Poorly soluble active ingredient delivery systems containing transporters

Abstract

This specification relates to a delivery system for poorly soluble active ingredients. This disclosure includes a transfersome, thereby enabling the inclusion of poorly soluble active ingredients in high concentrations and stabilizing the ingredients. Furthermore, the delivery system of this disclosure has a small particle size, thus facilitating the in vivo delivery of the poorly soluble active ingredient. Therefore, cosmetic or pharmaceutical compositions containing the delivery system of this disclosure can significantly enhance the efficacy of the active ingredient.

Description

Technical Field

[0001] This specification relates to a delivery system capable of stabilizing poorly soluble active ingredients. Background Technology

[0002] In the cosmetics and pharmaceutical industries, when topical skin formulations contain active ingredients that are difficult to penetrate the stratum corneum, synthetic surfactants are used to promote the skin absorption of these ingredients. Alternatively, methods such as utilizing synthetic polymer nanoparticles like polyethylene glycol or liposomes containing amphiphilic compounds and cholesterol as a co-stabilizing agent are widely employed to improve the skin penetration of the active ingredients. However, when used with poorly soluble active ingredients such as phytosterols, the active ingredients precipitate out upon initial preparation, making them difficult to stabilize. Therefore, it is necessary to develop delivery systems that can effectively stabilize poorly soluble active ingredients.

[0003] [Existing Technical Documents]

[0004] [Patent Documents]

[0005] (Patent Document 1) Republic of Korea Patent Publication No. 10-0648535 Summary of the Invention

[0006] Technical issues

[0007] On the one hand, the problem that this disclosure aims to solve is to provide a delivery system that can stabilize poorly soluble active ingredients and promote their absorption in the body.

[0008] On the one hand, the problem that this disclosure aims to solve is to provide a composition comprising a delivery system capable of stabilizing poorly soluble active ingredients and promoting their absorption in vivo.

[0009] Technical solution

[0010] On one hand, this disclosure provides a poorly soluble active ingredient delivery system, which includes a transfersome comprising a bilayer structure containing a phospholipid and a single-chain nonionic surfactant, wherein the phospholipid is a saturated phospholipid, and the hydrophobic tail of the phospholipid and the hydrophobic tail of the single-chain nonionic surfactant have different numbers of carbon atoms.

[0011] In one aspect, this disclosure provides a composition comprising a poorly soluble active ingredient and a carrier of the poorly soluble active ingredient.

[0012] Invention Effects

[0013] On one hand, this disclosure provides a delivery system for poorly soluble active ingredients. According to one embodiment of this disclosure, the delivery system can stabilize poorly soluble active ingredients at high concentrations and has a particle size approximately 10 times smaller than that of liposomes. Therefore, using the delivery system of this disclosure can promote the in vivo absorption of poorly soluble active ingredients. Thus, cosmetic or pharmaceutical compositions including the poorly soluble active ingredient delivery system of this disclosure can significantly enhance the efficacy of the active ingredients. Attached Figure Description

[0014] Figure 1 This is a diagram that schematically illustrates the morphology of liposomes as a comparative example of this disclosure;

[0015] Figure 2 This is a diagram schematically illustrating the spherical shape of a transporter according to an embodiment of the present disclosure;

[0016] Figure 3 This is a schematic diagram illustrating the discoidal shape of a transporter according to an embodiment of the present disclosure;

[0017] Figure 4 This is a graph showing the particle size distribution of liposomes as a comparative example of this disclosure, with the main peak shown at a size of 155 nm;

[0018] Figure 5 This is a graph showing the particle size distribution of a spherical transporter as an embodiment of the present disclosure, with the main peak shown at a size of 9.5 nm;

[0019] Figure 6 This is a graph showing the efficacy satisfaction evaluation results of Preparation Example 1 according to an embodiment of the present disclosure;

[0020] Figure 7 This is a graph illustrating the efficacy and effect evaluation results of Preparation Example 2 according to an embodiment of the present disclosure;

[0021] Figure 8 This is a graph showing the additional evaluation results of the effects of Preparation Example 2 according to an embodiment of the present disclosure. Detailed Implementation

[0022] The embodiments of this application are described in more detail below with reference to the accompanying drawings. However, the technology disclosed in this application is not limited to the embodiments described herein and can be embodied in other forms. The embodiments described herein are provided to ensure a thorough and complete disclosure and to fully convey the concept of this application to those skilled in the art. In the drawings, the width or thickness of the constituent elements is shown at a slightly enlarged scale to clearly illustrate each constituent element. Furthermore, for ease of explanation, only a portion of the constituent elements is shown; however, those skilled in the art can easily grasp the remaining portions. Those with conventional knowledge in the art can implement the concept of this application in various different forms without departing from the scope of the technical concept of this application.

[0023] In this specification, unless otherwise explicitly defined in the context, singular expressions include plural expressions. In this application, terms such as "comprising," "containing," or "having" are used to specify the presence of features, figures, steps, operations, components, or compositions thereof described in the specification, and do not preclude the presence or additional possibilities of one or more other features or figures, steps, operations, components, or compositions thereof.

[0024] One embodiment of this disclosure provides a poorly soluble active ingredient delivery system comprising a transfersome.

[0025] Specifically, this disclosure provides a poorly soluble active ingredient delivery system, which includes a transporter comprising a bilayer structure containing phospholipids and a single-chain nonionic surfactant. The phospholipids are saturated phospholipids, and the hydrophobic tails of the phospholipids and the single-chain nonionic surfactants have different numbers of carbon atoms.

[0026] In this specification, the term "hydrophobic tail" refers to the major tail of a phospholipid or single-chain nonionic surfactant, where the major tail indicates the major fatty acid in the tail of the phospholipid or single-chain nonionic surfactant.

[0027] In this specification, the term "transfersome" refers to a structure comprising two or more amphiphilic substances having a hydrophilic head and a hydrophobic tail, wherein each hydrophobic tail of the two or more amphiphilic substances comprises a bilayer structure arranged in a regular or irregular cross pattern. The transfersome may possess various properties depending on the type, size, and preparation method of the amphiphilic substances it contains.

[0028] Accompanying Figures 1 to 3 Each of these liposomes is shown as a delivery system for existing active ingredients. Figure 1 ) and the transporter disclosed herein ( Figure 2 as well as Figure 3 An exemplary form of ). (See reference) Figure 1 as well as Figure 2 In summary, both liposomes and transporters share the ability to capture hydrophilic substances within the hydrophilic region of the central part of each structure and to capture poorly soluble substances within the space of the bilayer structure. However, liposomes, being bilayer structures composed of phospholipids as double-chain amphiphilic substances, have very little space within the bilayer structure to capture hydrophobic substances. In contrast, the transporter according to an embodiment of this disclosure, comprising two or more amphiphilic substances, including phospholipids with hydrophobic tails having different carbon numbers and single-chain nonionic surfactants arranged in a regular or irregular cross-linking manner, forms a bilayer structure. Therefore, due to the difference in length of the hydrophobic tails and the single chain of the nonionic surfactant, sufficient space can be formed within the bilayer structure to capture poorly soluble substances in high quantities.

[0029] In this specification, the term "insoluble substance" refers to a substance with low solubility in water; for example, the insoluble substance may be an oil-soluble, hydrophobic, or water-insoluble substance. In this specification, the term "functional substance" refers to a substance that has beneficial effects on the skin or body. Specifically, as a poorly soluble active ingredient according to an embodiment of the present disclosure, any substance that can be captured within the bilayer structure of the transporter according to an embodiment of the present disclosure may be included without limitation, for example, it may include one or more selected from the group consisting of phytosterol, phytosphingosine, salicyloyl phytosphingosine, thymol trimethoxycinnamate, ceramide NP, ceramide NS, ceramide AS, ceramide AP, ceramide EOP, hydroxypropyl bislauramide MEA, hydroxypropyl bispalmitamide MEA, asiaticoside, asiatic acid, madecassic acid, and ferulic acid. For example, phytosterols, also known as β-sitosterol, are effective substances used as allergy sedatives, but they have a melting point of 140°C and are poorly soluble, thus precipitating easily when contained in conventional compositions or existing liposome-based delivery systems. However, when captured by a delivery system according to an embodiment of this disclosure, even with a high content of phytosterols, it can be provided as a dosage form with excellent stability.

[0030] As an embodiment, the difference in the number of carbon atoms between the hydrophobic tail of the phospholipid contained in the transporter and the hydrophobic tail of the single-chain nonionic surfactant is not limited depending on the type of phospholipid and single-chain nonionic surfactant contained in the transporter, including all cases where the number of carbon atoms in the hydrophobic tail of the phospholipid, i.e., the length of the hydrophobic tail of the phospholipid is longer or shorter than that of the hydrophobic tail of the single-chain nonionic surfactant. For example, the difference in the number of carbon atoms between the hydrophobic tail of the phospholipid and the hydrophobic tail of the single-chain nonionic surfactant can be 3 or more. More specifically, the difference in the number of carbon atoms between the hydrophobic tail of the phospholipid and the hydrophobic tail of the single-chain nonionic surfactant can be 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more. More specifically, the difference in the number of carbon atoms between the hydrophobic tail of the phospholipid and the hydrophobic tail of the single-chain nonionic surfactant can be less than 13, 12, 11, 10, 9, or 8. If the difference in the number of carbon atoms is less than 3, the difference in length between the hydrophobic tail of the phospholipid and the hydrophobic tail of the single-chain nonionic surfactant is not significant, resulting in a low capture rate of poorly soluble active ingredients. If the difference in the number of carbon atoms exceeds 13, the particle size of the transporter increases or no transporter is formed, thereby reducing skin absorption and decreasing the capture rate or stability of the active ingredients.

[0031] As an example, the phospholipid is not limited in type as long as it is an amphiphilic saturated phospholipid having a hydrophilic head and a hydrophobic tail. As an example, the carbon atom length of the hydrophobic tail of the phospholipid can be from 10 to 26. Specifically, the carbon atom length of the hydrophobic tail of the single-chain nonionic surfactant can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26. Specifically, the phospholipid can include one or more selected from the group consisting of hydrogenated lecithin, hydrogenated phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, and phosphatidylglycerol. Wherein, "hydrogenated lecithin" refers to a hydrogenated form of lecithin, and "hydrogenated phosphatidylcholine" refers to a hydrogenated form of phosphatidylcholine. As one embodiment, the poorly soluble active ingredient delivery system may contain 0.01 to 50% by weight of the phospholipids relative to the total weight of the delivery system. As one embodiment, the poorly soluble active ingredient delivery system may contain 0.01% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, or 45% or more of the phospholipids relative to the total weight of the delivery system. As an example, the poorly soluble active ingredient carrier may contain 50% by weight or less, 45% by weight or less, 40% by weight or less, 35% by weight or less, 30% by weight or less, 25% by weight or less, 20% by weight or less, 15% by weight or less, 10% by weight or less, 5% by weight or less, 1% by weight or less, or 0.1% by weight or less of the phospholipid relative to the total weight of the carrier. When the content of the phospholipid in the carrier is less than 0.01% by weight, it is difficult to form a transport carrier by combining it with a single-chain nonionic surfactant. When it exceeds 50% by weight, problems such as hindering the formation of the transport carrier, increased cost, hindering the user experience, reducing skin absorption, reducing the capture rate of the active ingredient, and stability may occur.

[0032] As one embodiment, the type of single-chain nonionic surfactant is not limited as long as it can form a transporter with the phospholipid. For example, it may include one or more species selected from the group consisting of PPGs, PEGs, polysorbates, polyglycerols, sugars, and biosurfactants. As one embodiment, the number of carbon atoms in the hydrophobic tail of the single-chain nonionic surfactant can be from 8 to 30. Specifically, the number of carbon atoms in the hydrophobic tail of the single-chain nonionic surfactant can be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. More specifically, the single-chain nonionic surfactant may include, selected from PPG-13-decyltetradeceth-24, PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, polysorbate 20, PPG polyglyceryl-6 caprylate, polyglyceryl-10 stearate, polyglyceryl-10 laurate, isotrideceth-9, sucrose stearate, sodium surfactin, nonadecanoyl nitrilotriacetic acid, and arachidonicyl nitrilotriacetic acid. It is composed of one or more of the group consisting of triacetic acid, pentadecanoyl nitrilotriacetic acid, and pentadecanodiynoyl nitrilotriacetic acid. As an example, the poorly soluble active ingredient delivery system may contain 0.01 to 95% by weight of the single-chain nonionic surfactant relative to the total weight of the delivery system.As one embodiment, the poorly soluble active ingredient delivery system may contain, relative to the total weight of the delivery system, 0.01% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, or 90% or more of the single-chain nonionic surfactant. As another embodiment, the poorly soluble active ingredient delivery system may contain, relative to the total weight of the delivery system, less than 95% or less, less than 90% or less, less than 85% or less, less than 80% or less, less than 75% or less, less than 70% or less, less than 65% or less, less than 60% or less, less than 55% or less, less than 50% or less, less than 45% or less, less than 40% or less, less than 35% or less, less than 30% or less of the single-chain nonionic surfactant. When the content of the single-chain nonionic surfactant in the transporter is less than 0.01% by weight, it is difficult to form a transporter by combining with phospholipids with double chains. When it exceeds 95% by weight, problems such as hindering the formation of the transporter, increased cost, hindering the user experience, reducing skin absorption, reducing the capture rate of active ingredients, and stability may occur.

[0033] As an example, the weight ratio of the phospholipid to the single-chain nonionic surfactant can be 1:1 or higher. For example, the weight ratio of the phospholipid to the single-chain nonionic surfactant can be 1:1 or higher, 1:2 or higher, 1:3 or higher, 1:4 or higher, 1:5 or higher, 1:6 or higher, 1:7 or higher, 1:8 or higher, 1:9 or higher, 1:10 or higher, 1:11 or higher, 1:12 or higher, 1:13 or higher, 1:14 or higher, 1:15 or higher, 1:16 or higher, 11:17 or higher, 1:18 or higher, or 1:19 or higher. Additionally, for example, the weight ratio of the phospholipids to the single-chain nonionic surfactant can be less than 1:20, less than 1:19, less than 1:18, less than 1:17, less than 1:16, less than 1:15, less than 1:14, less than 1:13, less than 1:12, less than 1:11, less than 1:10, less than 1:9, less than 1:8, less than 1:7, less than 1:6, less than 1:5, less than 1:4, less than 1:3, or less than 1:2. More specifically, the weight ratio of the phospholipids to the single-chain nonionic surfactant can be from 1:1 to 20. When this range is exceeded, a transporter cannot be formed, thereby reducing the capture rate of the active ingredient or decreasing its stability.

[0034] As one embodiment, the poorly soluble active ingredient delivery system may include a transporter comprising a bilayer structure containing phospholipids and two or more single-chain nonionic surfactants. For example, the poorly soluble active ingredient delivery system may include two, three, four, or more single-chain nonionic surfactants. In this case, as an embodiment, the hydrophobic tails of one or more of the two or more single-chain nonionic surfactants may have different numbers of carbon atoms than the hydrophobic tails of the phospholipids.

[0035] Furthermore, as an embodiment, the two or more single-chain nonionic surfactants can be substances with different HLB (hydrophile-lipophile-balance) values. For example, the difference in HLB values ​​between the two or more single-chain nonionic surfactants can be 1.5 or more. If the difference in HLB values ​​between the two or more single-chain nonionic surfactants is less than 1.5, the difference in insoluble capture rate based on the HLB difference is weak. Specifically, the difference in HLB values ​​between the two or more single-chain nonionic surfactants can be from 1.5 to 18. More specifically, the difference in HLB values ​​between the two or more single-chain nonionic surfactants can be 1.5 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, or 17 or more. More specifically, the difference in HLB values ​​between the two or more single-chain nonionic surfactants can be less than 18, less than 17, less than 16, less than 15, less than 14, less than 13, less than 12, less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, or less than 2.

[0036] Furthermore, as an embodiment, the two or more single-chain nonionic surfactants can have different structures from each other. For example, the structure of the single-chain nonionic surfactant can be linear, nonlinear, branched, or cyclic.

[0037] As one embodiment, the particle shape of the poorly soluble active ingredient delivery system is not limited and can include all types of particles as long as they form a bilayer structure comprising phospholipids and single-chain nonionic surfactants. For example, the particle shape of the poorly soluble active ingredient delivery system can be spherical, disc-shaped, concave spherical, cylindrical, etc.

[0038] As one embodiment, the particle size of the poorly soluble active ingredient delivery body can be from 5 to 20 nm, but is not limited to this. In this specification, particle size refers to the size (nm) of the peak when the number of observations based on size is used as a benchmark. Specifically, the particle size represents the maximum diameter of the particle, and represents the size of at least 90% or more of the delivery body particles distributed in the structure, delivery body, or composition. Specifically, the delivery body particle size can represent the maximum diameter of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the delivery bodies contained in the composition. Additionally, as one embodiment, the particles of the poorly soluble active ingredient delivery body can have a uniform size. Specifically, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the poorly soluble active ingredient delivery system contained in the composition may have a particle size of 5 to 20 nm. Specifically, the particle size of the delivery system may be 5 nm or larger, 6 nm or larger, 7 nm or larger, 8 nm or larger, 9 nm or larger, 10 nm or larger, 11 nm or larger, 12 nm or larger, 13 nm or larger, 14 nm or larger, 15 nm or larger, 16 nm or larger, 17 nm or larger, 18 nm or larger, or 19 nm or larger. Specifically, the particle size of the delivery system may be less than 20 nm, less than 19 nm, less than 18 nm, less than 17 nm, less than 16 nm, less than 15 nm, less than 14 nm, less than 13 nm, less than 12 nm, less than 11 nm, less than 10 nm, less than 9 nm, less than 8 nm, less than 7 nm, or less than 6 nm. According to one embodiment of the present disclosure, the poorly soluble active ingredient delivery system has a particle size that is more than 10 times smaller than that of existing liposomes, and therefore can be absorbed more effectively when applied to the skin.

[0039] As one embodiment, the delivery system may further include oil within the bilayer structure. As another embodiment, the oil can more stabilize the poorly soluble active ingredient within the bilayer structure. The type of oil is not limited; any oil conventionally used in this art can be used. For example, the oil may be compatible with nonionic surfactants, specifically, it may include one or more hydrocarbon oils and silicone oils. More specifically, the oil may include one or more selected from the group consisting of squalane, caprylic / capric triglyceride, cetyl ethylhexanoate, dibutyl adipate, neoopentyl glycol diheptanoate, butylene glycol dicaprylate / dicaprate, phenyl trimethicone, methyl trimethicone, cyclopentasiloxane, cyclohexasiloxane, caprylyl methicone, dimethicone, and trisiloxane. As an embodiment, the oil may contain 0.001 to 25% by weight relative to the total weight of the transporter. Specifically, the oil may contain 0.001% or more by weight, 0.01% or more by weight, 0.05% or more by weight, 0.1% or more by weight, 0.5% or more by weight, 1% or more by weight, 5% or more by weight, 10% or more by weight, 15% or more by weight, or 20% or more by weight. Specifically, the oil may contain less than 25% by weight, less than 20% by weight, less than 15% by weight, less than 10% by weight, less than 5% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.1% by weight, or less than 0.05% by weight. When the oil contains more than 25% by weight, it may hinder the formation of transporters or increase particle size, turbidity, or reduce stability.

[0040] According to one embodiment of this disclosure, the poorly soluble active ingredient delivery system has excellent capture rate of poorly soluble active ingredients and small particle size, thereby effectively stabilizing high content of poorly soluble active ingredients without precipitation or gelling.

[0041] As an example, this disclosure may provide a composition comprising the above-described poorly soluble active ingredient delivery system and the poorly soluble active ingredient.

[0042] Another embodiment may provide a transporter for a poorly soluble active ingredient in the preparation of a composition comprising a poorly soluble active ingredient, the use of said transporter. Another embodiment may provide a method for in vivo delivery of a poorly soluble active ingredient, the method comprising the step of capturing an effective amount of the poorly soluble active ingredient in a transporter including said transporter. Another embodiment may provide providing said transporter to a composition comprising a poorly soluble active ingredient, said transporter serving as a transporter for promoting in vivo delivery of the poorly soluble active ingredient. Additionally, a transporter for a poorly soluble active ingredient may be provided, the use of said transporter.

[0043] As one embodiment, the poorly soluble active ingredient may be present in an amount of 0.001% to 10% by weight relative to the total weight of the composition. When the content is less than 0.001% by weight, the expected efficacy of the poorly soluble active ingredient may not be sufficiently demonstrated. As another embodiment, when the content of the poorly soluble active ingredient exceeds 10% by weight, it may have problems such as hindering the formation of transporters or increasing particle size, increasing turbidity, or decreasing stability. Specifically, the poorly soluble active ingredient may contain more than 0.001% by weight, more than 0.01% by weight, more than 0.02% by weight, more than 0.03% by weight, more than 0.04% by weight, more than 0.05% by weight, more than 0.06% by weight, more than 0.07% by weight, more than 0.08% by weight, more than 0.09% by weight, more than 0.1% by weight, more than 0.2% by weight, more than 0.3% by weight, more than 0.4% by weight, more than 0.5% by weight, more than 0.6% by weight, more than 0.7% by weight, more than 0.8% by weight, more than 0.9% by weight, more than 1% by weight, more than 2% by weight, more than 3% by weight, more than 4% by weight, more than 5% by weight, more than 6% by weight, more than 7% by weight, more than 8% by weight, more than 9% by weight, or more than 9.99% by weight, relative to the total weight of the composition. As an example, the poorly soluble active ingredient may contain less than 10% by weight, less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.9% by weight, less than 0.8% by weight, less than 0.7% by weight, less than 0.6% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.2% by weight, less than 0.1% by weight, less than 0.09% by weight, less than 0.08% by weight, less than 0.07% by weight, less than 0.06% by weight, less than 0.05% by weight, less than 0.04% by weight, less than 0.03% by weight, less than 0.02% by weight, or less than 0.01% by weight relative to the total weight of the composition.

[0044] As an example, the total weight ratio of the poorly soluble active ingredient carrier to the total weight of the poorly soluble active ingredient contained in the composition can be from 1:1 to 100. When this range is exceeded, it may hinder the formation of the transporter carrier or increase particle size, turbidity, stability, and skin absorption. Specifically, the total weight ratio of the poorly soluble active ingredient carrier to the total weight of the poorly soluble active ingredient can be 1:1 or more, 5 or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 35 or more, 40 or more, 45 or more, 50 or more, 55 or more, 60 or more, 65 or more, 70 or more, 75 or more, 80 or more, 85 or more, 90 or more, or 95 or more. Specifically, the total weight ratio of the poorly soluble active ingredient delivery system to the total weight of the poorly soluble active ingredient can be 1:100 or less, 95 or less, 90 or less, 85 or less, 80 or less, 75 or less, 70 or less, 65 or less, 60 or less, 55 or less, 50 or less, 45 or less, 40 or less, 35 or less, 30 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, or 2 or less.

[0045] As an embodiment, the poorly soluble active ingredient delivery system may further include oil within the bilayer structure. In this case, the type of oil is as described above. As an embodiment, the oil contained in the poorly soluble active ingredient delivery system may contain 0.01 to 10% by weight relative to the total weight of the composition, but is not limited thereto. Specifically, the oil may contain 0.01% or more by weight, 0.1% or more by weight, 1% or more by weight, 2% or more by weight, 3% or more by weight, 4% or more by weight, 5% or more by weight, 6% or more by weight, 7% or more by weight, 8% or more by weight, or 9% or more by weight relative to the total weight of the composition. Specifically, the oil may contain less than 10% by weight, less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or less than 0.1% by weight relative to the total weight of the composition. When the oil contains less than 0.01% by weight, it may have problems such as reduced solubility of poorly soluble active ingredients, hindered formation of transporters and carriers, increased particle size, increased turbidity, and decreased stability. When it contains more than 10% by weight, it may have problems such as hindered formation of transporters and carriers, increased particle size, increased turbidity, and decreased stability.

[0046] As an example, the in vivo dosage or usage of the poorly soluble active ingredient delivery system that captures the poorly soluble active ingredient can be from 50 mg / kg / day to 10,000 mg / kg / day. The dosage may vary depending on factors such as the subject's age, sex, weight, specific diseases or symptoms, severity of the disease or symptoms, and route of administration, and the dosage determined based on these factors is within the skill of a person skilled in the art. For example, the dosage may be 50 mg / kg / day or more, 100 mg / kg / day or more, 150 mg / kg / day or more, 200 mg / kg / day or more, 250 mg / kg / day or more, 300 mg / kg / day or more, 350 mg / kg / day or more, 400 mg / kg / day or more, 450 mg / kg / day or more, 500 mg / kg / day or more, 550 mg / kg / day or more, 600 mg / kg / day or more, 650 mg / kg / day or more, 700 mg / kg / day or more, 750 mg / kg / day or more, 800 mg / kg / day or more, 850 mg / kg / day or more, 900 mg / kg / day or more, or 1000 mg / kg / day or more. Additionally, the dosage may be, for example, less than 10 g / kg / day, less than 5000 mg / kg / day, less than 4500 mg / kg / day, less than 4000 mg / kg / day, less than 3500 mg / kg / day, less than 3000 mg / kg / day, less than 2500 mg / kg / day, less than 2000 mg / kg / day, less than 1500 mg / kg / day, less than 1000 mg / kg / day, or less than 500 mg / kg / day; however, the dosage does not limit the scope of this specification in any way.

[0047] The composition according to one embodiment of this disclosure can be a topical skin agent.

[0048] The composition according to one embodiment of this disclosure can be a cosmetic composition.

[0049] In one embodiment, the cosmetic composition according to the present disclosure may be formulated as a dosage form containing a cosmetically or dermatologically acceptable medium or matrix. As a dosage form suitable for topical application, it can be provided in the form of, for example, solutions, gels, solids, anhydrous pastes, emulsions obtained by dispersing an oil phase in an aqueous phase, suspensions, microemulsions, microcapsules, microspheres, or ionic (liposomes) and / or nonionic saccharin dispersants and films, or in the form of creams, lotions, emulsions, powders, ointments, sprays, or concealer sticks. Additionally, it can be used in the form of foam or further in the form of aerosol compositions containing compressed propellants. The composition can be prepared according to conventional methods in the art. As an embodiment, the cosmetic composition according to the present disclosure may, together with the active ingredient, preferably also contain other ingredients that can provide a synergistic effect on the main effect, without compromising the primary effect. Those skilled in the art can readily select other ingredients for formulation, in addition to the active ingredient of the present disclosure, depending on the dosage form or intended use of other cosmetic compositions. In addition, as an embodiment, the cosmetic composition of this disclosure may, along with the stated ingredients, include, as needed, other ingredients formulated in conventional cosmetic compositions. Examples include, for instance, thickeners, neutralizers, antioxidants, moisturizers, emollients, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, bactericides, other functional ingredients, pH adjusters, ethanol, pigments, fragrances, blood circulation promoters, cooling agents, antiperspirants, purified water, etc. Other formulation ingredients that may be included in the cosmetic composition of this disclosure are not limited to these, and the formulation amounts of these ingredients may be adjusted within a range that does not impair the purpose and effect of this disclosure.

[0050] The composition according to one embodiment of this disclosure can be a pharmaceutical composition. The pharmaceutical composition may further contain preservatives, stabilizers, wettable powders or emulsification promoters, adjuvants (such as salts and / or buffers for controlling osmotic pressure), and other therapeutically useful substances. As an embodiment, the pharmaceutical composition can be a non-oral administration agent, which can be a rectal, topical, subcutaneous, or transdermal dosage form. For example, it can be a dosage form such as an injection, drops, ointment, emulsion, gel, cream, spray, suspension, oil, suppository, patch, etc., but is not limited thereto. As an embodiment, the dosage of the pharmaceutical composition can vary depending on the age, sex, weight, specific disease or symptom to be treated, severity of the disease or symptom, route of administration, and the prescribing person's judgment. The dosage determined based on these factors is within the skill of a person skilled in the art. For example, the dosage may be 50 mg / kg / day or more, or 1000 mg / kg / day or less, or 10 g / kg / day or less, or 5000 mg / kg / day or less; however, the dosage does not limit the scope of this specification in any way.

[0051] The present disclosure is described in detail below with reference to embodiments, comparative examples, and test examples. These examples are provided merely to illustrate the present disclosure more specifically, and those skilled in the art should understand that the scope of the present disclosure is not limited to these embodiments, comparative examples, and test examples.

[0052] [Comparative Example]

[0053] As a comparative example of this disclosure, a composition comprising liposomes as functional substance delivery bodies was prepared. Specifically, liposomes were prepared by conventional composition preparation methods in the art, according to the components listed in Table 1 below, by adding oil to an aqueous phase consisting of components other than oil, and by high-speed emulsification mixing (homo mixing), agi mixing (agi mixing), and heating processes.

[0054] Table 1

[0055]

[0056] (weight%)

[0057] Then, the particle size distribution of the liposomes in Comparative Example 1 was analyzed using a DLS (dynamic light scattering) particle size analyzer (device name: Zetasizer Nano ZS, manufacturer: Malvern Instruments Ltd., UK). Figure 4 The result is shown in the figure. Figure 4The x-axis represents the particle size (nm), and the y-axis represents the percentage of particles of that size measured.

[0058] The result, such as Figure 4 As shown, even when the liposomes do not contain any active ingredients in vivo, they still exhibit a main peak at a particle size of 155 nm.

[0059] [Comparative Example 2]

[0060] As another comparative example of this disclosure, a composition comprising a poorly soluble functional substance and liposomes as a carrier of the poorly soluble functional substance that captures the poorly soluble functional substance was prepared.

[0061] Specifically, Comparative Example 2 was prepared by conventional composition preparation methods in the art, according to the components in Table 2 below, by adding an oil phase consisting of a poorly soluble active ingredient and an oil to an aqueous phase consisting of the other components after removing them, and by high-speed emulsification mixing (homo mixing), agi mixing (agi mixing), and heating processes.

[0062] Table 2

[0063]

[0064] (weight%)

[0065] The results showed that, in Comparative Example 2, phytosterols precipitated immediately after preparation, thus confirming that poorly soluble active substances such as phytosterols cannot be stabilized by liposomes.

[0066]

Example 1

[0067] As an embodiment of this disclosure, a composition comprising a poorly soluble active ingredient and a poorly soluble active ingredient delivery system for capturing the poorly soluble active ingredient is prepared.

[0068] Specifically, Example 1 was prepared by conventional composition preparation methods in the art, according to the components in Table 3 below, by adding an oil phase consisting of poorly soluble active ingredients and oil to an aqueous phase consisting of other components after removing them, and by high-speed emulsification mixing (homo mixing), agi mixing (agi mixing), and heating processes.

[0069] Table 3

[0070]

[0071] (weight%)

[0072] The results of analysis of the particle size distribution of the transporter contained in the composition of Example 1 prepared as follows: Figure 5As shown, a main peak is observed at a particle size of 9.5 nm, confirming that even with the presence of poorly soluble active ingredients, the particle size is significantly smaller and more uniform compared to the liposomes prepared in the comparative example. This indicates that using the delivery system according to an embodiment of this disclosure can improve the skin absorption of poorly soluble active ingredients.

[0073] Furthermore, the stability of the composition was observed for one month under ambient temperature, 30°C, 37°C, 45°C, 60°C, cycling (12 hours at 45°C to 12 hours at -15°C), freezing (-15°C), and refrigeration (5°C). The results confirmed that no precipitation or gelation of phytosterols occurred, demonstrating excellent stability. This indicates that the delivery system according to an embodiment of this disclosure effectively stabilizes poorly soluble active ingredients.

[0074]

Experimental Example 1

[0075] As embodiments and comparative examples of this disclosure, the composition was prepared by conventional composition preparation methods in the art, according to the components in Tables 4 and 5 below, by adding oil or an oil phase consisting of poorly soluble active ingredients and oil to an aqueous phase consisting of other components after removing them, and by high-speed emulsification mixing (homo mixing), agi mixing (agi mixing), and heating processes.

[0076] Then, the prepared compositions were observed for one month under the following conditions: room temperature, 30°C, 37°C, 45°C, 60°C, cycling (12 hours at 45°C to 12 hours at -15°C), freezing (-15°C), and refrigeration (5°C). The results are shown in the table below. After one month, good stability is indicated by ◎; good stability up to three weeks is indicated by ○; good stability at preparation but precipitation or gelation within 1-2 weeks is indicated by Δ; precipitation at the time of preparation is indicated by X.

[0077] Table 4

[0078]

[0079] (weight%)

[0080] Table 5

[0081]

[0082] (weight%)

[0083] Comparative Examples 2 to 8 (liposomes containing only phospholipids or single-chain nonionic surfactants) all precipitated poorly soluble active ingredients immediately after preparation. Furthermore, it was confirmed that even in transporter form, Comparative Example 1 (where the number of carbon atoms in the hydrophobic tails of the phospholipids and the hydrophobic tails of the single-chain nonionic surfactants is the same) and Comparative Examples 9 and 10 (where the number of carbon atoms in the hydrophobic tails of the phospholipids and the hydrophobic tails of the single-chain nonionic surfactants differs, and unsaturated phospholipids are also included) precipitated poorly soluble active ingredients within 1-2 weeks after preparation. Additionally, Comparative Examples 9 and 10 exhibited discoloration or foul odor due to the unsaturated phospholipids. In contrast, it was confirmed that Examples 1 to 5, as embodiments of this disclosure, did not exhibit precipitation or gelation for 3 weeks or more, thus effectively stabilizing the poorly soluble active ingredients.

[0084]

Experimental Example 2

[0085] As an embodiment of the composition of this disclosure, Preparation Example 1 (#232) was prepared as a thickener having the same components as in Example 1, and Preparation Example 2 (#260) was prepared as a thickener having the same components as in Example 1 except that it contains 0.3% by weight of phytosterols. Together with the following experiments, it was confirmed whether the delivery systems of the present disclosure could promote the skin absorption of poorly soluble active ingredients, thereby greatly increasing the effects based on poorly soluble active ingredients.

[0086] First, 50 women aged 20 to 30 with current allergy problems (allergic reactions) were selected as the evaluation subjects and divided into two groups of 30 each. Group 1 (30 women) used Preparation 1 (#232) locally on the face from day 1 to day 6, and applied it to the entire face on day 7. After 7 days, the improvement in allergy symptoms was evaluated. In addition to allergy improvement, improvements in skin texture, smoothness, hydration, and elasticity were also evaluated as additional skin improvement effects.

[0087] The result, such as Figure 6 As shown, Preparation Example 1 (#232) demonstrates immediate soothing effects on allergies, softening hardened allergic areas and reducing redness and size. The evaluation is as follows: with increasing usage days, excellent reduction in redness and size, and allergy pain was observed on day 1; the rate of allergy progression was shortened on day 3; and the size and number of allergies decreased and the appearance of uneven skin was improved on day 7. Preparation Example 2 (#260) was evaluated as follows: Figure 7 As shown, it demonstrates a reduction in flushing, such as Figure 8As shown, the skin becomes smoother, the oil-moisture balance is regulated, and the formation of allergies is prevented. Therefore, it has been confirmed that when using the composition disclosed herein (which uses a delivery system to capture poorly soluble active ingredients to stabilize them), poorly soluble active ingredients can be stably captured at high concentrations, thereby demonstrating excellent skin-improving effects.

[0088] This disclosure, as an embodiment, can provide the following implementation.

[0089] The first embodiment provides a poorly soluble active ingredient delivery system comprising a transfersome, the transfersome comprising a bilayer structure containing a phospholipid and a single-chain nonionic surfactant, the phospholipid being a saturated phospholipid, the hydrophobic tail of the phospholipid and the hydrophobic tail of the single-chain nonionic surfactant having different numbers of carbon atoms.

[0090] The second embodiment provides a poorly soluble active ingredient delivery system, wherein, in the first embodiment, the difference in the number of carbon atoms between the hydrophobic tail of the phospholipid and the hydrophobic tail of the single-chain nonionic surfactant is 3 or more.

[0091] The third embodiment provides a poorly soluble active ingredient delivery system, wherein, in the first or second embodiment, the phospholipid comprises one or more selected from the group consisting of hydrogenated lecithin, hydrogenated phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, and phosphatidylglycerol.

[0092] The fourth embodiment provides a poorly soluble active ingredient delivery system, wherein in any of the first to third embodiments, the single-chain nonionic surfactant comprises one or more substances selected from the group consisting of PPGs, PEGs, polysorbates, polyglycerols, sugars, and biosurfactants.

[0093] A fifth embodiment provides a poorly soluble active ingredient delivery system in which, in any of embodiments 1 to 4, the single-chain nonionic surfactant comprises a surfactant selected from PPG-13-decyltetradeceth-24, PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, polysorbate 20, PPG polyglyceryl-6-caprylate, polyglyceryl-10-stearate, polyglyceryl-10-laurate, isotrideceth-9, sucrose stearate, sodium surfactantin, and nonadecanoyl nitrilotriacetic acid. It comprises one or more of the following: triacetic acid, arachidonic nitrilo triacetic acid, pentacosanoyl nitrilo triacetic acid, and pentacosadiynoyl nitrilo triacetic acid.

[0094] The sixth embodiment provides a poorly soluble active ingredient delivery system in which, in any of the first to fifth embodiments, the phospholipids and single-chain nonionic surfactants are arranged in a regular or irregular cross-linked manner within a bilayer structure.

[0095] The seventh embodiment provides a poorly soluble active ingredient delivery system in which, in any one of the first to sixth embodiments, the weight ratio of the phospholipid to the single-chain nonionic surfactant is 1:1 or more.

[0096] The eighth embodiment provides a poorly soluble active ingredient delivery system in which, in any one of the first to seventh embodiments, the weight ratio of the phospholipid to the single-chain nonionic surfactant is 1:1 to 20.

[0097] The ninth embodiment provides a poorly soluble active ingredient delivery system in which, in any of the first to eighth embodiments, the poorly soluble active ingredient is captured within the bilayer structure.

[0098] The tenth embodiment provides a poorly soluble active ingredient delivery system, wherein in any of the first to ninth embodiments, the delivery system further includes oil within a bilayer structure.

[0099] The 11th embodiment provides a poorly soluble active ingredient delivery system, wherein in any of the 1st to 10th embodiments, the oil includes one or more of hydrocarbon oils and silicone oils.

[0100] The 12th embodiment provides a poorly soluble active ingredient delivery system, wherein in any one of the 1st to 11th embodiments, the oil comprises one or more selected from the group consisting of squalane, caprylic / capric triglyceride, cetyl ethylhexanoate, dibutyl adipate, neoopentyl glycol diheptanoate, butylenes glycol dicaprylate / dicaprate, phenyl trimethicone, methyl trimethicone, cyclopentasiloxane, cyclohexasiloxane, caprylyl methicone, dimethicone, and trisiloxane.

[0101] The 13th embodiment provides a poorly soluble active ingredient delivery system, wherein in any of the 1st to 12th embodiments, the poorly soluble active ingredient delivery system includes a transporter comprising a bilayer structure containing phospholipids and two or more single-chain nonionic surfactants, wherein the hydrophobic tails of one or more of the single-chain nonionic surfactants and the hydrophobic tails of the phospholipids have different numbers of carbon atoms.

[0102] The 14th embodiment provides a poorly soluble active ingredient delivery system in which, in any one of the 1st to 13th embodiments, the two or more single-chain nonionic surfactants have different HLB (hydrophile-lipophile-balance) values.

[0103] The 15th embodiment provides a poorly soluble active ingredient delivery system in which, in any one of the 1st to 14th embodiments, the difference in HLB of the two or more single-chain nonionic surfactants is 1.5 or more.

[0104] The 16th embodiment provides a poorly soluble active ingredient delivery system, wherein in any of the 1st to 15th embodiments, the particle size of the poorly soluble active ingredient delivery system is 5 to 20 nm.

[0105] The 17th embodiment provides a poorly soluble active ingredient delivery system, wherein in any of the 1st to 16th embodiments, the poorly soluble active ingredient is an oil-soluble, hydrophobic, or water-insoluble active ingredient.

[0106] The 18th embodiment provides a poorly soluble active ingredient delivery system, wherein, in any one of the 1st to 17th embodiments, the poorly soluble active ingredient comprises one or more substances selected from the group consisting of phytosterol, phytosphingosine, salicyloyl phytosphingosine, thymol trimethoxycinnamate, ceramide NP, ceramide NS, ceramide AS, ceramide AP, ceramide EOP, hydroxypropyl bislauramide MEA, hydroxypropyl bispalmitamide MEA, asiaticoside, asiatic acid, madecassic acid, and ferulic acid.

[0107] The 19th embodiment provides a composition comprising the poorly soluble active ingredient delivery system and the poorly soluble active ingredient as described in any one of the 1st to 18th embodiments.

[0108] The 20th embodiment provides a composition in which, in the 19th embodiment, the content of the poorly soluble active ingredient relative to the total weight of the composition is from 0.001% by weight to 10% by weight.

[0109] The 21st embodiment provides a composition in which, in the 19th or 20th embodiment, the total weight ratio of the insoluble active ingredient carrier to the total weight of the insoluble active ingredient contained in the composition is 1:1 to 100.

[0110] The 22nd embodiment provides a composition in any of the 19th to 21st embodiments, wherein the oil contained in the poorly soluble active ingredient delivery body contains 0.001 to 10% by weight relative to the total weight of the composition.

[0111] The 23rd embodiment provides a composition, wherein in any of the 19th to 22nd embodiments, the composition is a topical skin agent.

[0112] The 24th embodiment provides a composition, which is a cosmetic composition according to any one of the 19th to 23rd embodiments.

[0113] The 25th embodiment provides a composition, wherein in any of the 19th to 24th embodiments, the composition is a pharmaceutical composition.

Claims

1. A poorly soluble active ingredient delivery system comprising a transporter, said transporter comprising a bilayer structure containing a phospholipid and a single-chain nonionic surfactant, wherein: The phospholipid is one or more saturated phospholipids selected from the group consisting of hydrogenated lecithin and hydrogenated phosphatidylcholine; The single-chain nonionic surfactant is selected from one or more of the group consisting of polyglycerol-10 stearate, polyglycerol-10 lauryl ester, sucrose stearate, sodium subtilisin, and PPG-13-decyltetradecyl alcohol polyether-24. The double-layer structure also includes oil; The oil is selected from one or more of the following: squalane, caprylic / capric triglyceride, cetyl ethylhexanoate, dibutyl adipate, neopentyl glycol diheptanoate, butanediol dicaprylate / didecanoate, phenyl polytrimethylsiloxane, methyl polytrimethylsiloxane, cyclopentadimethylsiloxane, cyclohexylsiloxane, octyl polymethylsiloxane, polydimethylsiloxane, and trisiloxane; The poorly soluble active ingredient is captured within the bilayer structure; The particle size of the poorly soluble active ingredient delivery system is 5 to 20 nm.

2. The poorly soluble efficacy delivery system according to claim 1, wherein: The weight ratio of the phospholipid to the single-chain nonionic surfactant is 1:1 or higher.

3. The poorly soluble efficacy delivery system according to claim 1, wherein: The weight ratio of the phospholipid to the single-chain nonionic surfactant is 1:1 to 20.

4. The poorly soluble efficacy delivery system according to claim 1, wherein: The poorly soluble active ingredient delivery system includes a transporter, which comprises a bilayer structure containing phospholipids and two or more single-chain nonionic surfactants. The hydrophobic tails of one or more of the two or more single-chain nonionic surfactants and the hydrophobic tails of the phospholipids have different numbers of carbon atoms.

5. The poorly soluble efficacy delivery system according to claim 4, wherein: The two or more single-chain nonionic surfactants have different HLB values.

6. The poorly soluble efficacy delivery system according to claim 5, wherein: The difference in HLB values ​​between the two or more single-chain nonionic surfactants is 1.5 or more.

7. The poorly soluble efficacy delivery system according to claim 1, wherein: The poorly soluble active ingredient is an oil-soluble active ingredient.

8. The poorly soluble efficacy delivery system according to claim 1, wherein: The poorly soluble active ingredient is a hydrophobic active ingredient.

9. The poorly soluble efficacy delivery system according to claim 1, wherein: The poorly soluble active ingredient is a water-insoluble active ingredient.

10. The poorly soluble efficacy delivery system according to claim 1, wherein: The poorly soluble active ingredient is selected from one or more substances in the group consisting of phytosterols, phytosphingosine, salicylphytosphingosine, thymol trimethoxycinnamate, ceramide NP, ceramide NS, ceramide AS, ceramide AP, ceramide EOP, hydroxypropyl dilauramide MEA, hydroxypropyl bispalmitamide MEA, asiaticoside, asiatic acid, hydroxyasiatic acid, and ferulic acid.

11. A composition comprising the poorly soluble active ingredient delivery system and the poorly soluble active ingredient as described in any one of claims 1 to 10.

12. The composition according to claim 11, wherein: In the composition, the content of the poorly soluble active ingredient relative to the total weight of the composition is from 0.001% to 10% by weight.

13. The composition according to claim 11, wherein: The total weight ratio of the insoluble active ingredient carrier to the total weight of the insoluble active ingredient contained in the composition is from 1:1 to 100.

14. The composition according to claim 11, wherein: The oil contained in the poorly soluble active ingredient delivery system comprises 0.001 to 10% by weight relative to the total weight of the composition.

15. The composition according to claim 11, wherein: The composition is a topical skin agent.

16. The composition according to claim 11, wherein: The composition is a cosmetic composition.

17. The composition according to claim 11, wherein: The composition is a pharmaceutical composition.

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