Method for manufacturing a multilayer microneedle structure

Abstract

To provide a multi-layered microneedle structure capable of preventing medicament from being lost in a manufacturing process while transmitting a fixed amount of medicament, and a manufacturing method for the same.SOLUTION: A manufacturing method for a multi-layered microneedle structure 10 includes: a first dispensing step for dispensing a first composition to a supporting body 11; a drying step which dries the first composition and forms a base layer 12; a second dispensing step for dispensing a second composition containing medicament on the base layer; a third dispensing step for dispensing a third composition so as to place the second composition on the base layer; and a molding step which forms a core layer 13 by the second composition and a shell layer 14 by the third composition with fluidization, a centrifugal lithography technique or droplet born air blowing (DAB).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for manufacturing a multi-layer microneedle structure. [Background technology]

[0002] Dissolving microneedles (DMNs) are a promising alternative to subcutaneous injections and oral administration, the most widely used drug delivery systems in the medical field. Microneedles improve the delivery rate of therapeutic agents through a mechanism that delivers drugs directly to the epidermis or dermis, and are less painful than subcutaneous injections, improving patient convenience.

[0003] However, drug loss, especially the loss of biopharmaceuticals or oxygen-sensitive drugs, during the manufacturing and storage processes of microneedle structures poses a significant obstacle to the replacement of conventional drug delivery systems by microneedle structures.

[0004] Although many attempts have been made to achieve quantitative drug delivery and maintenance, each of the drug preservation and quantitative drug delivery technologies only solves one problem, and therefore a new strategy that can simultaneously solve both problems is required.

[0005] [Patent Document 1] KR2019-0123642A Summary of the Invention [Problem to be solved by the invention]

[0006] In order to solve the above-mentioned problems of the conventional technology, one embodiment of the present invention aims to provide a multi-layer microneedle structure and a manufacturing method thereof that can deliver a fixed amount of drug while preventing drug loss during the manufacturing process.

[0007] However, the problems to be solved by the present invention are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description. [Means for solving the problem]

[0008] According to one aspect of the present invention to solve the above problems, a multi-layer microneedle structure is provided, which includes a base layer formed on a support; a core layer formed on the base layer and containing a drug; and a shell layer formed on the base layer to cover the core layer, wherein the relationship between the thickness T of the shell layer outside the core layer and the height H2 of the core layer is determined by the material forming the core layer.

[0009] In one embodiment, the core layer is made of a hydrophilic material, and the height H2 of the core layer may be inversely proportional to the thickness T of the shell layer outside the core layer.

[0010] In one embodiment, the core layer is made of a hydrophobic material, and the height H2 of the core layer may be constant regardless of the thickness T of the shell layer outside the core layer.

[0011] In one embodiment, the thickness T of the shell layer outside the core layer may be inversely proportional to the duration of the fluidization process to form the core layer and the shell layer.

[0012] In one embodiment, the thickness T of the shell layer outside the core layer may be smallest at the interface between the core layer and the base layer.

[0013] In one embodiment, the thickness T of the shell layer outside the core layer may be uniform throughout the core layer.

[0014] In one embodiment, when the total height H of the base layer, the core layer, and the shell layer and the height H1 of the base layer are constant, the height H2 of the core layer and the height H3 from the tip of the core layer to the tip of the shell layer may be inversely proportional.

[0015] In one embodiment, the base layer has microcavities on the top side, and the core layer is made of powder or liquid and can be provided in the microcavities.

[0016] In one embodiment, the height H2 of the core layer may be determined by the height of the microcavity.

[0017] In one embodiment, the base layer may be formed on microprojections formed on the support.

[0018] In one embodiment, the support is a pegboard having openings formed therein, and the base layer can be formed by filling the openings.

[0019] According to another aspect of the present invention, there is provided a method for manufacturing a multi-layer microneedle structure, comprising: a first dispensing step of dispensing a first composition onto a support; a drying step of drying the first composition to form a base layer; a second dispensing step of dispensing a second composition containing a drug onto the base layer; a third dispensing step of dispensing a third composition onto the base layer so as to cover the second composition; and a molding step of forming a core layer made of the second composition and a shell layer made of the third composition.

[0020] In one embodiment, the shaping step can be performed by fluidization, the centrifugal lithography technique, or droplet born air blowing (DAB).

[0021] In one embodiment, the second composition comprises a hydrophilic material, and the height H2 of the core layer may be proportional to the fluidization step time.

[0022] In one embodiment, the second composition comprises a hydrophobic material, and the height H2 of the core layer may be constant regardless of the fluidization process time.

[0023] In one embodiment, the thickness T of the shell layer outside the core layer and the height H3 from the tip of the core layer to the tip of the shell layer may be inversely proportional to the fluidization step time.

[0024] In one embodiment, the drying step further includes forming microcavities on the base layer, the second composition being in powder or liquid form, and the second dispensing step can dispense the second composition into the microcavities.

[0025] In one embodiment, the support includes micro-projections, and the first dispensing step can dispense the first composition formed on the micro-projections.

[0026] In one embodiment, the support is a pegboard having openings formed therein, and the first dispensing step can fill the openings with the first composition.

[0027] In one embodiment, the second dispensing step may further include the step of drying the second composition. [Effects of the Invention]

[0028] The multi-layer microneedle structure and its manufacturing method according to one embodiment of the present invention have a multi-layer structure in which a core layer containing a drug is covered with a shell layer, and the shell layer can block exposure and release of the drug, thereby preventing loss of the drug during the manufacturing process.

[0029] Furthermore, in the present invention, by forming a core layer on a drug-free base layer, the drug-containing core layer can be sufficiently inserted into the skin, thereby ensuring the delivery of a fixed amount of drug.

[0030] Furthermore, since the present invention allows for the manufacture of a multi-layer microneedle structure using a shell layer placed on the outermost surface, microneedle structures for a variety of drugs can be manufactured using the same manufacturing conditions and the same process regardless of the type of drug contained in the core layer.

[0031] Furthermore, since the core layer is not exposed to the outside, the manufacturing process does not need to be optimized depending on the type of drug, simplifying the manufacturing process and improving manufacturing efficiency.

[0032] Furthermore, the present invention can improve the physical properties of the entire multilayer microneedle structure by changing the manufacturing conditions for the shell layer, and can safely protect the drug from the external environment. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 is a perspective view showing a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 2] 1 is a diagram showing an application example of a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 3] 1 is a diagram showing an in vitro experiment and the results of the experiment on a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 4] 1 is a diagram illustrating an example of a core layer in a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 5] 1 is a graph showing the results of an experiment verifying the role of the shell layer of a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 6] 1 is a diagram illustrating a manufacturing process of a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 7] 1 is a view showing a modified example of a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 8]10 is a view showing another modified example of a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 9] 10 is a view showing yet another modified example of a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 10] 1 is a diagram showing a confocal laser scanning microscope analysis of a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 11] 1 is a diagram showing each factor and shell structure of a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 12] 1 is a graph showing the formation height depending on the core layer material of a multi-layer microneedle structure according to an embodiment of the present invention. [Figure 13] 1 is a graph showing the height of the core layer and the thickness of the shell layer outside the core layer according to the fluidization process time of a multi-layer microneedle structure according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0034] Hereinafter, with reference to the accompanying drawings, embodiments of the present invention will be described in detail so that those skilled in the art can easily carry out the present invention. The present invention may be embodied in various different forms and is not limited to the embodiments described herein. In order to clearly explain the present invention in the drawings, parts that are not relevant to the description are omitted, and the same reference numerals are used throughout the specification to refer to the same or similar components.

[0035] The examples of the present invention are provided to more completely explain the present invention to those skilled in the art, and the examples described below can be modified in various different forms, and the scope of the present invention is not limited to the following examples. Rather, these examples are provided to more faithfully and completely explain the present invention and to fully convey the concept of the present invention to those skilled in the art.

[0036] Hereinafter, embodiments of the present invention will be described with reference to the drawings, which schematically illustrate embodiments of the present invention. In the drawings, variations in the illustrated shapes are to be expected due to, for example, manufacturing techniques and / or tolerances. Therefore, embodiments of the present invention should not be construed as being limited to the specific shapes of regions illustrated herein, but should also include variations in shapes resulting from, for example, manufacturing.

[0037] FIG. 1 is a perspective view showing a multi-layer microneedle structure according to one embodiment of the present invention, FIG. 2 is a diagram showing an application example of a multi-layer microneedle structure according to one embodiment of the present invention, and FIG. 3 is a diagram showing an in vitro experiment of a multi-layer microneedle structure according to one embodiment of the present invention and the results thereof.

[0038] Referring to FIG. 1, a multi-layer microneedle structure 10 according to one embodiment of the present invention includes a base layer 12, a core layer 13 and a shell layer 14.

[0039] The base layer 12 is formed at a certain height on the support 11. The base layer 12 is intended to aid in the quantitative delivery of the drug, and as shown in Figure 2, may be formed at a certain height so that the core layer 13 containing the drug can be sufficiently inserted into the skin. Therefore, the base layer 12 does not contain a drug.

[0040] As a result, the multi-layer microneedle structure 10 according to one embodiment of the present invention can reliably ensure quantitative delivery of the drug since the core layer 13 containing the drug can be sufficiently inserted into the skin 1.

[0041] The core layer 13 is a portion carrying an active drug and is formed on the base layer 12. Here, the core layer 13 may be made of a hydrophilic or hydrophobic material. For example, the core layer 13 may include, but is not limited to, hyaluronic acid (HA) or PCL (Polycaprolactone). The core layer 13 may also be in powder or liquid form.

[0042] At this time, the core layer 13 may have various shapes depending on the material used to manufacture it. For example, if the core layer 13 is made of a hydrophilic material, it may have a shape similar to that of the shell layer 14 (see FIG. 6). That is, since the core layer 13 is affected by the fluidization process, it may be formed to have a shape similar to that of the tip portion 14b of the shell layer 14.

[0043] Alternatively, when the core layer 13 is made of a hydrophobic material, it may be provided in a circular shape within the shell layer 14, as shown in Fig. 1. Here, the shape of the core layer 13 is not particularly limited. However, the core layer 13 has a shape that is unrelated to the shape of the shell layer 14. That is, unlike the case of a hydrophilic material, the core layer 13 is not affected much by the fluidization process, and therefore is not formed to resemble the shape of the tip portion 14b of the shell layer 14.

[0044] The shell layer 14 is for forming the overall shape of the multi-layer microneedle structure 10 and is formed on the base layer 12 to cover the core layer 13. Here, the shell layer 14 may be made of a polymer that is not loaded with a drug. As shown in FIG. 1, the shell layer 14 may include a cover layer 14a and a tip portion 4b.

[0045] The cover layer 14a is for protecting the drug in the core layer 13, and can completely cover the core layer 13 so that it is not exposed to the outside.

[0046] The tip portion 4b may be formed to have a pointed tip for easy insertion into the skin 1. In this case, the shell layer 14 may be made of a material having high physical strength or may be manufactured using a manufacturing process suitable for this.

[0047] In this way, the multi-layer microneedle structure 10 can include only the base layer 12 and the shell layer 14 in appearance, since the core layer 13 is not exposed to the outside.

[0048] As a result, the multi-layer microneedle structure 10 according to one embodiment of the present invention can prevent the exposure and release of the drug contained in the core layer 13 by the shell layer 14, thereby preventing the loss of the drug during the manufacturing and storage processes.

[0049] Here, the shell layer 14 can be formed by a centrifugal lithography method using a fluidization process, and therefore the shape of the shell layer 14 can be changed depending on the fluidization process time.

[0050] At this time, the relationship between the thickness T of the shell layer 14 outside the core layer 13 and the height H2 of the core layer 13 can be determined depending on the material of the core layer 13. Here, the thickness T of the shell layer 14 outside the core layer 13 can be affected by the fluidization process time. That is, the thickness T of the shell layer 14 outside the core layer 13 can be inversely proportional to the fluidization process time (see FIG. 11).

[0051] For example, when the core layer 13 is made of a hydrophilic material, the height H2 of the core layer 13 may be affected by the fluidization process time. More specifically, the height H2 of the core layer 13 may be inversely proportional to the thickness T of the shell layer 14 outside the core layer 13. That is, the height H2 of the core layer 13 may increase as the thickness T of the shell layer 14 outside the core layer 13 decreases.

[0052] At this time, the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 may decrease as the thickness T of the shell layer 14 outside the core layer 13 decreases. Therefore, the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 may be proportional to the thickness T of the shell layer 14 outside the core layer 13.

[0053] Here, when the total height H of the base layer 12, core layer 13, and shell layer 14 and the height H1 of the base layer 12 are constant, the height H2 of the core layer 13 and the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 may be affected by the fluidization process time. At this time, since the height H2 of the core layer 13 increases in proportion to the fluidization process time, the height H2 of the core layer 13 and the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 may be inversely proportional to each other.

[0054] As another example, when the core layer 13 is made of a hydrophobic material, the height H2 of the core layer 13 is not affected by the fluidization process time. That is, the height H2 of the core layer 13 can be constant regardless of the thickness T of the shell layer 14 outside the core layer 13.

[0055] In this case, the thickness T of the shell layer 14 outside the core layer 13 may be 1 to 50 μm. If the thickness T of the shell layer 14 outside the core layer 13 is less than 1 μm, the shell layer 14 may not provide sufficient strength and may be exposed to the outside of the core layer 13 or leak from the cover layer 14a. Therefore, the multi-layer microneedle structure 10 cannot guarantee the safe protection of the drug.

[0056] On the other hand, if the thickness T of the shell layer 14 outside the core layer 13 exceeds 50 μm, the shell layer 14 is formed more than necessary, the effect of the shell layer 14 is not improved, and material may be wasted.

[0057] Furthermore, the thickness T of the shell layer 14 outside the core layer 13 may vary depending on the physical properties or shape of the core layer 13. For example, the thickness T of the shell layer 14 outside the core layer 13 may be smallest at the interface between the core layer 13 and the base layer 12 (see FIG. 11). This allows the multi-layer microneedle structure 10 to be easily manufactured without optimizing the fluidization process conditions.

[0058] As another example, the thickness T of the shell layer 14 outside the core layer 13 may be uniform throughout the core layer 13 (see FIG. 6 ), thereby enabling the shell layer 14 to more safely protect the drug contained in the core layer 13.

[0059] 2, when the multi-layer microneedle structure 10 is inserted into the skin 1, the core layer 13 is positioned within the skin 1 (see (a)). Thereafter, when the base layer 12 is dissolved by the skin 1 or physically or chemically separated from the support 11 (see (b)), the cover layer 14a and tip portion 4b of the shell layer 14 dissolve in the skin 1, and the drug 13a is delivered to the skin 1 (see (c)). As a result, the drug 13a contained in the core layer 13 can be delivered to the skin 1 quantitatively without loss.

[0060] Referring to Figure 3, all of the core layers 13 are delivered into the skin 1. After loading different fluorescent materials into each layer of the multi-layer microneedle structure 10, an in vitro insertion test was carried out (see (a)). Here, the core layer 13 was loaded with a red fluorescent material, and the shell layer 14 was loaded with a green fluorescent material (see (b)). As shown in the photograph of the skin delivery surface, it can be seen that all of the core layers 13 were delivered into the skin 1.

[0061] Meanwhile, the multi-layer microneedle structure 10 according to an embodiment of the present invention can be configured in various forms.

[0062] For example, the multi-layer microneedle structure 10 may be formed on a support 11 provided with microprotrusions. In this case, the multi-layer microneedle structure 10 may be formed on the microprotrusions.

[0063] As another example, the multi-layer microneedle structure 10 may be provided on a pegboard attached to an applicator. At this time, an opening may be formed in the pegboard, and the pegboard may be used as a support. That is, the base layer 12 may be formed by filling the opening in the pegboard. As a result, the multi-layer microneedle structure 10 may be provided on the opening in the pegboard.

[0064] FIG. 4 is a diagram illustrating an example of a core layer in a multi-layer microneedle structure according to an embodiment of the present invention.

[0065] Referring to FIG. 4, the multi-layer microneedle structure 10 has a core layer 13 containing a drug, which may be in powder or liquid form.

[0066] In this case, the base layer 12 may have a microcavity 121 on the upper side thereof. The powder core layer 131 or the liquid core layer 132 may be provided in the microcavity 121. The microcavity 121 may be provided in the center of the upper side of the base layer 12. The microcavity 121 may have any shape suitable for accommodating the powder core layer 131 or the liquid core layer 132.

[0067] Here, the height H2 of the core layer 13 may be determined by the height of the microcavity 121. That is, since the powder core layer 131 or the liquid core layer 132 is filled into the microcavity 121 and cannot be formed high above the microcavity 121 due to its characteristics, the height H2 of the core layer 13 may be substantially the same as the height of the microcavity 121 or may be higher by a few μm.

[0068] As a result, the core layer 13 containing the drug is completely surrounded by not only the shell layer 14 but also the base layer 12, so that the multi-layer microneedle structure 10 can safely protect the drug.

[0069] FIG. 5 is a graph showing the results of an experiment verifying the role of the shell layer of a multi-layer microneedle structure according to one embodiment of the present invention.

[0070] The present inventors conducted the following experiment to confirm the role of the shell layer 14. First, a multi-layer microneedle structure 10 according to one embodiment of the present invention was prepared. As a comparative example, a microneedle structure was prepared that did not have a shell layer and only had a core layer 13 containing a drug on a base layer. In this case, ascorbic acid was used as the drug contained in the microneedle structure.

[0071] As shown in Figure 5, in the case of droplets before the formation of the microstructure, the activity rate of ascorbic acid was 100% both with and without a shell layer, but in the microneedle structures after the fabrication, the activity rate of ascorbic acid was 91% with a shell layer and 65% without a shell layer. This shows that the shell layer effectively prevents drug loss.

[0072] FIG. 6 is a diagram schematically illustrating a manufacturing process of a multi-layer microneedle structure according to an embodiment of the present invention.

[0073] 6, in the manufacturing process of a multi-layer microneedle structure according to one embodiment of the present invention, first, a first composition 12' is dispensed onto a support 11 ((a) first dispensing step). Here, the support 11 may be made of a biocompatible material. Also, the first composition 12' does not contain a drug.

[0074] Next, the first composition 12' is dried to form the base layer 12 ((b) drying step). At this time, the base layer 12 is intended to aid in the quantitative delivery of the drug, and may be formed to a certain height so that the core layer 13 containing the drug can be sufficiently inserted into the skin.

[0075] Alternatively, when the second composition 13′ is in powder or liquid form, microcavities can be formed on the base layer 12 (see FIG. 4). In this case, the microcavity 121 can be provided in the center on the upper side of the base layer 12.

[0076] Next, a second composition 13' is dispensed onto the base layer 12 ((c) second dispensing step). At this time, the second composition 13' may be loaded with an active drug.

[0077] Alternatively, when the second composition 13′ is in the form of a powder or liquid, it can be dispensed into the microcavities (see FIG. 4). In this case, the second composition 13′ can be made of a hydrophilic or hydrophobic material.

[0078] At this time, the second composition 13' can be dried, which can prevent the core layer 13 formed by the second composition 13' from diffusing.

[0079] Next, a third composition 14' is dispensed onto the base layer 12 so as to cover the second composition 13' ((d) third dispensing step). At this time, the third composition 14' may be composed of a polymer not loaded with a drug.

[0080] Next, a core layer 13 made of the second composition 13' and a shell layer 14 made of the third composition 14' are formed by fluidization, centrifugal lithography, or droplet-born air blowing (DAB) ((e) molding step). For example, the third composition 14' can be fluidized using a solvent, and an upper plate can be placed on the side facing the support 11 to form the shell layer 14 by centrifugal lithography.

[0081] As another example, the shell layer 14 can be formed by droplet-borne air blowing (DAB), in which an upper plate is placed on the side opposite the support 11 and dried by air at a low temperature.

[0082] Here, if the second composition 13' is hydrophilic, it is affected by the fluidization process, so that the core layer 13 can be manufactured in a similar form to the shell layer 14.

[0083] Through this, the manufacturing method of a multi-layer microneedle structure according to one embodiment of the present invention can manufacture a multi-layer microneedle structure 10 according to the manufacturing conditions of the shell layer 14. Therefore, regardless of the type of drug contained in the core layer 13, the multi-layer microneedle structure 10 can be manufactured under the same manufacturing conditions, and therefore microneedle structures for various drugs can be manufactured using the same process.

[0084] Furthermore, in the manufacturing method of a multi-layer microneedle structure according to one embodiment of the present invention, the core layer 13 is not exposed to the outside by the shell layer 14, so there is no need to optimize the manufacturing process depending on the type of drug, and therefore the manufacturing process can be simplified, thereby improving manufacturing efficiency.

[0085] Furthermore, the manufacturing method of a multi-layer microneedle structure according to one embodiment of the present invention can improve the physical properties of the entire multi-layer microneedle structure 10 by changing the manufacturing conditions for the shell layer 14, thereby safely protecting the drug from the external environment.

[0086] FIG. 7 is a diagram showing a modified example of a multi-layer microneedle structure according to an embodiment of the present invention.

[0087] Referring to FIG. 7, the manufacturing method of the present invention can manufacture multilayer microneedle structures 10-1 to 10-4 in various shapes.

[0088] As shown in FIG. 7(a), the first dispensing step and drying step can produce a semicircular base layer 12-1, a trapezoidal base layer 12-2, a concave base layer 12-3, and a cylindrical base layer 12-4.

[0089] As shown in FIG. 7(b), a second composition 13' containing a drug is dispensed onto each of the base layers 12-1 to 12-4.

[0090] 7(c), the third composition 14' is dispensed onto the base layers 12-1 to 12-4 so as to cover the second composition 13'. At this time, the area where the third composition 14' is dispensed may vary depending on the shape of the base layers 12-1 to 12-4.

[0091] For example, in the case of a semicircular base layer 12-1, the third composition 14' may be formed up to a certain height on the semicircular base layer 12-1. That is, the third composition 14' may be formed on both sides of the center of the semicircular base layer 12-1 to a certain angle. In the case of a trapezoidal base layer 12-2, the third composition 14' may be formed on the entire top surface of the trapezoidal base layer 12-2. In the case of a base layer 12-3 with a concave center, the third composition 14' may be formed only on a portion of the concave base layer 12-3, excluding both sides. In the case of a cylindrical base layer 12-4, the third composition 14' may be formed on the entire top surface of the cylindrical base layer 12-4.

[0092] As shown in Figure 7(d), the shell layers 14-1 to 14-4 are formed by fluidization and centrifugal lithography techniques. At this time, the overall shape of the multilayer microneedle structures 10-1 to 10-4 can be made different depending on the shape of the base layers 12-1 to 12-4.

[0093] For example, in the case of a semicircular base layer 12-1, the shell layer 14-1 may be formed in a conical shape following the semicircular base layer 12-1. Therefore, the multilayer microneedle structure 10-1 may be manufactured in a shape having a continuous curve on the cross section, with the lower side bulging outward and the upper side recessed toward the center.

[0094] In the case of a trapezoidal base layer 12-2, the shell layer 14-2 may be formed in a conical shape following the upper surface of the trapezoidal base layer 12-2. Therefore, the multi-layer microneedle structure 10-2 may be formed in a cross-sectional shape that is straight up to a certain height and then curved to converge to the center.

[0095] In the case of a base layer 12-3 having a concave middle, the shell layer 14-3 may be formed in a conical shape on the upper side of the base layer 12-3 having a concave middle. Therefore, the multi-layer microneedle structure 10-3 may be formed in the form of a curve that converges to the center following a neck portion having a concave middle in cross section.

[0096] In the case of a cylindrical base layer 12-4, the shell layer 14-4 may be formed in a conical shape following the upper surface of the cylindrical base layer 12-4. Therefore, the multi-layer microneedle structure 10-4 may be formed in the form of a curve that converges to the center in a curved shape following a straight lower portion at a certain height.

[0097] FIG. 8 is a view showing another modified example of a multi-layer microneedle structure according to an embodiment of the present invention.

[0098] 8(a), the multi-layer microneedle structure 20 may be provided on a pegboard 21 attached to an applicator 100. Here, the applicator 100 may include microprojections 110 and a piston 120. As the piston 120 descends, the microprojections 110 are inserted into openings 21a of the pegboard 21, and the multi-layer microneedle structure 20 may be inserted into the skin 1.

[0099] As shown in Figure 8(b), the support is a pegboard 21 having openings 21a. In the method for manufacturing a multi-layer microneedle structure according to one embodiment of the present invention as described above, the first dispensing step can fill the openings 21a with a first composition 22'.

[0100] As shown in FIG. 8(c), the first composition 22' may form a base layer 22 in the opening 21a upon drying.

[0101] As shown in (d) of Figure 8, similar to the method for manufacturing a multi-layer microneedle structure according to one embodiment of the present invention as described above, the second dispensing step dispenses a second composition 23' onto the base layer 22.

[0102] As shown in (d) of Figure 8, similar to the manufacturing method of a multilayer microneedle structure according to one embodiment of the present invention as described above, after dispensing the third composition, a multilayer microneedle structure 20 including a base layer 22, a core layer 23 and a shell layer 24 can be formed on a pegboard 21 by fluidization and centrifugal lithography.

[0103] FIG. 9 is a view showing yet another modified example of a multi-layer microneedle structure according to an embodiment of the present invention.

[0104] 9(a), a multi-layer microneedle structure may be formed on a support 31 having microprotrusions 31a. Similar to the method for manufacturing a multi-layer microneedle structure according to one embodiment of the present invention described above, a first composition, a second composition, and a third composition may be sequentially dispensed onto the microprotrusions 31a of the support 31.

[0105] As shown in FIG. 9(b), fluidization and centrifugal lithography can be performed on the composition 34' on the microprojections 31a.

[0106] As shown in FIG. 9(c), a shell layer 34 may be formed on the fine protrusions 31a formed on the support 31.

[0107] Figure 10 is a diagram showing a confocal laser scanning microscope analysis of a multi-layer microneedle structure according to one embodiment of the present invention, and Figure 11 is a diagram showing each factor and shell structure of a multi-layer microneedle structure according to one embodiment of the present invention.

[0108] Referring to FIG. 10, the multi-layer microneedle structure 10 fabricated by the above-described method was analyzed by a confocal laser scanning microscope.

[0109] Cross-sectional images of the multi-layer microneedle structure 10 shown in Figure 10(a) for each height are shown in Figure 10(b). At this time, as shown in Figure 10(c), the distance when viewing the multi-layer microneedle structure from the top end is used as the basis. In Figures 10 and 11, green indicates the shell layer 14, and red indicates the core layer 13 containing the drug. The mixed portion of the shell layer 14 and the core layer 13 containing the drug is shown in yellow.

[0110] The upper end (0 μm and 200 μm) of the multilayer microneedle structure 10 does not contain a drug, while the lower end (400 μm and 600 μm) contains a drug. The cross-sectional image at 600 μm shows that the core layer 13 is completely surrounded by the shell layer 14.

[0111] 11(a), the factors for each region of the multi-layer microneedle structure 10 are defined. Here, H is the total height of the base layer 12, core layer 13, and shell layer 14, H1 is the height of the base layer 12, H2 is the height of the core layer 13, and H3 is the height from the tip of the core layer 13 to the tip of the shell layer 14. Also, D1 is the diameter of the base layer 12, and D2 is the diameter of the lower surface of the core layer 13.

[0112] 11(b), the shell layer 14 forms the outer shape of the multi-layer microneedle structure 10. At this time, the shell layer 14 surrounds the core layer 13, and therefore has an internal space corresponding to the core layer 13.

[0113] 11(c), T is the thickness of the shell layer 14 outside the core layer 13. That is, T is the thickness of the shell layer 14 surrounding the core layer 13 on a horizontal cross section.

[0114] Figure 12 is a graph showing the formation height depending on the core layer material of a multi-layer microneedle structure according to one embodiment of the present invention, and Figure 13 is a graph showing the height of the core layer and the thickness of the shell layer outside the core layer depending on the fluidization process time of a multi-layer microneedle structure according to one embodiment of the present invention.

[0115] In order to confirm the influence of the manufacturing process conditions on the multi-layer microneedle structure 10, the following experiment was carried out.

[0116] First, in order to confirm the change in the shape of the core layer 13 due to the manufacturing process, multilayer microneedle structures 10 having different core layers 13 were prepared. Here, the core layers 13 were made of hyaluronic acid (HA), PCL, and powder.

[0117] As shown in Figure 12, hyaluronic acid (HA) is hydrophilic, so the height of the core layer 13 varies depending on the manufacturing process (particularly the fluidization process) of the multilayer microneedle structure 10. This varies depending on the fluidization process time, and when the fluidization process time was fixed at 30 seconds, the height of the core layer 13 was 280 µm.

[0118] In the case of PCL, since it is hydrophobic, there was almost no change in the core height during the manufacturing process (especially the fluidization process) of the multilayer microneedle structure 10. When the fluidization process time was fixed at 30 seconds, the height of the core layer 13 was 250 μm.

[0119] In the case of powder, there was almost no change in the core height during the manufacturing process (particularly the fluidization process) of the multilayer microneedle structure 10. In this case, the height is determined by the height of the microcavities in the base layer 12. The height of the core layer 13 was 200 μm.

[0120] As can be seen from this, the multi-layer microneedle structure 10 is affected by the manufacturing process depending on the composition of the core layer 13. In particular, when the core layer 13 is hydrophilic, the manufacturing process can affect the morphology of the core layer 13.

[0121] Next, an experiment was conducted to examine the change in the morphology of the hydrophilic core layer 13, which is greatly affected by the fluidization process. In this case, hyaluronic acid (HA) was used as the core layer 13. With the overall height H of the multi-layer microneedle structure 10, the height H1 of the base layer 12, and the diameter D1 of the base layer 12 fixed, the fluidization process time was increased from 10 seconds to 60 seconds to manufacture the multi-layer microneedle structure 10.

[0122] Here, the overall height H of the multilayer microneedle structure 10 was 800 μm, the height H1 of the base layer 12 was 200 μm, and the diameter D1 of the base layer 12 was 400 μm.

[0123] 13, the height H2 of the core layer 13 is proportional to the fluidization time, whereas the thickness T of the shell layer 14 outside the core layer 13 is inversely proportional to the fluidization time.

[0124] That is, as the fluidization process time increases, the core layer 13 deforms to resemble the shell layer 14, so the height H2 of the core layer 13 increases gradually. Also, as the fluidization process time increases, the shell layer 14 deforms in the height direction, so the thickness T of the shell layer 14 outside the core layer 13 decreases gradually. Therefore, the height H2 of the core layer 13 is inversely proportional to the thickness T of the shell layer 14 outside the core layer 13.

[0125] At this time, it can be seen that the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 is affected by the height H2 of the core layer 13, since the overall height H of the multilayer microneedle structure 10 and the height H1 of the base layer 12 are fixed.

[0126] That is, the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 is the total height H of the multi-layer microneedle structure 10 minus the height H1 of the base layer 12 and the height H2 of the core layer 13. Therefore, the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 decreases as the height H2 of the core layer 13 increases. That is, the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 is inversely proportional to the height H2 of the core layer 13. As a result, the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 is inversely proportional to the fluidization process time.

[0127] Furthermore, the height H3 from the tip of the core layer 13 to the tip of the shell layer 14 is proportional to the thickness T of the shell layer 14.

[0128] Although one embodiment of the present invention has been described above, the concept of the present invention is not limited to the embodiment presented in this specification, and a person skilled in the art who understands the concept of the present invention may easily propose other embodiments by adding, changing, deleting, or adding components within the scope of the same concept, which may also be considered to fall within the scope of the concept of the present invention.

Claims

1. a first dispensing step of dispensing a first composition onto a substrate; a drying step of drying the first composition to form a base layer; a second dispensing step of dispensing a second composition containing a drug onto the base layer; a third dispensing step of dispensing a third composition onto the base layer so as to cover the second composition; and A method for producing a multi-layer microneedle structure, comprising a molding step of forming a core layer of the second composition and a shell layer of the third composition by fluidization and centrifugal lithography technique or fluidization and droplet born air blowing (DAB), When the core layer is made of a hydrophilic material, the height H2 of the core layer is inversely proportional to the thickness T of the shell layer outside the core layer, When the core layer is made of a hydrophobic material, the height H2 of the core layer is constant regardless of the thickness T of the shell layer outside the core layer, The base layer has any one of a semicircular shape, a trapezoidal shape, a shape with a concave middle, and a cylindrical shape. A method for manufacturing a multilayer microneedle structure.

2. the drying step further comprises forming microcavities on the base layer; The second composition is in the form of a powder or a liquid. The method for manufacturing a multi-layer microneedle structure according to claim 1 , wherein the second dispensing step dispenses the second composition into the microcavities.

3. the support comprises microprojections; The method for manufacturing a multi-layer microneedle structure according to claim 1 , wherein the first dispensing step dispenses the first composition formed on the microprojections.

4. the support is a pegboard with openings formed therein; The method for manufacturing a multi-layer microneedle structure according to claim 1 , wherein the first dispensing step fills the openings with the first composition.

5. The method for manufacturing a multi-layer microneedle structure according to claim 1 , wherein the second dispensing step further comprises the step of drying the second composition.

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