple surfaces, and the purpose of the method of this invention is not to induce / promote / cause a thermodynamic phase transition, such as solidification (crystallization or amorphization) or precipitation of the target substance within the medium having multiple surfaces (which may be in pores). If the target substance is retained in the medium having multiple surfaces through a phase transition, such as solidification or precipitation, it is difficult to achieve the results or effects / efficacy of this invention (solid target substance (or solid matter) or dispersion composition). Therefore, in the method of this invention, it is important to adjust / control the process conditions (e.g., residence time or flow rate) so that the target substance is not retained in the medium having multiple surfaces.

[0161] In the method of the present invention, when the mixture comes into contact with a medium having multiple surfaces, the residence time (t) corresponding to the total contact time between the mixture and the medium having multiple surfaces is defined as follows: ret The value is calculated by Equation 7 below. In Equation 7 below, q is the Darcy flux, which is the volume of fluid flowing through a unit cross-sectional area of ​​a medium with multiple surfaces per unit time, and L is the dimension of the medium with multiple surfaces in the direction in which the fluid flows through the medium with multiple surfaces (or, if the medium with multiple surfaces is a packed bed, the dimension corresponds to the height of the packed bed).

[0162] Equation 7

[0163] t ret = L / q

[0164] In the method of this invention, in order to induce / promote / cause specific types of molecular aggregation or alignment or uniformity of target substance molecules, the advection rate that induces ordering must be advantageous relative to the diffusion rate that induces randomization. When expressed in terms of residence time, if the residence time is too long, it becomes difficult for specific forms of molecular aggregation or alignment or uniformity to occur due to sufficient time for diffusion, and therefore, a long residence time is undesirable. On the other hand, if the flow rate is too high, resulting in a residence time that is too short, turbulence will occur, which will also interfere with the molecular aggregation or alignment or uniformity of the target substance. Therefore, if the invention is carried out by flowing the mixture through a medium having multiple surfaces, there is a suitable range of residence times. For carrying out the invention, it is suitable to adjust the residence time to be greater than about 30 seconds and less than about 390 seconds. On the other hand, according to Equation 7, since the residence time is proportional to the packed bed height (L), setting the ratio (aspect ratio) of the packed bed height (L), more precisely the ratio of the packed bed height to the packed bed diameter (height / diameter), to be greater than about 0.01 and less than about 1 helps to obtain a suitable residence time.

[0165] In the effluent, it is presumed that the surface properties of the solid target material (or solid substance) obtained by removing all solvents used to prepare the mixture or process fluid are altered to be more compatible with the dispersion medium. This is due to the physicochemical interactions that occur as the mixture flows through a medium with multiple surfaces, changing the molecular aggregation or arrangement / alignment or uniformity of the target material molecules. Therefore, the solid target material (or solid substance) of one embodiment of the present invention can be stably dispersed in a dispersion medium containing a surfactant at a concentration higher than the maximum amount (S) that can be solubilized by existing micellar solubilization techniques. 胶束 ).

[0166] When a target substance is mixed with a dispersion medium, one or more surfactants, and desired additives to prepare a dispersion composition, it is presumed that the surface properties of the particles containing the target substance are altered to be more compatible with the dispersion medium, thereby improving the dispersibility of the dispersion medium and thus reducing the amount of surfactant required for solubilization. Furthermore, it is presumed that since the solid target substance (or solid material) obtained by removing the dispersion medium from the dispersion composition retains the surface properties of these particles even when re-dispersed in the dispersion medium, similarly, the dispersibility of the dispersion medium is improved, leading to a reduction in the amount of surfactant required for solubilization.

[0167] In one embodiment of the invention, the step of contacting the mixture with a medium having multiple surfaces as described above is referred to as a unit operation. In one embodiment of the invention, a dispersion composition in which particles containing a target substance (or substance) are dispersed can be prepared by performing a single unit operation. In one embodiment of the invention, a dispersion composition in which particles containing a target substance (or substance) are dispersed can be prepared by repeating several unit operations under the same process conditions. In one embodiment of the invention, a dispersion composition in which particles containing a target substance (or substance) are dispersed can be prepared by performing several unit operations while changing / adjusting the process conditions of each unit operation. In this case, the process conditions of each unit operation can be changed / adjusted individually or gradually.

[0168] In one embodiment of the invention, a solid target substance (or solid material) obtained by removing all solvents used for preparing a mixture or process fluid from an effluent through freeze-drying, atmospheric / reduced pressure / vacuum drying, or distillation can be mixed with a dispersion medium, one or more surfactants, and various additives (osmotic pressure regulators, thickeners, pH buffers, etc.) to obtain a desired final dispersion composition, depending on the purpose and use of the final composition. In another embodiment, the dispersion medium and one or more surfactants can be mixed in the effluent, and then the solvents used for preparing the mixture or process fluid can be preferentially separated / removed, after which desired additives can be added to obtain the desired final dispersion composition. As a method for preferentially separating / removing only the solvents used for preparing the mixture or process fluid, there are methods using separation techniques such as distillation. For example, if the boiling point of the solvent used for preparing the mixture or process fluid is lower than the boiling point of the dispersion medium, the solvent used for preparing the mixture or process fluid can be preferentially separated / removed by heating to a temperature higher than the boiling point of the solvent used for preparing the mixture or process fluid but lower than the boiling point of the dispersion medium. In addition, solvents used to prepare mixtures or process fluids can be preferentially separated / removed by using various separation techniques, taking advantage of the differences in physicochemical properties between the solvents used to prepare mixtures or process fluids and the dispersion medium.

[0169] The dispersion composition may include a small amount of solvent used to prepare the mixture or process fluid that has not been partially removed. The content of the solvent used to prepare the mixture or process fluid can be determined depending on the application. For example, when preparing a composition as a pharmaceutical, the content can be determined based on the in vivo toxicity of the solvent used to prepare the mixture or process fluid. For example, if the solvent used to prepare the mixture or process fluid is ethanol, the dispersion composition may contain less than about 0.5% (w / w) of ethanol (United States Pharmacopeia). <467> Residual solvent (December 1, 2020).

[0170] The method for preparing the dispersion composition may further include separating and removing the medium having multiple surfaces. The medium having multiple surfaces can be separated, for example, by using a filter; in addition, various separation methods can be used, such as physical removal, centrifugation, coagulation, precipitation, and electrostatic attraction, but are not limited thereto. The method for preparing the dispersion composition may also optionally include removing or adding a certain amount of the dispersion medium to the dispersion composition to determine / adjust the final content / concentration of the target substance.

[0171] In one embodiment of the present invention,

[0172] This invention provides a method for preparing a solid target substance (or solid substance), comprising the following steps:

[0173] The mixture is prepared by mixing the target substance and a solvent used to prepare the mixture;

[0174] Prepare media with multiple surfaces;

[0175] The mixture is brought into contact with the medium having multiple surfaces; and

[0176] The target substance is separated from the mixture to obtain a solid target substance.

[0177] In one embodiment of the present invention,

[0178] This invention provides a method for preparing a solid target substance (or solid substance), comprising the following steps:

[0179] The mixture is prepared by mixing the target substance and a solvent used to prepare the mixture;

[0180] Prepare media with multiple surfaces in the form of a packed bed, membrane, or sheet;

[0181] The mixture and optionally the process fluid are passed through the medium having multiple surfaces;

[0182] Collect the mixture that has flowed through the medium having multiple surfaces and the optionally used process fluid; and

[0183] Remove the solvent used to prepare the mixture and process fluid from the collected effluent.

[0184] In one embodiment of the present invention,

[0185] This invention provides a method for preparing a dispersion composition in which particles are dispersed, the particles comprising a target substance in the dispersed phase, the method comprising the following steps:

[0186] The mixture is prepared by mixing the target substance and a solvent used to prepare the mixture;

[0187] Prepare media with multiple surfaces in the form of a packed bed, membrane, or sheet;

[0188] The mixture and optionally the process fluid are passed through the medium having multiple surfaces;

[0189] Collect the mixture that has flowed through the medium having multiple surfaces and the optional process fluid;

[0190] Remove the solvent used to prepare the mixture and process fluid from the collected effluent; and

[0191] The solid target substance is mixed with a dispersion medium, one or more surfactants and / or desired additives.

[0192] The dispersion composition of one embodiment of the present invention may be a dispersion composition prepared by obtaining a solid target substance (or solid substance) and then mixing a dispersion medium, one or more surfactants and / or desired additives with the solid target substance (or solid substance) as described above.

[0193] In one embodiment of the present invention,

[0194] This invention provides a method for preparing a dispersion composition in which particles are dispersed, the particles comprising a target substance in the dispersed phase, the method comprising the following steps:

[0195] The mixture is prepared by mixing the target substance and a solvent used to prepare the mixture;

[0196] Prepare media with multiple surfaces in the form of a packed bed, membrane, or sheet;

[0197] The mixture and optionally the process fluid are passed through the medium having multiple surfaces;

[0198] Collect the mixture that has flowed through the medium having multiple surfaces and the optional process fluid;

[0199] The dispersion medium and one or more surfactants are mixed in the collected effluent; and

[0200] Preferably, the solvent used to prepare the mixture or process fluid is removed from the mixture.

[0201] In one embodiment of the present invention, the present invention provides a medicine for animals or humans containing the solid substance (or solid target substance).

[0202] In one embodiment of the invention, the invention provides a pharmaceutical product for animals or humans containing the dispersion composition.

[0203] The following describes embodiments and comparative examples of the present invention. These embodiments are merely examples of the present invention, and the present invention is not limited to these embodiments.

[0204] (Example)

[0205] In the following description, the units used to indicate content / concentration in the examples included in this specification will be described.

[0206] %(w / v): The percentage of the mass (g) of the analyte to the total volume (ml) of the system. For example, the mass (g) of the target substance / the volume (ml) of the dispersion composition. 100, or the mass of solute (g) / the volume of the solution (ml). 100

[0207] %(w / w) = The percentage of the mass of the analyte relative to the total mass of the system. For example, the mass of the target substance / the mass of the dispersion composition. 100, or the mass of the target substance / the mass of the mixture. 100

[0208] %(v / v) = The percentage of the volume of the measured substance relative to the total volume of the system. For example, the volume of the process fluid / the volume of the solution. 100

[0209] Examples 1-1 to 1-4: Preparation of CsA Powder

[0210] Ethanol (hereinafter referred to as 95% v / v ethanol) was prepared as the solvent for the preparation of the mixture at a volume ratio of 95:5 between ethanol and water. 5 g of cyclosporine A (purity 99.1%, TEVA batch number 7414004320, hereinafter referred to as CsA), the target substance, was dissolved in 995 g of 95% v / v ethanol by stirring at 500 rpm for 30 minutes using a magnetic rod and magnetic stirrer, resulting in a CsA mixture with a final concentration of 0.5% w / w. A Buchner funnel (90 mm inner diameter) was placed in a 250 ml Erlenmeyer flask, and 1 μm filter paper was placed on the funnel and soaked in 95% v / v ethanol. A suction pump was then operated at a pressure differential of 0.8 bar to adsorb the filter paper (1 μm) to the bottom of the Buchner funnel. 10 g of mesoporous silica powder (ABC Nanotech company, XL-100) was weighed and placed in a 250 ml beaker. Add 100 g of 95% v / v ethanol to a beaker containing mesoporous silica, and then thoroughly wet the silica with ethanol using a spatula to ensure thorough mixing of the silica powder and ethanol. Slowly pour the mesoporous silica containing the 95% v / v ethanol into a Buchner funnel lined with filter paper, while maintaining a pressure differential of 0.8 bar using a suction pump to form a mesoporous silica packed bed with a height of 8 mm and a diameter of 90 mm at the bottom of the Buchner funnel (90 mm diameter, 8 mm packed bed height, aspect ratio (height / diameter) 0.09). When approximately 1 cm of supernatant remains on the mesoporous silica packed bed, stop the suction pump and discard the filter filtrate collected in the conical flask. Then, replace the 250 ml conical flask with a 3000 ml one. A 1 μm filter paper was placed on a mesoporous silica packed bed formed in a Buchner funnel. 1000 g of a pre-prepared 0.5% w / w CsA mixture was poured into the Buchner funnel in several portions. As the process fluid, 95% v / v ethanol was prepared in the same manner as the solvent used to prepare the mixture, and 500 g of this process fluid was separately poured into the Buchner funnel. The mixture and process fluid flowed through the mesoporous silica packed bed at an average volumetric flow rate of 13.76 ml / min and were collected in a 3000 ml Erlenmeyer flask over a total of 145 minutes. Therefore, the Darcy flux (which is obtained by dividing the average volumetric flow rate by the cross-sectional area of ​​the packed bed (diameter 90 mm)) was 0.216 cm / min, and the total residence time of the mixture in the mesoporous silica packed bed, calculated according to Equation 7, was 222 seconds (L = 0.8 cm, q = 0.216 cm / min). The effluent collected using mesoporous silica was filtered using a 0.45 μm membrane filter.The product was then concentrated for 4 hours at 25°C, 150 rpm, and 20 mbar using a rotary evaporator (Eyela, OSB-2200). The resulting concentrate was then dried under reduced pressure in a vacuum oven for 12 hours, and all solvents used to prepare the mixture and process fluids were removed from the effluent, ultimately yielding 4.84 g of CsA powder. The recovery rate (yield) was defined as the percentage obtained 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), and this value was calculated to be 96.8%. In other words, it was found that most of the CsA (over 95%) flowed through the mesoporous silica packed bed. This process is referred to as Example 1-1. Processes in which the residence time was varied by changing the average volumetric flow rate in the same manner are referred to as Examples 1-2, 1-3, and 1-4, and the main process conditions for each example are listed in Table 1.

[0211] Table 1:

[0212]

[0213] Examples 2-1 to 2-3: CsA Aqueous Dispersion Compositions

[0214] Kolliphor EL (manufacturer: BASF, lot number 55573988Q0), polysorbate 80 (Tween 80, manufacturer: Croda, lot number 45971), and the CsA powder from Examples 1-1 were added sequentially to 10 ml clear vials in the amounts shown in Table 2, and stirred at 300 rpm for 12 hours at room temperature to ensure thorough mixing. First, 5 ml of pure water was added to the stirring CsA / Kolliphor EL / Tween 80 mixture, and stirred at 600 rpm for 30 minutes to ensure thorough mixing. Then, additional pure water was added to adjust the total volume to 200 ml. Finally, an aqueous CsA dispersion composition in which CsA particles are dispersed in a continuous phase was prepared according to the composition shown in Table 2.

[0215] Table 2:

[0216]

[0217] As a control group, to compare / contrast with existing known technologies, commercially available CsA powder (manufacturer: TEVA, batch number 7414004320) was used instead of the CsA powder used in Examples 1-1 (hereinafter referred to as control groups 2-1, 2-2, and 2-3). CsA aqueous dispersion compositions prepared with commercially available CsA powder were prepared by adding the same amounts of each component as the CsA aqueous dispersion compositions of Examples 2-1, 2-2, and 2-3 in Table 2 above. It was confirmed that control groups 2-1, 2-2, and 2-3 prepared with commercially available CsA powder all exhibited immediate precipitation after preparation, and were either translucent or opaque, thus failing to achieve a dispersion composition. In contrast, the CsA aqueous dispersion compositions with the same composition prepared in Examples 2-1, 2-2, and 2-3 were confirmed to have no precipitation after preparation and were entirely transparent, thus achieving a dispersion composition.

[0218] The CsA aqueous dispersions prepared in Examples 2-1, 2-2, and 2-3, and the Control Groups 2-1, 2-2, and 2-3, were filtered using a 0.22 μm PES (polyethersulfone) filter to obtain filter filtrates. The filter filtrates were analyzed by HPLC under the following conditions, and the CsA content / concentration was measured, as shown in Table 3. Since the content in the filter filtrate corresponds to the amount of CsA stably dispersed in water (excluding the amount of CsA precipitated during or immediately after preparation), the CsA content / concentration shown in Table 3 corresponds to the actual content / concentration of CsA stably dispersed in the CsA aqueous dispersions prepared using Examples 2-1, 2-2, and 2-3, and the Control Groups 2-1, 2-2, and 2-3.

[0219] Instrument: Agilent 1260 Infinity II

[0220] Column: Hypersil ODF (4.6 × 250 mm, 3 μm)

[0221] Column temperature: 50℃

[0222] Flow rate: 1 ml / min

[0223] Detector: Ultraviolet absorbance spectrophotometer (measurement wavelength: 210 nm)

[0224] Injection volume: 40 μL

[0225] As shown in Table 3 below, it can be seen that the actual CsA content in the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 is within + / - 5% of the nominal content of 0.02% w / v in Table 2. In contrast, it was confirmed that the actual CsA content in the CsA aqueous dispersion compositions prepared using control groups 2-1, 2-2, and 2-3 was less than the nominal content of 0.02% w / v, therefore a dispersion composition containing 0.02% w / v CsA was not achieved.

[0226] Table 3:

[0227]

[0228] Evaluation of S-parameters of CsA aqueous dispersion compositions

[0229] Table 4 shows the physical properties of CsA required to calculate the S-parameters of the CsA aqueous dispersion, the physical properties of the surfactants Tween 80 and Kolliphor EL used, and the molar solubilizing power of the surfactants used for CsA (Feng et al., J. Pharmaceutical Sciences, Vol. 107(8), 2018, 2079-2090).

[0230] Table 4:

[0231]

[0232] By substituting the physical properties from Table 4, the surfactant content from Table 2, and the actual CsA content from Table 3 into Equations 1, 3, 4, and 5, the S-parameters of the CsA aqueous dispersion compositions implemented in Examples 2-1, 2-2, and 2-3 were calculated. Table 5 lists each process and the final results. (Since molar solubilization is the ratio of the number of moles of CsA to the number of moles of the surfactant used, when calculating Equation 4, the % w / v composition of the surfactant was converted to moles using the molecular weight of the surfactant and substituted. Furthermore, since the calculated value is the number of moles of CsA, it was again converted to CsA % w / v using the molecular weight of CsA to obtain the S-parameters.) surf The contents / compositions in Tables 5 and 6 are obtained through these conversion processes (% w / v).

[0233] Table 5:

[0234]

[0235] In the same manner, by substituting the physical properties in Table 4, the surfactant content in Table 2, and the actual CsA content in Table 3 into Equations 1, 3, 4, and 5, the S-parameters of the CsA aqueous dispersion compositions implemented in control groups 2-1, 2-2, and 2-3 were calculated, and Table 6 lists each process and the final results.

[0236] Table 6:

[0237]

[0238] As shown in Table 5, the S-parameters of the CsA dispersion compositions implemented in Examples 2-1, 2-2, and 2-3 are 1.12, 1.18, and 1.17, respectively, all greater than 1. This means that in the CsA dispersion compositions implemented in Examples 2-1, 2-2, and 2-3, which can be solubilized using two surfactants (Tween 80 and Kolliphor EL), they exceed the existing limits (S-parameters) of CsA. 胶束 The amounts were 12%, 18%, and 17%. In contrast, as shown in Table 6, all S-parameters of the dispersion compositions of control groups 2-1, 2-2, and 2-3, prepared using known techniques, were below 1. In other words, it can be seen that even when prepared by adding the same amount of surfactant and the same amount of CsA, the known techniques do not contain the target amount of CsA in the dispersion composition because exceeding the S-parameters... 胶束 The amount of CsA will precipitate. Therefore, by using the present invention, high concentrations of CsA can be dispersed, which is not possible with existing known technologies. In terms of surfactant, this means that less surfactant is needed than with known technologies when dispersing the same concentration (0.02%) of CsA.

[0239] Experimental Example 1-1: Dispersion stability of CsA aqueous dispersion composition: visual inspection

[0240] To examine the stability of the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3, these compositions were stored at 25±2°C and 60±5% relative humidity for 2 to 4 weeks after preparation, and changes in precipitation or transparency over time were visually inspected. Table 7 shows the visual results based on the time elapsed since preparation. As shown in Table 7, it was confirmed that all CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3 remained transparent without precipitation for 2 to 4 weeks. Therefore, it can be seen that during this period, CsA was stably dispersed in water in the CsA aqueous dispersion compositions prepared in Examples 2-1, 2-2, and 2-3, without CsA precipitation or particle aggregation / agglomeration.

[0241] Table 7:

[0242]

[0243] Experimental Example 1-2: Dispersion stability of CsA aqueous dispersion composition: HPLC content

[0244] To examine the stability of the CsA aqueous dispersions prepared in Examples 2-1, 2-2, and 2-3, these compositions were stored at 25±2°C and 60±5% relative humidity for 2 to 4 weeks after preparation, and the change in CsA content over time was measured by HPLC. Immediately after preparation, 1 week later, 2 weeks later, and 4 weeks later, the CsA aqueous dispersions prepared in Examples 2-1, 2-2, and 2-3 were filtered through a 0.22 μm PES (polyethersulfone) filter, and the filter filtrate was then analyzed by HPLC under the following conditions to measure the rate of change of CsA content over time (the HPLC content at "immediately after preparation" was set to 100% for calculating the rate of change of content over time). The results are listed in Table 8.

[0245] Instrument: Agilent 1260 Infinity II

[0246] Column: Hypersil ODF (4.6 × 250 mm, 3 μm)

[0247] Column temperature: 50℃

[0248] Flow rate: 1 ml / min

[0249] Detector: Ultraviolet absorbance spectrophotometer (measurement wavelength: 210 nm)

[0250] Injection volume: 40 μL

[0251] Table 8:

[0252]

[0253] As shown in Table 8, the content of CsA in the aqueous dispersions prepared in Examples 2-1, 2-2, and 2-3 was maintained even after 2 to 4 weeks. Therefore, it can be seen that during these periods, CsA did not precipitate and was stably dispersed in the aqueous dispersions of CsA prepared in Examples 2-1, 2-2, and 2-3.

[0254] Examples 2-4: CsA Aqueous Dispersion Compositions

[0255] Ethanol (hereinafter referred to as 95% v / v ethanol) was prepared as the solvent for preparing the mixture at a volume ratio of 95:5 between ethanol and water. 0.06 g of cyclosporine A (purity: 99.1%, manufacturer: TEVA, lot number 7414004320, hereinafter referred to as CsA) as the target substance was dissolved in 29.94 g of 95% v / v ethanol by stirring at 500 rpm for 30 minutes using a magnetic stirrer and a magnetic rod, ultimately obtaining a CsA mixture with a concentration of 0.2% w / w. A Buchner funnel (90 mm inner diameter) was placed in a 250 ml Erlenmeyer flask, and 1 μm filter paper was placed on the funnel and soaked in 95% v / v ethanol. A suction pump was then operated at a pressure differential of 0.8 bar to adsorb the filter paper (1 μm) to the bottom of the Buchner funnel. Weigh 10 g of mesoporous silica powder (ABC Nanotech company, XL-100) and place it in a 250 ml beaker. Add 100 g of 95% v / v ethanol to the beaker containing the mesoporous silica, and then thoroughly mix the silica powder and ethanol by stirring with a spatula until the ethanol fully wets the silica. Slowly pour the mesoporous silica containing the 95% v / v ethanol into a Buchner funnel lined with filter paper, while using a suction pump to maintain a pressure difference of 0.8 bar to form a mesoporous silica packed bed with a height of 8 mm and a diameter of 90 mm 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 remains on the mesoporous silica packed bed, stop the suction pump and discard the filter filtrate collected in the conical flask. Then, replace the above 250 ml conical flask with another 250 ml conical flask. A 1 μm filter paper was placed on a mesoporous silica-filled bed formed in a Buchner funnel. 30 g of a pre-prepared 0.2% w / w CsA mixture was poured into the Buchner funnel in several portions. As the process fluid, 95% v / v ethanol was prepared in the same manner as the solvent used to prepare the mixture. 120 g of this process fluid was mixed with 80 g of pure water, and 200 g of this mixture was separately poured into the Buchner funnel. 205 g of the effluent collected from the mesoporous silica was filtered using a 0.45 μm membrane filter.

[0256] Prepare a 250 ml concentration flask, place a magnetic stir bar inside, and aliquot 10 g of the eluent. Add 6 mg each of polysorbate 80 (Tween 80, manufacturer: TCI, XHLAA-GM) and polyoxyethylene 35 castor oil (manufacturer: ACROS, batch number A0403500) to 10 g of 95% v / v ethanol, and then mix thoroughly with a magnetic stirrer for 10 minutes. After 10 minutes, add 40 ml of pure water to the 250 ml concentration flask and stir the mixture with a magnetic stirrer at 500 rpm for 30 minutes. Selectively remove ethanol from the mixture using a rotary evaporator (Eyela, OSB-2200) at 25°C, 150 rpm, and 20 mbar for 2 hours and 20 minutes, and distill off a portion of the pure water to finally obtain 15.8 ml of CsA aqueous dispersion. The obtained liquid was filtered using a 0.45 μm (manufacturer: FUTECS, PVDF) syringe filter and a 0.22 μm (manufacturer: FUTECS, PTFE) filter to obtain filter filtrate. The obtained filter filtrate was analyzed by HPLC under the following conditions to measure the CsA content / concentration, and the results are shown in Table 9.

[0257] HPLC instrument: Waters

[0258] Model name: e2695

[0259] Column: RP C18 (250 × 4.6 mm) Average particle size 5 μm

[0260] Column temperature: 65℃

[0261] Flow rate: 1 ml / min

[0262] Detector: Ultraviolet absorbance spectrophotometer (measurement wavelength: 204 nm)

[0263] Injection volume: 10 μL

[0264] Examples 2-5: CsA Aqueous Dispersion Compositions

[0265] Ethanol (hereinafter referred to as 95% v / v ethanol) was prepared as the solvent for preparing the mixture at a volume ratio of 95:5 between ethanol and water. 0.06 g of cyclosporine A (99.1% purity, manufacturer: TEVA, lot number 7414004320, hereinafter referred to as CsA) as the target substance was dissolved in 29.94 g of 95% v / v ethanol by stirring at 500 rpm for 30 minutes using a magnetic rod and magnetic stirrer, ultimately obtaining a CsA mixture with a concentration of 0.2% w / w. A Buchner funnel (90 mm inner diameter) was placed in a 250 ml Erlenmeyer flask, and 1 μm filter paper was placed on the funnel and soaked in 95% v / v ethanol. A suction pump was then operated at a pressure differential of 0.8 bar to adsorb the filter paper (1 μm) to the bottom of the Buchner funnel. Weigh 10 g of mesoporous silica powder (ABC Nanotech company, XL-100) and place it in a 250 ml beaker. Add 100 g of 95% v / v ethanol to the beaker containing the mesoporous silica, and then thoroughly mix the silica powder and ethanol by stirring with a spatula until the ethanol fully wets the silica. Slowly pour the mesoporous silica containing the 95% v / v ethanol into a Buchner funnel lined with filter paper, while using a suction pump to maintain a pressure difference of 0.8 bar to form a mesoporous silica packed bed with a height of 8 mm and a diameter of 90 mm 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 remains on the mesoporous silica packed bed, stop the suction pump and discard the filter filtrate collected in the conical flask. Then, replace the above 250 ml conical flask with a new 250 ml conical flask. A 1 μm filter paper was placed on a mesoporous silica-filled bed formed in a Buchner funnel. 30 g of a pre-prepared 0.2% w / w CsA mixture was poured into the Buchner funnel in several portions. 95% v / v ethanol was prepared as the process fluid in the same manner as the solvent used to prepare the mixture, and 120 g of this process fluid was mixed with 80 g of pure water. 200 g of this mixture was then poured into the Buchner funnel. 205 g of the effluent collected from the mesoporous silica was filtered using a 0.45 μm membrane filter.

[0266] Prepare a 250 ml concentration flask, place a magnetic stir bar inside, and aliquot 10 g of the eluent into a container. Add 3 mg of polysorbate 80 (Tween 80, manufacturer: TCI, XHLAA-GM) and 9 mg of polyoxyethylene 35 castor oil (manufacturer: ACROS, batch number A0403500) to 10 g of 95% v / v ethanol, and then mix thoroughly using a magnetic stirrer for 10 minutes. After 10 minutes, add 40 ml of pure water to the 250 ml concentration flask and stir the mixture at 500 rpm for 30 minutes using a magnetic stirrer. Selectively remove ethanol from the mixture using a rotary evaporator (Eyela, OSB-2200) at 25°C, 150 rpm, and 20 mbar for 1 hour and 20 minutes, and distill off a portion of the pure water to finally obtain 15.6 ml of CsA aqueous dispersion. The obtained liquid was filtered using a 0.45 μm (manufacturer: FUTECS, PVDF) syringe filter and a 0.22 μm (manufacturer: FUTECS, PTFE) filter to obtain filter filtrate. The obtained filter filtrate was analyzed by HPLC under the following conditions to measure the CsA content / concentration, and the results are shown in Table 9.

[0267] HPLC instrument: Waters

[0268] Model name: e2695

[0269] Column: RP C18 (250 × 4.6 mm), average particle size 5 μm

[0270] Column temperature: 65℃

[0271] Flow rate: 1 ml / min

[0272] Detector: Ultraviolet absorbance spectrophotometer (measurement wavelength: 204 nm)

[0273] Injection volume: 10 μL

[0274] Table 9 shows the composition of the final CsA aqueous dispersion compositions of Examples 2-4 and 2-5.

[0275] Table 9:

[0276]

[0277] By substituting the physical properties in Table 4, the surfactant content in Table 9, and the actual CsA content into Equations 1, 3, 4, and 5, the S-parameters of the CsA aqueous dispersion compositions implemented in Examples 2-4 and 2-5 were calculated. Table 10 lists each process and the final results. (Since molar solubilization is the ratio of the number of moles of CsA to the number of moles of the surfactant used, when calculating Equation 4, the % w / v composition of the surfactant was converted to moles using the surfactant molecular weight and substituted. Furthermore, since the calculated value is the number of moles of CsA, it was again converted to CsA % w / v using the molecular weight of CsA to obtain the S-parameters.) surf The contents / compositions in Table 10 are all obtained through this conversion process (% w / v).

[0278] Table 10:

[0279]

[0280] As shown in Table 10, the S-parameters of the CsA aqueous dispersion compositions implemented in Examples 2-4 and 2-5 are 1.90 and 2.19, respectively, both greater than 1. This means that in the CsA dispersion compositions implemented in Examples 2-4 and 2-5, which can be solubilized using two surfactants (Tween 80 and polyoxyethylene 35 castor oil), they exceed the existing limits (S-parameters) of CsA. 胶束 ) 90% and 119%.

[0281] Although the invention has been described above, it is not limited to the embodiments disclosed herein. It will be apparent to those skilled in the art that various modifications can be made within the spirit of the invention. Furthermore, even though the working effects of the configurations according to the invention have not been explicitly described and explained in the explanation of the embodiments described above, it should naturally be recognized that the predictable effects of such configurations are possible.

Claims

1. A dispersion composition comprising: Dispersion medium; and Particles containing the target substance in, The dispersion composition contains at least one surfactant with a critical micelle concentration above a certain level. The dispersion composition does not contain a solubilizer. The particles containing the target substance are an aggregate of multiple molecules of cyclosporine A. The combination of the multiple molecules is prepared by the following steps: The mixture is prepared by mixing cyclosporine A and a solvent used to prepare the mixture; Prepare a medium having multiple surfaces in the form of a packed bed, membrane, or sheet, wherein the medium having multiple surfaces includes one or more of silica gel, silica dry gel, mesoporous silica, and fumed silica; The mixture is allowed to flow through the medium having multiple surfaces; Collect the mixture that has flowed through the medium having multiple surfaces; Remove the solvent used to prepare the mixture from the collected mixture. The dispersion medium is water. The surfactant is one or more of polysorbate and polyethoxylated castor oil. If the dispersion composition contains at least one surfactant, then the S-parameter of Equation 3, calculated from Equations 1 and 2, satisfies S-parameter > 1, and If the dispersion composition contains at least two surfactants with a critical micelle concentration of 4 or higher, then S is calculated for each surfactant using the following Equation 4. surf(i) Then, these S are obtained from the following equation 5. surf(i) The sum of S surf The value, and by calculating S surf The S-parameter of Equation 3 obtained by applying the value to Equation 1 above satisfies S-parameter > 1; Equation 1 S 胶束 = S w + S surf Among them, S w S is the concentration corresponding to the saturated solubility of the target substance in the dispersion medium. surf Calculate using the following equation 2; Equation 2 S surf = k(C surf - CMC) Where k is the molar solubilizing capacity, defined as the number of moles of the target substance that can be dispersed in the dispersion medium by a surfactant at a critical micelle concentration of 1 mole or higher, and C surf CMC is the molar concentration of the surfactant component in the composition, and CMC is the critical micelle molar concentration of the surfactant in the composition. Equation 3 S-parameter = S tot / S 胶束 Among them, S tot It is the total molar content of the target substance contained in the dispersion composition; Equation 4 S surf(i) = k surf(i) (C surf(i) - CMC surf(i) ) Where, k surf(i) Molar solubilizing capacity is defined as the number of moles of the target substance that can be dispersed in the dispersion medium by any surfactant component with a critical micelle concentration of 1 mole or higher. surf(i) It is the concentration of any surfactant component above the critical micelle concentration, and CMC surf(i) It is the critical micelle concentration of any surfactant component in the dispersion medium that is above the critical micelle concentration; Equation 5 Where m is the total number of surfactant components above the critical micelle concentration.

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

3. The dispersion composition according to claim 1, wherein, If two surfactants with a critical micelle concentration or higher are included, the types of surfactants are selected such that the total content of dispersible cyclosporine A is consistent with the sum of the dispersible cyclosporine A content of each surfactant.

4. The dispersion composition according to claim 1, wherein, The number-average diameter of the particles is less than 100 nm.

5. The dispersion composition according to claim 1, wherein, The number-average diameter of the particles is less than 50 nm.

6. A pharmaceutical product for use in animals or humans, comprising the dispersible composition of claim 1.

7. A solid cyclosporine A, wherein, The solid cyclosporine A is prepared by the following steps: The mixture is prepared by mixing cyclosporine A and a solvent used to prepare the mixture; Prepare a medium having multiple surfaces in the form of a packed bed, membrane, or sheet, wherein the medium having multiple surfaces includes one or more of silica gel, silica dry gel, mesoporous silica, and fumed silica; The mixture is allowed to flow through the medium having multiple surfaces; Collect the mixture that has flowed through the medium having multiple surfaces; Remove the solvent used to prepare the mixture from the collected mixture.

8. A pharmaceutical product for use in animals or humans, comprising the solid cyclosporine A of claim 7.

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