KR101103612B1 - Microneedle for trans dermal injection, preparation method of the microneedle, mold for preparing microneedle and preparation method of the mold - Google Patents

Abstract

The present invention relates to a percutaneous permeable microneedle, a method for preparing the same, a mold for percutaneous permeable microneedle, and a method for manufacturing the same, which is one of the drug delivery systems used as a transdermal drug delivery method. The present invention can be prepared by a simple process compared to the conventional method for producing a transdermal microneedle and can provide a method for producing a transdermal microneedle excellent in reproducibility and a mold for a transdermal microneedle.

Transdermal Microneedle, Microneedle Template, Mold, Transdermal Solid Pharmaceutical, Laminated Structure, Lithography Process

Description

Percutaneous microneedle, its manufacturing method, mold for transdermal microneedle and its manufacturing method {MICRONEEDLE FOR TRANS DERMAL INJECTION, PREPARATION METHOD OF THE MICRONEEDLE, MOLD FOR PREPARING MICRONEEDLE AND PREPARATION METHOD OF THE MOLD}

The present invention relates to a percutaneous permeable microneedle, a method for preparing the same, a mold for percutaneous permeable microneedle, and a method for manufacturing the same, which is one of the drug delivery systems used as a transdermal drug delivery method.

Drug delivery system (DDS) refers to a series of technologies that control the delivery of substances with pharmacological activity to cells, tissues, organs and organs to achieve optimal potency using various physicochemical techniques. The most common drug delivery system is the human ingestion of drugs for oral use, and there are other transdermal drug delivery systems that can be applied locally.

The importance for the efficient and safe administration of pharmaceutical substances such as drugs has long been recognized. Conventional methods for injecting liquid medications have been used for the administration of drugs in patients with metal syringes for more than 150 years, but suffer from pain and the infusion of drugs is temporary.

In order to improve the drug administration method using such a metal syringe, micro-sized transdermal microneedle (microscopic needle) much smaller than a pen-type syringe has been manufactured and utilized.

Microneedles are generally devices for injecting skin cosmetics or drugs into skin tissue or for extracting body fluids, such as blood, from the interior of the skin. Microneedle is a local and continuous drug injection, and can minimize the pain when inserted into the skin has recently been used in a variety of fields are increasing rapidly. Incorporating skin cosmetics or drugs into the skin tissue can be performed continuously without pain, which is very useful because it is easy to use. On the other hand, the absorption rate is low, especially when the hydrophilicity or molecular weight is large, the absorption rate is lower. do. This is caused by the property that the outermost stratum corneum of the skin prevents the penetration of foreign substances into the body or the outflow of bodily fluids. It is possible to improve the transmission method of.

Korean Patent No. 793615 discloses a method of manufacturing a microneedle using the same after forming a mold with a nano dip pen. As disclosed in Korean Patent No. 793615, when a microneedle is formed by forming a mold with a nano dip pen, there is a problem of poor reproducibility.

Therefore, the inventors of the present invention not only have excellent reproducibility in preparing the percutaneous microneedle, but also can study the method of preparing the microneedle by a simple method. When the microneedle template having a laminated structure is manufactured to form a mold and then used for the preparation of the transdermal microneedle, it is found that the transdermal microneedle can be manufactured with excellent reproducibility through a simple process to complete the present invention. Reached.

SUMMARY OF THE INVENTION An object of the present invention is to provide a transdermal microneedle, a method for preparing the same, a mold for transdermal microneedle, and a method for producing the same, which is one of the drug delivery systems used as a transdermal drug delivery method.

In order to achieve the above object, the present invention,

Coating a photosensitive polymer comprising a photosensitive initiator on a substrate (step A);

Performing a lithography process on the photosensitive polymer coated on the substrate in step A to form a first polymer layer (step B);

The microneedle template having a laminated structure was repeatedly formed by repeatedly coating and lithography a photosensitive polymer including a photosensitive initiator so that a plurality of polymer layers having a smaller size may be sequentially stacked on the first polymer layer formed in step B. Forming (step C); And

It provides a method for producing a transdermal permeable microneedle mold comprising the step (step D) of applying a polymer on the microneedle template formed in step C to form a mold.

In addition, the present invention,

Coating the photosensitive polymer including the photosensitive initiator on the substrate (step 1);

Performing a lithography process on the photosensitive polymer coated on the substrate in step 1 to form a first polymer layer (step 2);

Repeating the coating and lithography process of the photosensitive polymer including the photosensitive initiator so that the plurality of polymer layers of which the size is sequentially reduced on the first polymer layer formed in step 2 is repeated to form a microneedle template having a laminated structure Forming (step 3);

Forming a mold by applying a polymer on the microneedle template formed in step 3 (step 4); And

It provides a method for producing a transdermal permeable microneedle comprising the step (step 5) of preparing a microneedle by applying a transdermal permeable solid drug to the mold formed in step 4.

The microneedle template having the laminated structure preferably has a laminated structure of 3 to 6 steps in total and a total height of 0.3 to 1.5 mm.

The first polymer layer of the microneedle template having the laminated structure is manufactured in a square, circle, triangle or star shape having a width of 100 to 300 μm and a height of 100 to 300 μm, and the top polymer layer of the microneedle template is 5 to It may be prepared in the form of a square, circle, triangle or star having a width of 20 μm and a height of 20 to 100 μm.

In the present invention, the polymer used to form the mold may be a single or copolymerized polydimethyl siloxane, polyurethane, polyisoprene and the like.

The present invention can be produced in a simple process compared to the conventional method for producing a transdermal microneedle and has an effect of providing a method for producing a transdermal microneedle and a method for producing a mold for transdermal microneedle having excellent reproducibility.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The present invention,

Coating a photosensitive polymer comprising a photosensitive initiator on a substrate (step A);

Performing a lithography process on the photosensitive polymer coated on the substrate in step A to form a first polymer layer (step B);

The microneedle template having a laminated structure was repeatedly formed by repeatedly coating and lithography a photosensitive polymer including a photosensitive initiator so that a plurality of polymer layers having a smaller size may be sequentially stacked on the first polymer layer formed in step B. Forming (step C); And

It provides a method for producing a transdermal permeable microneedle mold comprising the step (step D) of applying a polymer on the microneedle template formed in step C to form a mold.

The method for manufacturing a mold for transdermal microneedle according to the present invention will be described in detail step by step with reference to the accompanying drawings.

Step A is a step of coating a photosensitive polymer including a photosensitive initiator on a substrate. More specifically, it is a step of coating a photosensitive polymer including a photosensitive initiator to form a desired pattern through a lithography process on a substrate such as a silicon wafer.

It is preferable to use a silicon wafer as the substrate used in step A, but glass, quartz and ceramic plate materials may be used.

The photosensitive polymer that can be used in the present invention can be used without limitation as long as it can be used in the lithography process. For example, SU-8 epoxy polymer, polyvinyl alcohol, copolymers thereof, and the like can be used.

The photosensitive initiator may include triarylium-sulfonium salts, benzoyl peroxide, azobisisobutylonitrile (AIBN), Benzionalkylether, benzophenone, benzyl dimethyl katal, hydroxycyclohexyl phenylketone, 1,1-dichloro acetophenone, 2-Chloro thioxanthone may be used, but is not limited thereto.

Step B is a step of forming a first polymer layer by performing a lithography process on the photosensitive polymer coated on the substrate in step A.

In step B, a mask film designed to form a pattern of a first polymer layer to form a first polymer layer corresponding to a lowermost end of a microneedle template is formed on the photosensitive polymer, and then subjected to a lithography process to perform a first polymer layer. To form.

The first polymer layer of the microneedle template may be prepared in the form of a square, circle, triangle or star, preferably 100-300 μm wide and 100-300 μm high.

In order to form the first polymer layer of the microneedle template, the method of spin coating the photosensitive polymer on the substrate and then performing the lithography process is already well known in the field of integrated circuit, electronic device packaging, etc. Description is omitted.

Step C is a microstructure having a laminated structure by repeatedly performing a coating and lithography process of a photosensitive polymer including a photosensitive initiator so that a plurality of polymer layers of which sizes are sequentially reduced may be stacked on the first polymer layer formed in Step B. It is a step of forming a needle template.

1 is a view schematically showing a microneedle template formed in a total of four stages on a substrate by performing steps A to C.

Referring to FIG. 1, the lowermost first polymer layer 101 is formed on the substrate 200 through a lithography process as in step B. The size of the first polymer layer 101 is greater than that of the first polymer layer 101. In order to form a small second polymer layer, the photosensitive polymer layer is coated and a lithography process is performed. By repeating the above process, as shown in FIG. 1, the microneedle template 100 having a stack structure of four stages can be formed.

The microneedle template 100 having the lamination structure may be manufactured to have a lamination structure of a total of 3 to 6 steps, and the polymer layer 102 of the uppermost end of the microneedle template 100 is 5 to 20 μm wide and 20 It may be manufactured in the form of a square, circle, triangle or star having a height of ˜100 μm, but preferably the same as the first polymer layer 101 of the micro template 100.

The overall height of the microneedle template 102 is preferably 0.3 to 1.5 mm.

When the total height of the microneedle template 102 is manufactured to 0.3 mm or less, there is a problem that the structure having a laminated structure has only three steps or less, and is a patch-type skin that is curved when the percutaneous microneedle is manufactured. There is a limit to the application, on the other hand there is a problem that the mechanical strength and hardness of the photosensitive polymer layer may be lowered if it is produced in excess of 1.5 mm.

2 shows a state in which a mask film is formed on a substrate before performing a lithography process for manufacturing a microneedle template.

As shown in FIG. 2, the microneedle template having the laminated structure forms the first polymer layer and then coats the photosensitive polymer and manufactures the second polymer layer by making the pattern forming portion of the mask film smaller as shown in the enlarged view. By repeating the above process, a microneedle template having a laminated structure can be manufactured.

Step D is a step of forming a mold by applying a polymer on the microneedle template formed in step C.

As described above, after forming the microneedle template having a laminated structure on the substrate, a polymer may be applied to form a mold. In this step, a method of forming a mold using a polymer on a microneedle template may be easily performed by a person skilled in the art.

In the present invention, in order to manufacture a mold for transdermal microneedle, a polymer having elasticity and cooling and curing may be used when heated to room temperature or more. Such polymers include poly dimethyl siloxane (PDMS) and polyurethane ( polyurethane), polyisoprene may be used alone or copolymerized.

In addition, the present invention is to repeat the coating and lithography process of the photosensitive polymer including a photosensitive initiator to form a plurality of polymer layers of sequentially decreasing size on the substrate to form a microneedle template having a laminated structure, And it provides a mold for transdermal permeable microneedle, characterized in that to form a mold by applying a polymer on the formed microneedle template.

The microneedle template having the laminated structure preferably has a laminated structure of 3 to 6 steps in total and a total height of 0.3 to 1.5 mm.

As described above, the first polymer layer of the microneedle template having a laminated structure may be manufactured in a square, circle, triangle or star shape having a width of 100 to 300 μm and a height of 100 to 300 μm.

In addition, the polymer layer at the top of the microneedle template may be manufactured in the form of a square, circle, triangle or star having a width of 5 to 20 μm and a height of 20 to 100 μm, but preferably the same as the first polymer layer. .

In addition, the present invention,

Coating the photosensitive polymer including the photosensitive initiator on the substrate (step 1);

Performing a lithography process on the photosensitive polymer coated on the substrate in step 1 to form a first polymer layer (step 2);

Repeating the coating and lithography process of the photosensitive polymer including the photosensitive initiator so that the plurality of polymer layers of which the size is sequentially reduced on the first polymer layer formed in step 2 is repeated to form a microneedle template having a laminated structure Forming (step 3);

Forming a mold by applying a polymer on the microneedle template formed in step 3 (step 4); And

It provides a method for producing a transdermal permeable microneedle comprising the step (step 5) of preparing a microneedle by applying a transdermal permeable solid drug to the mold formed in step 4.

Steps 1 to 4 of the method for preparing a transdermal microneedle of the present invention are performed in the same manner as steps A to D of the method for preparing a mold for transdermal microneedle described above.

In addition, the present invention is to repeat the coating and lithography process of the photosensitive polymer including a photosensitive initiator to form a plurality of polymer layers of sequentially decreasing size on the substrate to form a microneedle template having a laminated structure, The present invention provides a transdermal microneedle, which is formed by applying a polymer onto a formed microneedle template, and applying a percutaneous solid drug to the formed mold.

The percutaneous microneedle prepared according to the present invention may be used as a transdermal drug delivery system that may be formed in the size of several to several tens of micrometers to replace a pen-type syringe.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

< Example >

Example  One - Percutaneous penetration type For microneedle Of mold  Produce

SU-8 epoxy photosensitive polymers containing triarylium sulfonium salt photosensitive initiator were spin coated onto silicon wafers having a size of 4 inches (10 cm in diameter). As described above, after forming a mask on the silicon wafer coated with the photosensitive polymer, a square pattern of 280 × 280 μm is formed at a position for forming a microneedle template. Thereafter, UV (365 nm) was irradiated to form a first polymer layer. Thereafter, the photosensitive polymer was spin-coated on the formed first polymer layer, a mask having a square pattern of 140 × 140 μm was formed, and then a second polymer layer was formed by irradiating UV (365 nm) light. Thereafter, spin-coating the photosensitive polymer on the formed second polymer layer, forming a mask having a square pattern of 20 × 20 μm, and then irradiating UV (365 nm) light to form a third polymer layer to increase the height of 900 μm. A total of three stages of the microneedle template was prepared, which was shown in FIG. 3 by scanning electron microscopy. The mold was formed by applying polydimethyl siloxane (PDMS) heated to 65 ° C. on a silicon wafer on which the total three-stage microneedle template was formed. The microneedle template and the silicon wafer were then cooled to room temperature and cured. Was removed to prepare a mold for transdermal microneedle.

1 is a view schematically showing a microneedle template formed of a laminated structure of a total of four stages on a substrate according to the present invention.

FIG. 2 is a schematic illustration of a method of forming a mask film on a substrate prior to performing a lithography process to fabricate a microneedle template.

3 is a photograph taken with a scanning electron microscope of the microneedle template prepared in Example 1 of the present invention.

Explanation of symbols on the main parts of the drawings

100: microneedle template 101: first polymer layer

102: top polymer layer 200: substrate

300: mask

Claims (19)

Coating the photosensitive polymer including the photosensitive initiator on the substrate (step 1); Performing a lithography process on the photosensitive polymer coated on the substrate in step 1 to form a first polymer layer (step 2); Repeating the coating and lithography process of the photosensitive polymer including the photosensitive initiator so that the plurality of polymer layers of which the size is sequentially reduced on the first polymer layer formed in step 2 is repeated to form a microneedle template having a laminated structure Forming (step 3); Forming a mold by applying an elastic polymer on the microneedle template formed in step 3 (step 4), wherein the elastic polymer is one or more selected from the group consisting of polydimethyl siloxane, polyurethane and polyisoprene or At least two copolymers; And A method for producing a transdermal permeable microneedle, comprising the step (step 5) of preparing a microneedle by applying a percutaneous solid drug to the mold formed in step 4. The method of claim 1, The method of claim 4 further comprising the step of removing the microneedle template after forming a mold by applying a polymer. The method of claim 1, The microneedle template having the laminated structure has a laminated structure of a total of 3 to 6 stages and the total height is 0.3 to 1.5 mm, characterized in that the percutaneous microneedle manufacturing method. The method of claim 1, The photosensitive initiator is triarylium sulfonium salt, benzoyl peroxide, azobisisobutyronitrile, benzionalkyl ether, benzophenone, benzyl dimethyl catal, hydroxycyclohexyl phenyl ketone, 1,1-dichloro acetophenone and 2 -Chloro thioxanthone is selected from the group consisting of, the photosensitive polymer is a method of producing a transdermal permeable microneedle, characterized in that selected from the group consisting of SU-8 epoxy polymer, polyvinyl alcohol and copolymers thereof. The method of claim 1, The first polymer layer of the microneedle template having the laminated structure is manufactured in a square, circle, triangle or star shape having a width of 100 to 300 μm and a height of 100 to 300 μm, and the top polymer layer of the microneedle template is 5 to A method for producing a transdermal microneedle having a width of 20 μm and having a height of 20 to 100 μm in the form of a square, circle, triangle or star. delete Repeating the coating and lithography process of the photosensitive polymer including the photosensitive initiator to form a plurality of polymer layers that are sequentially reduced in size on the substrate to form a microneedle template having a laminated structure, and formed on the formed microneedle template To form a mold by applying an elastic polymer which is one or more than one copolymer selected from the group consisting of poly dimethyl siloxane, polyurethane and polyisoprene to form a mold, and is applied to the formed mold by applying a percutaneous solid drug Percutaneous microneedle, characterized in that. The method of claim 7, wherein The microneedle template having the laminated structure has a total of 3 to 6 stacked stacking structures and has a total height of 0.3 to 1.5 mm. The method of claim 7, wherein The lowest layer of the microneedle template having the laminated structure is manufactured in a square, circle, triangle or star shape having a width of 100 to 300 μm and a height of 100 to 300 μm, and the top layer of the microneedle template is 5 to 20 μm wide. Percutaneous permeable microneedle, characterized in that produced in the form of a square, circle, triangle or star having a height of 20 to 100 ㎛. Coating a photosensitive polymer comprising a photosensitive initiator on a substrate (step A); Performing a lithography process on the photosensitive polymer coated on the substrate in step A to form a first polymer layer (step B); The microneedle template having a laminated structure was repeatedly formed by repeatedly coating and lithography a photosensitive polymer including a photosensitive initiator so that a plurality of polymer layers having a smaller size may be sequentially stacked on the first polymer layer formed in step B. Forming (step C); And Forming a mold by applying an elastic polymer on the microneedle template formed in the step C (step D), wherein the elastic polymer is selected from the group consisting of polydimethyl siloxane, polyurethane and polyisoprene alone or Method of producing a mold for transdermal microneedle comprising the step of two or more copolymers. The method of claim 10, Forming a mold by applying a polymer in the step D and removing the microneedle template further comprising the step of removing the microneedle template. The method of claim 10, The microneedle template having the laminated structure is a method for manufacturing a mold for transdermal microneedle, characterized in that having a laminated structure of a total of 3 to 6 steps. The method of claim 10, The total height of the microneedle template having the laminated structure is 0.3 ~ 1.5 mm, characterized in that the manufacturing method of the mold for transdermal microneedle. The method of claim 10, The photosensitive initiator is triarylium sulfonium salt, benzoyl peroxide, azobisisobutyronitrile, benzionalkyl ether, benzophenone, benzyl dimethyl catal, hydroxycyclohexyl phenyl ketone, 1,1-dichloro acetophenone and 2 It is selected from the group consisting of -chloro thioxanthone, the photosensitive polymer is a method for producing a mold for transdermal microneedle, characterized in that selected from the group consisting of SU-8 epoxy polymer, polyvinyl alcohol and copolymers thereof. The method of claim 10, The first polymer layer of the microneedle template having the laminated structure is manufactured in a square, circle, triangle or star shape having a width of 100 to 300 μm and a height of 100 to 300 μm, and the top polymer layer of the microneedle template is 5 to A method for manufacturing a mold for transdermal microneedle, characterized in that it is manufactured in the form of square, circle, triangle or star having a width of 20 μm and a height of 20 to 100 μm. delete Repeating the coating and lithography process of the photosensitive polymer including the photosensitive initiator to form a plurality of polymer layers that are sequentially reduced in size on the substrate to form a microneedle template having a laminated structure, and formed microneedle template A mold for transdermal microneedle, characterized in that a mold is formed by applying an elastic polymer, which is one or a copolymer of two or more, selected from the group consisting of polydimethyl siloxane, polyurethane, and polyisoprene. The method of claim 17, The microneedle template having the laminated structure has a total laminated structure of 3 to 6 stages and the total height is 0.3 to 1.5 mm, the mold for transdermal microneedle. The method of claim 17, The first polymer layer of the microneedle template having the laminated structure is manufactured in a square, circle, triangle or star shape having a width of 100 to 300 μm and a height of 100 to 300 μm, and the polymer layer on the top of the microneedle template is Mold for transdermal microneedle, characterized in that it is manufactured in the form of square, circle, triangle or star having a width of 5 to 20 ㎛, 20 to 100 ㎛.

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