Transdermal delivery complexes using covalent organic frameworks and polymers

Abstract

To provide a new composite for transdermal delivery capable of efficiently delivering an active ingredient to the skin in a stable state, to provide a cosmetic composition containing the composite for transdermal delivery, and to provide a method for producing the composite for transdermal delivery.SOLUTION: The present invention relates to a transdermal delivery complex comprising a cyclodextrin-based covalent organic framework and a polymer. The present invention also relates to a cosmetic composition comprising the composite for transdermal delivery and a method for preparing the composite for transdermal delivery.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a transdermal delivery complex comprising a cyclodextrin-based covalent organic framework and a polymer. The present invention also relates to a cosmetic composition containing the complex for transdermal delivery. Furthermore, the present invention relates to a method for producing the above-mentioned complex for transdermal delivery. [Background technology]

[0002] It is not easy to get active ingredients in cosmetics to penetrate the skin. To stabilize active ingredients and increase their transdermal penetration efficiency, active efforts and research have been actively conducted to utilize transdermal delivery systems (TDS) in functional cosmetics. To develop functional materials, various functionalization methods have been widely studied to impart higher stability to such materials.

[0003] Skin is a vital organ constantly exposed to the external environment. It is the most important first line of defense, preventing fluid loss and protecting the body from harmful environments. Specifically, the skin functions as a barrier, preventing water and electrolyte loss, providing a normal biochemical metabolic environment, and protecting the body from mechanical stimuli, UV rays, and various microorganisms. Skin is broadly divided into the dermis and epidermis. The dermis is in close contact with the underlying subcutaneous fat. The epidermis is part of the epithelial tissue and consists of five cell layers: the basal layer, spinous layer, granular layer, lucid layer, and stratum corneum. The stratum corneum, located in the outermost part of the skin, is the primary barrier layer. Since Elias et al. proposed the two-compartment model of plaster (keratinocyte interstitial lipids) and bricks (keratinocytes), interest in the stratum corneum and skin barrier has grown. Specifically, the stratum corneum is composed of keratinocytes stacked like bricks, and the keratinocyte interstitial lipids function as the plaster supporting these keratinocytes. The stratum corneum is composed of approximately 40% protein, 40% water, and 10-20% lipids. Its structure is composed of protein-rich keratinocytes and lipids that fill the spaces between them. Among these, lipids, in particular, play a major role as a barrier. The stratum corneum contains hydrophilic, hygroscopic substances called natural moisturizing factors (NMFs), which play an important role in skin hydration. NMFs include amino acids, pyrrolidone carboxylic acid, urea, ammonia, uric acid, glycosamine, creatinine, citrate, sodium, potassium, calcium, chlorine, magnesium, sugars, organic acids, and peptides. To maximize the effectiveness of active ingredients, active ingredients must be sized below 100-200 nm to be easily absorbed deep into the skin, between the intercellular lipids.

[0004] Covalent organic frameworks (COFs) are two- or three-dimensional organic solids with extended structures, in which building blocks are connected by strong covalent bonds. Similar to metal-organic frameworks (MOFs), the synthesis of covalent organic frameworks can also be designed using the principles of reticular chemistry, developed by Professor Omar M. Yaghi in the United States. The main design concerns for both COFs and MOFs are porosity and structural regularity. Assembling building units to form crystalline MOFs using coordinate bonds is relatively simpler than fabricating crystalline COFs using covalent bonds. The design principles for synthesizing inorganic zeolites may provide additional inspiration for COF design.

[0005] As with other porous organic polymers, the fabrication of COFs requires careful consideration of porosity. Design strategies for forming porous solids using covalent bonds can be divided into two categories. The first is the templating method, which synthesizes porous zeolites and mesoporous organosilicas. This is a synthetic method in which structure-directing agents are used to form building blocks. After synthesis, the final porous polymer can be produced by removing the template. The second method uses rigid building units to fabricate porous structures. Various types of porous polymer composites have been successfully synthesized from rigid monomers through coupling reactions. Most porous COFs are synthesized using the second method. Meanwhile, the molecular length of the building units used determines the pore size of the resulting COF, and the shape of the building units determines the topology of the porous structure. Most linking groups are rigid and flat, such as boroxines, triazines, imines, and hydrazones. In many cases, rigid aromatic materials are preferred as building units because they can efficiently form porous structures.

[0006] As an example of the use of such a covalent organic framework, Patent Document 1 discloses the use of an organic framework having a triazine group formed by nitrile trimerization as a gas collector. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Korean Patent Publication No. 10-2018-0069242 Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, the technical object of the present invention is to provide a novel complex for transdermal delivery that can efficiently deliver an active ingredient to the skin in a stable state. Another technical object of the present invention is to provide a cosmetic composition containing the complex for transdermal delivery. A further technical object of the present invention is to provide a manufacturing method for producing the above-mentioned complex for transdermal delivery. [Means for solving the problem]

[0009] To solve the above problems, the present invention provides a complex for transdermal delivery comprising a cyclodextrin-based covalent organic framework (CD-COF) and a polymer. The present invention also provides a cosmetic composition comprising the complex for transdermal delivery. The present invention further provides a method for producing a complex for transdermal delivery, comprising: i) dissolving a cyclodextrin, a potassium base, and a polymer in a solvent; ii) forming crystals from the solution obtained in step i) in a crystallization solvent using a vapor diffusion crystallizer; and iii) washing and drying the crystals formed in step ii).

[0010] The present invention will be described in detail below. According to one aspect of the present invention, there is provided a complex for transdermal delivery comprising a cyclodextrin-based covalent organic framework and a polymer. In the present invention, a cyclodextrin-based covalent organic framework (or cyclodextrin-based covalent organic framework: CD-COF) is contained as one component of the complex for transdermal delivery. In the present invention, a covalent organic framework based on cyclodextrin is produced. Cyclodextrin is a cyclic oligosaccharide produced by enzymatic conversion of starch, and is composed of five or more D-glucopyranoside units linked together via 1→4 bonds. Cyclodextrins with six, seven, and eight glucose subunits are called α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, respectively.

[0011] In one embodiment according to the invention, the cyclodextrin is α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin. In another embodiment according to the invention, the cyclodextrin is γ-cyclodextrin. In another embodiment according to the present invention, the cyclodextrin-based covalent organic framework is prepared from cyclodextrin and a potassium salt, wherein the potassium salt is potassium hydroxide (KOH). In the present invention, a polymer is included as one component of the complex for transdermal delivery.

[0012] In another embodiment of the present invention, the polymer is a biodegradable polymer. In another embodiment of the present invention, the polymer is selected from the group consisting of chitosan, pullulan, polylactic acid, succinylated chitosan, pullulan-poly-(L)-lactic acid, polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymers, and mixtures thereof. In another embodiment of the present invention, the polymer is selected from the group consisting of succinylated chitosan, pullulan-poly-(L)-lactic acid, polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymers, and mixtures thereof.

[0013] In the present invention, succinylated chitosan can be synthesized according to methods known in the art, for example, by reacting succinyl anhydride with chitosan. In the present invention, polylactic acid can be synthesized according to methods known in the art, for example, by reacting pullulan with lactide using triethylamine (TEA) as a catalyst. In the present invention, a polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymer can be synthesized according to methods known in the art. For example, the triblock copolymer PEG-PCL-PEG can be synthesized by forming a PEG-PCL diblock copolymer with methoxypoly(ethylene glycol) (mPEG) and ε-caprolactone, and then coupling them together.

[0014] In the present invention, the polymer is complexed with a cyclodextrin-based covalent organic framework to enhance transdermal delivery. In another embodiment of the present invention, a complex for transdermal delivery is formed using 0.01 to 10 parts by weight of a polymer per 10 parts by weight of a cyclodextrin-based covalent organic framework. In another embodiment of the present invention, the complex for transdermal delivery further comprises an active ingredient, which may be, for example, one or more selected from the group consisting of moisturizers, whitening agents, anti-wrinkle agents, UV blocking agents, hair growth agents, vitamins or derivatives thereof, amino acids or peptides, anti-inflammatory agents, anti-acne agents, disinfectants, female hormone agents, keratolytic agents, and natural products, but is not limited thereto.

[0015] Examples of moisturizing agents include, but are not limited to, creatine, polyglutamic acid, sodium lactate, hydroproline, sodium 2-pyrrolidone-5-carboxylate, hyaluronic acid, sodium hyaluronate, ceramide, phytosterol, cholesterol, sitosterol, proteoglycan, etc. Examples of whitening agents include, but are not limited to, arbutin and arbutin derivatives, kojic acid, bisabolol, niacinamide, vitamin C and vitamin C derivatives, placenta, allantoin, etc. Examples of anti-wrinkle agents include, but are not limited to, retinol, retinol derivatives, adenosine, licorice extract, Panax ginseng extract, Korean ginseng extract, etc. Examples of UV blocking agents include, but are not limited to, benzophenone derivatives, para-aminobenzoic acid derivatives, methoxycinnamic acid derivatives, salicylic acid derivatives, etc. There are no particular limitations on the hair growth agent, but it may preferably be a blood circulation promoter and / or a local stimulant. Examples of blood circulation promoters include, but are not limited to, Swertia japonica extract, cepharanthine, vitamin E and its derivatives, gamma oryzanol, etc. Local irritants include, but are not limited to, capsicum tincture, ginger tincture, cantharides tincture, nicotinic acid benzyl ester, etc. Examples of vitamins or their derivatives include vitamin A (retinol) and its derivatives, vitamins B1, B2, B6, vitamin E and its derivatives, vitamin D, vitamin H, vitamin K, pantothenic acid and its derivatives, biotin, panthenol, and coenzyme Q. 10, idebenone, etc. Examples of amino acids or peptides include, but are not limited to, cystine, cysteine, methionine, serine, lysine, tryptophan, amino acid extract, epidermal growth factor (EGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF), copper tripeptide-1, tripeptide-29, tripeptide-1, acetyl hexapeptide-8, nicotinoyl tripeptide-35, hexapeptide-12, hexapeptide-9, palmitoyl pentapeptide-4, palmitoyl pentapeptide-3, palmitoyl tetrapeptide-7, palmitoyl tripeptide-29, palmitoyl tripeptide-1, nonapeptide-7, tripeptide-10, citrulline, sh-polypeptide-15, palmitoyl tripeptide-5, diaminopropionoyl tripeptide-33, r-spider polypeptide-1, etc. Anti-inflammatory agents include, but are not limited to, β-glycyrrhetinic acid, glycyrrhetinic acid derivatives, aminocaproic acid, hydrocortisone, β-glucan, madeccaide, licorice, etc. Examples of acne treatment agents include, but are not limited to, estradiol, estrogen, ethinylestradiol, triclosan, azelaic acid, etc. Examples of disinfectants include, but are not limited to, benzalkonium chloride, benzethonium chloride, halocarban, etc. There are no particular limitations on female hormones, but estrogens may be preferred. Preferred estrogens include estradiol, ethinylestradiol, and isoflavones, which are phytoestrogens. Examples of keratolytic agents include, but are not limited to, sulfur, salicylic acid, AHA (Anti-Hypoallergenic Acid), BHA (BHA), resorcinol, etc. Examples of extracts of natural products or components obtained therefrom include, but are not limited to, extracts of witch hazel, dead nettle, sedge, rhubarb, licorice, aloe, chamomile, rose hip, horse chestnut, ginseng, loofah, cucumber, seaweed, wakame seaweed, hemp, snail, Chinese yam, green tea, etc., or curcumin, hinokitiol, β-carotene, etc.

[0016] Additionally, cosmetic ingredients such as oils, waxes, butters, paraffins, higher fatty acids such as stearic acid, esters such as cetyl ethylhexanoate, and silicones can be used as active ingredients. Oils include, but are not limited to, olive oil, camellia oil, avocado oil, macadamia oil, castor oil, sunflower oil, jojoba oil, almond oil, apricot seed oil, green tea oil, meadowfoam seed oil, and argan oil. Waxes include, but are not limited to, carnauba wax, candelilla wax, jojoba oil, beeswax, lanolin, soybean wax, rice wax, and silicone wax. Butters include, but are not limited to, shea butter, mango butter, green tea butter, and soybean butter. Hydrocarbons include, but are not limited to, liquid paraffin, paraffin, petrolatum, ceresin, microcrystalline wax, and squalane. Examples of higher fatty acids include, but are not limited to, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, and linolenic acid. Examples of higher alcohols include, but are not limited to, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, and behenyl alcohol. Examples of esters include, but are not limited to, 2-octyldodecyl myristate, cetyl 2-ethylhexanoate, diisostearyl malate, and cetyl ethylhexanoate. Examples of silicones include, but are not limited to, dimethicones, cyclomethicones, silicone polymers, and silicone oils.

[0017] In addition to the above, yeast extract, collagen, elastin, sucrose octasulfate Al, DHA, EPA, fragrance components, etc. can be used. According to another aspect of the present invention, there is provided a cosmetic composition comprising the complex for transdermal delivery of the present invention. In the present invention, the cosmetic composition can be formulated into, for example, but not limited to, a toner, a lotion, a body lotion, a cream, an essence, etc. The cosmetic composition preferably contains 1 to 60 wt %, more preferably 2 to 50 wt %, of the complex for transdermal delivery according to the present invention. In the present invention, if the cosmetic composition contains less than 1 wt % of the complex for transdermal delivery, the effect of the active ingredient will be weakened, and if it contains more than 60 wt %, the increase in the effect of the active ingredient commensurate with the amount added cannot be expected, which may be economically undesirable.

[0018] According to another aspect of the present invention, there is provided a method for producing a complex for transdermal delivery, comprising: i) dissolving a cyclodextrin, a potassium base, and a polymer in a solvent; ii) forming crystals from the solution obtained in step i) in a crystallization solvent using a vapor diffusion crystallizer; and iii) washing and drying the crystals formed in step ii). In another embodiment according to the invention, the cyclodextrin is α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin. In another embodiment according to the invention, the cyclodextrin is γ-cyclodextrin. In another embodiment according to the present invention, the potassium base is potassium hydroxide (KOH).

[0019] In another embodiment according to the present invention, the polymer is a biodegradable polymer. In another embodiment according to the present invention, the polymer is selected from the group consisting of chitosan, pullulan, polylactic acid, succinylated chitosan, pullulan-poly-(L)-lactic acid, polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymers, and mixtures thereof. In another embodiment according to the present invention, the polymer is selected from the group consisting of succinylated chitosan, pullulan-poly-(L)-lactic acid, polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymers, and mixtures thereof.

[0020] In another embodiment according to the present invention, the solvent in step i) is selected from the group consisting of water, propylene glycol and mixtures thereof. In another embodiment of the present invention, in step i), 10 to 200 parts by weight of cyclodextrin, 1 to 100 parts by weight of potassium base, and 0.01 to 50 parts by weight of polymer are dissolved in 100 parts by weight of solvent.

[0021] In the present invention, the step ii) proceeds by forming crystals from the solution obtained in step i) in a crystallization solvent using a vapor diffusion crystallizer. In the present invention, crystals are formed using a vapor diffusion crystallizer by setting up a column in the center of the vapor diffusion crystallizer, adding the solution obtained in step i) (without closing the cap), placing a crystallization solvent around the column, and then sealing the vapor diffusion crystallizer to prevent air from passing through and leaving it to stand, whereby the crystallization solvent is diffused and crystals are formed in the column.

[0022] In one embodiment according to the present invention, the crystallization solvent in step ii) is selected from the group consisting of methanol, ethanol and mixtures thereof. In one embodiment according to the present invention, in step i), the active ingredient can further be dissolved in a solvent. In one embodiment according to the present invention, the active ingredient may be one or more selected from the group consisting of moisturizers, whitening agents, anti-wrinkle agents, UV blocking agents, hair growth agents, vitamins or derivatives thereof, amino acids or peptides, anti-inflammatory agents, anti-acne agents, disinfectants, female hormone agents, keratolytic agents, natural products, oils, waxes, butters, paraffins, higher fatty acids, esters, and silicones. [Effects of the Invention]

[0023] The complex for transdermal delivery of the present invention efficiently delivers the active ingredient into the skin in a highly stable form, and is therefore capable of exerting excellent effects over a long period of time even with a small amount of the active ingredient. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 is a schematic diagram showing the structure of a cyclodextrin-based covalent organic framework. [Figure 2] Chemical structures of (a) succinylated chitosan and (b) pullulan-poly(L)-lactic acid. [Figure 3] 1 is a schematic diagram showing the synthesis process of PEG-PCL-PEG triblock copolymer. [Figure 4] FIG. 1 is a schematic diagram showing a vapor diffusion crystallizer. [Figure 5] FIG. 1 is a schematic diagram showing the formation of crystals using a vapor diffusion crystallizer. [Figure 6] The particle size of a complex of a covalent organic framework based on retinol-containing cyclodextrin and succinylated chitosan was measured using Photal and ELS-Z. [Figure 7] The zeta potential was measured using Photal and ELS-Z to measure the stability of a complex between a retinol-containing cyclodextrin-based covalent organic framework and succinylated chitosan. [Figure 8] The results show the stability of a complex between a retinol-containing cyclodextrin-based covalent organic framework and succinylated chitosan, as measured by Turbiscan. [Figure 9] These are the results of powder X-ray diffraction (XRD) tests (γ-CD: γ-cyclodextrin, COF: covalent organic framework, PEG-PCL-PEG: PEG-PCL-PEG triblock copolymer, SC: succinylated chitosan, PL: pullulan-poly(L)-lactic acid). [Figure 10] 1 shows the results of Fourier transform infrared spectroscopy measurement of a composite of a curcumin-containing cyclodextrin-based covalent organic framework and a polymer, prepared in Example 3. [Figure 11] These are enlarged photographs taken using cryo-electron microscopy of the cyclodextrin-based covalent organic frameworks and complexes produced in the Production Examples and Working Examples (γ-CD: γ-cyclodextrin, COF: covalent organic framework, PEG-PCL-PEG: PEG-PCL-PEG triblock copolymer, SC: succinylated chitosan, PL: pullulan-poly-(L)-lactic acid). BEST MODE FOR CARRYING OUT THE INVENTION

[0025] The present invention will now be described in more detail with reference to the following examples, but it should be understood that the scope of protection of the present invention is not limited to the following examples.

[0026] Production Example 1: Production of succinylated chitosan 160 mL of methanol was added to 40 mL of aqueous lactic acid (5% v / v), and 0.5 g of chitosan was dissolved with stirring. 1.0 g of succinyl anhydride was added, and the resulting solution was left at room temperature with stirring for 24 hours. Succinylated chitosan was precipitated by adjusting the pH to 7.4 with 5 N NaOH and centrifuged at 5,000 rpm for 5 minutes at 37°C. The centrifuged product was resuspended in distilled water and subsequently dialyzed against distilled water for 72 hours (cellulose dialysis tubing, molecular weight cutoff 14,000) and then lyophilized for 3 days.

[0027] Production Example 2: Production of pullulan-poly-(L)-lactic acid 0.2 g of purified pullulan was dissolved in 11 mL of DMSO by stirring at room temperature under dry nitrogen. 1 g of L-lactide was added to the resulting pullulan solution and stirred in a preheated oil bath at 70-75 °C. When the mixture was completely dissolved, 0.17 mL of triethylamine (TEA) was added as a catalyst. After 12 h of reaction, the reaction solution was filtered through a 0.5 μm syringe filter. The filtrate was dialyzed against distilled water using a dialysis membrane (MWCO: 10,000) for 2 days, with the distilled water replaced every 2 h for the first 12 h. The product was lyophilized for 3 days and stored at -20 °C until use.

[0028] Preparation Example 3: Preparation of PEG-PCL-PEG triblock copolymer Polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymers were prepared in two steps: the first step was the formation of a diblock copolymer of methoxypoly(ethylene glycol) (mPEG) and ε-caprolactone (ε-PCL), and the second step was the conjugation of two diblock copolymer molecules using hexamethylene diisocyanate (HMDI). After removing residual moisture using a Dean-Stark trap, 8.06 g of mPEG was completely dissolved in 80 mL of anhydrous toluene for 25 minutes and then vacuum-dried for 3 hours. Then, 4.03 g of ε-CL as a monomer and 1.61 g of SnOct2 as a catalyst were added and reacted at 140 °C for 14 hours. HMDI was then added to the reaction mixture and reacted at 60 °C for 8 hours. The resulting product was isolated with diethyl ether, and the residual solvent was removed under vacuum to yield a PEG-PCL-PEG triblock copolymer. All reactions were performed under a nitrogen atmosphere. A schematic diagram of the synthesis of the PEG-PCL-PEG triblock copolymer is shown in Figure 2. The weight-average molecular weight of the synthesized PEG-PCL-PEG triblock copolymer was set to 10,000.

[0029] Production Example 4: Production of cyclodextrin-based covalent organic framework (hereinafter referred to as "CD-COF") 390 g of cyclodextrin (α, β, or γ) and 135 g of KOH were dissolved in 600 g of distilled water. After preparing the vapor diffusion crystallizer as shown in Figure 4, a column was placed in the center, and a solution of cyclodextrin and KOH dissolved in distilled water was added. The column was then left uncapped and the crystallization solvent (ethanol or methanol) was added around the column. The vapor diffusion crystallizer was then sealed to prevent air from passing through. After 12 hours at room temperature, crystals began to form within the column as the crystallization solvent diffused (Figure 5). The experiment was terminated after 24 hours, and the crystals were washed and dried for 24 hours.

[0030] Example 1: Preparation of CD-COF and polymer composite 390 g of cyclodextrin (α, β, or γ), 135 g of KOH, and 5 g of polymer (succinylated chitosan, pullulan-poly(L)-lactic acid, or PEG-PCL-PEG triblock copolymer) were dissolved in 600 g of distilled water. After preparing the vapor diffusion crystallizer, a column was placed in the center, and the solution of cyclodextrin, KOH, and polymer dissolved in distilled water was added. The column was left uncapped and the crystallization solvent (ethanol or methanol) was poured around the column. The vapor diffusion crystallizer was sealed to prevent airflow and allowed to stand. After 12 h at room temperature, crystals began to form within the column as the crystallization solvent diffused. The experiment was terminated after 24 h, and the crystals were washed and dried for 24 h.

[0031] Example 2: Preparation of CD-COF and polymer composites containing retinol 390 g of cyclodextrin (α, β, or γ), 135 g of KOH, 10 g of polymer (succinylated chitosan, pullulan-poly(L)-lactic acid, or PEG-PCL-PEG triblock copolymer), and 20 g of retinol were dissolved in 700 g of distilled water. After preparing the vapor diffusion crystallizer, a column was placed in the center, and the solution of cyclodextrin, KOH, polymer, and retinol dissolved in distilled water was added. The column was left uncapped and the crystallization solvent (ethanol or methanol) was poured around the column. The vapor diffusion crystallizer was sealed airtight and left standing. Crystals began to form in the column after 12 h at room temperature as the crystallization solvent diffused. The experiment was terminated after 24 h, and the crystals were washed and dried for 24 h.

[0032] Example 3: Preparation of curcumin-containing CD-COF and polymer composites 390 g of cyclodextrin (α, β, or γ), 135 g of KOH, 10 g of polymer (succinylated chitosan, pullulan-poly(L)-lactic acid, or PEG-PCL-PEG triblock copolymer), and 20 g of curcumin were dissolved in 700 g of distilled water. After preparing the vapor diffusion crystallizer, a column was placed in the center, and the solution of cyclodextrin, KOH, polymer, and curcumin dissolved in distilled water was added. The column was left uncapped and the crystallization solvent (ethanol or methanol) was poured around the column. The vapor diffusion crystallizer was sealed airtight and left standing. Crystals began to form within the column after 12 h at room temperature as the crystallization solvent diffused. The experiment was terminated after 24 h, and the crystals were washed and dried for 24 h.

[0033] Example 4: Preparation of CD-COF and polymer composites containing plant natural products It was produced in the same manner as in Example 2 using the composition shown in Table 1 below. [Table 1]

[0034] Example 5: Preparation of CD-COF and polymer composites containing marine natural products It was produced in the same manner as in Example 2 using the composition shown in Table 2 below. [Table 2]

[0035] Example 6: Preparation of oil-containing CD-COF and polymer composites It was produced in the same manner as in Example 2 using the composition in Table 3 below. [Table 3]

[0036] Example 7: Preparation of CD-COF and polymer composites containing wax It was produced in the same manner as in Example 2 using the composition in Table 4 below. [Table 4]

[0037] Example 8: Preparation of CD-COF and polymer composites containing butter It was produced in the same manner as in Example 2 using the composition in Table 5 below. [Table 5]

[0038] Example 9: Preparation of CD-COF and polymer composites containing paraffin It was produced in the same manner as in Example 2 using the composition in Table 6 below. [Table 6]

[0039] Example 10: Preparation of CD-COF and polymer composites containing higher fatty acids It was produced in the same manner as in Example 2 using the composition in Table 7 below. [Table 7]

[0040] Example 11: Preparation of CD-COF and polymer composites containing esters It was produced in the same manner as in Example 2 using the composition in Table 8 below. [Table 8]

[0041] Example 12: Preparation of silicone-containing CD-COF and polymer composites It was produced in the same manner as in Example 2 using the composition in Table 9 below. [Table 9]

[0042] Example 13: Preparation of CD-COF and polymer composite containing humectant It was produced in the same manner as in Example 2 using the composition in Table 10 below. [Table 10]

[0043] Example 14: Preparation of CD-COF and polymer composite containing skin whitening agent It was produced in the same manner as in Example 2 using the composition in Table 11 below. [Table 11]

[0044] Example 15: Preparation of CD-COF and polymer composites containing UV-blocking agents It was produced in the same manner as in Example 2 using the composition in Table 12 below. [Table 12]

[0045] Example 16: Preparation of CD-COF and polymer complexes containing vitamins It was produced in the same manner as in Example 2 using the composition in Table 13 below. [Table 13]

[0046] Example 17: Preparation of CD-COF and polymer conjugates containing amino acids It was produced in the same manner as in Example 2 using the composition in Table 14 below. [Table 14]

[0047] Example 18: Preparation of peptide-containing CD-COF and polymer conjugates It was produced in the same manner as in Example 2 using the composition in Table 15 below. [Table 15]

[0048] Example 19: Preparation of CD-COF and polymer composites containing anti-inflammatory agents It was produced in the same manner as in Example 2 using the composition in Table 16 below. [Table 16]

[0049] Example 20: Preparation of CD-COF and polymer composite containing anti-acne agent It was produced in the same manner as in Example 2 using the composition in Table 17 below. [Table 17]

[0050] Example 21: Preparation of CD-COF and polymer composites containing biocides It was produced in the same manner as in Example 2 using the composition in Table 18 below. [Table 18]

[0051] Experimental example 1: Measurement of particle distribution The particle size distribution of the retinol-containing CD-COF and succinylated chitosan complex prepared in Example 2 was measured using Photal and ELS-Z, and is shown in Figure 6. The measurement results showed that the average particle size of the complex was 408.8 nm.

[0052] Experimental Example 2: Stability measurement of CD-COF and polymer complexes containing retinol To evaluate the stability of the retinol-containing CD-COF and succinylated chitosan complex prepared in Example 2, the zeta potential was measured using Photal ELS-Z, and the results are shown in Figure 7. The measurement results showed that the particle potential was stable at -60.55 mV.

[0053] Experimental Example 3: Stability measurement of CD-COF and polymer composites containing retinol The stability of the retinol-containing CD-COF and succinylated chitosan complex prepared in Example 2 was measured using Turbiscan. The results showed that there was almost no change in △T and △BS over time, indicating that the complex was stable (Figure 8).

[0054] Experimental Example 4: Powder X-ray diffraction test Powder X-ray diffraction (XRD) tests were performed on the retinol-containing CD-COF and polymer composite prepared in Example 2 and the curcumin-containing CD-COF and polymer composite prepared in Example 3, and the results are shown in Figure 9. As can be seen from the results in Figure 9, specific peaks appeared, indicating that each composite was fully synthesized.

[0055] Experimental Example 5: Fourier Transform Infrared Spectroscopy (FTIR) Test The curcumin-containing CD-COF and polymer composite prepared in Example 3 were measured by Fourier transform infrared spectroscopy (FTIR), and the results are shown in FIG. 10.

[0056] Experimental Example 6: Cryo-electron microscopy The CD-COF and the composites produced in the Preparation Examples and Examples were photographed. Because the particle size was too small to measure using a general optical microscope, images were taken using a cryo-electron microscope (JEM1010, JEOL, Japan) (Figure 11). It was found that the CD-COF and polymer composites were well formed, and that retinol was well attached to them.

[0057] Experimental Example 7: Transdermal absorption enhancement effect experiment Liposomes (liposome A) containing a complex of CD-COF and succinylated chitosan containing 10% retinol and having the composition shown in Table 19 below, and general liposomes (liposome B) were prepared. [Table 19]

[0058] The experiment was performed by attaching artificial skin Neoderm (Tego Science, Korea) to a Franz diffusion cell (Lab Fine Instruments, Korea). 50 mM phosphate buffer (pH 7.4, 0.1 M NaCl) was added to the receptor cell (5 mL) of the Franz diffusion cell. Next, the diffusion cell was mixed and dispersed at 32°C and 600 rpm, and 50 μL each of liposome A and liposome B was added to the donor cell. Absorption and diffusion were performed for a predetermined time, and the area of ​​the skin where absorption and diffusion occurred was 0.64 cm. 2 After the active ingredient was absorbed and diffused, any unabsorbed residue remaining on the skin was washed with dry Kimwipes® or 10 mL of ethanol. The skin into which the active ingredient had been absorbed and diffused was homogenized using a tip-type homogenizer, and the retinol absorbed into the skin was extracted with 4 mL of dichloromethane. The extract was then filtered through a 0.45 μm nylon membrane filter, and the retinol content was measured by high-performance liquid chromatography under the following conditions. The results are shown in Table 20. [Table 20]

[0059] As can be seen from Table 20 above, in the present invention, retinol was encapsulated in a complex of CD-COF and a polymer and was efficiently delivered to the skin.

Claims

1. A complex for transdermal delivery comprising a crystal formed from cyclodextrin and a potassium salt, a polymer, and an active ingredient, The complex for transdermal delivery is a complex in which the polymer and the active ingredient are complexed to form crystals by vapor diffusion of a crystallization solvent into a solution containing cyclodextrin, potassium hydroxide (KOH), the polymer, and the active ingredient; The complex for transdermal delivery, wherein the polymer is selected from the group consisting of chitosan, pullulan, polylactic acid, succinylated chitosan, pullulan-poly-(L)-lactic acid, polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymer, and mixtures thereof.

2. 2. The complex for transdermal delivery according to claim 1, wherein the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

3. 3. The complex for transdermal delivery according to claim 2, wherein the cyclodextrin is γ-cyclodextrin.

4. The complex for transdermal delivery according to claim 1, characterized in that the polymer is selected from the group consisting of succinylated chitosan, pullulan-poly-(L)-lactic acid, polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymer, and mixtures thereof.

5. 2. The complex for transdermal delivery according to claim 1, wherein the polymer is contained in an amount of 0.01 to 10 parts by weight per 10 parts by weight of the crystals formed from the cyclodextrin and the potassium salt.

6. 2. The complex for transdermal delivery according to claim 1, wherein the active ingredient is one or more selected from the group consisting of moisturizers, whitening agents, anti-wrinkle agents, UV blocking agents, hair growth agents, vitamins or derivatives thereof, amino acids or peptides, anti-inflammatory agents, acne treatment agents, bactericides, female hormones, keratolytic agents, natural products, oils, waxes, butters, paraffins, higher fatty acids, esters, and silicones.

7. A cosmetic composition comprising the complex for transdermal delivery according to any one of claims 1 to 6.

8. 8. The cosmetic composition according to claim 7, comprising 1 to 60% by weight of the complex for transdermal delivery.

9. i) dissolving cyclodextrin, potassium hydroxide (KOH), polymer and active ingredient in a solvent; ii) forming crystals from the solution obtained in step i) in a crystallization solvent using a vapor diffusion crystallizer; iii) washing and drying the crystals formed in step ii); This includes: A method for producing a complex for transdermal delivery, wherein the polymer is selected from the group consisting of chitosan, pullulan, polylactic acid, succinylated chitosan, pullulan-poly-(L)-lactic acid, polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymer, and mixtures thereof.

10. 10. The method for producing a complex for transdermal delivery according to claim 9, wherein the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

11. 11. The method for producing a complex for transdermal delivery according to claim 10, wherein the cyclodextrin is γ-cyclodextrin.

12. 10. The method for producing a complex for transdermal delivery according to claim 9, wherein the polymer is selected from the group consisting of succinylated chitosan, pullulan-poly-(L)-lactic acid, polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymer, and mixtures thereof.

13. 10. The method for producing a complex for transdermal delivery according to claim 9, wherein the solvent in step i) is selected from the group consisting of water, propylene glycol, and mixtures thereof.

14. 10. The method for producing a complex for transdermal delivery according to claim 9, wherein 10 to 200 parts by weight of cyclodextrin, 1 to 100 parts by weight of potassium base, and 0.01 to 50 parts by weight of polymer are dissolved in 100 parts by weight of the solvent in step i).

15. 10. The method for producing a complex for transdermal delivery according to claim 9, wherein the crystallization solvent in step ii) is selected from the group consisting of methanol, ethanol, and mixtures thereof.

16. 10. The method for producing a complex for transdermal delivery according to claim 9, wherein the active ingredient is one or more selected from the group consisting of moisturizers, whitening agents, anti-wrinkle agents, UV blocking agents, hair growth agents, vitamins or derivatives thereof, amino acids or peptides, anti-inflammatory agents, acne treatment agents, bactericides, female hormones, keratolytic agents, natural products, oils, waxes, butters, paraffins, higher fatty acids, esters, and silicones.

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