Ursolic acid with improved solubility and dispersibility, and method for producing same

Abstract

The present application relates to ursolic acid with improved solubility and dispersibility, a method for producing same, and a method for improving the solubility of ursolic acid. In the present application, a complex of ursolic acid, an emulsifier, and a nonionic surfactant is formed and made into microparticles, thereby improving the solubility and dispersibility of poorly soluble ursolic acid and facilitating the utilization of ursolic acid as a nutritional material.

Description

Ursolic acid with improved solubility and dispersibility and a method for preparing the same

[0001] [Cross-reference with related applications]

[0002] This application claims the benefit of priority based on Korean Patent Application No. 10-2024-0175315 filed on November 29, 2024, and all contents disclosed in said Korean Patent Application are incorporated herein as part of this specification.

[0003] The present application relates to ursolic acid with improved solubility and dispersibility, a method for manufacturing the same, and a method for improving the solubility of ursolic acid.

[0004]

[0005] Ursolic acid (UA) is a natural triterpene compound with various biological activities, and its efficacy in antioxidant, anti-inflammatory, anticancer, and anti-obesity effects has been reported. Despite these excellent benefits, ursolic acid is a fat-soluble substance with very low water solubility, which limits its absorption rate in the body. Ursolic acid is hardly soluble in water on its own, and consequently, the amount absorbed into the body upon oral ingestion is limited. This acts as a significant limiting factor in the use of ursolic acid as a nutritional material.

[0006] To solve these problems, special technical treatments are required to enhance the solubility of ursolic acid. Conventional technologies such as nanoparticle formation, polymerization, or liposome encapsulation have been attempted to improve ursolic acid solubility; however, it remains difficult to strike a balance between the effectiveness of improved solubility and the economic feasibility of the manufacturing process.

[0007] In addition, when ursolic acid is dissolved using organic solvents, primarily ethanol, which are utilized in existing processes, there is a concern regarding the harmful effects of the residual solvent on the human body.

[0008] Accordingly, there is a need to develop technology that can increase bioavailability by improving the solubility of ursolic acid while reducing the use of organic solvents.

[0009]

[0010] One objective of the present application is to provide ursolic acid-containing microparticles with improved solubility and dispersibility.

[0011] Another objective of the present application is to provide a method for manufacturing ursolic acid-containing microparticles with improved solubility and dispersibility.

[0012] Another objective of the present application is to provide a method for improving the solubility of ursolic acid.

[0013]

[0014] To achieve the above objective, one aspect of the present application provides microparticles comprising ursolic acid (UA), an emulsifier, and a nonionic surfactant, wherein the particle size of the microparticles has a d50 value of 2 to 7 μm.

[0015] In addition, another aspect of the present application provides a method for producing ursolic acid-containing microparticles comprising: (a) mixing ursolic acid (UA), water, an emulsifier, and a nonionic surfactant; and (b) homogenizing the mixture under high pressure.

[0016] In addition, another aspect of the present application provides a method for improving the solubility of ursolic acid, comprising: (a) mixing ursolic acid (UA), water, an emulsifier, and a nonionic surfactant; and (b) homogenizing the mixture under high pressure.

[0017]

[0018] The present application will be described in detail below.

[0019]

[0020] One aspect of the present application provides microparticles comprising ursolic acid (UA), an emulsifier, and a nonionic surfactant.

[0021] In this application, the term "micro particle" refers to a particle having a size at the micrometer (μm) level.

[0022] The above ursolic acid is a compound of an α-amyrin triterpene represented by the following chemical formula 1.

[0023] [Chemical Formula 1]

[0024]

[0025] The aforementioned ursolic acid is widely distributed in the waxy coatings of fruits and leaves such as apples and cherries, and is used as an active ingredient in pharmaceuticals due to its anti-inflammatory and anti-tumor effects. From a dermatological perspective, it is also known as an ingredient with excellent effects in improving fine wrinkles, fibroblast activation, and skin elasticity.

[0026] In one embodiment, the ursolic acid may be in powder form.

[0027] In this application, the term "melts" may have the meaning of including a conventional state of dissolution or dispersion.

[0028] In this application, the term "dissolution" may refer to the phenomenon in which the ursolic acid is uniformly dissolved, dispersed, or suspended in a solution or solvent.

[0029] In this application, the term "dispersion" may mean a state in which crystallization or aggregation does not occur in the ursolic acid in the dispersion or suspension.

[0030] In one embodiment, the content of the ursolic acid may be 15 to 45 weight percent based on the total weight of the microparticles. Specifically, the content of ursolic acid in the microparticles may be a range selected from the group consisting of a lower limit selected from the group consisting of 15, 16, 17, 18, 19, 20, 21, 22, and 23 weight% based on the total weight of the microparticles, and an upper limit selected from the group consisting of 41, 42, 43, 44, and 45 weight%. For example, the ursolic acid content of the ursolic acid-containing microparticles of the present application may be 15 to 45 weight%, 16 to 45 weight%, 17 to 44 weight%, 18 to 44 weight%, 19 to 43 weight%, 20 to 43 weight%, 21 to 42 weight%, 22 to 42 weight%, or 23 to 41 weight%.

[0031] The above emulsifier may be a substance that lowers interfacial tension when mixing two types of immiscible liquids (e.g., water and an organic liquid such as oil that does not easily mix with water), and may be a substance that disperses or stabilizes the two types of liquids, and a mixture of the two types of liquids mixed using the above emulsifier may be called an emulsion. The above emulsifier may be used without limitation as long as it is a substance that a person skilled in the art can adopt to disperse or stabilize two immiscible liquids, and the above emulsifier may contain both hydrophilic and lipophilic groups within its molecule.

[0032] In one embodiment, the emulsifier may be glycerophospholipid, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, soybean phospholipid, or calcium stearyl lactate.

[0033] In one embodiment, the glycerophospholipid may include phosphatidylcholine (lecithin), phosphatidylethanolamine, phosphatidylinositol, or plasmalogen.

[0034] In one embodiment, the emulsifier may include lecithin, specifically soybean lecithin.

[0035] In one embodiment, the content of the emulsifier may be 10 to 55 weight% based on the total weight of the microparticles. Specifically, the content of the emulsifier in the microparticles may be a range selected from the group consisting of a lower limit selected from the group consisting of 10, 11, 12, 13, 14, 15, and 16 weight% based on the total weight of the microparticles, and an upper limit selected from the group consisting of 48, 49, 50, 51, 52, 53, 54, and 55 weight% based on the total weight of the microparticles. For example, the emulsifier content in the ursolic acid-containing microparticles of the present application may be 10 to 55 weight%, 11 to 54 weight%, 12 to 53 weight%, 13 to 52 weight%, 14 to 51 weight%, 15 to 50 weight%, or 16 to 48 weight%.

[0036] The above-mentioned nonionic surfactant refers to a surfactant having the characteristic of not ionizing in an aqueous solution.

[0037] The above nonionic surfactants may include nonionic surfactants of the low molecular weight class, such as alkyl glycol, or nonionic surfactants of the high molecular weight class, such as polyethylene glycol and polyvinyl alcohol. For example, the above nonionic surfactant is poly(ethylene glycol) alkyl ethers, polypropylene glycol alkyl ethers, glycoside alkyl ethers, poly(ethylene glycol) octylphenyl ethers, poly(ethylene glycol) alkylphenyl ethers, glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters, sorbitan alkyl esters, cocamide MEA, dodecyldimethylamine oxide, and block copolymers of poly(ethylene glycol) and propylene glycol It may include polyethylene glycol and polypropylene glycol) or polyethoxylated tallow amine.

[0038] In one embodiment, the nonionic surfactant may include polysorbate.

[0039] In one embodiment, the polysorbate may be a polyoxyethylene sorbitan fatty acid ester, a material in which a polyoxyethylene group is added to acyl sorbitan, and a Tween series surfactant.

[0040] In one embodiment, the polysorbate may be a mixture of 1,4-sorbitan with a five-membered ring and a 1,5-sorbitan derivative with a six-membered ring. The polysorbate may include, for example, Tween20, Tween21, Tween40, Tween60, Tween80, or Tween81.

[0041] In one embodiment, the nonionic surfactant may be Tween80.

[0042] In one embodiment, the content of the nonionic surfactant may be 1 to 15 weight percent based on the total weight of the microparticles. Specifically, the content of the nonionic surfactant in the microparticles may be a range selected from the group consisting of a lower limit selected from the group consisting of 1, 1.1, 1.2, 1.3, 1.4, 1.5, and 1.6 weight% based on the total weight of the microparticles, and an upper limit selected from the group consisting of 8, 9, 10, 11, 12, 13, 14, and 15 weight%. For example, the content of the nonionic surfactant in the ursolic acid-containing microparticles of the present application may be 1 to 15 weight%, 1.1 to 14 weight%, 1.2 to 13 weight%, 1.3 to 12 weight%, 1.4 to 11 weight%, 1.5 to 10 weight%, or 1.6 to 8 weight%.

[0043] In one embodiment, the weight ratio of ursolic acid to emulsifier in the microparticles may be 1:0.3 to 1:2.2, and for example, the weight ratio of ursolic acid to emulsifier may be 1:0.31 to 1:2.15, 1:0.32 to 1:2.15, 1:0.33 to 1:2.15, 1:0.34 to 1:2.1, 1:0.35 to 1:2.1, 1:0.36 to 1:2.1, 1:0.37 to 1:2, 1:0.38 to 1:2, 1:0.39 to 1:2, or 1:0.4 to 1:2.

[0044] In one embodiment, the weight ratio of ursolic acid to nonionic surfactant in the microparticles may be 1:0.02 to 1:0.7, and for example, the weight ratio of ursolic acid to nonionic surfactant may be 1:0.025 to 1:0.6, 1:0.03 to 1:0.6, 1:0.033 to 1:0.5, 1:0.035 to 1:0.5, 1:0.037 to 1:0.4, 1:0.039 to 1:0.4, 1:0.039 to 1:0.3, or 1:0.039 to 1:0.2.

[0045] In one embodiment, the weight ratio of ursolic acid, emulsifier, and nonionic surfactant of the microparticles may be 1:0.44 to 2:0.44 to 0.2.

[0046] The microparticles of the present application may further include dietary fiber.

[0047] In one embodiment, the content of the dietary fiber may be 8 to 25 weight% based on the total weight of the microparticles. Specifically, the content of the dietary fiber in the microparticles may be a range selected from the group consisting of a lower limit selected from the group consisting of 8, 9, 10, and 11 weight% based on the total weight of the microparticles, and an upper limit selected from the group consisting of 21, 22, 23, 24, and 25 weight%. For example, the content of the dietary fiber in the ursolic acid-containing microparticles of the present application may be 8 to 25 weight%, 9 to 24 weight%, 10 to 23 weight%, 11 to 22 weight%, or 11 to 21 weight%.

[0048] In one embodiment, the dietary fiber may include soluble dietary fiber or insoluble dietary fiber, and the soluble dietary fiber may include, but is not limited to, indigestible maltodextrin, polydextrose, inulin, pectin, gum, or mucilage, and the insoluble dietary fiber may include, but is not limited to, cellulose, hemicellulose, lignin, or chitin.

[0049] In one embodiment, the dietary fiber may include dietary fiber having an average particle size of a micrometer level or smaller. For example, the dietary fiber may include dietary fiber having an average particle size of 1,000 micrometers (㎛) or less, specifically 500㎛ or less, 100㎛ or less, 10㎛ or less, or 1㎛ or less, but may be used without limitation as long as it is a size suitable for use in the manufacture of the microparticles of the present application.

[0050] The microparticles of the present application may further contain water.

[0051] In one embodiment, the water may include purified water.

[0052] In one embodiment, the microparticles of the present application may comprise ursolic acid, an emulsifier, a nonionic surfactant, and water.

[0053] The microparticles of the present application may be formed by creating a complex of ursolic acid with a water-soluble polymer such as an emulsifier and a nonionic surfactant, and then micronizing the complex.

[0054] In one embodiment, the microparticles may have the structure of a microemulsion.

[0055] The particle size of the microparticles of the present application may be 2 to 7 μm based on the d50 value. Specifically, the ursolic acid-containing microparticles of the present application may be a range selected from the group consisting of a lower limit selected from the group consisting of 2, 2.1, 2.2, 2.3, and 2.4 μm based on the d50 value, and an upper limit selected from the group consisting of 3.5, 4, 5, 6, and 7 μm. For example, the particle size of the ursolic acid-containing microparticles of the present application may be 2 to 7 μm, 2.1 to 6 μm, 2.2 to 5 μm, 2.3 to 4 μm, or 2.4 to 3.5 μm based on the d50 value.

[0056] The particle size of the microparticles of the present application may be 0.5 to 1.5 μm based on the d10 value. Specifically, the ursolic acid-containing microparticles of the present application may have a particle size selected from a group consisting of a lower limit selected from the group consisting of 0.5, 0.6, 0.7, 0.8, and 0.9 μm based on the d10 value, and an upper limit selected from the group consisting of 1, 1.1, 1.2, 1.3, 1.4, and 1.5 μm based on the d10 value. For example, the particle size of the ursolic acid-containing microparticles of the present application may be 0.5 to 1.5 μm, 0.6 to 1.4 μm, 0.7 to 1.3 μm, 0.8 to 1.2 μm, or 0.9 to 1 μm based on the d10 value.

[0057] The particle size of the microparticles of the present application may be 7.5 to 15 μm based on the d90 value. Specifically, the ursolic acid-containing microparticles of the present application may be a range selected from the group consisting of a lower limit selected from the group consisting of 7.5, 7.7, 7.9, 8.1, 8.3, and 8.5 μm based on the d90 value, and an upper limit selected from the group consisting of 11, 12, 13, 14, and 15 μm based on the d90 value. For example, the particle size of the ursolic acid-containing microparticles of the present application may be 7.5 to 15 μm, 7.7 to 14 μm, 7.9 to 13 μm, 8.1 to 12 μm, 8.3 to 11 μm, or 8.5 to 1 μm based on the d90 value.

[0058] By using the ursolic acid-containing microparticles of the present application, the dissolution and dispersion efficiency of ursolic acid can be improved.

[0059] In one embodiment, the ursolic acid-containing microparticles of the present application may be prepared using water as a solvent for ursolic acid.

[0060] As the solvent mentioned above, water may include distilled water.

[0061] As the above solvent, water may be pure water, but a small amount of organic solvent mixed with impurities, etc., may not be excluded.

[0062] The above organic solvent may include C1-C4 lower alcohols such as methanol, ethanol, propyl alcohol, or butyl alcohol; polyalcohols such as glycerin, butylene glycol, or propylene glycol; and hydrocarbon solvents such as methyl acetate, ethyl acetate, acetone, benzene, hexane, diethyl ether, or dichloromethane.

[0063] The above water content may be 90 to 100 parts by weight based on 100 parts by weight of the combined content of water and organic solvent, for example, 95 to 100 parts by weight, 98 to 100 parts by weight, 99 to 100 parts by weight, 99.5 to 100 parts by weight, or 99.9 to 100 parts by weight.

[0064] In one embodiment, the ursolic acid-containing microparticles of the present application may be produced by a manufacturing method comprising: (a) mixing ursolic acid, water, an emulsifier, and a nonionic surfactant; and (b) homogenizing the mixture under high pressure.

[0065] In step (a) above, the ursolic acid can be added to water to prepare an ursolic acid suspension, and the microparticles of the present application can be prepared using the water suspension of the ursolic acid.

[0066] In one embodiment, the ursolic acid-containing microparticles of the present application may be water-dispersible microparticles.

[0067] The specific technical configuration and details of steps (a) and (b) above are identical to those described in the method for manufacturing ursolic acid-containing microparticles, which is another aspect of the present application described below; therefore, they are cited and will not be described redundantly.

[0068]

[0069] Another aspect of the present application provides a method for manufacturing ursolic acid-containing microparticles.

[0070] The method for manufacturing ursolic acid-containing microparticles of the present application comprises: (a) mixing ursolic acid (UA), water, an emulsifier, and a nonionic surfactant; and (b) homogenizing the mixture under high pressure.

[0071] The description of the above ursolic acid, water, emulsifier, nonionic surfactant, and microparticles is the same as that described in microparticles containing ursolic acid, which is one aspect of this application; therefore, it is cited and will not be described again.

[0072] The above step (a) may include a step of mixing ursolic acid and water; and a step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water.

[0073] In the step of mixing the ursolic acid and water, when mixing the ursolic acid and water, the weight ratio of ursolic acid to water may be 1:10 to 1:30, and for example, the weight ratio of ursolic acid to water may be 1:15 to 1:25, 1:17 to 1:23, 1:19 to 1:21, or 1:20.

[0074] The step of mixing the ursolic acid and water above may involve adding ursolic acid to water to prepare a water suspension of ursolic acid.

[0075] In the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, when adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, the weight ratio of ursolic acid to emulsifier may be 1:0.3 to 1:2.2, and for example, the weight ratio of ursolic acid to emulsifier may be 1:0.31 to 1:2.15, 1:0.32 to 1:2.15, 1:0.33 to 1:2.15, 1:0.34 to 1:2.1, 1:0.35 to 1:2.1, 1:0.36 to 1:2.1, 1:0.37 to 1:2, 1:0.38 to 1:2, 1:0.39 to 1:2, or 1:0.4 to 1:2.

[0076] In the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, when adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, the weight ratio of ursolic acid to nonionic surfactant may be 1:0.02 to 1:0.7, and for example, the weight ratio of ursolic acid to nonionic surfactant may be 1:0.025 to 1:0.6, 1:0.03 to 1:0.6, 1:0.033 to 1:0.5, 1:0.035 to 1:0.5, 1:0.037 to 1:0.4, 1:0.039 to 1:0.4, 1:0.039 to 1:0.3, or 1:0.039 to 1:0.2.

[0077] The step of mixing the ursolic acid and water may include a step of homogenizing the ursolic acid and water.

[0078] The step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water may include the step of homogenizing the mixture of ursolic acid, water, emulsifier, and nonionic surfactant.

[0079] The above homogenization may mean dispersing each component of a heterogeneous mixture into fine particles or molecules to make the whole homogeneous. The above homogenization may be performed using means or equipment that a person skilled in the art can adopt for homogenization, for example, using a high-speed agitator, a colloid mill, an ultrasonicator, etc.

[0080] In one embodiment, step (a) may include adding ursolic acid to water and mixing, homogenizing the ursolic acid and water, adding the emulsifier and nonionic surfactant to the mixture of ursolic acid and water (ursolic acid suspension), and homogenizing the mixture of ursolic acid, water, emulsifier, and nonionic surfactant. Specifically, step (a) may include adding ursolic acid to water and homogenizing it with a homogenizer at 5,000 rpm, adding the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, and homogenizing the mixture of ursolic acid, water, emulsifier, and nonionic surfactant by grinding it with a homogenizer at 5,000 rpm.

[0081] In one embodiment, step (a) may be to mix the ursolic acid into the microparticles in an amount of 15 to 45 weight percent based on the total weight of the microparticles.

[0082] In one embodiment, step (a) may involve mixing the emulsifier into the microparticles in an amount of 10 to 55 weight percent based on the total weight of the microparticles.

[0083] In one embodiment, step (a) may involve mixing the nonionic surfactant into the microparticles in an amount of 1 to 15 weight percent based on the total weight of the microparticles.

[0084] Step (b) above may involve high-pressure homogenizing the mixture of ursolic acid, water, emulsifier, and nonionic surfactant, and specifically may include forming the mixture into microparticles through high-pressure homogenization.

[0085] The above high-pressure homogenization may mean homogenizing under high pressure conditions, and the above high-pressure homogenization may be performed using means or equipment that a person of ordinary skill in the art can adopt for high-pressure homogenization, for example, it may be performed using a High Pressure Homogenizer (HPH).

[0086] In one embodiment, high-pressure homogenization using the high-pressure homogenizer may be achieved by passing the mixture through the high-pressure homogenizer 1 to 5 times at a passing pressure of 400 to 1000 bar to micronize it.

[0087] In one embodiment, the mixture of ursolic acid, water, emulsifier, and nonionic surfactant can be high-pressure homogenized by passing it through a high-pressure homogenizer 1 to 4 times at 400 to 600 bar.

[0088] In one embodiment, the mixture of ursolic acid, water, emulsifier, and nonionic surfactant can be high-pressure homogenized by passing it through a high-pressure homogenizer 1 to 4 times at 700 to 900 bar.

[0089]

[0090] Another aspect of the present application provides a method to improve the solubility of ursolic acid.

[0091] The method for improving the solubility of ursolic acid according to the present application comprises: (a) mixing ursolic acid (UA), water, an emulsifier, and a nonionic surfactant; and (b) homogenizing the mixture under high pressure.

[0092] The description of steps (a) and (b) in the method for improving the solubility of ursolic acid is identical to that described in the method for preparing ursolic acid-containing microparticles, which is another aspect of this application; therefore, it is cited and not repeated.

[0093]

[0094] In this application, the solubility and dispersibility of sparingly soluble ursolic acid are improved by forming a complex of ursolic acid, an emulsifier, and a nonionic surfactant and micronizing it. Since water is used as a solvent for ursolic acid in the process of improving its solubility and dispersibility, it is easy to utilize ursolic acid as a nutritional material.

[0095] However, the effects of the present application are not limited to those mentioned above, and other unmentioned effects will be clearly understood by those skilled in the art from the description below.

[0096]

[0097] Figure 1 is a schematic diagram showing the manufacturing process of ursolic acid-containing microparticles.

[0098]

[0099] The present application will be explained in detail below through examples.

[0100] However, the following examples are intended to specifically illustrate the present application, and the content of the present application is not limited by the following examples.

[0101]

[0102] [Preparation Example] Preparation of ursolic acid-containing microparticles

[0103] According to the content listed in Table 1 below, ursolic acid (UA, 50 wt% purity, containing 25% dietary fiber, Kemin), lecithin (Lecithin, 100% purity, Cargill), and Tween80 (Tween80, Daejeong Hwakum, Chemical Pure, moisture 3% or less) were mixed to prepare ursolic acid microparticles of Examples 1 to 3 and Comparative Examples 1 to 2. Comparative Example 1 was prepared using only ursolic acid without the addition of lecithin and Tween80, Comparative Example 2 was prepared using only lecithin and ursolic acid without the addition of Tween80, and Examples 1 to 3 were prepared with different amounts of lecithin and Tween80. Specifically, 20 g of ursolic acid (50% purity, Kemin) was added to 200 mL of water and ground using a homogenizer (5000 rpm) to prepare a mixture of ursolic acid and water (ursolic acid suspension). 4.0 g of soybean lecithin (100% purity, Cargill) and 2 g of Tween80 were added to the ursolic acid suspension and ground using a homogenizer (HG-15D, Daehan Science, 5000 rpm). Subsequently, in order to homogenize the mixture of the ground ursolic acid, lecithin, and Tween 80 and form it into micro-sized particles, ursolic acid microparticles were prepared by high-pressure homogenization of the mixture by passing it through a High Pressure Homogenizer (HPH, Bertoli ATOMO) three times at 500 bar. The prepared ursolic acid microparticles were dried for 12 hours in a temperature range of 60 to 70 °C, and then ground using a Co-Mill to obtain final ursolic acid microparticles. The ursolic acid content in the dried and ground final ursolic acid microparticles is as follows: The ursolic acid microparticles of Example 1 contain approximately 23% ursolic acid based on the total weight of the microparticles.It contains 81% by weight, and the ursolic acid microparticles of Example 2 contain about 37.88% by weight of ursolic acid based on the total weight of the microparticles, and the ursolic acid microparticles of Example 3 contain about 40.32% by weight of ursolic acid based on the total weight of the microparticles.

[0104] Weight (g) Comparative Example 1 Comparative Example 2 Example 1 Example 2 Example 3 UA (50 wt% purity) 20.0 20.0 20.0 20.0 20.0 Lecithin (100% purity) 0.0 4.4 20.0 4.4 4.4 Tween 800.0 0.0 2.0 2.0 0.4 DW 200.0 200.0 200.0 200.0 200.0

[0105]

[0106] [Experimental Example 1] Analysis of Physical Properties of Ursolic Acid Microparticles

[0107] The particle size of the ursolic acid microparticles prepared in the above preparation examples was analyzed. Specifically, the particle size of the microparticles was measured using particle size analysis - laser diffraction methods, with water as the analysis solvent and a wet particle size analyzer (LS 13 320, Beckman Coulter) used for measurement. As a result, as shown in Table 2 below, it was confirmed that the particle size of the ursolic acid microparticles of Examples 1 to 3 was reduced by 58 to 62% compared to the particles of Comparative Example 1, which were prepared using only ursolic acid without the addition of lecithin and Tween 80.

[0108] Comparative Example 1 Comparative Example 2 Example 1 Example 2 Example 3 Particle Size (μm) d 10 2.2 0.9 0.9 0.9 d 5 0 8.1 3.0 3.1 3.0 3.4 d 9 0 3 3.2 8.7 8.9 8.6 10.3

[0109]

[0110] [Experimental Example 2] Solubility Analysis of Ursolic Acid Microparticles

[0111] The solubility of ursolic acid microparticles according to Comparative Examples 1 and 2 and Examples 1 to 3 prepared in the above preparation examples was analyzed. Specifically, the ursolic acid microparticles (containing 450 mg of ursolic acid) of Comparative Examples 1 and 2 and Examples 1 to 3 were suspended in 200 mL of a fasting small intestinal fluid simulation solution (FaSSIF pH 6.5, BioLlevant), stirred at 25°C for 0.5 to 2 hours, and then the undissolved solids were disintegrated. After stirring, the supernatant was filtered through a hydrophilic 0.2 μm PTFA filter, and the concentration (g / L) of the filtered ursolic acid was measured by high performance liquid chromatography (HPLC).

[0112] As a result, as shown in Table 3, when the ursolic acid raw material of Comparative Example 1 was dissolved in a small intestine fluid simulation, it was impossible to measure the concentration of ursolic acid, whereas when the ursolic acid microparticles of Examples 1 to 3 were dissolved in the small intestine fluid simulation, it was confirmed that ursolic acid of about 0.01 to 0.054 g / L was detected. In addition, it was found that when using the ursolic acid microparticles of Examples 1 to 3, the solubility of ursolic acid increased by about 1.4 to 5.4 times compared to the ursolic acid microparticles of Comparative Example 2 to which only lecithin was added.

[0113] FaSSIF Test Comparative Example 1 Comparative Example 2 Example 1 Example 2 Example 3 UA Concentration (g / L) 0.5 hr N.D 0.00 7 0.03 3 0.01 5 0.01 11 hr N.D 0.00 9 0.04 0 0.02 3 0.01 7

[0114]

[0115] [Experimental Example 3] Analysis of the characteristics of ursolic acid microparticles according to high-pressure homogenization conditions

[0116] When preparing ursolic acid microparticles in the same manner as the above preparation example, changes in particle size and solubility of the ursolic acid microparticles were analyzed according to the use of a High Pressure Homogenizer (HPH; Bertoli ATOMO) and the number of repetitions of homogenizer treatment. Specifically, ursolic acid microparticles were prepared as in the above preparation example, but in Examples 3-1 and 3-2, a High Pressure Homogenizer (HPH) was not used. That is, Example 3-1 is the ursolic acid raw material powder itself, and Example 3-2 is a mixture of ursolic acid, lecithin, and Tween80 mixed in the ratio of raw material components of Example 1. Examples 3-3 to 3-6 were prepared using a mixture of ursolic acid, lecithin, and Tween80 mixed in the ratio of raw materials of Example 1, Example 3-3 used a high-pressure homogenizer once, Example 3-4 used a high-pressure homogenizer twice, Example 3-5 used a high-pressure homogenizer three times, and Example 3-6 used a high-pressure homogenizer four times.

[0117] 3-1. Physical Properties of Ursolic Acid Microparticles

[0118] For the above Examples 3-1 to 3-6, the particle size was measured using a wet particle size analyzer in the same manner as in Experimental Example 1.

[0119] As a result, as shown in Table 4 below, it was confirmed that the particle size of the ursolic acid microparticles of Examples 3-3 to 3-6 using HPH was reduced by about 57 to 68% compared to the simple mixture of Example 3-2 without HPH. Meanwhile, it was confirmed that the change in particle size according to the number of HPH treatments was not significant.

[0120] HPH Usage HPH Not Used HPH Used HPH Number of HPH Repetitions -1 2 3 4 Samples Example 3-1 Example 3-2 Example 3-3 Example 3-4 Example 3-5 Example 3-6 Particle size (μm) d 10 2.2 1.3 0.8 0.8 0.9 0.6 d 5 0 8.1 7.4 3.2 2.8 3.0 2.4 d 9 0 3.2 3.8 5 9.9 8.3 8.6 7.3

[0121] 3-2. Solubility of Ursolic Acid Microparticles

[0122] For the above Examples 3-1 to 3-6, solubility was measured in the same manner as in Experimental Example 2.

[0123] As a result, as shown in Table 5, when Examples 3-1 and 3-2, which did not use HPH, were dissolved, no ursolic acid was detected, confirming that ursolic acid was not dissolved. On the other hand, when the ursolic acid microparticles of Examples 3-3 to 3-6 were dissolved, the concentration of ursolic acid was found to be 0.062 to 0.072 g / L, indicating that the ursolic acid microparticles prepared using HPH could improve the solubility of ursolic acid by approximately 12 to 14 times compared to Examples 3-1 and 3-2, which did not use HPH. Meanwhile, no difference in the solubility of ursolic acid was observed depending on the number of HPH repetitions.

[0124] HPH Usage HPH Not Used HPH Used HPH Number of Repetitions -1 2 3 4 Samples Example 3-1 Example 3-2 Example 3-3 Example 3-4 Example 3-5 Example 3-6 FaSSIF testUA Concentration (g / L) 0.5 hr N.DN.D 0.046 0.050 0.042 0.0531.0 hr N.DN.D 0.054 0.058 0.051 0.0632.0 hr N.D 0.005 0.068 0.07 0.062 0.072

[0125]

[0126] Although the present application has been described in detail above only with respect to the described embodiments, it is obvious to those skilled in the art that various modifications and variations are possible within the scope of the technical spirit of the present application, and it is natural that such modifications and variations fall within the scope of the appended claims.

Claims

1. Microparticles comprising ursolic acid (UA), an emulsifier, and a nonionic surfactant, Microparticles having a particle size of 2 to 7 μm based on the d50 value.

2. In Claim 1, The above emulsifier is a microparticle containing glycerophospholipid.

3. In Claim 2, The above glycerophospholipid is a microparticle containing lecithin.

4. In Claim 1, The above nonionic surfactant is a microparticle containing polysorbate.

5. In Claim 1, Microparticles having a particle size of 0.5 to 1.5 μm based on the d10 value.

6. In Claim 1, The above microparticles have a particle size of 7.5 to 15 μm based on the d90 value.

7. In Claim 1, The microparticles are microparticles containing ursolic acid in an amount of 15 to 45 weight percent based on the total weight of the microparticles.

8. In Claim 1, Microparticles having a weight ratio of ursolic acid to emulsifier of 1:0.3 to 1:2.

2.

9. In Claim 1, Microparticles having a weight ratio of ursolic acid to a nonionic surfactant of 1:0.02 to 1:0.

7.

10. In Claim 1, The above microparticles further contain dietary fiber, and The microparticles are microparticles containing dietary fiber in an amount of 8 to 25 weight percent based on the total weight of the microparticles.

11. In Claim 1, The above microparticles are water-dispersible microparticles.

12. In Claim 1, The above microparticles are microparticles prepared using water or a mixture of water and an organic solvent as a solvent for ursolic acid.

13. In Claim 12, The above microparticles are produced by (a) mixing ursolic acid (UA), water, an emulsifier, and a nonionic surfactant; and (b) Microparticles produced by a method comprising the step of high-pressure homogenizing the above mixture.

14. A method for preparing ursolic acid-containing microparticles comprising the following steps: (a) mixing ursolic acid (UA), water, an emulsifier, and a nonionic surfactant; and (b) A step of high-pressure homogenizing the above mixture.

15. In Claim 14, The above step (a) is A step of mixing ursolic acid and water; and A method for preparing ursolic acid-containing microparticles, comprising the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water.

16. In Claim 15, A method for manufacturing ursolic acid-containing microparticles, comprising the step of mixing ursolic acid and water, a step of homogenizing ursolic acid and water.

17. In Claim 15, A method for preparing ursolic acid-containing microparticles, comprising the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, and the step of homogenizing the mixture of ursolic acid, water, emulsifier, and nonionic surfactant.

18. In Claim 15, A method for preparing ursolic acid-containing microparticles, wherein, in the step of mixing the ursolic acid and water, the weight ratio of ursolic acid to water when mixing the ursolic acid and water is 1:10 to 1:

30.

19. In Claim 15, A method for preparing ursolic acid-containing microparticles, wherein, in the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, the weight ratio of ursolic acid to emulsifier is 1:0.3 to 1:2.2 when the emulsifier and nonionic surfactant are added and mixed to the mixture of ursolic acid and water.

20. In Claim 15, A method for preparing ursolic acid-containing microparticles, wherein, in the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, the weight ratio of ursolic acid to nonionic surfactant is 1:0.02 to 1:0.7 when the emulsifier and nonionic surfactant are added and mixed to the mixture of ursolic acid and water.

21. In Claim 14, A method for manufacturing ursolic acid-containing microparticles, wherein the high-pressure homogenization step described above utilizes a High Pressure Homogenizer (HPH).

22. A method for improving the solubility of ursolic acid comprising the following steps: (a) mixing ursolic acid (UA), water, an emulsifier, and a nonionic surfactant; and (b) A step of high-pressure homogenizing the above mixture.

23. In Claim 22, The above step (a) is A step of mixing ursolic acid and water; and A method for improving the solubility of ursolic acid, comprising the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water.

24. In Claim 23, A method for improving the solubility of ursolic acid, comprising the step of mixing ursolic acid and water, and the step of homogenizing ursolic acid and water.

25. In Claim 23, A method for improving the solubility of ursolic acid, comprising the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, and the step of homogenizing the mixture of ursolic acid, water, emulsifier, and nonionic surfactant.

26. In Claim 23, A method for improving the solubility of ursolic acid, wherein in the step of mixing the ursolic acid and water, when mixing the ursolic acid and water, the weight ratio of ursolic acid to water is 1:10 to 1:

30.

27. In Claim 23, A method for improving the solubility of ursolic acid, wherein, in the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, the weight ratio of ursolic acid to emulsifier is 1:0.3 to 1:2.2 when adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water.

28. In Claim 23, A method for improving the solubility of ursolic acid, wherein, in the step of adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water, the weight ratio of ursolic acid to nonionic surfactant is 1:0.02 to 1:0.7 when adding and mixing the emulsifier and nonionic surfactant to the mixture of ursolic acid and water.

29. In Claim 22, A method for improving the solubility of ursolic acid, wherein the high-pressure homogenization step described above utilizes a High Pressure Homogenizer (HPH).

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