KR102458630B1 - Cubosome composition containing retinal and covalent organic framework, and cosmetic composition comprising thereof - Google Patents

Abstract

The present invention relates to a cubosome composition containing retinal and covalently bonded organic framework and, more particularly, to a composition for transdermal delivery obtained by firstly stabilizing the retinal with a cyclodextrin-based covalent organic framework, and then secondarily stabilizing the retinal in a cubosome formulation, and to a cosmetic composition containing the same.

Description

CUBOSOME COMPOSITION CONTAINING RETINAL AND COVALENT ORGANIC FRAMEWORK, AND COSMETIC COMPOSITION COMPRISING THEREOF;

The present invention relates to a cubosome composition containing retinal and a covalent organic framework. More particularly, retinal is primarily used as a cyclodextrin-based covalent organic framework. The present invention relates to a composition for transdermal delivery stabilized with a cubosome formulation and then secondaryly stabilized with a cubosome formulation, and a cosmetic composition comprising the same.

Cosmetic consumers are demanding safe and high efficacy and effectiveness while avoiding skin irritation. As a result, the term “cosmeceutical”, which is a combination of cosmetics and pharmaceuticals, has emerged due to consumers’ desire for high-functional cosmetics. With the development of cosmeceuticals, the number of products that incorporate technologies from other fields such as medical technology into cosmetics is increasing. Due to the development of such functional materials, various functionalization methods capable of imparting higher stability to cosmetic raw materials have been extensively studied. In particular, it is well known that light, heat and oxygen in the air severely reduce the biological activity of functional raw materials. Therefore, there is a need for a new functionalization technology for stabilizing various cosmetic raw materials.

Vitamin A is involved in visual function and is a vitamin that acts as a growth factor. Vitamin A works in the retina of the eye in the form of a metabolite, the light-absorbing molecule retinal, which is absolutely necessary for twilight vision (the ability to see objects in dark environments) and color perception. Vitamin A also functions as an important epidermal growth factor like a hormone in epithelial cells in the form of retinoic acid, which is an irreversibly oxidized form of retinol. Most vitamin A in animal foods exists in the form of esters such as retinyl palmitate, and after ingestion with food, it is converted into retinol, an alcohol, in the small intestine. The human body stores vitamin A in the form of retinol and converts it into retinal, retinaldehyde, which is an aldehyde that acts in the visual system whenever needed. Both retinol and retinal are precursors of tretinoin (all- trans retinoic acid) and are synthesized from retinol and retinal through retinoid metabolism. The transition from retinol to retinal is the most difficult step in retinoid metabolism. That is, no matter how high a concentration of retinol is applied, this step cannot be passed and the concentration of tretinoin does not increase in proportion to the amount of retinol. However, since retinal has passed this stage, it is likely to be easily converted to tretinoin. Retinal helps to remove comedones (blackheads, whiteheads) by controlling keratinization of the skin, helps to improve skin wrinkles and skin texture, and can improve skin barrier function and moisture. However, since retinal is unstable to heat, light, and moisture, and skin absorption is not smooth, efforts to improve these are required.

A covalent organic framework (COF) is a two-dimensional or three-dimensional organic solid with an extended structure, in which building blocks are connected by strong covalent bonds. The synthesis of covalent organic frameworks can also be designed through the principles of reticular chemistry developed by Professor Omar M. Yaghi of the United States, similar to the metal-organic framework (MOF). The primary concerns for design in both COF and MOF are porosity and structural regularity. Meanwhile, assembling a building unit for forming a crystalline MOF using a coordination bond is relatively easier than making a crystalline COF using a covalent bond. Design principles for synthesizing inorganic zeolites may also provide additional inspiration for COF designs.

Like other porous organic polymers, attention should be paid to porosity in order to make COF. The design strategy for forming porous solids using covalent bonds can be divided into the following two categories. The first is the templating method, which is a method for synthesizing porous zeolite and mesoporous organosilica. Synthesis using structural-directing agents to form building blocks. After synthesis, the final porous polymer can be made by removing the template. The second method uses rigid building units to create porous structures. Various types of porous polymer composites were successfully synthesized from rigid monomers by coupling reaction. Most of the porous COF synthesis uses the second method. On the other hand, the molecular length of the used building unit governs the pore size of the produced COF, and the shape of the building unit determines the topology of the porous structure. Most bonding groups are rigid, flat structures such as boroxines, triazines, imines, and hydrazones. In many cases, hard aromatics are preferred as building units because they can efficiently form porous structures. As an example of using such a covalent organic framework, Korean Patent Application Laid-Open No. 10-2018-0069242 discloses the use of an organic framework having a triazine group formed through nitrile trimerization as a gas collector.

A cubosome is composed of a specific amphiphilic lipid, and is a cubic liquid crystal structure formed spontaneously by hydration of an amphiphilic lipid. Due to their molecular structural properties, cubosomes have a cube-shaped double continuous aqueous channel in aqueous solution, and can be delivered by improving the delivery ability of nutrients and drugs and controlling the release of molecules. Since cubosomes have an affinity for the cell membrane of skin cells, they can easily penetrate into the cell gap.

Republic of Korea Patent Publication No. 10-2018-0069242

Accordingly, an object of the present invention is to provide a novel composition for transdermal delivery that can efficiently deliver retinal into the skin in a stable state.

Another technical object of the present invention is to provide a cosmetic composition comprising the composition for transdermal delivery.

In addition, another technical object of the present invention is to provide a preparation method for efficiently preparing the composition for transdermal delivery.

In order to solve the above problems, the present invention includes a cyclodextrin-based covalent organic framework (CD-COF) containing retinal as an active ingredient, an amphiphilic lipid, a surfactant and water. It provides a cubosome composition for transdermal delivery.

In addition, the present invention provides a cosmetic composition comprising the cubosome composition for transdermal delivery.

In addition, the present invention provides: i) dissolving retinal, cyclodextrin and potassium base as active ingredients in a solvent; ii) forming crystals from the solution obtained in step (i) in a crystallization solvent using a gas diffusion crystallizer; iii) washing the crystals formed in step (ii) and drying them to prepare a cyclodextrin-based covalent organic framework (CD-COF) containing retinal; iv) cubosome for transdermal delivery, comprising mixing a cyclodextrin-based covalent organic framework containing retinal obtained in step (iii), an amphiphilic lipid, a surfactant, and water, and then preparing a cubosome A method of making the composition is provided.

Hereinafter, the present invention will be described in detail.

According to one aspect of the present invention, there is provided a cubosome composition for transdermal delivery comprising a covalent organic framework based on a cyclodextrin containing retinal as an active ingredient, an amphiphilic lipid, a surfactant, and water.

In the present invention, as a component of the cubosome composition for transdermal delivery, it includes a cyclodextrin-based covalent organic framework (CD-COF) containing retinal as an active ingredient. In the present invention, retinal, an unstable active ingredient, is primarily stabilized with a covalent organic framework based on cyclodextrin.

In the present invention, a covalent organic framework is prepared based on cyclodextrin. Cyclodextrin is a cyclic oligosaccharide, produced through enzymatic conversion from starch, and 5 or more D-glucopyranoside units are linked through 1→4 bonds. Those having 6, 7 and 8 glucose subunits in cyclodextrins are called alpha(α)-cyclodextrin, beta(β)-cyclodextrin and gamma(γ)-cyclodextrin, respectively.

According to one embodiment of the present invention, the cyclodextrin may be alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin. According to another embodiment of the present invention, the cyclodextrin may be gamma-cyclodextrin.

According to another embodiment of the present invention, the cyclodextrin-based covalent organic framework may be prepared from cyclodextrin and potassium salt. According to another embodiment of the present invention, the potassium salt may be potassium hydroxide (KOH).

In the present invention, an amphiphilic lipid is included as a component of the cubosome composition for transdermal delivery. In the present invention, amphiphilic lipids, surfactants and water are used to form cubosomes to secondaryly stabilize retinal, an unstable active ingredient.

According to another embodiment of the present invention, the amphiphilic lipid may be glyceryl monooleate.

In the present invention, a surfactant (stabilizer) is included as a component of the cubosome composition for transdermal delivery.

According to another embodiment of the present invention, the surfactant is selected from the group consisting of polyethylene glycol (PEG)-polypropylene glycol (PPG)-triblock copolymer of polyethylene glycol (PEG), polyethylene glycol (PEG), and mixtures thereof. can be selected. According to another embodiment of the present invention, the triblock copolymer of polyethylene glycol (PEG)-polypropylene glycol (PPG)-polyethylene glycol (PEG) is poloxamer 407 (poloxamer 407) or poloxamer 188 (poloxamer 188) can Poloxamer 407 is commercially available from BASF under the trade name Pluracare F127. According to another embodiment of the present invention, the polyethylene glycol (PEG) may have an average molecular weight of 5,000 to 20,000 g/mol. According to another embodiment of the present invention, the polyethylene glycol (PEG) may have an average molecular weight of 10,000 g/mol.

According to another embodiment of the present invention, the cubosome composition for transdermal delivery contains 1 to 30% by weight of a cyclodextrin-based covalent organic framework containing retinal, 2 to 40% by weight of an amphiphilic lipid, 5 to 50% by weight of surfactant and 10 to 80% by weight of water. According to another embodiment of the present invention, the cubosome composition for transdermal delivery contains 2 to 25% by weight of a cyclodextrin-based covalent organic framework containing retinal, 5 to 35% by weight of an amphiphilic lipid, 10 to 45% by weight of surfactant and 20 to 70% by weight of water. According to another embodiment of the present invention, the cubosome composition for transdermal delivery contains 5 to 20 wt% of a cyclodextrin-based covalent organic framework containing retinal, 8 to 30 wt% of an amphiphilic lipid, 15 to 40% by weight of surfactant and 30 to 60% by weight of water.

According to another embodiment of the present invention, the cubosome composition for transdermal delivery may further include a preservative. According to another embodiment of the present invention, the preservative may be selected from the group consisting of, for example, 1,2-hexanediol, pentylene glycol, phenoxyethanol, ethylhexylglycerin, and mixtures thereof, but is not limited thereto. it is not According to another embodiment of the present invention, the cubosome composition for transdermal delivery may contain 0.5 to 5% by weight or 1 to 3% by weight of a preservative.

According to another aspect of the present invention, there is provided a cosmetic composition comprising the cubosome composition for transdermal delivery of the present invention. In the present invention, the cosmetic composition may be formulated in, for example, skin, lotion, body lotion, cream, essence, BB (blemish balm) cream, lipstick, face powder, foundation, etc., but is not limited thereto.

The cosmetic composition contains the cubosome composition for transdermal delivery according to the present invention in an amount of preferably 0.01 to 60% by weight, more preferably 0.1 to 50% by weight. In the present invention, if the cosmetic composition contains less than 0.01% by weight of the cubosome composition for transdermal delivery, the effect by the active ingredient retinal may be insignificant, and even if it contains more than 60% by weight, the effect by the active ingredient retinal It is not desirable for the economy because it is no longer expected to increase in proportion to its addition.

According to another aspect of the present invention, i) dissolving retinal, cyclodextrin and potassium base in a solvent as active ingredients;

ii) forming crystals from the solution obtained in step (i) in a crystallization solvent using a gas diffusion crystallizer;

iii) washing the crystals formed in step (ii) and drying them to prepare a cyclodextrin-based covalent organic framework (CD-COF) containing retinal;

iv) cubosome for transdermal delivery, comprising mixing a cyclodextrin-based covalent organic framework containing retinal obtained in step (iii), an amphiphilic lipid, a surfactant, and water, and then preparing a cubosome A method of making the composition is provided.

According to another embodiment of the present invention, the cyclodextrin may be alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin. According to another embodiment of the present invention, the cyclodextrin may be gamma-cyclodextrin. According to another embodiment of the present invention, the potassium base may be potassium hydroxide (KOH).

According to another embodiment of the present invention, the solvent of step (i) may be selected from the group consisting of water, propylene glycol, and mixtures thereof. According to another embodiment of the present invention, in step (i), 5 to 80 parts by weight of retinal, 30 to 200 parts by weight of cyclodextrin and 5 to 100 parts by weight of potassium base based on 100 parts by weight of the solvent may be dissolved.

In the present invention, step (ii) proceeds by forming crystals in the crystallization solvent of the solution obtained in step (i) using a gas diffusion crystallizer. In the present invention, the formation of crystals using the gas diffusion crystallizer is performed by erecting a column in the center of the gas diffusion crystallization apparatus and then putting the solution obtained in step (i), which does not close the cap, and the crystallization solvent is placed around the column, and then gas diffusion If the crystallizer is sealed so that air is not passed and left alone, crystals are formed in the column as the crystallization solvent is diffused. According to another embodiment of the present invention, the crystallization solvent in step (ii) may be selected from the group consisting of methanol, ethanol, and mixtures thereof.

According to another embodiment of the present invention, the amphiphilic lipid of step (iv) may be glyceryl monooleate. According to another embodiment of the present invention, the surfactant in step (iv) is a triblock copolymer of polyethylene glycol (PEG)-polypropylene glycol (PPG)-polyethylene glycol (PEG), polyethylene glycol (PEG) and mixtures thereof. may be selected from the group consisting of According to another embodiment of the present invention, the triblock copolymer of polyethylene glycol (PEG)-polypropylene glycol (PPG)-polyethylene glycol (PEG) is poloxamer 407 (poloxamer 407) or poloxamer 188 (poloxamer 188) can Poloxamer 407 is commercially available from BASF under the trade name Pluracare F127. According to another embodiment of the present invention, the polyethylene glycol (PEG) may have an average molecular weight of 5,000 to 20,000 g/mol. According to another embodiment of the present invention, the polyethylene glycol (PEG) may have an average molecular weight of 10,000 g/mol. According to another embodiment of the present invention, in step (iv), a covalent organic framework based on a cyclodextrin containing 1 to 30% by weight of retinal, 2 to 40% by weight of an amphiphilic lipid, 5 to 50% by weight % by weight of surfactant and 10 to 80% by weight of water may be mixed. According to another embodiment of the present invention, a preservative may be further mixed in step (iv). According to another embodiment of the present invention, the preservative may be 1,2-hexanediol. According to another embodiment of the present invention, the preservative may be mixed in an amount of 0.5 to 5% by weight. In the present invention, the preparation of the cubosome in step (iv) may be performed by an emulsification method known in the art, and there is no particular limitation thereto.

The cubosome composition for transdermal delivery of the present invention efficiently delivers retinal, an active ingredient, into the skin in a very stable form, so that even a small amount of active ingredient can show a very excellent effect for a long period of time.

1 is a schematic diagram showing a gas diffusion crystallizer.
2 is a schematic diagram showing that a crystal is formed using a gas diffusion crystallizer.
3 is a photograph of a general cubosome (a) and a cubosome (b) containing a covalent organic framework based on cyclodextrin containing retinal (Pluracare F127: Poloxamer 407, PEG-10K: polyethylene glycol with an average molecular weight of 10,000 g/mol).
4 is an enlarged photograph of cubosomes using an optical microscope.
5 is an enlarged photograph of a covalent organic framework based on cyclodextrin containing retinal using a cryoelectron microscope.
6 is an enlarged photograph of a cubosome including a covalent organic framework based on a cyclodextrin containing retinal using a freezing electron microscope.
7 is a graph showing the particle size after measuring the particle distribution of a cubosome including a covalent organic framework based on a cyclodextrin containing retinal using Photal and ELS-Z.
8 shows the results of measuring the zeta potential using Photal and ELS-Z to measure the stability of a cubosome including a covalent organic framework based on a cyclodextrin containing retinal.
9 is a result of measuring the elasticity index and viscosity index for measuring the rheology stability of a cubosome including a covalent organic framework based on a cyclodextrin containing retinal; to be.
10 is a result of measuring the stability of a cubosome including a covalent organic framework based on a cyclodextrin containing retinal using Turbiscan.
11 is a result of HPLC analysis of long-term stability of cubosomes including a covalent organic framework based on cyclodextrin containing retinal.

Hereinafter, the present invention will be described in more detail through examples. However, the following examples are merely illustrative to aid the understanding of the present invention, and the scope of the present invention is not limited thereto.

Preparation Example 1: Preparation of a cyclodextrin-based covalent organic framework (hereinafter, “retinal-COF”) containing retinal

390 g of cyclodextrin (alpha, beta or gamma), 135 g of KOH and 100 g of retinal were dissolved in 600 g of distilled water. After preparing a gas diffusion crystallizer as shown in Figure 1, a column is erected in the center, and a solution in which cyclodextrin, KOH, and retinal are dissolved in distilled water is put there, without closing the cap, and a crystallization solvent (ethanol or methanol) is placed around the column. Then, when the gas diffusion crystallizer was sealed so that air was not passed and left to stand, crystals began to form in the column after about 12 hours at room temperature as the crystallization solvent was diffused (FIG. 2). The experiment was terminated after 24 hours, and the formed crystals were washed and dried for 24 hours.

Preparation Example 2: Preparation of cubosome

Cubosomes were prepared using various weight ratios of glyceryl monooleate (GMO), surfactant, water and preservatives in Tables 1 to 3 below. Each component in the composition of Tables 1 to 3 was introduced into a container and dissolved at a temperature of 80° C., then mixed for 5 minutes using a homomixer, and then passed through a high-pressure homogenizer at 1,000 bar three times consecutively, followed by cooling. , to obtain cubosomes by defoaming. As the surfactant, three types of polymers were used: poloxamer 407, polyethylene glycol (PEG) (PEG-10K) having an average molecular weight of 10,000 g/mol, and poloxamer 188. Glyceryl monooleate (GMO) was used after purchasing “Monomuls ^® 90-O18” from BASF, and poloxamer 407 was purchased with “Pluracare ^® F127” from BASF.

Example 1: Preparation of cubosomes containing retinal-COF

Among the cubosomes prepared in Preparation Example 2, the most favorable and stable weight ratio was selected, each component was introduced into a container with the composition shown in Table 4 below, dissolved at a temperature of 80° C., and then using a homomixer for 5 minutes. After mixing, the mixture was passed through a high pressure homogenizer at 1,000 bar three times consecutively, cooled and defoamed to obtain cubosome. As a polymer, Pluracare F127, PEG-10K or Poloxamer 188 was used.

Example 2: Preparation of skin using retinal-COF cubosome

Skins were prepared using cubosomes containing retinal-COF with the composition shown in Table 5 below.

Example 3: Preparation of lotion using retinal-COF cubosome

A lotion was prepared using cubosomes containing retinal-COF with the composition shown in Table 6 below.

Example 4: Preparation of cream using retinal-COF cubosome

A cream was prepared using cubosomes containing retinal-COF with the composition shown in Table 7 below.

Comparative Example: Preparation of cream containing retinal

A cream containing retinal was prepared with the composition shown in Table 8 below.

Example 5: Preparation of essence using retinal-COF cubosome

Essence was prepared using cubosome containing retinal-COF with the composition shown in Table 9 below.

Example 6: Preparation of lipstick using retinal-COF cubosome

After mixing the raw materials in the composition of Table 10 below, after heating to 90 to 95 ℃, put in a lipstick mold and cooled.

Example 7: Preparation of face powder using retinal-COF cubosome

The raw materials were mixed with the composition shown in Table 11 below, and then put in a mixer and pulverized.

Experimental Example 1: Optical Microscopy

Using an optical microscope (OLYMPUS BX50), the cubosomes of Preparation Examples 2 and 1 were photographed at 100 times magnification to observe the structure (FIG. 4).

Experimental Example 2: Freeze electron microscopy

The cubosomes containing the retinal-COF of Preparation Example 1 and the retinal-COF of Example 1 were photographed using a freezing electron microscope (JEM 1010, JEOL, Japan) ( FIGS. 5 and 6 ). As can be seen in FIG. 6 , it was confirmed that cubosomes were well formed.

Experimental Example 3: Dynamic Light Scattering (DLS) Analysis

The result of measuring the particle distribution of the cubosome of Preparation Example 2 using Photal, ELS-Z As the polymer content of the cubosome increased, the particle size increased ( FIG. 7 ).

Zeta potential indicates the degree of repulsion between charged adjacent particles in a dispersion, and is an important measure for evaluating colloidal dispersion stability. The zeta potential of cubosomes was stably measured using Pluracare F2127. A stable zeta potential was also measured for cubosomes containing retinal-COF ( FIG. 8 ).

Experimental Example 4: Measurement of rheological stability of retinal-COF cubosomes

The viscoelasticity of the cubosome was measured using Rheolaser (Formulaction, France), and the analysis conditions were measured at room temperature (25-30° C.) for 25 hours. The higher the EI and MVI on the Y-axis, the higher the elastic and viscous aspects of the sample. Most of the cubosomes with high polymer content had high viscoelasticity, and among them, it was analyzed that cubosomes prepared with Pluracare F127 had high viscoelasticity (FIG. 9).

Experimental Example 5: Measurement of stability of retinal-COF cubosome

Based on the results of rheological properties with high viscoelasticity, changes in dispersion stability with time for three types of cubosomes including retinal-COF were analyzed using Turbiscan (Formulaction, France). Assay conditions were determined by scanning 50 times at 45°C for 2 days. Overall, aggregation occurred in the upper layer, but there was no significant change and it was maintained in a stable state (FIG. 10).

Experimental Example 6: Measurement of long-term stability of retinal-COF cubosomes

The stability of cubosomes containing retinal-COF for long-term storage was analyzed using HPLC under the conditions shown in Table 12 below.

The content of cubosomes containing retinal-COF was initially analyzed at 1% or more, and the titer did not decrease even after 1 month and was stably maintained ( FIG. 11 ).

Experimental Example 7: Transdermal absorption promotion effect test

Neoderm of Taego Science, an artificial skin, was tested by mounting it in a Franz-type diffusion cell (Lab fine instruments, Korea). After putting 50 mM phosphate buffer (pH 7.4, 0.1 M NaCl) into the receptor container (5 mL) of the Franz-type diffusion cell, the diffusion cell was mixed and dispersed at 32 ° C., 600 rpm, and the letty of Example 4 50 μL each of the cream using the raw-COF cubosome and the cream containing retinal of Comparative Example was put into the donor container. Absorption and diffusion were given according to a predetermined time, and the skin where absorption and diffusion occurred was 0.64 cm ² . After the absorption and diffusion of the active ingredient is finished, wash the emulsion remaining on the skin without being absorbed with dried kimwipes or 10 mL of ethanol, and use a tip-type homogenizer to allow the active ingredient to be absorbed After changing the diffused skin, retinal absorbed into the skin was extracted using 4 mL of dichloromethane. Then, the extract was filtered through a 0.45 μm nylon membrane filtration membrane, and the retinal content was measured by HPLC under the following conditions, and the results are shown in Table 13.

As can be seen from Table 13, it was found that retinal was efficiently delivered into the skin in the present invention.

Claims (30)

a cyclodextrin-based covalent organic framework (CD-COF) containing retinal as an active ingredient in an amount of 5 to 20% by weight;
glyceryl monooleate as an amphiphilic lipid from 2 to 40% by weight;
5 to 50% by weight of a surfactant selected from the group consisting of polyethylene glycol (PEG)-polypropylene glycol (PPG)-triblock copolymer of polyethylene glycol (PEG), polyethylene glycol (PEG) and mixtures thereof; and
A cubosome composition for transdermal delivery comprising 10 to 80% by weight of water. The cubosome composition for transdermal delivery according to claim 1, wherein the cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin. The cubosome composition for transdermal delivery according to claim 2, wherein the cyclodextrin is gamma-cyclodextrin. The cubosome composition for transdermal delivery according to claim 1, wherein the cyclodextrin-based covalent organic framework is prepared from cyclodextrin and potassium salt. The cubosome composition for transdermal delivery according to claim 4, wherein the potassium salt is potassium hydroxide (KOH). delete delete According to claim 1, wherein the triblock copolymer of polyethylene glycol (PEG)-polypropylene glycol (PPG)-polyethylene glycol (PEG) is poloxamer 407 (poloxamer 407) or poloxamer 188 (poloxamer 188), characterized in that cubosome composition for transdermal delivery. delete 2. The covalent organic framework according to claim 1, containing 5 to 20% by weight of retinal, a covalent organic framework based on cyclodextrin, 5 to 35% by weight of an amphiphilic lipid, 10 to 45% by weight of a surfactant and 20 to 70% by weight. A cubosome composition for transdermal delivery, characterized in that it contains water in weight %. 11. The method according to claim 10, wherein the covalent organic framework based on cyclodextrin contains 5 to 20% by weight retinal, 8 to 30% by weight amphiphilic lipid, 15 to 40% by weight surfactant and 30 to 60% by weight. A cubosome composition for transdermal delivery, characterized in that it contains water in weight %. The cubosome composition for transdermal delivery according to claim 1, further comprising a preservative. The cubosome composition for transdermal delivery according to claim 12, wherein the preservative is selected from the group consisting of 1,2-hexanediol, pentylene glycol, phenoxyethanol, ethylhexylglycerin, and mixtures thereof. The cubosome composition for transdermal delivery according to claim 12, comprising 0.5 to 5 wt% of a preservative. A cosmetic composition comprising the cubosome composition for transdermal delivery of any one of claims 1 to 5, 8, and 10 to 14. The cosmetic composition according to claim 15, comprising 1 to 60 wt% of the cubosome composition for transdermal delivery. i) dissolving retinal, cyclodextrin and potassium base as active ingredients in a solvent;
ii) forming crystals from the solution obtained in step (i) in a crystallization solvent using a gas diffusion crystallizer;
iii) washing the crystals formed in step (ii) and drying them to prepare a cyclodextrin-based covalent organic framework (CD-COF) containing retinal;
iv) a covalent organic framework based on cyclodextrin containing retinal obtained in step (iii); glyceryl monooleate as an amphiphilic lipid; Polyethylene glycol (PEG) - polypropylene glycol (PPG) - triblock copolymer of polyethylene glycol (PEG), polyethylene glycol (PEG) and a surfactant selected from the group consisting of mixtures thereof and water are mixed, and then cubosome includes making;
In step (iv), a covalent organic framework based on a cyclodextrin containing 5 to 20% by weight of retinal, 2 to 40% by weight of an amphiphilic lipid, 5 to 50% by weight of a surfactant and 10 to 80% by weight mixing weight % of water,
A method for preparing a cubosome composition for transdermal delivery. The method of claim 17, wherein the cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin. The method of claim 18, wherein the cyclodextrin is gamma-cyclodextrin. The method of claim 17, wherein the potassium base is potassium hydroxide (KOH). The method according to claim 17, wherein the solvent in step (i) is selected from the group consisting of water, propylene glycol, and mixtures thereof. 18. The transdermal delivery according to claim 17, wherein in step (i), 5 to 80 parts by weight of retinal, 30 to 200 parts by weight of cyclodextrin and 5 to 100 parts by weight of potassium base are dissolved with respect to 100 parts by weight of the solvent. A method for preparing a cubosome composition for use. The method of claim 17, wherein the crystallization solvent in step (ii) is selected from the group consisting of methanol, ethanol, and mixtures thereof. delete delete 18. The method of claim 17, wherein the triblock copolymer of polyethylene glycol (PEG)-polypropylene glycol (PPG)-polyethylene glycol (PEG) is poloxamer 407 or poloxamer 188 (poloxamer 188). A method for producing a cubosome composition for transdermal delivery. delete The method according to claim 17, wherein a preservative is additionally mixed in step (iv). 29. The preparation of a cubosome composition for transdermal delivery according to claim 28, wherein the preservative is selected from the group consisting of 1,2-hexanediol, pentylene glycol, phenoxyethanol, ethylhexylglycerin, and mixtures thereof. Way. The method of claim 28, wherein the preservative is mixed in an amount of 0.5 to 5% by weight.

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