Transdermal delivery complex using metal-organic framework and nanocellulose

Abstract

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

Claims

1. A transdermal delivery composite comprising a metal-organic framework, nanocellulose, and a cosmetically active ingredient; wherein the metal-organic framework is a zeolite imidazolate framework (ZIF)-8; and wherein an imine group of the ZIF-8 is combined with the nanocellulose.

2. The transdermal delivery composite according to claim 1, which comprises 0.01 to 20 parts by weight of the nanocellulose based on 10 parts by weight of the metal-organic framework.

3. The transdermal delivery composite according to claim 1, wherein the cosmetically 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.

4. A cosmetic composition comprising the transdermal delivery composite according to claim 1.

5. The cosmetic composition according to claim 4, which comprises 1 to 60% by weight of the transdermal delivery composite.

6. A method for preparing a transdermal delivery composite comprising: i) adding a nanocellulose and a cosmetically active ingredient solution to a metal-organic framework 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); wherein the metal-organic framework is a zeolite imidazolate framework (ZIF)-8; and an imine group of the ZIF-8 is combined with the nanocellulose.

7. The method for preparing a transdermal delivery composite according to claim 6, wherein the concentration of the nanocellulose solution is 5 to 20% by weight.

8. The method for preparing a transdermal delivery composite according to claim 6, wherein the step (iii) is carried out by high-temperature vacuum drying at 60° C. or higher, or freeze-drying.

9. The method for preparing a transdermal delivery composite according to claim 6, which further comprises a step of washing the composite after the step (iii).

10. The method for preparing a transdermal delivery composite according to claim 9, wherein the washing is carried out by using ethanol.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a schematic diagram representing the structure of ZIF-8.

(2) FIG. 2 is scanning electron microscopy photographs of nanocellulose.

(3) FIG. 3 is photographs of the prepared ZIF-8 and ZIF-8-nanocellulose composite comprising retinol.

(4) FIG. 4 is a result of measuring the diameter of the ZIF-8-nanocellulose composite by the use of Photal ELS-Z.

(5) FIG. 5 is a cryo-electron microscopy photographs of the ZIF-8 and ZIF-8-nanocellulose composite containing retinol.

(6) FIG. 6 is a result of measuring H-NMR of the ZIF-8-nanocellulose composite prepared in Example 1-5.

(7) FIG. 7 is a result of measuring zeta potential by the use of Photal ELS-Z to measure the stability of the ZIF-8-nanocellulose composite.

(8) FIG. 8 is a result of measuring the stability of the ZIF-8-nanocellulose composite by the use of Turbiscan.

(9) FIG. 9 is X-ray powder diffraction (XRD) spectrums of the ZIF-8 and ZIF-8-nanocellulose composite containing retinol.

(10) FIG. 10 is results of measuring NMR of the ZIF-8 and ZIF-8-nanocellulose composite containing retinol.

DETAILED DESCRIPTION

(11) 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.

(12) Preparation Example: Preparation OF ZIF-8

(13) Preparation Example 1-1: Preparation of Zinc Nitrate Hexahydrate Solution

(14) 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.

(15) Preparation Example 1-2: Preparation of 2-methylimidazole Solution

(16) 4.0 g of 2-ethylimidazole 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.

(17) Preparation Example 1-3: Synthesis of ZIF-8

(18) 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.

(19) Preparation Example 1-4: Washing of ZIF-8

(20) 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).

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

(22) 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, nanocellulose (CelluForce NCC™, CelluForce Inc., Canada) 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.

(23) TABLE-US-00001 TABLE 1 Example Example Example Example Example 1-1 1-2 1-3 1-4 1-5 ZIF-8 29 ml 27 ml 25 ml 23 ml 20 ml solution 10% nano-  1 ml  3 ml  5 ml  7 ml 10 ml cellulose solution
Example 2: Preparation of Composite Via Sonication and High-Temperature Vacuum Drying

(24) 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, nanocellulose 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.

(25) TABLE-US-00002 TABLE 2 Example Example Example Example Example 2-1 2-2 2-3 2-4 2-5 ZIF-8 29 ml 27 ml 25 ml 23 ml 20 ml solution 10% nano-  1 ml  3 ml  5 ml  7 ml 10 ml cellulose solution
Example 3: Preparation of Composite Via Sonication and Freeze-Drying

(26) 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, nanocellulose 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.

(27) TABLE-US-00003 TABLE 3 Example Example Example Example Example 3-1 3-2 3-3 3-4 3-5 ZIF-8 29 ml  27 ml  25 ml  23 ml  20 ml solution 10% nano- 1 ml 3 ml 5 ml 7 ml 10 ml cellulose solution
Example 4: Preparation of ZIF-8-Nanocellulose Composite Containing Retinol

(28) 10 g of ZIF-8, 6 g of nanocellulose, 3, 5 or 8 g of retinol and 38.5 g of water were mixed, and the mixture was treated with an ultrasonic mixer, washed and then vacuum dried at 70° C. for 7 hours and 30 minutes. As can be seen from FIG. 3, it can be known that as the retinol content increases, the color becomes darker. (Hereinafter, the composites manufactured with 3, 5 or 8 g of retinol were referred to as “R3@ZIF-8,” “R5@ZIF-8” and “R8@ZIF-8” respectively.)

(29) Example 5: Preparation of ZIF-8-Nanocellulose Composite Containing Arbutin

(30) 10 g of ZIF-8, 8 g of nanocellulose, 10 g of arbutin and 72 g of water were mixed, and the mixture was treated with an ultrasonic mixer, washed and then freeze-dried.

(31) Example 6: Preparation of ZIF-8-Nanocellulose Composite Containing Plant Natural Product

(32) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 4.

(33) TABLE-US-00004 TABLE 4 Content Ingredient (part by weight) ZIF-8 5 Nanocellulose 1 Cucumber extract 20 Distilled water 18.5
Example 7: Preparation of ZIF-8-Nanocellulose Composite Containing Marine Natural Product

(34) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 5.

(35) TABLE-US-00005 TABLE 5 Content Ingredient (part by weight) ZIF-8 8 Nanocellulose 0.5 Sea mustard extract 20 Distilled water 22
Example 8: Preparation of ZIF-8-Nanocellulose Composite Containing Oil

(36) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 6.

(37) TABLE-US-00006 TABLE 6 Content Ingredient (part by weight) ZIF-8 10 Nanocellulose 5 Olive oil 1 Camellia oil 1 Macadamia nut oil 2 Castor oil 2 Sunflower oil 2 Jojoba oil 2 Almond oil 0.5 Meadowfoam seed oil 2 Argan oil 2 Distilled water 42
Example 9: Preparation of ZIF-8-Nanocellulose Composite Containing Wax

(38) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 7.

(39) TABLE-US-00007 TABLE 7 Content Ingredient (part by weight) ZIF-8 8 Nanocellulose 2 Beeswax 5 Candelilla wax 5 Distilled water 35
Example 10: Preparation of ZIF-8-Nanocellulose Composite Containing Butter

(40) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 8.

(41) TABLE-US-00008 TABLE 8 Content Ingredient (part by weight) ZIF-8 15 Nanocellulose 3 Shea butter 1 Mango butter 5 Green tea butter 1 Distilled water 47
Example 11: Preparation of ZIF-8-Nanocellulose Composite Containing Paraffin

(42) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 9.

(43) TABLE-US-00009 TABLE 9 Content Ingredient (part by weight) ZIF-8 20 Nanocellulose 10 Liquid paraffin 20 Distilled water 60
Example 12: Preparation of ZIF-8-Nanocellulose Composite Containing Higher Fatty Acid

(44) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 10.

(45) TABLE-US-00010 TABLE 10 Content Ingredient (part by weight) ZIF-8 10 Nanocellulose 0.5 Palmitic acid 10 Distilled water 33
Example 13: Preparation of ZIF-8-Nanocellulose Composite Containing Ester

(46) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 11.

(47) TABLE-US-00011 TABLE 11 Content Ingredient (part by weight) ZIF-8 13 Nanocellulose 1.5 Cetyl ethylhexanoate 20 Distilled water 49
Example 14: Preparation of ZIF-8-Nanocellulose Composite Containing Silicone

(48) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 12.

(49) TABLE-US-00012 TABLE 12 Content Ingredient (part by weight) ZIF-8 30 Nanocellulose 10 Dimethicone 6CS 20 Distilled water 65
Example 15: Preparation of ZIF-8-Nanocellulose Composite Containing Moisturizer

(50) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 13.

(51) TABLE-US-00013 TABLE 13 Content Ingredient (part by weight) ZIF-8 30 Nanocellulose 15 Ceramide 5 Hyaluronic acid 0.5 Polyglutamic acid 0.1 Distilled water 73
Example 16: Preparation of ZIF-8-Nanocellulose Composite Containing Whitening Agent

(52) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 14.

(53) TABLE-US-00014 TABLE 14 Content Ingredient (part by weight) ZIF-8 16 Nanocellulose 0.5 Arbutin 10 Distilled water 55
Example 17: Preparation of ZIF-8-Nanocellulose Composite Containing UV Blocking Agent

(54) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 15.

(55) TABLE-US-00015 TABLE 15 Content Ingredient (part by weight) ZIF-8 20 Nanocellulose 1.5 Octyl methoxycinnamate 15 Distilled water 58
Example 18: Preparation of ZIF-8-Nanocellulose Composite Containing Vitamin

(56) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 16.

(57) TABLE-US-00016 TABLE 16 Content Ingredient (part by weight) ZIF-8 30 Nanocellulose 10 Vitamin E (tocopherol) 15 Distilled water 80
Example 19: Preparation of ZIF-8-Nanocellulose Composite Containing Amino Acid

(58) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 17.

(59) TABLE-US-00017 TABLE 17 Content Ingredient (part by weight) ZIF-8 20 Nanocellulose 0.1 Epidermal growth factor (EGF) 0.01 Insulin-like growth factor (IGF) 0.0001 Distilled water 58
Example 20: Preparation of ZIF-8-Nanocellulose Composite Containing Peptide

(60) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 18.

(61) TABLE-US-00018 TABLE 18 Content Ingredient (part by weight) ZIF-8 30 Nanocellulose 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 90
Example 21: Preparation of ZIF-8-Nanocellulose Composite Containing Anti-Inflammatory Agent

(62) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 19.

(63) TABLE-US-00019 TABLE 19 Content Ingredient (part by weight) ZIF-8 10 Nanocellulose 1.5 Hydrocortisone 5 Distilled water 46
Example 22: Preparation of ZIF-8-Nanocellulose Composite Containing Acne Therapeutic Agent

(64) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 20.

(65) TABLE-US-00020 TABLE 20 Content Ingredient (part by weight) ZIF-8 4 Nanocellulose 0.5 Azelaic acid 10 Distilled water 38
Example 23: Preparation of ZIF-8-Nanocellulose Composite Containing Microbicide

(66) A composite was prepared by the same method as described in Example 4 with the constitutional composition of Table 21.

(67) TABLE-US-00021 TABLE 21 Content Ingredient (part by weight) ZIF-8 30 Nanocellulose 15 Halocalban 20 Distilled water 77
Experimental Example 1: Measurement of Particle Size Distribution

(68) The particle size distribution of the ZIF-8-nanocellulose composite prepared in Example 1-2 was measured by the use of Photal, ELS-Z, and the result is represented in FIG. 4. From the result of the measurement, it can be known that the average particle size of the composite is 281.8 nm.

(69) Experimental Example 2: Cryo-Electron Microscopy

(70) Photographs of the ZIF-8 prepared in the Preparation Example and the ZIF-8-nanocellulose composite containing retinol prepared in Example 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 (FIG. 5).

(71) Experimental Example 3: NMR Test

(72) The ZIF-8-nanocellulose composite prepared in Example 1-5 was measured by H-NMR (FIG. 6).

(73) Experimental Example 4: Measurement of Stability of ZIF-8-Nanocellulose Composite

(74) To measure the stability of the ZIF-8-nanocellulose composite prepared in Example 1-2, zeta potential was measured by the use of Photal, ELS-Z, and the result is represented in FIG. 7. From the result of the measurement, it can be known that the potential of particle is −53.09 mV, and the composite is stable.

(75) Experimental Example 5: Measurement of Stability of ZIF-8-Nanocellulose Composite

(76) The stability of the ZIF-8-nanocellulose composite prepared in Example 1-2 was measured by the use of Turbiscan. As a result, the stability of the composite was confirmed (FIG. 8).

(77) Experimental Example 6: X-Ray Powder Diffraction Test

(78) A powder X-ray powder diffraction (XRD) test of the ZIF-8 prepared in the Preparation Example and the ZIF-8-nanocellulose composite containing retinol prepared in Example 4 was carried out, and the results are represented in FIG. 9. As can be seen from FIG. 9, it can be known that each of the composites were synthesized well as constant peaks appear.

(79) Experimental Example 7: NMR Test

(80) From the results of NMR measurement of the ZIF-8 prepared in the Preparation Example and the ZIF-8-nanocellulose composite containing retinal prepared in Example 4, it can be known that the intensity of the peaks increased as the content of retinol increased (FIG. 10).

(81) Experimental Example 8: Test for Effect of ZIF-8-Nanocellulose Composite on Promoting Transdermal Absorption

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

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

(84) 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 was measured by high-performance liquid chromatography with the following conditions, and the results are represented in Table 23.

(85) TABLE-US-00023 TABLE 23 Transdermal absorption Rate of (μg) increase Liposome A 0.4004 15.64% Liposome B 0.2560 — 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

(86) As can be seen from Table 23, in the present invention retinol—which is encapsulated in the ZIF-8-nanocellulose composite—can be efficiently delivered into the skin.