KR20210048013A - Pigment encapsulated micro structures - Google Patents

Abstract

Pigment microstructures for transdermal delivery are provided. The pigment microstructures for transdermal delivery according to an embodiment of the present invention include: a base part formed on a sheet; and a tip part formed on the base part and containing a dye, wherein the length of each of the base part and the tip part is determined according to a remaining period for a pigment to remain in the skin. An embodiment of the present invention is to provide the pigment microstructures for transdermal delivery that can accurately deliver an accurate amount of a pigment to a skin layer at a desired depth.

Description

Pigment encapsulated micro structures for transdermal delivery

The present invention relates to a pigment microstructure for transdermal delivery.

In general, alopecia, characterized by clogging of hair follicles and hair loss, interferes with the normal cycle of hair growth. Although not a life-threatening condition, it has been reported that the psychological condition of individuals suffering from alopecia is greatly affected. Despite considerable research in the treatment of hair loss, interest in micro-pigmentation has increased in recent decades.

Micropigmentation is an effective way to disguise the visual contrast between the scalp and hair. However, the localization, intensity and size of the microdots are highly dependent on the doctor performing the transplant. Microscopic spots that are incorrectly localized within the skin can cause uneven or faint micropigmentation.

On the other hand, tattooing refers to injecting pigment into the skin by piercing the skin with a needle. However, commonly used needles are painful and can cause skin irritation. Moreover, depending on the amount or depth of pigment added, there is a risk of the tattoo spreading.

KR 2017-0129685 A

In order to solve the problems of the prior art as described above, an embodiment of the present invention is to provide a pigment microstructure for transdermal delivery capable of accurately delivering an accurate amount of pigment to the skin layer at a desired depth.

However, the problem to be solved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned will be clearly understood by those skilled in the art from the following description.

According to an aspect of the present invention for solving the above problems, the base portion formed on the sheet; And a tip portion formed on the base portion and including a pigment, wherein a length of each of the base portion and the tip portion is determined according to a remaining period in which the pigment is intended to remain in the skin. A structure is provided.

In one embodiment, the tip portion and the base may have a candle shape in which a vertical cross section has a continuous curvature.

In one embodiment, the length of the base portion and the total length of the base portion and the tip portion may be shorter in the case of the first remaining period than in the case of the second remaining period, and the second remaining period may be longer than the first remaining period. have.

In one embodiment, the first remaining period may be less than 6 months, and the total length of the base portion and the tip portion may be 100 to 300 μm.

In one embodiment, the second remaining period may be at least 1 year, and the total length of the base portion and the tip portion may be 300 to 2000 μm.

In one embodiment, the length of the base portion may be greater than 30 μm.

In one embodiment, the sheet may be made of a soluble material.

In one embodiment, the sheet, the base portion, and the tip portion may include a biodegradable material.

In one embodiment, the base portion and the tip portion may be formed in an array shape on the sheet.

In one embodiment, the base portion and the tip portion may be randomly formed on the sheet at a predetermined density.

In one embodiment, the base portion and the tip portion may have different sizes depending on the position on the sheet.

In one embodiment, the cross-sectional shape and the cross-sectional size may be determined according to the shape and size of a tattoo formed by the remaining of the pigment in the base portion and the tip portion.

The pigment microstructure for transdermal delivery according to an embodiment of the present invention is implanted into the skin by mounting the pigment on the microstructure, so that an accurate amount of pigment can be accurately delivered to the skin layer at a desired depth, thereby improving the efficiency of a skin tattoo. .

In addition, since the pigment microstructure for transdermal delivery according to an embodiment of the present invention is made of a biodegradable material, it recovers quickly after perforation of the skin by the microstructure, so that skin damage can be minimized.

In addition, in the dye microstructure for transdermal delivery according to an embodiment of the present invention, by determining the total length of the microstructure or the length of the base portion according to the remaining period of the dye, it is possible to easily manufacture the dye microstructure according to the desired tattoo period.

1 is a diagram schematically illustrating a scalp transplantation of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, (a) is before scalp transplantation, and (b) is a view showing after scalp transplantation;
2 is a cross-sectional view of a dye microstructure for transdermal delivery according to an embodiment of the present invention,
3 is a schematic diagram showing a manufacturing process of a pigment microstructure for transdermal delivery according to an embodiment of the present invention,
Figure 4 is a micrograph of a dye microstructure for transdermal delivery according to an embodiment of the present invention, (a) in the case of a 5 × 5 array form, (b) is made of a soluble biodegradable sheet, (c) is The top view of (b),
5 is an exemplary pattern of a dye microstructure for transdermal delivery according to an embodiment of the present invention, (a) a 5×5 array, (b) a low density random pattern, (c) a high density random pattern,
6 is a diagram schematically showing the shape and implantation state according to the skin remaining period of the pigment microstructure for transdermal delivery according to an embodiment of the present invention, where (a) is a case where the remaining period is short, and (b) is the remaining Drawings for long periods of time,
7 is a schematic diagram showing a first modified example of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, where (a) is a case where a small point is large, (b) is a case where a small point is intermediate, (c) is Schematic diagram of a case where the microscopic point is small,
8 is a schematic diagram showing a second modified example of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, where (a) is a triangle, (b) is a square, and (c) is a circle , (d) is a schematic diagram when the minute point is a straight line,
9 is a plan view showing a third modified example of a pigment microstructure for transdermal delivery according to an embodiment of the present invention;
10 is a photograph showing the degree of dissolution after implantation of the pigment microstructure for transdermal delivery according to an embodiment of the present invention, (a) a photograph in the case of a total length of 800 μm, (b) a total length of 1000 μm,
11 is a photograph of a display state after implantation of a dye microstructure for transdermal delivery according to an embodiment of the present invention, (a) a photograph of a total length of 800 µm, (b) a photograph of a total length of 1000 µm,
12 is a graph showing a state after implantation of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, (a) is a graph showing the relative area of the pigment microdots, (b) is a graph showing the relative area of the diffusion ring; And,
13 is a diagram showing the results of a mouse transplantation experiment of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, (a) is a photograph of the skin condition by time after transplantation, (b) is a photograph of the skin after hair growth, (c) ) Is a graph of the relative area of the dye micropoint, (d) is a graph of the relative area of the diffusion ring, and (e) is a graph of TEWL.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those of ordinary skill in the art may easily implement the present invention. The present invention may be implemented in various different forms and is not limited to the embodiments described herein. In the drawings, parts irrelevant to the description are omitted in order to clearly describe the present invention, and the same reference numerals are assigned to the same or similar components throughout the specification.

The embodiments of the present invention are provided to more fully describe the present invention to those of ordinary skill in the art, and the embodiments described below may be modified in various other forms, and The scope is not limited to the following examples. Rather, these examples are provided to make the present invention more faithful and complete, and to fully convey the spirit of the present invention to those skilled in the art.

Hereinafter, embodiments of the present invention will be described with reference to the drawings schematically showing embodiments of the present invention. In the drawings, for example, depending on manufacturing techniques and/or tolerances, variations of the illustrated shape can be expected. Accordingly, the embodiments of the present invention should not be construed as being limited to the specific shape of the region shown in the present specification, but should include, for example, a change in shape caused by manufacturing.

1 is a schematic diagram of a scalp transplantation of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, (a) is before scalp transplantation, (b) is a view showing after scalp transplantation, and FIG. 2 Is a cross-sectional view of a dye microstructure for transdermal delivery according to an embodiment of the present invention.

Referring to FIG. 1, the pigment microstructure 10 for transdermal delivery according to an embodiment of the present invention can accurately implant the pigment P under the epithelial-dermal junction of the scalp 1 in a minimally invasive manner. Here, a very accurate implantation system is required for accurate implantation of the pigment (P). Therefore, the present invention applies a microstructure, which is a highly accurate transdermal delivery system. In the present specification, the skin 1 is described by taking the scalp as an example, but is not limited thereto, and can be applied to all skin such as eyebrow tattoos, lip tattoos, arm tattoos, leg tattoos, and body tattoos. Therefore, it goes without saying that the description of the skin or the scalp in the present specification may be equally applied to each other.

Upon complete implantation, the pigment microstructure 10 for transdermal delivery may be implanted into the dermal layer, as shown in FIG. 1(b). As a result, the pigment P is dissolved in the dermal layer to reduce the visual contrast between the scalp 1 and the hair, so that the hair loss region as shown in FIG. 1A can be disguised.

The pigment microstructure 10 for transdermal delivery can accurately implant the pigment without using an applicator due to its unique shape. Therefore, the individual can achieve very accurate implantation of the pigment P by applying the pigment microstructure 10 for transdermal delivery to a desired scalp region using a finger force or an applicator. Thereby, the pigment microstructure 10 for transdermal delivery can improve the efficiency of the scalp tattoo.

Referring to FIG. 2, the dye microstructure 10 for transdermal delivery according to an embodiment of the present invention includes a sheet 11, a base portion 12, and a tip portion 13.

The sheet 11 may be a base layer on which the microstructure 10 for transdermal delivery is formed.

Here, in order to accurately implant the pigment P into the scalp 1, complete insertion and interlocking of the entire array of pigment microstructures 10 for transdermal delivery play an important role. Moreover, since each individual applies the force differently, the risk of incomplete insertion of the pigment microstructure 10 for transdermal delivery is high, resulting in non-uniform dissolution of the pigment encapsulated in the tip portion 13. To prevent this, the dye microstructure 10 for transdermal delivery is manufactured on a flexible sheet.

In addition, the flexible sheet 11 may be made of a biodegradable material. For example, the flexible sheet 11 may be made of hyaluronic acid (HA). Therefore, the sheet 11 can be simply washed after complete dissolution of the pigment microstructure 10 for transdermal delivery.

The base portion 12 may be formed on the sheet 11. The base portion 12 does not contain a pigment. Since the pigment P must remain dissolved in the skin at a certain depth, the base portion 12 has a certain length.

As shown in (b) of FIG. 1, the base portion 12 serves to implant the tip portion 13 into the scalp 1 in order to retain the pigment P at a desired depth in the skin. That is, the base portion 12 acts as a shaft, allowing the pigment P to be implanted at a target skin depth.

The tip portion 13 may be formed on the opposite side of the sheet 11 in the base portion 12. The tip part 13 may include a pigment P.

Here, the base portion 12 and the tip portion 13 may include a biodegradable material. For example, the base portion 12 and the tip portion 13 may include hyaluronic acid (HA).

In addition, the base portion 12 and the tip portion 13 may be formed in a substantially candle shape. That is, the base portion 12 and the tip portion 13 may be formed so that their vertical cross section has a continuous curvature. That is, the base portion 12 and the tip portion 13 may be formed of a continuous curved surface in a direction away from the sheet 11 of the outer surface. However, according to the manufacturing process of the base portion 12 and the tip portion 13, the base portion 12 and the tip portion 13 may be formed to have a discontinuous surface. Here, the base portion 12 and the tip portion 13 may have a circular horizontal cross section, but are not limited thereto.

The base portion 12 may include a first cross-section in contact with the sheet 11. In addition, the base portion 12 may be formed such that the area of the cross-section becomes narrower toward a direction away from the sheet 11. In this case, the base portion 12 may include a second cross-section having the smallest cross-sectional area.

The base portion 12 may be formed so that the area of the cross-section from the second cross-section increases in a direction away from the sheet 11. In this case, the base portion 12 may include a third cross-section having the largest cross-sectional area.

In addition, the base portion 12 may be formed so that the area of the cross-section from the third cross-section in a direction away from the sheet 11 becomes narrower again. At this time, the base portion 12 may have a wine glass shape.

The tip portion 13 may be formed on the upper surface of the base portion 12. The tip portion 13 may be formed such that the area of the cross section becomes narrower in a direction away from the sheet 11.

Here, the length L1 of the base portion 12 and the length L2 of the tip portion 13 may be determined according to the remaining period in which the pigment P is intended to remain on the scalp 1. Therefore, while the overall shape of the base portion 12 and the tip portion 13 maintains the candle shape, the position of the interface between the base portion 12 and the tip portion 13 is the length L1 of the base portion 12 and the tip portion 13 It can be changed according to the length (L2) of ). That is, the interface between the base portion 12 and the tip portion 13 may be disposed at an arbitrary position on the opposite side of the sheet 11 at a portion having the smallest cross-sectional area in the shape of a candle. Preferably, the base portion 12 may include a portion with the largest cross-sectional area.

Thereby, the pigment microstructure 10 for transdermal delivery can be easily manufactured according to the desired tattoo period on the scalp.

The length L1 of the base portion 12 and the total lengths L1+L2 of the base portion 12 and the tip portion 13 may be shorter in the case of the first remaining period than in the case of the second remaining period. Here, the second remaining period may be longer than the first remaining period. For example, the first remaining period may be several weeks to several months, and the second remaining period may be 1 year or more.

That is, the remaining period of the pigment P may be determined according to the dissolving position in the scalp 1. At this time, as the location of the implanted pigment P is closer to the surface of the scalp 1, the residual period of the pigment P may be shorter, and the closer to the dermis layer from the scalp 1, the longer the residual period of the pigment P may be. . In conclusion, the length L1 of the base 12 and the total lengths L1+L2 of the base 12 and the tip 13 may be determined according to the remaining period of the pigment P in the scalp 1 .

For example, the length L1 of the base portion 12 may be greater than 30 μm. When the length L1 of the base portion 12 is less than 30 μm, since the pigment P is dissolved in the epidermal layer of the scalp 1, a spreading phenomenon such as a diffusion ring may occur on the surface.

3 is a schematic diagram showing a manufacturing process of a dye microstructure for transdermal delivery according to an embodiment of the present invention. Figure 4 is a micrograph of a dye microstructure for transdermal delivery according to an embodiment of the present invention, (a) in the case of a 5 × 5 array form, (b) is made of a soluble biodegradable sheet, (c) is It is a top view of (b).

The pigment microstructure 10 for transdermal delivery may be manufactured in a two-stage structure of a base portion 12 that does not contain a pigment P and a tip portion 13 that includes an encapsulated pigment P.

Here, hyaluronic acid (HA), a natural glycosaminoglycan widely used to increase skin elasticity and hydration, is used as the backbone matrix of the pigment microstructure 10 for transdermal delivery. I can.

First, as shown in (a) and (b) of Fig. 3, a hyaluronic acid (HA) viscous composition 12a that does not contain a pigment (P) is applied to a thin film of a flexible sheet 11 by a drop (draw Ping), and centrifuging in a state where the plate (2) is placed on the opposite side of the sheet (11).

As shown in (c) of FIG. 3, by separating the plate 2 and then solidifying the viscous composition 12a, the base portion 12 in the shape of a wine glass is formed.

As shown in (d) and (e) of FIG. 3, the hyaluronic acid (HA) viscous composition 13a containing the pigment (P) is dropped (dropped) on the base portion 12 and centrifuged. .

As shown in (f) of FIG. 3, by forming the tip part 13 by solidifying the viscous composition 13a, the dye microstructure 10 for transdermal delivery of a bilayer structure with a narrow neck, a wide middle part, and a sharp tip is formed. .

Here, the thickness of an individual's scalp is different according to race, sex, and age. Therefore, by adjusting the volume of the viscous composition 13a and the length of the base portion 12, the volume and length of the tip portion 13 can be optimized.

Referring to FIG. 4A, the base portion 12 and the tip portion 13 may be formed on the sheet 11 in an array form. For example, the base portion 12 and the tip portion 13 may be formed in a 5×5 array on the sheet 11.

The scalp (1) is not a flat surface. Therefore, when the dye microstructure 10 for transdermal delivery is formed on the hard sheet 11, the dye microstructure 10 for transdermal delivery is disproportionately inserted into the scalp 1. To this end, the sheet 11 may be a soluble sheet, as shown in (b) and (c) of FIG. 4. Accordingly, the accuracy of implantation of the array of pigment microstructures 10 for transdermal delivery may be further improved.

5 is an exemplary pattern of a dye microstructure for transdermal delivery according to an embodiment of the present invention, wherein (a) a 5×5 array, (b) a low density random pattern, and (c) a high density random pattern.

Referring to FIG. 5A, the base portion 12 and the tip portion 13 may be formed on the sheet 11 in an array form. For example, the base portion 12 and the tip portion 13 may be formed in a 5×5 array to have a pitch of 1.5 mm.

In addition, the pigment microstructure 10 for transdermal delivery may be formed in a random arrangement based on an individual's hair density and hair growth pattern. Thereby, the most realistic visual shape can be provided. In addition, the density of the base portion 12 and the tip portion 13 may be adjusted to a predetermined density based on the hair density of the patient.

Referring to FIG. 5B, when the hair density is high and hair growth is relatively fast, the base portion 12 and the tip portion 13 may be randomly formed on the sheet 11 with low density. Referring to FIG. 5C, when the hair density is low and hair growth is relatively slow, the base portion 12 and the tip portion 13 may be randomly formed on the sheet 11 with high density.

6 is a diagram schematically showing the shape and implantation state according to the skin remaining period of the pigment microstructure for transdermal delivery according to an embodiment of the present invention, where (a) is a case where the remaining period is short, and (b) is the remaining This is a diagram for a long period.

Referring to Figure 6 (a), when the remaining period of the pigment (P) in the scalp (1) is short, for example, from several weeks to several months, the pigment microstructure 10' for transdermal delivery is a pigment ( It can be formed short so that P) is implanted and maintained in the epithelium (epidermis) of the scalp 1.

For example, when the remaining period of the pigment P is 6 months, the total length of the base portion 12 and the tip portion 13 may be 100 to 300 μm. Here, when the total length of the dye microstructure 10' for transdermal delivery is less than 100 μm, since the dye P diffuses to the surface side, the spreading shape by the diffusion ring increases on the surface. In addition, when the total length of the pigment microstructure 10' for transdermal delivery exceeds 300 μm, the pigment P remains on the scalp 1 for a period longer than a desired short remaining period.

Referring to FIG. 6B, when the remaining period of the pigment (P) in the scalp (1) is long, for example, if it is more than one year, the pigment microstructure 10" for transdermal delivery has a pigment (P). It can be formed long so that it is implanted and maintained in the dermis of the scalp (1).

For example, when the remaining period of the pigment P is 1 year or more, the total length of the base portion 12 and the tip portion 13 may be 300 to 2000 μm. Here, when the total length of the pigment microstructure 10" for transdermal delivery is less than 300 μm, the pigment P is not maintained within the desired remaining period and the pigment P is faded. In addition, the total length of the pigment microstructure 10" for transdermal delivery is less than 300 μm. When the length exceeds 2000 µm, recovery of microscopic wounds on the scalp 1 may be delayed and contaminated by pathogens.

The cross-sectional shape and the cross-sectional size of the base 12 and the tip 13 may be determined according to the shape and size of a tattoo formed by the remainder of the pigment P in the scalp 1.

7 is a schematic diagram showing a first modified example of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, where (a) is a case where a small point is large, (b) is a case where a small point is intermediate, (c) is Fig. 8 is a schematic diagram showing a second modified example of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, where (a) is a triangle, and (b) is a square. , (c) is a schematic diagram of a case where the minute point is circular, (d) is a straight line, and FIG. 9 is a plan view showing a third modified example of the dye microstructure for transdermal delivery according to an embodiment of the present invention.

Referring to FIG. 7, in order to increase the size of microscopic spots in which the pigment P is formed on the scalp 1 according to the hair loss state, the dye microstructure 10 for transdermal delivery may increase the diameter of its horizontal cross section. have.

Referring to FIG. 8, in order to form the pigment P in a triangular, square, polygonal, or linear shape on the scalp 1 according to the shape of the hair loss area, the dye microstructure 10 for transdermal delivery has a horizontal cross section. The shape can be deformed.

Referring to FIG. 9, the base portion 12 and the tip portion 13 may have different sizes depending on the position on the sheet 11 according to the density of the hair loss area.

With this configuration, since the pigment microstructure 10 for transdermal delivery can accurately deliver an accurate amount of pigment to the scalp layer at a desired depth, the efficiency of the scalp tattoo can be improved, and it is quickly recovered after the scalp puncture by the microstructure. Scalp damage can be minimized, and pigment microstructures can be easily manufactured according to the desired tattoo period.

Hereinafter, an experiment and a result of the dye microstructure 10 for transdermal delivery according to an embodiment of the present invention will be described with reference to FIGS. 10 to 13.

A solution was prepared by mixing hyaluronic acid (HA, 32 kDa, Soliance, France, Pomacle, France) with distilled water and safety approved black tattoo ink (INT019-1, Intenze, Rochelle Park, USA). The dye microstructure 10 for transdermal delivery irradiated in the in vitro evaluation was prepared in two lengths of 800 ± 45 µm and 1000 ± 51 µm using a microneedle manufacturing technique by centrifugation lithography.

First, 20% hyaluronic acid (HA) (w/w) was coated on a metal plate to prepare a thin-film soluble biodegradable sheet 11. Subsequently, a hyaluronic acid (HA) viscous composition (12a) that does not contain a pigment (P) was dropped onto the flexible sheet 11 in a 5Х5 array (SHOT mini 100-s, Musashi, Tokyo, Japan), and non-adhesive It was placed 200 μm and 400 μm away from the plate 2, and centrifuged at 300×g for 1 minute (Hanil Combi Centrifuge).

Subsequently, the non-adhesive plate 2 was removed, and the resulting viscous composition 12a in the form of a wine glass having a length of 200 μm and 400 μm was solidified for an additional 5 minutes. Subsequently, the viscous composition 13a containing the pigment (P) was dropped onto the base portion 12 and centrifuged at 500 x g for 1 minute.

The length of the tip portion 13 including the dye P prepared on the base portion 12 having a length of 200 μm and 400 μm was fixed at 600 ± 48 μm. Accordingly, the total lengths of the dye microstructures 10 for transdermal delivery prepared on the base portion 12 of 200 μm and 400 μm were 800±45 μm and 1000±51 μm, respectively. At this time, in order to investigate the transmission and diffusion characteristics of the dye microstructure 10 for transdermal delivery, it was manufactured with a pitch of 1.5 mm.

10 is a photograph showing the degree of dissolution after transplantation of the pigment microstructure for transdermal delivery according to an embodiment of the present invention, (a) a photograph of a total length of 800 μm, (b) a total length of 1000 μm, and FIG. 11 Is a photograph of a display state after implantation of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, (a) a total length of 800 μm, (b) a total length of 1000 μm.

Permeation and dissolution properties of the dye microstructures (10) for transdermal delivery of 800 μm and 1000 μm in length were evaluated up to 28 days (n = 4 / group) using the Franz cell diffusion system (Hanson, Los Angeles, CA, USA). Became. The temperature of the Franz cell chamber was set to 35±1° C. and stirred at 250 rpm to mimic blood circulation in the body. The pigment microstructure 10 for transdermal delivery completely dissolved 30 minutes after transplantation was gently washed off the skin. The skin surface was recorded on days 1, 7 and 28 under a bright field light microscope. Subsequently, the treated skin was cut individually to evaluate the transmission pattern of the pigment (P) across the dermal layer.

Referring to FIG. 10, both the dye microstructure 10 for transdermal delivery with a length of 800 µm (Fig. 10 (a)) and the dye microstructure 10 for transdermal delivery with a length of 1000 µm (Fig. 10 (b)) After transplantation, the tip portion 13 containing the pigment P was dissolved in 15 minutes. 30 minutes after recognition, the base portion 12 that did not contain the pigment P was also completely dissolved.

In addition, the percutaneous dissolution and permeation properties of the pigment microstructure 10 for transdermal delivery were evaluated by implantation into the skin of a porcine carcass placed on the Franz cell diffusion system for 28 days.

Referring to FIG. 11, the initial intensity of the pigment was maintained in all of the dye microstructures 10 for transdermal delivery of 800 μm and 1000 μm in length for up to 28 days. However, a diffusion ring surrounding each implantation site was observed on the 1st and 7th days in the skin implanted with the 800 μm-long transdermal delivery pigment microstructure 10. The size of the microspots was wider up to 28 days after implantation, and at day 28 the diffusion rings showed sharper edges and smaller diffusion rings compared to the diffusion rings of day 1 (Fig. 11(a)).

In contrast, in the skin implanted with the pigmented microstructure 10 for transdermal delivery of 1000 μm in length, the microspots appeared sharp and distinct with a fairly small diffusion ring around the microspots of 1 day (Fig. 11(b)). . Compared to day 1, on day 28, the dimensions of the microspots remained high, indicating localization of the pigment in the skin tissue.

The cross-sectional image confirmed the localization of the pigment in the tissue treated with the dye microstructure 10 for transdermal delivery of 800 μm and 1000 μm in length 28 days after transplantation. In addition, the localization of the dye microstructure 10 for transdermal delivery having a length of 1000 μm was less diffuse than the dye microstructure 10 for transdermal delivery having a length of 800 μm, and thus it was clear. Individuals with distinct skin characteristics may exhibit different penetration and dissolution patterns of the transdermal delivery pigment microstructure 10 implanted inside the skin.

12 is a graph showing a state after implantation of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, (a) is a graph showing the relative area of the pigment microdots, (b) is a graph showing the relative area of the diffusion ring .

The pigmentation area of the pigmented microstructure (10) for transdermal delivery on the skin was determined using ImageJ software (National Institutes of Health, Bethesda, MD, USA) in two categories (i) the main pigmentation area (the highest pigment intensity ( 90 to 100%), and (ii) the diffusion ring area (a low intensity (10 to 90%) faint pigmented area surrounding the microspot). In order to quantify the microspot area, the dimension of the layer (tip 13) containing the pigment in the pigment microstructure 10 (250 ± 25 μm) for transdermal delivery is set to 1, and the relative pigmentation area is determined accordingly. Calculated. The relative area of the diffusion ring was measured individually every day based on the average pigmentation area set to 1 and was thus quantified using ImageJ.

Referring to Figure 12, the microspots on the skin surface were quantified into two separate categories: (i) core pigmentation and (ii) diffusion rings. The core pigmentation represents the region with the highest pigment intensity detected by ImageJ software, and the diffusion ring is the peripheral region with the lower pigment intensity. On day 1 after transplantation, the area of the pigment microspot was expanded to 2.11 ± 0.04 and 1.66 ± 0.09 for 800 μm in the 1000 μm long transdermal delivery pigment microstructure (10) (Fig. 12(a)).

On the 28th day after transplantation, the pigmentation area was further increased to 2.31 ± 0.17 in the skin implanted with the 800 μm-long transdermal delivery pigment microstructure (10), while the 1000 μm-long transdermal delivery pigment microstructure (10) was further increased. ) Was maintained at 1.71 ± 0.18 in the implanted skin. These results showed that deep implantation of the pigment microstructure 10 for transdermal delivery at 1000 μm results in accurate localization of the pigment and minimizes diffusion over time.

In addition, the continuous expansion of the pigment area in the skin implanted with the dye microstructure 10 for transdermal delivery having a length of 800 μm may cause an uneven appearance over time.

In order to investigate the transdermal transmission characteristics of the dye microstructure 10 for transdermal delivery, the dimensions of the diffusion ring surrounding the micro-points were measured (Fig. 12(b)). In the skin implanted with the dye microstructure 10 for transdermal delivery with a length of 800 μm, the diffusion ring extended to 2.59 ± 0.07 on day 1, and significantly decreased to 1.67 ± 0.19 on day 28 as time passed. The skin treated with the pigment microstructure 10 for transdermal delivery with a length of 1.44 ± 0.10 (1 day) decreased to 1.27 ± 0.11 on the 28th day.

Consistent with the core pigmentation results, it can be seen that deep implantation of the pigment microstructure 10 for transdermal delivery improves the localization of microspots and prevents the risk of spreading until 28 days after implantation.

13 is a diagram showing the results of a mouse transplantation experiment of a pigment microstructure for transdermal delivery according to an embodiment of the present invention, (a) is a photograph of the skin condition by time after transplantation, (b) is a photograph of the skin after hair growth, (c) ) Is a graph of the relative area of the dye micropoint, (d) is a graph of the relative area of the diffusion ring, and (e) is a graph of TEWL.

The dye microstructure 10 for transdermal delivery was manufactured using the same method with a total length of 400 ± 26 µm on the base portion 12 that does not contain the dye P having a length of 100 µm.

Male BALB/c mice (8 weeks old) were purchased from YoungBio (Korea) and acclimated to the new environment for 1 week. The back skin of the mice was shaved using a clipper and left for 1 day to avoid skin damage. Subsequently, the mice were individually treated for 28 days with a control group and a pigmented microstructure 10 for transdermal delivery of 400 ± 26 μm in length (n=4/group). Throughout the experiment, mice were maintained on a 12 hour light/dark cycle with random access to food and water.

Transepidermal water loss (TEWL) evaluation was performed in a control group and a pigmented microstructure (10) transplant group for transdermal delivery using ^{AquaFlux™ (Biox Systems, London, UK).} Briefly, the pigment microstructure 10 for transdermal delivery was implanted into the skin and completely dissolved for 30 minutes, and then the flexible sheet 11 was removed. TEWL readings were measured at 0, 1, 2, 3, 4, 5, 6, 12 and 24 hours post implantation (n=4/group).

Closure of microscopic wounds formed upon implantation of the pigment microstructure 10 for transdermal delivery affects the localization and strength of pigmentation. Mice have a thinner dermal layer than pigs. Therefore, in this experiment, the length of the pigment microstructure 10 for transdermal delivery was optimized to 400 ± 26 μm composed of the base portion 12 that does not contain the pigment 100 μm in length based on the thickness of the mouse skin.

In order to investigate the effect of wound healing and skin re-epithelial on pigment, the pigment microstructure (10) for transdermal delivery was implanted into the back skin of mice and evaluated for up to 28 days (Fig. 13 (a)). Comparison of the visual intensity of the microspots on the skin on days 1 and 28 reveals the localization of the pigment under the epidermis. Contrary to in vitro results, remarkably small core pigmentation and diffusion rings were observed. The difference was assumed to reflect the higher structural density of the mouse skin compared to the porcine carcass skin, resulting in a concentrated localization of the pigment. In addition, the results of the in vivo study showed that the visual intensity of the pigment was well maintained even after hair growth in the back (FIG. 13(b)).

As a result, in order to quantify the size and pattern of dissolution of the pigment, the area of each micropoint was measured with a peripheral diffusion ring. Similar to the ex vivo pattern, the microspot expanded to 1.34 ± 0.18 (day 1) followed by a significant decrease on day 7. The size of the microspot was maintained at 1.25 ± 0.16 until 28 days after transplantation (Fig. 13 (c)). Crucially, as the diffusion ring fades over time, in order to achieve a well-maintained pigmentation, the pigmentation must be concentrated at the implantation point. It was found that the diffuse ring surrounding each microspot was small and no significant change until 28 days after implantation, suggesting a highly concentrated localization of the pigment at each point (Fig. 13(d)). In this experiment, the structure of the tip portion 13 containing the pigment P was fixed. However, by adjusting the volume of the viscous composition containing the pigment (P) during the manufacturing process, it was possible to further reduce the size of the microspots. It can be seen that in order to achieve highly maintained pigmentation, the target insertion depth should be below the epithelial-tradial junction.

Transplantation of the pigment microstructure 10 for transdermal delivery may expose the skin to pathogens and create microscopic wounds that may affect the barrier function of the skin. Therefore, it is important to allow the microscopic wounds to heal after transplantation. To evaluate the effect of the pigment microstructure 10 for transdermal delivery on the barrier function of the skin, the mice's vapor flux was measured up to 24 hours after transplantation using TEWL analysis. Before transplantation, the average TEWL values in the pigment microstructures for transdermal delivery (10) and the control group were approximately the same at ^{14.35 ± 1.94 g/m 2} h ^-1 and 15.71 ± 1.47 g/m ² h ^{-1, respectively.} However, transplantation of the pigment microstructure (10) for transdermal delivery significantly increased ^{TEWL to 23.15 ± 2.78 g/m 2} h ^-1.

After 1 hour, the vapor flow ^{decreased to 16.47 ± 2.09 g/m 2} h ^-1 , and reached the baseline 2 hours after implantation (Fig. 13 (e)). By TEWL analysis, it can be seen that the microscopic wounds generated at the time of implantation of the pigment microstructure 10 for transdermal delivery were completely healed, and the skin barrier function was restored to a normal state. Hyaluronic acid (HA) can accelerate the wound healing process, and therefore, it has been found that the polymer backbone matrix of the pigment microstructure 10 for transdermal delivery plays an important role in rapid skin recovery.

Overall, in vivo evaluation shows that the pigment microstructure 10 for transdermal delivery is a simple, minimally invasive, and effective pigmentation platform. In contrast, the wound healing process has been shown to upregulate β-catenin levels, which are known to cause hair regrowth. Therefore, it is estimated that microscopic wounds generated inside the skin can up-regulate β-catenin levels and cause hair regrowth.

Although an embodiment of the present invention has been described above, the spirit of the present invention is not limited to the embodiments presented in the present specification, and those skilled in the art who understand the spirit of the present invention can add components within the scope of the same idea. It will be possible to easily propose other embodiments by changing, deleting, adding, etc., but it will be said that this is also within the spirit scope of the present invention.

10: pigment microstructure for transdermal delivery 11: sheet
12: base portion 13: tip portion

Claims (12)

A base portion formed on the sheet; And
It is formed on the base portion and includes a tip portion including a pigment,
The length of each of the base portion and the tip portion is determined according to a remaining period in which the pigment is intended to remain in the skin. The method of claim 1,
The tip portion and the base is a dye microstructure for transdermal delivery having a candle shape made of a continuous curvature of the vertical cross section. The method of claim 1,
The length of the base portion and the total length of the base portion and the tip portion are shorter in the case of the first remaining period than in the case of the second remaining period,
The second residual period is a pigment microstructure for transdermal delivery longer than the first residual period. The method of claim 3,
The first remaining period is less than 6 months, the total length of the base portion and the tip portion is 100 ~ 300㎛ dye microstructure for transdermal delivery. The method of claim 3,
The second remaining period is more than 1 year, the total length of the base portion and the tip portion is 300 ~ 2000㎛ percutaneous dye microstructure for delivery. The method of claim 1,
The length of the base portion is a pigment microstructure for transdermal delivery greater than 30㎛. The method of claim 1,
The sheet is a pigment microstructure for transdermal delivery made of a soluble material. The method of claim 1,
The sheet, the base portion, and the tip portion is a pigment microstructure for transdermal delivery comprising a biodegradable material. The method of claim 1,
The base portion and the tip portion is a dye microstructure for transdermal delivery formed in an array form on the sheet. The method of claim 1,
The base portion and the tip portion is a dye microstructure for transdermal delivery that is randomly formed on the sheet at a predetermined density. The method of claim 1,
The base portion and the tip portion is a pigment microstructure for transdermal delivery formed in different sizes depending on the position on the sheet. The method of claim 1,
A dye microstructure for transdermal delivery in which a cross-sectional shape and a cross-sectional size are determined according to the shape and size of a tattoo formed by the remaining of the pigment and the base portion and the tip portion.

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