KR102567995B1 - Multi layered micro needle - Google Patents

Abstract

The present invention relates to a microneedle with a multi-layered structure, and specifically, includes a tip portion containing an active ingredient and a biodegradable polymer and dissolving when inserted into the skin to provide an active ingredient; A base portion supporting the tip portion, the tip portion including at least two or more tip sublayers stacked in a direction to be inserted into the skin, all of the tip sublayers including a biodegradable polymer, and among the tip sublayers At least one contains an active ingredient. According to the present invention, it is possible to quickly provide a quantity of active ingredient according to the usage according to the type of active ingredient. In addition, since the tip portion containing the active ingredient is quickly separated from the microneedle and provided to the target, there is no concern about inflammation due to application of the microneedle.

Description

Multi-layer structure micro needle {MULTI LAYERED MICRO NEEDLE}

The present invention relates to a multi-layered microneedle. Specifically, the present invention includes a multi-layered microneedle capable of rapidly delivering a quantity of useful substances through the skin.

Until now, many types of drugs have been delivered to target sites in the human body through oral administration and injection therapy according to the characteristics of each drug. However, in the case of oral administration, there are problems in that it is easily decomposed and denatured when passing through the gastrointestinal tract, is unstable, has a low absorption rate in the body, and easily causes side effects such as gastrointestinal disorders. In addition, in the case of injection therapy, there are various problems such as causing pain to the patient and reducing administration compliance, and the risk of infection of the injection needle. In order to overcome the limitations of these drug delivery methods, microneedles have been developed that are smaller in size than conventional injection needles, have little pain, and can prevent degradation and denaturation of drugs due to passage through the gastrointestinal tract. Microneedles for transdermal drug delivery include solid microneedles, coated microneedles, and soluble microneedles.

However, in the case of the existing microneedle patch, the time required for the active ingredient to completely dissolve by the moisture in the skin after application to the skin was very long, tens of minutes or more. Accordingly, as the microneedle is attached to the skin for a long time, side effects such as rash in the skin occur. In order to solve these problems, a technology is needed to quickly and accurately deliver only the drug into the dermis and then remove the microneedle patch.

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Japanese Patent Laid-Open No. 2020-130544 (2020.08.31) "Tip-detachable microneedle"

An object of the present invention is to provide a microneedle capable of easily and efficiently delivering a quantitative amount of an active ingredient to a target, and is separable and has excellent solubility.

In order to achieve the object to be solved, the multi-layer microneedle of the present invention includes an active ingredient and a biodegradable polymer, and is dissolved when inserted into the skin to provide an active ingredient; A base portion supporting the tip portion, the tip portion including at least two or more tip sublayers stacked in a direction to be inserted into the skin, all of the tip sublayers including a biodegradable polymer, and among the tip sublayers At least one containing an active ingredient, and further comprising a guide portion provided inside the tip portion and extending from the base portion toward the tip portion, wherein the tip portion and the guide portion are separated from each other when the tip portion is inserted into the object.

In addition, the guide part of the multi-layered microneedle of the present invention further includes a plurality of guide part protrusions provided on the outer circumferential surface of the guide part.

The multi-layered microneedle may further include a base holder provided on a rear surface of a surface where the base part and the tip part are coupled to provide a coupling site so that the base part and the external member may be coupled.

In addition, a plurality of tip parts are provided on the base part of the multi-layered microneedle of the present invention.

In addition, the tip portion of the multi-layered microneedle of the present invention has a structure in which a length in a height direction perpendicular to the base portion is greater than a length in a width direction parallel to the base portion.

In addition, the tip portion of the multi-layered microneedle of the present invention includes two tip sublayers or three tip sublayers sequentially stacked.

In addition, the plurality of tip sub-layers of the multi-layered microneedle of the present invention have different compositions, and the biodegradable polymer content in the layer provided adjacent to the base part among the plurality of tip sub-layers is spaced apart from the base part. greater than the biodegradable polymer content in the provided layer.

In addition, the active material is provided in a layer spaced apart from the base part among the plurality of sub-layers of the tip part of the multi-layered microneedle of the present invention.

In addition, the effective material is provided in a layer adjacent to the base portion among the plurality of sub-layers of the tip portion of the multi-layered microneedle of the present invention.

According to one embodiment of the present invention, it is possible to rapidly provide a quantity of active ingredient according to the usage according to the type of active ingredient.

In addition, according to one embodiment of the present invention, since the tip portion containing the active ingredient is quickly separated from the microneedle and provided to the target, there is no concern about inflammation due to application of the microneedle.

1 is a perspective view of a multi-layered microneedle according to one embodiment of the present invention.
2 is a perspective view of a multi-layered microneedle according to another embodiment of the present invention.
3 is a cross-sectional view of a multi-layered microneedle according to one embodiment of the present invention.
4 is a perspective view of a multi-layer microneedle structure further provided with a base holder part according to another aspect of the present invention.
5 is an image of a multi-layered microneedle fabricated according to an embodiment of the present invention.
6 is an image of a microneedle including a fluorescent composition prepared according to an embodiment of the present invention.
7 is an image of a microneedle provided with three tip sub-layers manufactured according to an embodiment of the present invention.
8 is an image of a microneedle mounted on an applicator.
9 is an image of microneedles manufactured according to Examples and Comparative Examples of the present invention.
10 is an image showing a form in which microneedles are separated and attached to the skin.
11 is a skin histology observation result after in-vitro skin penetration of a microneedle.

Since the present invention may have various changes and various forms, specific embodiments are illustrated in the drawings and described in detail in the text. However, it should be understood that this is not intended to limit the present invention to the specific disclosed form, and includes all modifications, equivalents, and substitutes included in the spirit and scope of the present invention.

According to one aspect of the present invention, a microneedle including a tip portion and a base portion is provided, and the tip portion includes a plurality of tip sublayers having different compositions. As the microneedle has a structure in which a tip portion including a plurality of tip portion sublayers and a base portion are coupled, a fixed amount of drug can be rapidly delivered.

1 is a perspective view of a multi-layered microneedle according to one embodiment of the present invention.

Referring to FIG. 1 , the multi-layered microneedle according to one embodiment of the present invention includes an active ingredient and a biodegradable polymer, and includes a tip portion 100 that dissolves and provides an active ingredient when inserted into the skin; It includes a base part 200 supporting the tip part 100, the tip part 100 includes at least two or more tip part sub-layers 110 and 120 stacked in a direction to be inserted into the skin, and the tip part sub-layer Both layers 110 and 120 include a biodegradable polymer, and at least one of the tip sub-layers 110 and 120 includes an active ingredient.

Hereinafter, each configuration will be described in more detail.

First, the tip part 100 is a member for delivering an active ingredient to a target, and includes an active ingredient and a biodegradable polymer.

The tip portion 100 may have a shape extending in at least one direction. Specifically, the tip portion 100 may have a structure in which a length in a height direction perpendicular to the base portion 200 is greater than a length in a width direction parallel to the base portion 200. Therefore, at the end of the tip portion 100 A relatively large pressure is applied, and the tip portion 100 can easily penetrate into the target.

The tip part 100 may have a tapered shape in some cases. Accordingly, the tip portion 100 has a narrow cross-sectional area at the distal end and is thus easy to penetrate into the target. For example, the tip portion 100 can easily penetrate into the skin of a target by having the aforementioned tapered shape. Examples of the shape of the tip portion 100 described above include a cone, a quadrangular pyramid, and a triangular pyramid, and may have various shapes other than the above-listed examples. In addition, when a plurality of tip portions 100 are provided, each tip portion 100 may have the same or different shapes.

Accordingly, when the active material is provided to the first tip sub-layer 110, the active material content per volume may be relatively increased.

The tip portion 100 includes an active ingredient and a biodegradable polymer, and after penetrating into the target, it can be decomposed to release the active ingredient. Active ingredients may include drugs suitable for transdermal administration rather than oral administration. When an active ingredient (eg, a drug) is provided through transdermal administration, a constant serum drug concentration or therapeutic target concentration can be obtained through constant permeation of the drug. Therefore, in the case of an active ingredient requiring continuous and constant concentration maintenance, it is advantageous to provide it by transdermal administration.

The above-described active ingredients included in the tip portion 100 include teriparatide, teriparatide acetate, α-interferon, β-interferon for multiple sclerosis, erythropoietin, polytropin β, poly Tropin α, G-CSF, GM-CSF, human chorionic gonadotropin, luteinizing hormone, salmon calcitonin, glucagon, GNRH antagonist, insulin, human growth hormone, filgrastin, heparin, low molecular weight heparin and somatro It may contain an active ingredient including at least one of the pins. Alternatively, the active ingredient, Japanese encephalitis vaccine, rotavirus vaccine, influenza vaccine, polio vaccine, chickenpox vaccine, Alzheimer's disease vaccine, atherosclerosis vaccine, cancer vaccine, nicotine vaccine, diphtheria vaccine, cervical cancer vaccine, meningococcal vaccine, tetanus vaccine , whooping cough vaccine, Lyme disease vaccine, rabies vaccine, pneumococcal vaccine, yellow fever vaccine, cholera vaccine, vaccinia vaccine, tuberculosis vaccine, rubella vaccine, measles vaccine, mumps vaccine, botulinum vaccine, herpesvirus vaccine, hepatitis B vaccine, Hyaluronic acid, Coenzymeq10, Chitosan, Botox, vitamins and vitamin derivatives, Hydroxy acid, Tetracycline, Oxytetracycline, Doxycycline (doxycycline), minocycline, benzocaine, mepivacaine, lidocaine, prilocaine, bupivacaine, etidocaine, articaine Articaine, Procaine, Propoxycaine, Tetracaine, Ropivacaine, Butacaine, Piperocaine, Cocaine, Chloropro Vaccines containing at least one of chloroprocaine, proparacaine and dyclonine may be included.

The biodegradable polymer included in the tip part 100 maintains the shape of the tip part 100 outside the target so that the active ingredient can be delivered to the inside of the target, and when it penetrates inside the target, it can be decomposed without affecting the target It is material. In this case, that the biodegradable polymer is decomposed inside the object may mean that the tip part 100 loses its original tapered shape and dissolves. Biodegradable polymers include carboxymethylcellulose (CMC), hyaluronic acid (HA), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC) and hydroxypropylcellulose (HPC). It may include at least one selected from the group consisting of.

At least a portion of the tip portion 100 may be coated with a waterproofing agent. The waterproofing agent prevents the tip part 100 from being formed by moisture including moisture in the air before penetrating into the inside of the object. The above-mentioned waterproofing agent is beeswax, oleic acid, soy fatty acid, castor oil, phosphatidylcholine, vitamin E (d-α-tocopherol/Vitamin E), corn Corn oil Mono-di-tridiglycerides, Cottonseed oil, Olive oil, Peaut oil, Peppermint oil , Safflower oil, Sesame oil, Soybean oil, Hydrogenated vegetable oils, Hydrogenated soybean oil, Caprylic/ capric triglycerides derived from coconut oil or palm see oil) and phosphatidylcholine, or may be formed of a mixture thereof.

The tip portion 100 includes a plurality of tip portion sublayers 110 and 120 having different compositions.

A plurality of tip sublayers 110 and 120 may be provided. However, in some cases, the tip portion may include two tip sublayers or three tip sublayers sequentially stacked. The number of tip sublayers 110 and 120 may be determined in consideration of the size of the microneedle, the height and width of the tip, and the type of active ingredient to be applied to the target. In the drawings, an example including two tip sub-layers 110 and 120, that is, a first tip sub-layer 110 and a second tip sub-layer 120 has been described, but the scope of the present invention is not limited to the tip sub-layer. (110, 120) is not limited to two examples.

Both the first tip sub-layer 110 and the second tip sub-layer 120 include a biodegradable polymer. As described above, the biodegradable polymer is carboxymethylcellulose (CMC), hyaluronic acid (HA), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC) and hydroxyl It may include at least one selected from the group consisting of propyl cellulose (HPC).

At least one of the first tip sub-layer 110 and the second tip sub-layer 120 may include an active material. Examples of active substances are as described above. Where to provide the active ingredient between the first tip sub-layer 110 and the second tip sub-layer 120 may be determined in consideration of the type of active ingredient.

When the active ingredient is provided to the first tip sublayer 110, that is, the layer spaced apart from the base part 200, the active ingredient can more immediately penetrate into the target, so rapid administration of the active ingredient is required. It is appropriate. Specifically, since the tip portion 100 has a tapered shape, the volume of the first tip portion sublayer 110 may be smaller than the volume of the second tip portion sublayer 120, and accordingly, the first tip portion sublayer 110 When an active substance is provided in the active substance content per volume may be relatively large. In addition, since the first tip sub-layer 110 penetrates into the object earlier than the second tip sub-layer 120, the second tip sub-layer 120 penetrates the target more than the case where the active material is included in the first tip sub-layer 110. ), it can spread inside the target more quickly. Accordingly, when an effective substance is provided to the first tip sub-layer 110, a relatively high concentration of the effective substance can be quickly diffused into the object. In particular, in this case, when the microneedle is inserted into the skin, the drug can be absorbed more quickly as it is adjacent to the capillaries as it is inserted deeper, and the release of the drug can be controlled in an immediate release form depending on the type and concentration of the biodegradable polymer and excipient. .

When the active ingredient is applied to the second tip sublayer 120, that is, a layer adjacent to the base portion 200, the active ingredient can be released in a relatively sustained release. Specifically, since the tip 100 has a tapered shape, the volume of the second tip sub-layer 120 may be greater than that of the first tip sub-layer 110, and accordingly, the second tip sub-layer 120 When an active substance is provided in the active substance content per volume can be relatively small. In addition, since the second tip sub-layer 120 has a blunter shape than the first tip sub-layer 110 and penetrates into the target later, the active substance included in the second tip sub-layer 120 penetrates the inside of the target. can spread relatively slowly. Accordingly, when sustained release of the active substance is required, the active substance may be provided to the second tip sub-layer 120 . In particular, in this case, when the microneedle is inserted into the skin, drug release becomes slower as it is in the epidermal layer, and drug release can be controlled in a sustained release form depending on the type and concentration of the biodegradable polymer and excipient.

When the active ingredient is provided to both the first tip sub-layer 110 and the second tip sub-layer 120, the type of active ingredient provided to the first tip sub-layer 110 and the second tip sub-layer 120 may be the same or different. For example, an active ingredient requiring immediate release is provided to the first tip sublayer 110, and an active ingredient requiring sustained release is provided to the second tip sublayer 120 after application of the active ingredient requiring immediate release. It can be configured in the form of In other cases, it is also possible to provide the same active ingredient to the first tip sub-layer 110 and the second tip sub-layer 120 but in different amounts.

Accordingly, since the tip portion 100 includes a plurality of tip portion sublayers, it is possible to provide various drugs or the same drug in various patterns.

The aforementioned tip portion 100 is supported by the base portion 200 .

The base part 200 is a body supporting the tip part 100, and can be brought into close contact with the target while supporting the tip part 100. Since the base part 200 adheres to the target without penetrating into the target, it is desirable to have low reactivity. For example, the base part 200 may be made of a material that does not dissolve in water and does not cause an inflammatory reaction or the like.

The base part 200 is, for example, polyethylene (PE), polypropylene (PP), polytetrafluoroethylene (PTFE), polymethyl methacrylate (PMMA), ethylene vinyl acetate (EVA), polycaprolactone (PCL), polyurethane (PU), polyethylene terephthalate (PET), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polylactide (PLA), polylactide-glycolide copolymer (PLGA) and It can be prepared from at least one of polyglycolide (PGA).

Since the base part 200 supports the tip part 100, it may have an area equal to or greater than the bottom area of the tip part 100. The shape of the base portion 200 is not limited, but may have various shapes such as a rectangle, a trapezoid, a circle, an ellipse, and a triangle on a plane.

The base part 200 may have flexibility in some cases. Accordingly, when the base part 200 is brought into close contact with the target surface, the base part 200 may be bent or folded along the curvature of the target surface. Accordingly, even when the target surface is curved, the base part 200 can be provided in close contact, and the tip part 100 can be penetrated into the target at a uniform depth.

In the foregoing, a multi-layered microneedle including a tip portion 100 having a plurality of tip sublayers 110 and 120 and a base portion 200 has been described. Since the microneedle according to one embodiment of the present invention has a multilayer structure, various drugs can be released as needed.

Hereinafter, various types of multi-layered microneedles will be examined in more detail.

2 is a perspective view of a multi-layered microneedle according to another embodiment of the present invention.

Referring to FIG. 2 , the multi-layered microneedle includes a plurality of tip parts 100 . A plurality of tip portions 100 may be arranged on the base portion 200 in a plurality of columns and/or a plurality of rows.

A plurality of tip parts 100 may be provided spaced apart from each other. The separation distance of the tip part 100 may be determined in consideration of the height and cross-sectional area of the tip part 100 . For example, the tip portion 100 may have a height of about 50 μm to about 2000 μm from the base portion 200. In this case, the separation distance between the tip portions 100 is about 30% to about 200% of the height of the tip portion 100. range can be

In this case, the base part 200 may have a large area to support the plurality of tip parts 100 . The shape of the base portion 200 is not limited as long as it can support a plurality of tip portions 100 .

3 is a cross-sectional view of a multi-layered microneedle according to one embodiment of the present invention.

The multi-layer microneedle according to FIG. 3 is provided inside the tip part 100 and further includes a guide part 250 extending from the base part 200 toward the tip part 100, and the tip part 100 is inserted into the target. When it is characterized in that the tip portion 100 and the guide portion 250 are separated.

The guide portion 250 may have a shape protruding in a penetration direction in which the tip portion 100 penetrates into the target. When a plurality of tip parts 100 are provided, a plurality of guide parts 250 may also be provided to be coupled to the plurality of tip parts 100 . The guide part 250 is provided between the base part 200 and the tip part 100 so as to be coupled to the rear end of the tip part 100 rather than the sharp tip. That is, the guide part 250 may have a shape extending from the base part 200 toward the tip part 100 .

The guide part 250 may further include a plurality of guide part protrusions provided on the outer circumferential surface according to circumstances. As the guide portion protrusion is provided, coupling force between the tip portion 100 and the guide portion 250 may further increase. The guide part protrusion supports the tip part 100 extending in the penetration direction and guides the penetration of the tip part 100 at the same time. At this time, the guide unit protrusion may be integrally provided with the guide unit 250 extending from the base unit 200 .

The geometrical structure of the guide part 250 protrudes into the tip part 100 to protect the tip part 100 from being damaged by a force applied in the horizontal direction so as to ensure stability in the vertical direction. As shown in the drawings, the guide portion 250 may have a shape protruding into the tip portion 100 corresponding to the tip portion 100 having a quadrangular pyramid shape, as well as various embodiments. The guide part 250 has a guide part protrusion protruding from one of the side surfaces of the guide part 250, a form protruding from two to four side surfaces, the guide part 250 is formed as a flat surface, and the guide part A plurality of protrusions may protrude from the upper surface of the guide unit 250 .

The guide portion 250 may increase coupling force between the tip portion 100 and the base portion 200 . Accordingly, the coupling force between the tip portion 100 and the target may be greater than the coupling force between the guide portion 250 and the tip portion 100 . Specifically, the guide part 250 may guide separation through adjusting the coupling force between the guide part 250 and the tip part 100 based on the geometric structure protruding from the base part 200 . The bonding force range between the tip portion 100 and the guide portion 250 is approximately 0.0001 N to 1 N or less, and the sum of the elasticity, frictional force, and adhesive force of the skin (S), which is the force for holding the tip portion 100 by an object (such as skin), is It may be 1N to 5N. Due to this, the force by which the skin (S) holds the tip portion 100 is relatively greater than the bonding force between the tip portion 100 and the guide portion 250, so that the tip portion 100 penetrated into the skin (S) is guided It is immediately separable from part 250 .

One of the biggest disadvantages of transdermal drug delivery is the potential for local irritation that can be exacerbated at the site of application. Skin flushing, itching, local swelling, etc. may be caused by other factors such as drugs and adhesives in the patch formulation. Most patients can reduce irritation by position cycling. However, some patients may develop a severe allergic reaction to the transdermal patch, in which case treatment must be discontinued. Therefore, in the case of a microneedle that provides an active substance transdermally, it is preferable to remove the active substance from the target after rapidly delivering the active substance. In the case of the present invention, since the guide portion 250 is provided as described above, the tip portion 100 can be immediately separated and provided inside the object, and then the microneedle can be removed from the object. Accordingly, stimulation by the microneedles is reduced.

Unlike the tip portion 100 that penetrates into the target, the guide portion 250 may be formed of an insoluble, water-insoluble material. Therefore, by not interfering with the penetrating power of the tip portion 100 being melted, it is possible to guide the supply of a fixed amount of the chemical solution into the skin (S).

4 is a perspective view of a multi-layer microneedle structure further provided with a base holder part according to another aspect of the present invention.

The base holder part 300 is provided on the back surface of the surface where the base part 200 and the tip part 100 are coupled to provide a coupling site so that the base part 200 and the external member can be coupled. The base holder part 300 may be detachably coupled to an external member. Therefore, since a plurality of microneedles loaded with different effective materials can be simultaneously provided and the type of microneedles can be changed as needed, usability is increased.

In the above, the microneedle according to one embodiment of the present invention has been looked at. Hereinafter, advantageous effects of the microneedle according to the present invention will be examined through comparative examination of Examples and Comparative Examples.

5 is an image of a multi-layered microneedle fabricated according to an embodiment of the present invention.

Preparation Example (1) - Double-layered microneedle

A microneedle formulation composition for forming the needle tip tip (first tip sublayer 110) and a microneedle formulation for forming the lower portion of the needle tip (second tip sublayer 120) as shown in the table below. composition was used.

biodegradable polymer excipient oil Surfactants Dye First tip sub layer Hyaluronic acid 11% w/w Trehalose 5% w/w Castor oil
1% w/w Tween 20, 0.4% w/w N/A Second tip sub layer Hyaluronic acid 11% w/w Sucrose 9% w/w Castor oil
1% w/w Tween 20, 0.4% w/w Gentian violet

As can be seen in the drawing, it can be confirmed that the first tip sub-layer 110 and the second tip sub-layer 120 are clearly separated and provided. In addition, the first tip sub-layer 110 and the second tip sub-layer 120 generally have a tapered shape as they move away from the base portion 200 .

6 is an image of a microneedle including a fluorescent composition prepared according to an embodiment of the present invention.

Preparation Example (2) - Double-layered microneedle fabricated using fluorescent microbeads

The microneedle formulation composition for forming the tip of the needle tip (first tip sublayer 110) and the formulation composition shown in the table below are used to form the lower portion of the needle tip (second tip sublayer 120). did

biodegradable polymer excipient oil Surfactants Dye 2nd floor part Hyaluronic acid 11% w/w Trehalose 5% w/w Castor oil
1% w/w Tween 20, 0.4% w/w Gentian violet 1st floor part Hyaluronic acid 11% w/w Sucrose 9% w/w Castor oil
1% w/w Tween 20, 0.4% w/w Fluorescent microbeads

As can be seen in the figure, even when the fluorescent microbeads are included, it can be confirmed that the first tip sublayer 110 and the second tip sublayer 120 show different colors and are clearly separated and provided. In addition, the first tip sub-layer 110 and the second tip sub-layer 120 generally have a tapered shape as they move away from the base portion 200 .

Preparation Example (3) - Double-layered microneedle fabricated using Calcein and Rhodamine B

The microneedle formulation composition for forming the tip of the needle tip (first tip sublayer 110) and the formulation composition shown in the table below are used to form the lower portion of the needle tip (second tip sublayer 120). did

biodegradable polymer excipient oil Surfactants Dye 2nd floor part Hyaluronic acid 11% w/w Trehalose 5% w/w Castor oil
1% w/w Tween 20, 0.4% w/w Calcein 1st floor part Hyaluronic acid 11% w/w Sucrose 9% w/w Castor oil
1% w/w Tween 20, 0.4% w/w Rhodamine B

As can be seen in the figure, even when the fluorescent microbeads are included, it can be confirmed that the first tip sublayer 110 and the second tip sublayer 120 show different colors and are clearly separated and provided. In addition, the first tip sub-layer 110 and the second tip sub-layer 120 generally have a tapered shape as they move away from the base portion 200 .

Preparation Example (4) - Three-layered microneedle

In order to manufacture a microneedle provided with three tip sub-layers, the formulation composition was prepared as follows.

7 is an image of a microneedle provided with three tip sub-layers manufactured according to an embodiment of the present invention.

biodegradable polymer excipient oil Surfactants Dye 3rd floor part Hyaluronic acid 11% w/w Trehalose 5% w/w Castor oil
1% w/w Tween 20, 0.4% w/w N/A 2nd floor part Hyaluronic acid 11% w/w Trehalose 5% w/w Castor oil
1% w/w Tween 20, 0.4% w/w Gentian violet 1st floor part Hyaluronic acid 11% w/w Sucrose 9% w/w Castor oil
1% w/w Tween 20, 0.4% w/w Nile Red

As can be seen from the above table, it was confirmed that when there are three or more tip sub-layers, some of the formulation compositions may have similar compositions, and some layers may be made of formulation compositions having different compositions.

Preparation Example (5) - Microneedle Complete Form

8 is an image of a microneedle mounted on an applicator.

Referring to FIG. 8 , it can be seen that a white circular applicator is attached to the microneedle. The applicator may detachably mount a microneedle. Therefore, after the microneedle is mounted and penetrated into the target, the applicator can be detached and used to mount another microneedle.

Using the applicator, you can conveniently use various types of microneedles.

As described above, it was confirmed that a multi-layered microneedle provided with a plurality of tip sub-layers can be manufactured according to the present invention.

In the following, after loading the effective material on the multi-layered microneedle, the difference from the non-multilayered microneedle was analyzed.

9 is an image of microneedles manufactured according to Examples and Comparative Examples of the present invention.

Experimental Example (1) - PTH content change according to the presence or absence of the layer

A double-layer microneedle or a one-layer microneedle was fabricated using a formulation composition containing PTH drug and a formulation composition not containing PTH drug, respectively. The formulation composition for preparing the microneedles of Examples and Comparative Examples was the same as the composition shown in Table 1, but the microneedles were prepared by varying the PTH drug content. The content of PTH was measured using HPLC.

category Whether active substances are loaded PTH content/1 MAP Example 1 - Double Layer Microneedles
Figure 9 (b) 2nd layer: use of formulation composition including PTH drug 21ug 1st layer: Use of formulation composition that does not contain PTH drug Example 2 - Double Layer Microneedles
Figure 9(c) 2nd layer: Use of formulation composition that does not contain PTH drug 17ug 1st floor: Use of formulation composition including PTH drug Comparative Example 1 - Single Layer Microneedle
Figure 9 (a) Both 1st and 2nd layers use formulation composition containing PTH drug 41ug Comparative Example 2 - Single Layer Microneedle
Figure 9(d) Both the 1st and 2nd layers use formulation compositions that do not contain PTH drugs 0ug

As can be seen from the table above, in the case of Comparative Example 1, when the PTH drug was provided to the single-layer microneedle, it was confirmed that the PTH content was remarkably high. Therefore, it can be confirmed that it is more advantageous to deliver a fixed amount of PTH drug when the PTH drug is provided only to one sublayer of the tip part of the multilayer structure.

Experimental Example (2) - Hepatitis B content change according to the presence or absence of the layer

A double-layer microneedle or a one-layer microneedle was manufactured using a formulation composition containing Hepatitis B vaccine as an effective material and a formulation composition not containing Hepatitis B vaccine, respectively. The content of Hepatitis B is measured using BCA and ELISA for protein content and antigenic value. In particular, in the case of ELISA, the content is measured through the relative antigen value compared to the vaccine stock solution.

sample form Information on each floor Hepatitis B
Content (BCA result) Hepatitis B
Content (relative antigen value) Example 3 - Double layer microneedle 2nd floor: Use of formulation composition including Hepatitis B vaccine 20ug 1.6 1st layer: Use of formulation composition not containing Hepatitis B vaccine Example 4 - Double Layer Microneedle 2nd floor: Use of formulation composition not containing Hepatitis B vaccine 18ug 1.54 1st floor: Use of formulation composition including Hepatitis B vaccine Comparative Example 3 - Single Layer Microneedle Both the 1st and 2nd layers use formulation compositions including Hepatitis B vaccine 40ug 1.4 Comparative Example 4 - Single Layer Microneedle All of the first and second layers use formulation compositions that do not contain Hepatitis B vaccine 0ug -

As can be seen from the table above, in the case of Comparative Example 3, when the Hepatitis B vaccine was provided to the single-layer microneedle, it was confirmed that the Hepatitis B content was remarkably high. Therefore, when the Hepatitis B vaccine is provided only in the tip sublayer of any one of the multilayer structures, it can be confirmed that it is more advantageous to deliver the Hepatitis B vaccine in quantity. It was confirmed that a multi-layered microneedle can be manufactured and applied regardless of the type of active material.

In the above, the manufacturability and application effect of multi-layered microneedles loaded with effective materials have been examined. Hereinafter, an actual embodiment for applying the microneedle and skin penetration ability and separation ability will be reviewed.

Experimental Example (3) - Microneedle's in-vitro skin penetration ability and separation ability

Next, the in-vitro skin penetration ability and separation ability of the prepared microneedles were evaluated. In order to evaluate permeation and separation ability, porcine pig skin stored at -20 ° C was thawed for 1 hour or more, and then the moisture remaining on the skin was removed using a wiper. After mounting the microneedle patch prepared in Example (1) on an applicator, it is applied to pig skin.

10 is an image showing a form in which microneedles are separated and attached to the skin. Referring to FIG. 10 , as a result of the experiment, it can be seen that the needle tip portion is 100% skin permeable and separated. Specifically, it can be confirmed that all the microneedles have been separated and penetrated into the skin.

Experimental Example (4) - Observation of skin histology after in-vitro skin penetration of microneedle

The microneedle formulation composition for forming the tip of the needle tip (first tip sublayer 110) and the formulation composition shown in the table below are used to form the lower portion of the needle tip (second tip sublayer 120). did

biodegradable polymer excipient oil Surfactants Dye 2nd floor part Hyaluronic acid 11% w/w Trehalose 5% w/w Castor oil
1% w/w Tween 20, 0.4% w/w Calcein 1st floor part Hyaluronic acid 11% w/w Sucrose 9% w/w Castor oil
1% w/w Tween 20, 0.4% w/w Rhodamine B

After defrosting the Porcine Pig skin stored at -20 degrees Celsius for more than 1 hour, remove the moisture remaining on the skin using a wiper. After attaching the microneedle patch made using the above formulation composition to the applicator, it is applied to the pig skin. Then, after snap-freezing the pig skin in Isopentane, it was cryosectioned to a uniform thickness of 15 μm using a microtome device. Thereafter, observation is performed using a fluorescence microscope. FIG. 11 is a result of skin histology observation after in-vitro skin penetration of microneedles.

As shown in FIG. 11, it can be seen that the layer 2 portion is located close to the dermis layer in the skin, and the layer 1 portion is located close to the epidermis and stratum corneum. Accordingly, it can be seen that drug release can be controlled according to the height.

Although the above has been described with reference to preferred embodiments of the present invention, those skilled in the art or those having ordinary knowledge in the art do not deviate from the spirit and technical scope of the present invention described in the claims to be described later. It will be understood that the present invention can be variously modified and changed within the scope not specified.

Therefore, the technical scope of the present invention is not limited to the contents described in the detailed description of the specification, but should be defined by the claims.

Claims (9)

A plurality of tip parts containing an active ingredient and a biodegradable polymer and dissolving when inserted into the skin to provide an active ingredient;
A base portion supporting the tip portion;
The tip portion includes two tip sublayers stacked in a direction to be inserted into the skin, and both of the tip sublayers include a biodegradable polymer;
Providing the active ingredient to only one of the two tip sublayers to deliver the active ingredient in a quantitative amount;
The active ingredient is a parathyroid hormone (PTH) drug or hepatitis B vaccine,
The tip is coated with a waterproofing agent,
A guide portion provided inside the tip portion and extending from the base portion toward the tip portion, wherein the tip portion and the guide portion are separated when the tip portion is inserted into the target;
The tip portion has a height of 50 μm to 2000 μm from the base portion, and a separation distance between the plurality of tip portions is 30% to 200% of the height of the tip portion,
The two tip sub-layers have different compositions,
Among the two sub-layers of the tip part, the content of the biodegradable polymer in the layer provided adjacent to the base part is greater than the content of the biodegradable polymer in the layer provided spaced apart from the base part.
According to claim 1,
A multi-layered microneedle having a multi-layered structure wherein the active ingredient is provided to a layer spaced apart from the base part among the two sub-layers of the tip part to control the release of the active ingredient in an immediate release form. According to claim 1,
A multi-layered microneedle structure wherein the active ingredient is provided to a layer adjacent to the base part among the two sub-layers of the tip part to control the release of the active ingredient in a sustained-release form. delete According to claim 1,
The tip portion has a structure in which a length in a height direction perpendicular to the base portion is greater than a length in a width direction parallel to the base portion. delete delete delete delete