TRANSDERMAL DELIVERY COMPOSITE USING COVALENT ORGANIC FRAMEWORK AND POLYMER

Abstract

The present invention relates to a transdermal delivery composite comprising a cyclodextrin-based covalent organic framework and polymer. In addition, the present invention relates to a cosmetic composition comprising the transdermal delivery composite, and a method for preparing the transdermal delivery composite.

Claims

1. A composite for transdermal delivery comprising a cyclodextrin-based covalent organic framework (CD-COF) and a polymer.

2. The composite for transdermal delivery according to claim 1, wherein the cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin.

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

4. The composite for transdermal delivery according to claim 1, wherein the cyclodextrin-based covalent organic framework is prepared from cyclodextrin and potassium salt.

5. The composite for transdermal delivery according to claim 4, wherein the potassium salt is potassium hydroxide (KOH).

6. The composite for transdermal delivery according to claim 1, wherein the polymer is selected from the group consisting of chitosan, pullulan, polylactic acid, succinylated chitosan, pullulan-poly-(L)-lactic acid, a triblock copolymer of polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) and mixtures thereof.

7. The composite for transdermal delivery according to claim 6, wherein the polymer is selected from the group consisting of succinylated chitosan, pullulan-poly-(L)-lactic acid, a triblock copolymer of polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) and mixtures thereof.

8. The composite for transdermal delivery according to claim 1, wherein 0.01 to 100 parts by weight of the polymer are included based on 10 parts by weight of the cyclodextrin-based covalent organic framework.

9. The composite for transdermal delivery according to claim 1, further comprising an active ingredient.

10. The composite for transdermal delivery according to claim 9, wherein the active ingredient is one or more selected from the group consisting of a moisturizer, a whitening agent, an anti-wrinkle agent, a UV blocking agent, a hair growth promoter, vitamin or a derivative thereof, amino acid or peptide, an anti-inflammatory agent, an acne therapeutic agent, a microbicide, female hormone, a keratolytic agent, a natural product, oil, wax, butter, paraffin, a higher fatty acid, an ester and a silicone.

11. A cosmetic composition comprising the composite for transdermal delivery according to claim 9.

12. The cosmetic composition according to claim 11, comprising 1 to 60% by weight of the composite for transdermal delivery.

13. A method for preparing a composite for transdermal delivery comprising: i) dissolving cyclodextrin, potassium base and a polymer in a solvent, ii) forming crystals in the crystallization solvent from the solution obtained in step (i) using a gas diffusion crystallizer and iii) washing the crystals formed in step (ii) and drying the crystals.

14. The method for preparing a composite for transdermal delivery according to claim 13, wherein the cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin or gamma-cyclodextrin.

15. The method for preparing a composite for transdermal delivery according to claim 14, wherein the cyclodextrin is gamma-cyclodextrin.

16. The method for preparing a composite for transdermal delivery according to claim 13, wherein the potassium salt is potassium hydroxide (KOH).

17. The method for preparing a composite for transdermal delivery according to claim 13, wherein the polymer is selected from the group consisting of chitosan, pullulan, polylactic acid, succinylated chitosan, pullulan-poly-(L)-lactic acid, a triblock copolymer of polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) and mixtures thereof.

18. The method for preparing a composite for transdermal delivery according to claim 17, wherein the polymer is selected from the group consisting of succinylated chitosan, pullulan-poly-(L)-lactic acid, a triblock copolymer of polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) and mixtures thereof.

19. The method for preparing a composite for transdermal delivery according to claim 13, wherein the solvent of step (i) is selected from the group consisting of water, propylene glycol and mixtures thereof.

20. The method for preparing a composite for transdermal delivery according to claim 13, 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 the polymer are dissolved based on 100 parts by weight of the solvent in step (i).

21. The method for preparing a composite for transdermal delivery according to claim 13, wherein the crystallization solvent in step (ii) is selected from the group consisting of methanol, ethanol and mixtures thereof.

22. The method for preparing a composite for transdermal delivery according to claim 13, wherein the active ingredient is further dissolved in a solvent in step (i).

23. The method for preparing a composite for transdermal delivery according to claim 22, wherein the active ingredient is one or more selected from the group consisting of a moisturizer, a whitening agent, an anti-wrinkle agent, a UV blocking agent, a hair growth promoter, vitamin or a derivative thereof, amino acid or peptide, an anti-inflammatory agent, an acne therapeutic agent, a microbicide, female hormone, a keratolytic agent, a natural product, oil, wax, butter, paraffin, a higher fatty acid, an ester and a silicone.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG. 1 is a schematic diagram representing the structure of a cyclodextrin-based covalent organic framework.

[0048] FIG. 2 is a chemical structural formula of (a) succinylated chitosan and (b) pullulan-poly-(L)-lactic acid.

[0049] FIG. 3 is a schematic diagram representing the synthetic procedure of a triblock copolymer of PEG-PCL-PEG.

[0050] FIG. 4 is a schematic diagram representing a gas diffusion crystallizer.

[0051] FIG. 5 is a schematic diagram representing the formulation of a crystal using a gas diffusion crystallizer.

[0052] FIG. 6 is a result of measuring the particle size of the composite of the cyclodextrin-based covalent organic framework containing retinol and succinylated chitosan using Photal, ELS-Z.

[0053] FIG. 7 is a result of measuring the zeta potential using Photal and ELS-Z to measure the stability of the composite of the cyclodextrin-based covalent organic framework containing retinol and succinylated chitosan.

[0054] FIG. 8 is a result of measuring the stability of the composite of the cyclodextrin-based covalent organic framework containing retinol and succinylated chitosan using Turbiscan.

[0055] FIG. 9 is a result of powder X-ray diffraction test (XRD) (γ-CD: gamma-cyclodextrin, COF: covalent organic framework, PEG-PCL-PEG: triblock copolymer of PEG-PCL-PEG, SC: succinylated chitosan, PL: pullulan-poly-(L)-lactic acid).

[0056] FIG. 10 is a result of measuring the composite of the cyclodextrin-based covalent organic framework containing curcumin and polymer prepared in Example 3 by Fourier transform infrared spectroscopy.

[0057] FIG. 11 is an enlarged photograph of the cyclodextrin-based covalent organic framework and the composite prepared in the Preparation Examples and Examples using a freezing electron microscope (γ-CD: gamma-cyclodextrin, COF: covalent organic framework, PEG-PCL-PEG: triblock copolymer of PEG-PCL-PEG, SC: succinylated chitosan, PL: pullulan-poly-(L)-lactic acid).

DETAILED DESCRIPTION

[0058] Hereinafter, the present invention is explained in more detail with the following examples. However, it must be understood that the protection scope of the present invention is not limited to the examples.

Preparation Example 1: Preparation of Succinylated Chitosan

[0059] 160 mL of methanol was added to 40 mL of lactic acid aqueous solution (5% v/v), and then 0.5 g of chitosan was dissolved with stirring. 1.0 g of succinyl anhydride was added thereto, and the resulting solution was left at room temperature for 24 hours while stirring. Succinylated chitosan was precipitated by adjusting the pH to 7.4 with 5N NaOH and centrifuged at 5,000 rpm for 5 min at 37° C. The centrifuged product was resuspended in distilled water, followed by dialysis against distilled water for 72 hours (dialysis tubing cellulose, molecular weight cut-off 14,000) and then lyophilized for 3 days. Preparation Example 2: Preparation of pullulan-poly-(L)-lactic acid

[0060] 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 obtained pullulan solution and then stirred in an oil bath preheated to 70 to 75° C. When the mixture was completely dissolved, 0.17 mL of triethylamine (TEA) as a catalyst was introduced. After 12 hours 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, and the distilled water was exchanged every 2 hours for the first 12 hours. The product was lyophilized for 3 days and then stored at −20° C. until use.

Preparation Example 3: Preparation of Triblock Copolymer of PEG-PCL-PEG

[0061] Polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) triblock copolymer was prepared by dividing it into two steps. The first step was the formation of a diblock copolymer of methoxypoly(ethylene glycol) (mPEG) and ε-caprolactone (ε-CL), and the second step was the linkage of two diblock copolymer molecules by the use of hexamethylene diisocyanate (HMDI).

[0062] First, 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. After that, 4.03 g of ε-CL as a monomer and 1.61 g of SnOct.sub.2 as a catalyst were added, respectively, and reacted at 140° C. for 14 hours. Then, HMDI was added to the reaction mixture and reacted at 60° C. for 8 hours. The obtained product was isolated in diethyl ether and the residual solvent was removed under vacuum to obtain a PEG-PCL-PEG triblock copolymer. All reactions were carried out under a nitrogen atmosphere. The synthesis schematic of the PEG-PCL-PEG triblock copolymer is shown in FIG. 2. The weight average molecular weight of the synthesized PEG-PCL-PEG triblock copolymer was set to 10,000.

Preparation Example 4: Preparation of a Cyclodextrin-Based Covalent Organic Framework (Hereinafter “CD-COF”)

[0063] 390 g of cyclodextrin (alpha, beta or gamma) and 135 g of KOH were dissolved in 600 g of distilled water. After preparing a gas diffusion crystallizer as shown in FIG. 4, a column was erected in the center, and a solution in which cyclodextrin and KOH are dissolved in distilled water was put there, without closing the cap, and a crystallization solvent (ethanol or methanol) was put around the column. When the gas diffusion crystallizer was sealed so that air was not passed and left to stand, crystals started to form in the column after about 12 hours at room temperature as the crystallization solvent was diffused (FIG. 5). The experiment was terminated after 24 hours, and the formed crystals were washed and dried for 24 hours.

Example 1: Preparation of a Composite of CD-COF and Polymer

[0064] 390 g of cyclodextrin (alpha, beta or gamma), 135 g of KOH and 5 g of polymer (succinylated chitosan, pullulan-poly-(L)-lactic acid or triblock copolymer of PEG-PCL-PEG) were dissolved in 600 g of distilled water. After preparing a gas diffusion crystallizer, a column was erected in the center, and a solution in which cyclodextrin, KOH and the polymer are dissolved in distilled water was put there, without closing the cap, and a crystallization solvent (ethanol or methanol) was put around the column. When the gas diffusion crystallizer was sealed so that air was not passed and left to stand, crystals started to form in the column after about 12 hours at room temperature as the crystallization solvent was diffused. The experiment was terminated after 24 hours, and the formed crystals were washed and dried for 24 hours.

Example 2: Preparation of a Composite of CD-COF Containing Retinol and Polymer

[0065] 390 g of cyclodextrin (alpha, beta or gamma), 135 g of KOH, 10 g of polymer (succinylated chitosan, pullulan-poly-(L)-lactic acid or triblock copolymer of PEG-PCL-PEG) and 20 g of retinol were dissolved in 700 g of distilled water. After preparing a gas diffusion crystallizer, a column was erected in the center, and a solution in which cyclodextrin, KOH, the polymer and retinol were dissolved in distilled water was put there, without closing the cap, and a crystallization solvent (ethanol or methanol) was put around the column. When the gas diffusion crystallizer was sealed so that air was not passed and left to stand, crystals started to form in the column after about 12 hours at room temperature as the crystallization solvent was diffused. The experiment was terminated after 24 hours, and the formed crystals were washed and dried for 24 hours.

Example 3: Preparation of a Composite of CD-COF Containing Curcumin and Polymer

[0066] 390 g of cyclodextrin (alpha, beta or gamma), 135 g of KOH, 10 g of polymer (succinylated chitosan, pullulan-poly-(L)-lactic acid or triblock copolymer of PEG-PCL-PEG) and 20 g of curcumin were dissolved in 700 g of distilled water. After preparing a gas diffusion crystallizer, a column was erected in the center, and a solution in which cyclodextrin, KOH, the polymer and curcumin were dissolved in distilled water was put there, without closing the cap, and a crystallization solvent (ethanol or methanol) was put around the column. When the gas diffusion crystallizer was sealed so that air was not passed and left to stand, crystals started to form in the column after about 12 hours at room temperature as the crystallization solvent was diffused. The experiment was terminated after 24 hours, and the formed crystals were washed and dried for 24 hours.

Example 4: Preparation of a Composite of CD-COF Containing Plant Natural Products and Polymer

[0067] It was prepared in the same manner as in Example 2 with the composition shown in Table 1 below.

TABLE-US-00001 TABLE 1 Content Ingredient (part by weight) CD-COF 5 PEG-PCL-PEG 5 triblock copolymer Extract of green tea 10 KOH 2 Distilled water 24

Example 5: Preparation of a Composite of CD-COF Containing Marine Natural Products and Polymer

[0068] It was prepared in the same manner as in Example 2 with the composition shown in Table 2 below.

TABLE-US-00002 TABLE 2 Content Ingredient (part by weight) CD-COF 6 Pullulan-poly-(L)- 7 lactic acid Extract of laver 10 KOH 3 Distilled water 22

Example 6: Preparation of a Composite of CD-COF Containing Oils and Polymer

[0069] It was prepared in the same manner as in Example 2 with the composition shown in Table 3 below.

TABLE-US-00003 TABLE 3 Content Ingredient (part by weight) CD-COF 5 Succinylated chitosan 5 Avocado oil 1 Olive oil 3 Camellia oil 1 Macadamia oil 1 Castor oil 2 Sunflower oil 2 Jojoba oil 2 Almond oil 1 Meadowfoam seed oil 2 Argan oil 2 KOH 3 Distilled water 38

Example 7: Preparation of a Composite of CD-COF Containing Waxes and Polymer

[0070] It was prepared in the same manner as in Example 2 with the composition shown in Table 4 below.

TABLE-US-00004 TABLE 4 Content Ingredient (part by weight) CD-COF 5 Succinylated chitosan 10 Beeswax 4 Silicone wax 4 KOH 4 Distilled water 33

Example 8: Preparation of a Composite of CD-COF Containing Butters and Polymer

[0071] It was prepared in the same manner as in Example 2 with the composition shown in Table 5 below.

TABLE-US-00005 TABLE 5 Content Ingredient (part by weight) CD-COF 15 PEG-PCL-PEG 1 triblock copolymer Shea butter 2 Mango butter 5 Green tea butter 1 KOH 5 Distilled water 45

Example 9: Preparation of a Composite of CD-COF Containing Paraffin and Polymer

[0072] It was prepared in the same manner as in Example 2 with the composition shown in Table 6 below.

TABLE-US-00006 TABLE 6 Ingredient Content (part by weight) CD-COF 20 Pullulan-poly-(L)-lactic acid 10 Paraffin 12 KOH 6 Distilled water 52

Example 10: Preparation of a Composite of CD-COF Containing Higher Fatty Acids and Polymer

[0073] It was prepared in the same manner as in Example 2 with the composition shown in Table 7 below.

TABLE-US-00007 TABLE 7 Ingredient Content (part by weight) CD-COF 10 PEG-PCL-PEG triblock copolymer 0.5 Stearic acid 10 KOH 3 Distilled water 32

Example 11: Preparation of a Composite of CD-COF Containing Esters and Polymer

[0074] It was prepared in the same manner as in Example 2 with the composition shown in Table 8 below.

TABLE-US-00008 TABLE 8 Ingredient Content (part by weight) CD-COF 13 Succinylated chitosan 1.5 Cetylethylhexanoate 20 KOH 3 Distilled water 46

Example 12: Preparation of a Composite of CD-COF Containing Silicones and Polymer

[0075] It was prepared in the same manner as in Example 2 with the composition shown in Table 9 below.

TABLE-US-00009 TABLE 9 Ingredient Content (part by weight) CD-COF 30 PEG-PCL-PEG triblock copolymer 10 Dimethicone 6CS 20 KOH 5 Distilled water 62

Example 13: Preparation of a Composite of CD-COF Containing Moisturizers and Polymer

[0076] It was prepared in the same manner as in Example 2 with the composition shown in Table 10 below.

TABLE-US-00010 TABLE 10 Ingredient Content (part by weight) CD-COF 25 Succinylated chitosan 10 Ceramide 3 3 Hyaluronic acid 0.5 Polyglutamic acid 1 KOH 5 Distilled water 65

Example 14: Preparation of a Composite of CD-COF Containing Whitening Agents and Polymer

[0077] It was prepared in the same manner as in Example 2 with the composition shown in Table 11 below.

TABLE-US-00011 TABLE 11 Ingredient Content (part by weight) CD-COF 16 Pullulan-poly-(L)-lactic acid 1 Arbutin 15 KOH 2 Distilled water 52

Example 15: Preparation of a Composite of CD-COF Containing UV Blocking Agents and Polymer

[0078] It was prepared in the same manner as in Example 2 with the composition shown in Table 12 below.

TABLE-US-00012 TABLE 12 Ingredient Content (part by weight) CD-COF 20 PEG-PCL-PEG triblock copolymer 10 Octyl methoxycinnamate 20 KOH 4 Distilled water 50

Example 16: Preparation of a Composite of CD-COF Containing Vitamins and Polymer

[0079] It was prepared in the same manner as in Example 2 with the composition shown in Table 13 below.

TABLE-US-00013 TABLE 13 Ingredient Content (part by weight) CD-COF 30 Succinylated chitosan 10 Alpha-tocopherol 10 KOH 5 Distilled water 72

Example 17: Preparation of a Composite of CD-COF Containing Amino Acids and Polymer

[0080] It was prepared in the same manner as in Example 2 with the composition shown in Table 14 below.

TABLE-US-00014 TABLE 14 Ingredient Content (part by weight) CD-COF 20 Pullulan 0.1 Fibroblast growth factor (FGF) 0.01 Epidermal growth factor (EGF) 0.0001 Insulin-like growth factor (IGF) 0.001 KOH 4 Distilled water 53

Example 18: Preparation of a Composite of CD-COF Containing Peptides and Polymer

[0081] It was prepared in the same manner as in Example 2 with the composition shown in Table 15 below.

TABLE-US-00015 TABLE 15 Ingredient Content (part by weight) CD-COF 30 Chitosan 20 Palmitoyl pentapeptide-3 0.0001 Hexa peptide-9 0.001 Palmitoyl tetrapeptide-7 0.00001 Nonapeptide-7 0.0001 Dipeptide-8 0.001 KOH 5 Distilled water 84

Example 19: Preparation of a Composite of CD-COF Containing Anti-Inflammatories and Polymer

[0082] It was prepared in the same manner as in Example 2 with the composition shown in Table 16 below.

TABLE-US-00016 TABLE 16 Ingredient Content (part by weight) CD-COF 10 Polylactic acid 1.5 Extract of Centella 15 asiatica (madecaside) KOH 3 Distilled water 38

Example 20: Preparation of a Composite of CD-COF Containing Acne Therapeutic Agents and Polymer

[0083] It was prepared in the same manner as in Example 2 with the composition shown in Table 17 below.

TABLE-US-00017 TABLE 17 Ingredient Content (part by weight) CD-COF 4 Pullulan 0.5 Azelic acid 10 KOH 4 Distilled water 38

Example 21: Preparation of a Composite of CD-COF Containing Microbicides and Polymer

[0084] It was prepared in the same manner as in Example 2 with the composition shown in Table 18 below.

TABLE-US-00018 TABLE 18 Ingredient Content (part by weight) CD-COF 30 Chitosan 15 Halocalban 20 KOH 5 Distilled water 65

Experimental Example 1: Measurement of Particle Distribution

[0085] The particle distribution of the composite of CD-COF containing retinol and succinylated chitosan prepared in Example 2 was measured using Photal and ELS-Z, and is shown in FIG. 6. As a result of the measurement, it can be known that the average particle size of the composite was 408.8 nm.

Experimental Example 2: Measurement of Stability of the Composite of CD-COF Containing Retinol and Polymer

[0086] In order to measure the stability of the composite of CD-COF containing retinol and succinylated chitosan prepared in Example 2, the zeta potential was measured using Photal and ELS-Z, and the results are shown in FIG. 7. As a result of the measurement, it can be known that the potential of the particle was stable at −60.55 mV.

Experimental Example 3: Measurement of Stability of the Composite of CD-COF Containing Retinol and Polymer

[0087] As a result of measurement of the stability of the composite of CD-COF containing retinol and succinylated chitosan prepared in Example 2 using Turbiscan, it can be known that the composite was stable since there was little change in ΔT and ABS over time (FIG. 8).

Experimental Example 4: Powder X-Ray Diffraction Test

[0088] A powder X-ray diffraction test (XRD) of the composite of CD-COF containing retinol and polymer prepared in Example 2 and the composite of CD-COF containing curcumin and polymer prepared in Example 3 was performed, and the results are shown in FIG. 9. As can be seen from the results of FIG. 9, it can be known that each complex was well synthesized as a certain peak appeared.

Experimental Example 5: Fourier-Transform Infrared Spectroscopy (FTIR) Test

[0089] The measurement results of the composite of CD-COF containing curcumin and the polymer prepared in Example 3 by Fourier-transform infrared spectroscopy (FTIR) are shown in FIG. 10.

Experimental Example 6: Freeze Electron Microscopy

[0090] The CD-COFs and composites prepared in Preparation Examples and Examples were photographed. Since the particle size is too fine to measure with a general optical microscope, it was photographed using a freezing electron microscope (JEM 1010, JEOL, Japan) (FIG. 11). It can be known that the composites of CD-COF and polymer were well formed, and retinol was well attached to them.

Experimental Example 7: Transdermal Absorption Promotion Effect Test

[0091] Liposomes (liposome A) having a composite of CD-COF containing 10% retinol and succinylated chitosan and general liposomes (liposome B) were prepared with the composition shown in Table 19 below, respectively.

TABLE-US-00019 TABLE 19 Ingredient Liposome A Liposome B Composite of CD-COF 10 — containing 10% retinol and succinylated chitosan Saturated lecithin 3 3 Sodium stearolyl glutamate 0.8 0.8 Beeswax 1 1 Macadamia nut oil 10 10 Retinol — 1 Distilled water 75.2 84.2 Total 100 100 (Unit: % by weight)

[0092] The artificial skin, Neoderm (Tego Science, Korea) was mounted to a Franz-type diffusion cell (Lab Fine Instruments, Korea). 50 mM phosphate buffer (pH 7.4, 0.1 M NaCl) was added to a receptor cell (5 ml) of the Franz-type diffusion cell. A diffusion cell was then mixed and diffused at 600 rpm, 32° C., and 50 μl of Liposome A and Liposome B, respectively, were added to donor cells. Absorption and diffusion were carried out at a predetermined time, and the area of the skin where the absorption and diffusion were carried out was 0.64 cm.sup.2. After finishing the absorption and diffusion of the active ingredient, the residues—which were not absorbed and remained on the skin—were cleaned with dried Kimwipes™ or 10 ml of ethanol. The skin in which the active ingredient was absorbed and diffused was homogenized by the use of a tip-type homogenizer, and retinol absorbed into the skin was then extracted with 4 ml of dichloromethane. The extract was then filtrated with a 0.45 μm nylon membrane filter. The content of retinol was measured by high-performance liquid chromatography with the following conditions, and the results are represented in Table 20.

TABLE-US-00020 TABLE 20 Transdermal absorption (μg) Rate of increase Liposome A 0.4640 15.73% Liposome B 0.2950 — A) Column: C18 (4.6 × 200 mm, 5 μm) B) Mobile phase: methanol:hexane = 2:1 C) Flow rate: 0.8 ml/min D) Detector: UV 275 nm

[0093] As can be seen from Table 20, it can be known that retinol was encapsulated in a composite of CD-COF and polymer, and efficiently delivered into the skin in the present invention.