Microstructure for transdermal absorption and method for manufacturing same

Abstract

The present invention relates to a microstructure including a biocompatible polymer or an adhesive and to a method for manufacturing the same. The present inventors optimized the aspect ratio according to the type of each microstructure, thereby ensuring the optimal tip angle and the diameter range for skin penetration. Especially, the B-type to D-type microstructures of the present invention minimize the penetration resistance due to skin elasticity at the time of skin attachment, thereby increasing the penetration rate of the structures (60% or higher) and the absorption rate of useful ingredients into the skin. In addition, the D-type microstructure of the present invention maximizes the mechanical strength of the structure by applying a triple structure, and thus can easily penetrate the skin. When the plurality of microstructures are arranged in a hexagonal arrangement type, a uniform pressure can be transmitted to the whole microstructures on the skin.

Claims

1. A method for manufacturing a microstructure, the method comprising: (a) supplying a biodegradable and biocompatible polymer or an adhesive into a micro-mold, wherein the biodegradable and biocompatible polymer or the adhesive comprise hyaluronic acid; (b) injecting the biodegradable and biocompatible polymer or adhesive into a hole of the micro-mold; (c) drying the biodegradable and biocompatible polymer or adhesive; and (d) separating the dried biocompatible polymer and biocompatible or adhesive from the micro-mold to form a microstructure, wherein the aspect ratio (w:h), configured of the diameter (w) of the bottom surface of the microstructure and the height (h) of the microstructure, is 1:5 to 1:1.5, and the angle of a distal tip (α) is 10°-40°, wherein injecting is carried out by (i) applying a centrifugal force of 800-1000 g to the micro-mold or (ii) applying a pressure of not less than 500 and less than 760 mmHg inside the micro-mold.

2. The method of claim 1, wherein step (c) is carried out (i) at room temperature for 36 to 60 hours, (ii) at 40 to 60° C. for 5 to 16 hours, or (iii) at 60 to 80° C. for 2 to 4 hours.

3. The method of claim 1, wherein the biodegradable and biocompatible polymer further comprises at least one polymer selected from the group consisting of carboxymethyl cellulose (CMC), alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide (PGA), polylactide-glycolide copolymer (PLGA), pullulan polyanhydride, polyorthoester, polyetherester, polycaprolactones, polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefin, polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), hydroxypropyl cellulose (HPC), cyclodextrin, copolymers of monomers forming these polymers, and cellulose.

4. The method of claim 1, wherein the hyaluronic acid has a molecular weight of 240 to 490 kDa.

5. The method of claim 1, wherein, in step (a), the solid content of the biodegradable and biocompatible polymer is 1 to 30% (w/v) on the basis of the entire composition of the microstructure.

6. The method of claim 1, wherein the adhesive further comprises at least one material selected from the group consisting of silicone, polyurethane, a physical adhesive, a polyacrylic material, ethylcellulose, hydroxymethyl cellulose, ethylene vinyl acetate, and polyisobutylene.

7. The method of claim 1, wherein a plurality of microstructures are arranged in a square or hexagonal shape.

8. The method of claim 7, wherein the plurality of microstructures are arranged at intervals (p) of 250 to 1500 μm.

9. The method of claim 1, wherein the microstructure has i) a cone shape; ii) a double structure of a cylinder and a cone; iii) a double structure of a truncated cone and a cone; or iv) a triple structure of two truncated cones and a cone.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1a, 1b, 1c, 1d, 1e and 1f show microstructures manufactured by the method of the present invention. diameter (w) of bottom surface, height (h), angle (α) of distal tip, diameter (t) of distal tip, distance (p) between microstructures, angle ranges of structure pillar (β1, 85-90°; β2-β4, 90-180°).

(2) FIGS. 2a, 2b, 2c and 2d show scanning electron microscopy (SEM) images of micro-molds used in the method of the present invention. 2a: type A, 2b: type B, 2c: type C, 2d: type D.

(3) FIGS. 3a, 3b, 3c and 3d show microscopy images of A-type to D-type microstructures, which were manufactured by the method of the present invention (Sunny SZMN, 40-70 folds). 3a: type A, 3b: type B, 3c: type C, 3d: type D.

(4) FIGS. 4a, 4b, 4c and 4d show scanning electron microscopy (SEM, JEOL JSM-7500F) mages of A-type to D-type microstructures, which were manufactured by the method of the present invention. In FIG. 4d, the arrows represent measurement points of w1, w2, and w. 4a: type A, 4b: type B, 4c: type C, 4d: type D.

(5) FIGS. 5a, 5b, 5c, 5d and 5e show test results of mechanical strength of A-type to D-type microstructures (5a to 5d), which were manufactured by the method of the present invention, and a pyramid-shaped control (5e).

(6) FIGS. 6a, 6b, 6c and 6d show test results of skin penetration (depth) of the microstructures manufactured by the method of the present invention (scanning electron microscopy images of the microstructures deformed after skin penetration). 6a: type A, 6b: type B, 6c: type C, 6d: type D.

MODE FOR CARRYING OUT THE INVENTION

(7) Hereinafter, the present invention will be described in detail with reference to examples. These examples are only for illustrating the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.

EXAMPLES

Example 1: Manufacturing of Microstructures

(8) 1. Manufacturing Process of A-Type Microstructures

(9) A positive or negative master mold was manufactured by subjecting a silicon wafer to a photolithography manufacturing technique, and then a final negative mold was manufactured using curable silicone (polydimethylsiloxane, PDMS) from the master mold.

(10) A hyaluronic acid was used as a biocompatible polymer. Hyaluronic acid (Bloomage Freda Biotechnology Co., Ltd., China) with an average molecular weight of 360 kDa (molecular weight range: 240-490 kDa) was completely dissolved in a concentration of 3% (w/v) in purified water before use.

(11) The hyaluronic acid was supplied into the PDMS micro-mold, and then injected and dried (without centrifugation and vacuum processes) at room temperature (25° C.) for 48 hours, at 50° C. for 6 hours, or at 70° C. for 3 hours, and then the mold was removed to manufacture hyaluronic acid microstructures.

(12) 2. Manufacturing Process of B-Type Microstructures

(13) A positive or negative master mold was manufactured by subjecting a silicon wafer to a photolithography manufacturing technique, and then a final negative mold was manufactured using curable silicone (polydimethylsiloxane, PDMS) from the master mold.

(14) A hyaluronic acid was used as a biocompatible polymer. Hyaluronic acid with an average molecular weight of 360 kDa (molecular weight range: 240-490 kDa) was completely dissolved in a concentration of 3% (w/v) in purified water before use.

(15) The hyaluronic acid was supplied into the PDMS micro-mold, and then injected into holes formed in the micro-mold using centrifugation at 900 g for 15 minutes. The hyaluronic acid was dried and injected at room temperature (25° C.) for 48 hours, at 50° C. for 6 hours, or at 70° C. for 3 hours, and then the mold was removed, thereby manufacturing hyaluronic acid microstructures.

(16) 3. Manufacturing Process of C-Type Microstructures

(17) A positive or negative master mold was manufactured by subjecting a silicon wafer to a photolithography manufacturing technique, and then a final negative mold was manufactured using curable silicone (polydimethylsiloxane, PDMS) from the master mold.

(18) A hyaluronic acid was used as a biocompatible polymer. Hyaluronic acid with an average molecular weight of 360 kDa (molecular weight range: 240-490 kDa) was completely dissolved in a concentration of 3% (w/v) in purified water before use.

(19) The hyaluronic acid was supplied into the PDMS micro-mold, and then injected into holes formed in the micro-mold for 10-30 minutes under a vacuum (600-760 mmHg) environment. The hyaluronic acid was dried and injected at room temperature (25° C.) for 48 hours, at 50° C. for 6 hours, or at 70° C. for 3 hours, and then the mold was removed, thereby manufacturing hyaluronic acid microstructures.

(20) 4. Manufacturing Process of D-Type Microstructures

(21) A positive master mold was manufactured by subjecting a silicon wafer to a photolithography manufacturing technique, and then a negative mold was manufactured using curable silicone (polydimethylsiloxane, PDMS) from the positive master mold.

(22) Carboxymethyl cellulose (CMC) was used as a biocompatible polymer. CMC was completely dissolved in a concentration of 3% (w/v) in purified water before use.

(23) The CMC was supplied into the PDMS micro-mold, and then injected into holes formed in the micro-mold for 10-30 minutes under a vacuum (600-760 mmHg) environment. The CMC was dried and injected at room temperature (25° C.) for 48 hours, at 50° C. for 6 hours, or at 70° C. for 3 hours, and then the mold was removed, thereby manufacturing CMC microstructures.

(24) 5. Standard Ranges of Microstructures (FIGS. 1a to 1f)

(25) TABLE-US-00001 TABLE 1 Tip Structure Structure Aspect Structure Tip Number of Structure Structure angle diameter height ratio interval diameter structures arrangment Type shape (α, °) (w, μm) (h, μm) (w:h) (p, μm) (t, μm) (per 1 cm.sup.2) type A Cone 12-40 50-400 100-1300 1:5-1:1.5 250-1500 2-20 25-1200 Square, Hexagonal B Cylinder + 12-40 35-400 100-1300 1:5-1:2 250-1500 2-20 25-1300 Square, Cone (h.sub.1: 55-1200, Hexagonal h.sub.2: 45-800) C Modified 12-40 80-650 150-1300 1:5-1:2 250-1500 2-20 20-1000 Square, cylinder + (w.sub.1: 30-400) (h.sub.1: 70-1200, Hexagonal Cone h.sub.2: 80-800) D Triple tower 12-40 100-650  150-1300 1:5-1:2 250-1500 2-20 20-1000 Square, struture (w.sub.1: 40-180, (h.sub.1: 60-500, Hexagonal w.sub.2: 60-400) h.sub.2: 40-350, h.sub.3: 50-450) *Angle range of microstructure pillar: β.sub.1, 85°-90°/β.sub.2 to β.sub.4, above 90° (90°-180°)

Example 2: Test on Mechanical Strength of Microstructure

(26) As for the mechanical strength of the microstructures manufactured by the present invention, the porcine skin was used, and when the microstructures were allowed to penetrate the porcine skin with predetermined force, the number of holes generated in the epidermis of the skin was checked and compared (FIGS. 5a to 5e).

(27) The microstructure sample for each type was cut into 0.7 cm×0.7 cm (100 or more structures) before use, and then the microstructures were allowed to penetrate the porcine skin by a vertical application of a force of 3-5 kg for 10 seconds. The microstructures were removed after skin penetration, and then 20 ml of Trypan blue (Sigma) was coated on the skin surface, stained the skin surface for 10 minutes, and then wiped out using cotton swabs and phosphate-buffered saline (PBS). The mechanical strength of the microstructures enabling successful skin penetration was observed by measuring the number of holes stained in the epidermal layer.

(28) Pyramid-shaped microstructures were tested by the same method to perform a comparison of mechanical strength.

(29) Mechanical strength test results for respective microstructures of the present invention are shown in the following table.

(30) TABLE-US-00002 TABLE 2 Polymer raw Mechanical strength Type Structure shape material (penetration, %) A Cone Hyaluronic acid 92 CMC 84 B Cyliner + Cone Hyaluronic acid 96 CMC 92 C Modified cylinder + Hyaluronic acid 98 Cone CMC 96 D Triple top structure Hyaluronic acid 99 CMC 98 Control Pyramid Hyaluronic acid 79 CMC 75

(31) The detail standards of the microstructures used in the test are shown as follows.

(32) TABLE-US-00003 TABLE 3 Tip angle Structure diameter Structure height Aspect ratio Type (α, °) (w, μm) (h, μm) (w:h) A 12 90 270 1:3 B 14 85 270   1:3.2 (h.sub.1: 145, h.sub.2: 125) C 16 90 270 1:3 (w.sub.1: 80) (h.sub.1: 150, h.sub.2: 120) D 16 90 270 1:3 (w.sub.1: 66, w.sub.2: 80) (h.sub.1: 110, h.sub.2: 90, h.sub.3: 70)

Example 3: Test on Skin Penetration (Depth) of Microstructures

(33) The skin penetrations of the microstructures manufactured in the present invention were compared with each other by allowing the structures to penetrate the porcine skin using predetermined force and then monitoring the deformation degree of the structure between before and after the penetration (FIGS. 6a to 6d).

(34) The microstructure sample for each type was cut into 0.7 cm×0.7 cm before use, and then the microstructures were allowed to penetrate the porcine skin by a vertical application of a force of 3-5 kg for 10-30 seconds. The insertion sites were observed using an optical microscope, and the deformation degree was monitored through the scanning electron microscopy (SEM) observation of the microstructures before and after the skin penetration, thereby measuring the penetrable depth.

(35) Skin penetration test results for respective microstructures of the present invention are shown in the following table.

(36) TABLE-US-00004 TABLE 4 Polymer raw Skin penetration Type Structure shape material (Deformation percent, %) A Cone Hyaluronic acid 50-85 B Cylinder + Cone Hyaluronic acid 65-90 C Modified cylinder + Hyaluronic acid 65-90 Cone D Triple top structure Hyaluronic acid 60-85

(37) Although the present invention has been described in detail with reference to the specific features, it will be apparent to those skilled in the art that this description is only for a preferred embodiment and does not limit the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.