TRANSDERMAL DELIVERY COMPLEX USING METAL-ORGANIC FRAMEWORK AND TRIBLOCK COPOLYMER

Abstract

The present invention relates to a transdermal delivery complex using a metal-organic framework (MOF) and a triblock copolymer. In addition, the present invention relates to a cosmetic composition comprising the transdermal delivery complex and a method for preparing a transdermal delivery complex.

Claims

1. A composite for transdermal delivery comprising a metal-organic framework and a triblock copolymer of polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG).

2. The composite for transdermal delivery according to claim 1, wherein the metal-organic framework is a zeolite imidazolate framework (ZIF).

3. The composite for transdermal delivery according to claim 2, wherein the zeolite imidazolate framework is ZIF-8.

4. The composite for transdermal delivery according to claim 3, wherein an imine group of the ZIF-8 is combined with the triblock copolymer of PEG-PCL-PEG.

5. The composite for transdermal delivery according to claim 1, which comprises 0.01 to 20 parts by weight of the triblock copolymer of PEG-PCL-PEG based on 10 parts by weight of the metal-organic framework.

6. The composite for transdermal delivery according to claim 1, which further comprises an active ingredient.

7. The composite for transdermal delivery according to claim 6, 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 and a natural product.

8.-22. (canceled)

23. A cosmetic composition comprising the composite for transdermal delivery according to claim 6.

24. The cosmetic composition according to claim 23, which comprises 1 to 60% by weight of the composite for transdermal delivery.

25. A method for preparing a composite for transdermal delivery comprising: i) mixing a metal-organic framework solution and a triblock copolymer of polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) solution; ii) treating the solution obtained in step (i) by stirring or sonication to form a composite; and iii) drying the composite obtained in step (ii).

26. A method for preparing a composite for transdermal delivery comprising: i) mixing a metal-organic framework solution and a triblock copolymer of polyethylene glycol (PEG)-polycaprolactone (PCL)-polyethylene glycol (PEG) solution; ii) treating the solution obtained in step (i) by sonication and then stirring to form a composite; and iii) drying the composite obtained in step (ii).

27. The method for preparing a composite for transdermal delivery according to claim 25, wherein the metal-organic framework is a zeolite imidazolate framework.

28. The method for preparing a composite for transdermal delivery according to claim 27, wherein the zeolite imidazolate framework is ZIF-8.

29. The method for preparing a composite for transdermal delivery according to claim 25, wherein the step (iii) is carried out by high-temperature vacuum drying at 60° C. or higher, or freeze-drying.

30. The method for preparing a composite for transdermal delivery according to claim 25, which further comprises a step of washing the composite after the step (iii).

31. The method for preparing a composite for transdermal delivery according to claim 30, wherein the washing is carried out by using ethanol.

32. The method for preparing a composite for transdermal delivery according to claim 26, wherein the metal-organic framework is a zeolite imidazolate framework.

33. The method for preparing a composite for transdermal delivery according to claim 32, wherein the zeolite imidazolate framework is ZIF-8.

34. The method for preparing a composite for transdermal delivery according to claim 26, wherein the step (iii) is carried out by high-temperature vacuum drying at 60° C. or higher, or freeze-drying.

35. The method for preparing a composite for transdermal delivery according to claim 26, which further comprises a step of washing the composite after the step (iii).

36. The method for preparing a composite for transdermal delivery according to claim 35, wherein the washing is carried out by using ethanol.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG. 1 is a schematic diagram representing the structure of ZIF-8.

[0044] FIG. 2 is a schematic diagram representing the synthetic procedure of a triblock copolymer of PEG-PCL-PEG.

[0045] FIG. 3 is cryo-electron microscopy photographs of the ZIF-8-triblock copolymer of PEG-PCL-PEG composite prepared in Example 1.

[0046] FIG. 4 is cryo-electron microscopy photographs of the ZIF-8-triblock copolymer of PEG-PCL-PEG composite prepared in Example 4 ((a) stirring at 25° C., (b) stirring at 40° C.).

[0047] FIG. 5 is a result of measuring the particle diameter of the ZIF-8-triblock copolymer of PEG-PCL-PEG composite by the use of Photal, ELS-Z.

[0048] FIG. 6 is a result of measuring zeta potential by the use of Photal, ELS-Z to measure the stability of the ZIF-8-triblock copolymer of PEG-PCL-PEG composite.

[0049] FIG. 7 is a result of measuring the stability of the ZIF-8-triblock copolymer of PEG-PCL-PEG composite by the use of Turbiscan.

[0050] FIG. 8 is X-ray powder diffraction (XRD) spectrums of the ZIF-8 and ZIF-8-triblock copolymer of PEG-PCL-PEG composite containing retinol.

[0051] FIG. 9 is results of measuring the ZIF-8-triblock copolymer of PEG-PCL-PEG composites prepared in Examples 1 to 3 by the use of a UV-visible spectrophotometer ((a) ZIF-8, (b) Example 1, (c) Example 2, (d) Example 3).

DETAILED DESCRIPTION

[0052] 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 ZIF-8

Preparation Example 1-1: Preparation of Zinc Nitrate Hexahydrate Solution

[0053] 0.4 g of zinc nitrate hexahydrate was completely dissolved in 1.6 g of H.sub.2O. At this time, H.sub.2O was used after adjusting to pH 8.0 using NaOH, and sonication was carried out for 5 minutes for complete dissolution. Then, 8 ml of non-ionized H.sub.2O was added and stirred at 300 rpm for 30 minutes.

Preparation Example 1-2: Preparation of 2-Methylimidazole Solution

[0054] 4.0 g of 2-methylimidazole was completely dissolved in 16.0 g of non-ionized H.sub.2O. At this time, sonication was carried out for 30 minutes or more for complete dissolution.

Preparation Example 1-3: Synthesis of ZIF-8

[0055] The 2-methylimidazole solution of Preparation Example 1-2 was added dropwise to the zinc nitrate hexahydrate solution of Preparation Example 1-1, and the mixture was stirred at 300 rpm for 30 minutes. Through this process, imidazole bridges were formed in Zn.sup.2+, and ligands were synthesized to form ZIF-8. The obtained ZIF-8 was washed and dried at 70° C. for 7 hours and 30 minutes.

Preparation Example 1-4: Washing of ZIF-8

[0056] After centrifugation twice using distilled water, washing was carried out by centrifugation twice using ethanol. At this time, the conditions of centrifugation were carried out at 4,000 rpm for 15 minutes (Universal 320/Germany).

Preparation Example 2: Preparation of Triblock Copolymer of PEG-PCL-PEG

[0057] 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).

[0058] 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.

Example 1: Preparation of Composite Via Stirring and High-Temperature Vacuum Drying

[0059] The 2-methylimidazole solution of Preparation Example 1-2 was added dropwise to the zinc nitrate hexahydrate solution of Preparation Example 1-1, and the mixture was stirred at 300 rpm for 15 minutes. After stirring, the PEG-PCL-PEG triblock copolymer synthesized in Preparation Example 2 prepared as 5% solution in ethanol was added according to the composition recited in Table 1, respectively, followed by stirring at 300 rpm for 15 minutes. After washing, vacuum drying at 70° C. for 7 hours and 30 minutes was carried out.

TABLE-US-00001 TABLE 1 Example Example Example Example Example 1-1 1-2 1-3 1-4 1-5 ZIF-8 solution 29 ml 27 ml 25 ml 23 ml 20 ml Triblock copolymer 1 ml 3 ml 5 ml 7 ml 10 ml solution

Example 2: Preparation of Composite Via Sonication and High-Temperature Vacuum Drying

[0060] The 2-methylimidazole solution of Preparation Example 1-2 was added to the zinc nitrate hexahydrate solution of Preparation Example 1-1, and sonication was carried out at 25° C. for 15 minutes. After sonication, the PEG-PCL-PEG triblock copolymer synthesized in Preparation Example 2 prepared as 5% solution in ethanol was added according to the composition recited in Table 2, respectively, and sonication was then carried out at 25° C. for 15 minutes. After washing, vacuum drying at 70° C. for 7 hours and 30 minutes was carried out.

TABLE-US-00002 TABLE 2 Example Example Example Example Example 2-1 2-2 2-3 2-4 2-5 ZIF-8 solution 29 ml 27 ml 25 ml 23 ml 20 ml Triblock copolymer 1 ml 3 ml 5 ml 7 ml 10 ml solution

Example 3: Preparation of Composite Via Sonication and Freeze-Drying

[0061] The 2-methylimidazole solution of Preparation Example 1-2 was added to the zinc nitrate hexahydrate solution of Preparation Example 1-1, and sonication was carried out at 25° C. for 15 minutes. After sonication, the PEG-PCL-PEG triblock copolymer synthesized in Preparation Example 2 prepared as 5% solution in ethanol was added according to the composition recited in Table 3, respectively, and sonication was then carried out at 25° C. for 15 minutes. After washing, the obtained composites were frozen at −120° C. for at least 3 hours, and then dried for 2 days.

TABLE-US-00003 TABLE 3 Example Example Example Example Example 3-1 3-2 3-3 3-4 3-5 ZIF-8 solution 29 ml 27 ml 25 ml 23 ml 20 ml Triblock copolymer 1 ml 3 ml 5 ml 7 ml 10 ml solution

Example 4: Preparation of Composite Via Stirring and High-Temperature Vacuum Drying after Sonication

[0062] ZIF-8 prepared as 1% solution in ethanol and the PEG-PCL-PEG triblock copolymer prepared as 1% solution in ethanol were mixed at 50:50 (47 g:47 g), and sonication was carried out for 20 minutes. One sample was stirred at 300 rpm at 25° C. for 17 hours, the other sample was stirred at 300 rpm at 40° C. for 17 hours, and then vacuum dried at 70° C. for 7 hours.

Example 5: Preparation of ZIF-8-Triblock Copolymer Composite Containing Retinol

[0063] 47 g of ZIF-8 prepared as 1% solution in ethanol, 47 g of the PEG-PCL-PEG triblock copolymer prepared as 1% solution in ethanol and 6 g of retinol were mixed, and sonication was carried out for 20 minutes. Then, the reaction mixture was stirred at 300 rpm at 40° C. for 17 hours and vacuum dried at 70° C. for 7 hours.

Example 6: Preparation of ZIF-8-Triblock Copolymer Composite Containing Plant Natural Product

[0064] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 4.

TABLE-US-00004 TABLE 4 Content Ingredient (part by weight) ZIF-8 5 Triblock copolymer 5 Strawberry extract 20 Distilled water 20

Example 7: Preparation of ZIF-8-Triblock Copolymer Composite Containing Marine Natural Product

[0065] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 5.

TABLE-US-00005 TABLE 5 Content Ingredient (part by weight) ZIF-8 8 Triblock copolymer 8 Sea mustard extract 20 Distilled water 22

Example 8: Preparation of ZIF-8-Triblock Copolymer Composite Containing Oil

[0066] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 6.

TABLE-US-00006 TABLE 6 Content Ingredient (part by weight) ZIF-8 5 Triblock copolymer 5 Avocado oil 1 Olive oil 3 Camellia oil 1 Macadamia nut oil 1 Castor oil 2 Sunflower oil 2 Jojoba oil 2 Almond oil 1 Meadowfoam seed oil 2 Argan oil 2 Distilled water 40

Example 9: Preparation of ZIF-8-Triblock Copolymer Composite Containing Wax

[0067] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 7.

TABLE-US-00007 TABLE 7 Content Ingredient (part by weight) ZIF-8 3 Triblock copolymer 1 Beeswax 4 Silicone wax 4 Distilled water 32

Example 10: Preparation of ZIF-8-Triblock Copolymer Composite Containing Butter

[0068] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 8.

TABLE-US-00008 TABLE 8 Content Ingredient (part by weight) ZIF-8 15 Triblock copolymer 1 Shea butter 2 Mango butter 5 Green tea butter 1 Distilled water 46

Example 11: Preparation of ZIF-8-Triblock Copolymer Composite Containing Paraffin

[0069] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 9.

TABLE-US-00009 TABLE 9 Content Ingredient (part by weight) ZIF-8 20 Triblock copolymer 10 Paraffin 20 Distilled water 55

Example 12: Preparation of ZIF-8-Triblock Copolymer Composite Containing Higher Fatty Acid

[0070] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 10.

TABLE-US-00010 TABLE 10 Content Ingredient (part by weight) ZIF-8 10 Triblock copolymer 0.5 Stearic acid 10 Distilled water 33

Example 13: Preparation of ZIF-8-Triblock Copolymer Composite Containing Ester

[0071] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 11.

TABLE-US-00011 TABLE 11 Content Ingredient (part by weight) ZIF-8 13 Triblock copolymer 1.5 Cetyl ethylhexanoate 20 Distilled water 48

Example 14: Preparation of ZIF-8-Triblock Copolymer Composite Containing Silicone

[0072] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 12.

TABLE-US-00012 TABLE 12 Content Ingredient (part by weight) ZIF-8 30 Triblock copolymer 10 Dimethicone 6CS 20 Distilled water 65

Example 15: Preparation of ZIF-8-Triblock Copolymer Composite Containing Moisturizer

[0073] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 13.

TABLE-US-00013 TABLE 13 Content Ingredient (part by weight) ZIF-8 30 Triblock copolymer 15 Ceramide 3 3 Hyaluronic acid 0.5 Polyglutamic acid 1 Distilled water 70

Example 16: Preparation of ZIF-8-Triblock Copolymer Composite Containing Whitening Agent

[0074] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 14.

TABLE-US-00014 TABLE 14 Content Ingredient (part by weight) ZIF-8 16 Triblock copolymer 0.5 Arbutin 10 Distilled water 55

Example 17: Preparation of ZIF-8-Triblock Copolymer Composite Containing UV Blocking Agent

[0075] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 15.

TABLE-US-00015 TABLE 15 Content Ingredient (part by weight) ZIF-8 20 Triblock copolymer 1.5 Octyl methoxycinnamate 20 Distilled water 53

Example 18: Preparation of ZIF-8-Triblock Copolymer Composite Containing Vitamin

[0076] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 16.

TABLE-US-00016 TABLE 16 Content Ingredient (part by weight) ZIF-8 30 Triblock copolymer 10 Alpha tocopherol 10 Distilled water 78

Example 19: Preparation of ZIF-8-Triblock Copolymer Composite Containing Amino Acid

[0077] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 17.

TABLE-US-00017 TABLE 17 Content Ingredient (part by weight) ZIF-8 20 Triblock copolymer 0.1 Fibroblast growth factor (FGF) 0.01 Epidermal growth factor (EGF) 0.0001 Insulin-like growth factor (IGF) 0.001 Distilled water 55

Example 20: Preparation of ZIF-8-Triblock Copolymer Composite Containing Peptide

[0078] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 18.

TABLE-US-00018 TABLE 18 Content Ingredient (part by weight) ZIF-8 30 Triblock copolymer 20 Palmitoyl pentapeptide-3 0.0001 Hexapeptide-9 0.001 Palmitoyl tetrapeptide-7 0.00001 Nonapeptide-7 0.0001 Dipeptide-8 0.001 Distilled water 85

Example 21: Preparation of ZIF-8-Triblock Copolymer Composite Containing Anti-Inflammatory Agent

[0079] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 19.

TABLE-US-00019 TABLE 19 Content Ingredient (part by weight) ZIF-8 10 Triblock copolymer 1.5 Centella asiatica 15 extract (madecassoside) Distilled water 40

Example 22: Preparation of ZIF-8-Triblock Copolymer Composite Containing Acne Therapeutic Agent

[0080] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 20.

TABLE-US-00020 TABLE 20 Content Ingredient (part by weight) ZIF-8 4 Triblock copolymer 0.5 Azelaic acid 10 Distilled water 38

Example 23: Preparation of ZIF-8-Triblock Copolymer Composite Containing Microbicide

[0081] A composite was prepared by the same method as described in Example 5 with the constitutional composition of Table 21.

TABLE-US-00021 TABLE 21 Content Ingredient (part by weight) ZIF-8 30 Triblock copolymer 15 Halocalban 20 Distilled water 70

Experimental Example 1: Cryo-Electron Microscopy

[0082] Photographs of the ZIF-8-triblock copolymer composite prepared in Examples 1 and 4 were taken. Due to very fine particle size, it was impossible to take photographs by a general optical microscope. Therefore, cryo-electron microscopy photographs (JEM 1010, JEOL Ltd., Japan) were taken (FIGS. 3 and 4).

Experimental Example 2: Measurement of Particle Size Distribution

[0083] The particle size distribution of the ZIF-8-triblock copolymer composite prepared in Example 1-3 was measured by the use of Photal, ELS-Z, and the result is represented in FIG. 5. From the result of the measurement, it can be known that the average particle size of the composite is 281.8 nm.

Experimental Example 3: Measurement of Stability of ZIF-8-Triblock Copolymer Composite

[0084] To measure the stability of the ZIF-8-triblock copolymer composite prepared in Example 1-3, zeta potential was measured by the use of Photal, ELS-Z, and the result is represented in FIG. 6. From the result of the measurement, it can be known that the potential of particle is −63.65 mV, and the composite is stable.

Experimental Example 4: Measurement of Stability of ZIF-8-Triblock Copolymer Composite

[0085] The stability of the ZIF-8-triblock copolymer composite prepared in Example 1-3 was measured by the use of Turbiscan. As a result, the stability of the composite was confirmed since there was little change in ΔT, ΔBS (FIG. 7).

Experimental Example 5: X-Ray Powder Diffraction Test

[0086] A powder X-ray powder diffraction (XRD) test of the ZIF-8 prepared in the Preparation Example 1 and the ZIF-8-triblock copolymer composite prepared in Example 4 was carried out, and the results are represented in FIG. 8. As can be seen from FIG. 8, it can be known that each of the composites were synthesized well as constant peaks appear.

Experimental Example 6: UV-Visible Spectrophotometry Test

[0087] The results of measuring the ZIF-8 prepared in the Preparation Example and the ZIF-8-triblock copolymer composite prepared in Examples 1 to 3 by UV-visible spectrophotometry are represented in FIG. 9.

Experimental Example 7: Test for Effect of ZIF-8-Triblock Copolymer Composite on Promoting Transdermal Absorption

[0088] With the constitutional composition recited in Table 22, liposomes having the ZIF-8-triblock copolymer composite containing 10% retinol (Liposome A) and general liposomes (Liposome B) were prepared, respectively.

TABLE-US-00022 TABLE 22 Ingredient Liposome A Liposome B ZIF-8- triblock copolymer 10 — composite containing 10% retinol Saturated lecithin 3 3 Sodium stearoyl glutamate 0.8 0.8 Shea butter 1 1 Macadamia nut oil 10 10 Retinol — 1 Distilled water 75.2 84.2 Total amount 100 100 (Unit: % by weight)

[0089] 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, 0.1M 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 according to the 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 23.

TABLE-US-00023 TABLE 23 Transdermal Rate of absorption (μg) increase Liposome A 0.4540 15.87% Liposome B 0.2860 — 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

[0090] As can be seen from Table 23, in the present invention retinol—which is encapsulated in the ZIF-8-triblock copolymer composite—can be efficiently delivered into the skin.