WO2020200194A1

WO2020200194A1 - Microneedle device and method for manufacturing same

Info

Publication number: WO2020200194A1
Application number: PCT/CN2020/082361
Authority: WO
Inventors: 刘大佼; 叶修锋; 吴佳育; 徐英华; 郑涵尹; 邱品齐; 陈家铭; 林宏谕
Original assignee: 宝龄富锦生技股份有限公司
Priority date: 2019-04-02
Filing date: 2020-03-31
Publication date: 2020-10-08
Also published as: TWI759712B; TW202039022A; CN113727751A; TW202220713A; CN113727751B

Abstract

Disclosed are a microneedle device (1) and a method for manufacturing same. The microneedle device (1) contains a plurality of needle bodies (11), wherein each of the plurality of needle bodies (11) contains a needle tip layer (111), a structural layer (112) and a base layer (113). The amount of material that needs to be added additionally in order to increase the structural strength can be reduced, and the microneedle device (1) having sufficient mechanical strength can be obtained. A melanin-reducing microneedle device obtained by using the method for manufacturing the microneedle device (1) has the advantages of the microneedle device (1), and due to the fact that the melanin-reducing microneedle device can penetrate the stratum corneum and then release effective constituents in the epidermis, the effect of reducing melanin may be achieved.

Description

Microneedle device and its manufacturing method

Technical field

This creation is about a percutaneous transmission device and its manufacturing method, especially a microneedle device and its manufacturing method.

Background technique

If the spots on the skin are caused by the deposition or uneven distribution of melanin, they are generally collectively referred to as dark spots or dark skin spots. Melanin is produced by the melanocytes located in the basal layer, and is encapsulated in the melanosome and transported to the surrounding keratinocytes. When the ultraviolet rays in the sun lead to a large amount of melanin production, or because of pigment metabolism disorders When melanin cannot be removed, dark spots are formed on the skin. In terms of depth, because melanocytes are located in the basal layer of the epidermis, the thickness of the epidermis of the face is about 100 microns. By the traditional transepidermal delivery method, the preparation containing the effective ingredients for lightening the pigment is directly applied to the skin Above, the percentage of effective ingredients that lighten pigments penetrate the stratum corneum is limited, and only a very low percentage can reach the position of melanocytes in the basal layer, so that the effect of lightening pigments or dark spots is limited. Therefore, how to improve the delivery and use efficiency of effective ingredients is the goal of continuous efforts in the field of dermatology and medical beauty in the past.

The microneedle device, also called microneedle array, or microneedle structure, has multiple microneedles with a height of 50 to 900 microns. It is a miniaturized invasive device that can It crosses the stratum corneum barrier to form a transdermal route different from the traditional one. The stratum corneum is the biggest obstacle for effective ingredients to penetrate the skin. Molecules with a molecular weight greater than 500 Daltons (Da) and hydrophilic molecules cannot easily penetrate the stratum corneum. However, since the microneedles can penetrate the stratum corneum and deliver the active ingredients to the epidermis, the selection of the active ingredients is not restricted by the stratum corneum, and the delivery and use efficiency of the active ingredients can be improved.

In the field of medicine, a dissolvable microneedle patch has been developed for transdermal drug delivery or vaccines. It has a microneedle array on the substrate. The length of these microneedles is designed to penetrate the stratum corneum and enter the epidermis. , But it will not touch the dermis that is full of nerves and blood vessels. Therefore, the effective ingredients can be delivered to the epidermal layer without pain.

In the field of medical cosmetology or skin repair and maintenance, soluble microneedles have also been developed, which are designed to penetrate the stratum corneum, and the needles of the microneedles can be quickly dissolved in the epidermis through the tissue fluid in the body and released. Active ingredients. At present, there is known a soluble microneedle that uses hyaluronic acid as a single material. It uses two plates to pull the hyaluronic acid between the plates by adhesion and dry them to form a microneedle. needle. However, the needle body of such a microneedle does not have sufficient mechanical strength and the shape of the needle tip is not sharp, and usually cannot penetrate the stratum corneum. In order to make the microneedles have sufficient mechanical strength, there is another kind of soluble microneedles made of polyvinyl alcohol (PVA) as the main material. Polyvinyl alcohol is a high-molecular polymer with good biocompatibility, quick dissolution, and excellent mechanical strength after drying. It is generally considered to be suitable as a carrier component of soluble microneedles. The carrier component is a structural material, and its function is to form the main structure of the needle body after solidification and molding. With polyvinyl alcohol as the carrier component, the microneedles can have sufficient mechanical strength to penetrate the stratum corneum of the skin. Although polyvinyl alcohol has good biocompatibility, it is a synthetic polymer after all. It is not a component of the human body itself, and there is still a potential risk of skin inflammation. Therefore, how to provide a microneedle device that does not need to add artificial materials to the needle tip but still has sufficient mechanical strength is a problem that needs to be overcome.

Summary of the invention

In view of the above problems, the present invention provides a microneedle device and a manufacturing method thereof. The microneedle device does not need to add artificial materials to the needle tip, but has sufficient mechanical strength, so it can effectively penetrate the stratum corneum and enter the epidermis. Release the active ingredients without worrying about inflammation. Secondly, the present invention also provides a microneedle device containing effective ingredients for lightening the pigment. The microneedle device can improve the use efficiency and delivery efficiency of the effective ingredients to enhance the effect of lightening the pigment. Here, the improvement in the use efficiency of active ingredients means that the same effect of lightening the pigment can be achieved with a smaller amount of active ingredients, and the improvement in delivery efficiency means that more active ingredients can be delivered to the target area (skin area) through the microneedle device per unit time. Base layer).

To achieve the above objective, the present invention provides a microneedle device comprising a plurality of needle bodies, each of the plurality of needle bodies includes a needle tip layer, a structure layer, and a base layer, the structure layer being located between the needle tip layer Above, the base layer is located on the structure layer, and the structure layer and the needle tip layer contain substantially the same carrier components. The carrier component referred to in the present invention is a structural material, which forms the main part of the needle tip layer and the structure layer to support the structure of the needle tip layer and the structure layer.

In one embodiment, the needle tip layer is formed by a first forming solution.

In one embodiment, the structure layer is formed by a second forming solution and formed on the formed needle tip layer.

In one embodiment, the base layer is formed on the formed structural layer.

In one embodiment, the carrier components in the structure layer and the needle tip layer include, but are not limited to, Maltose, Sucrose, Trehalose, Lactose, Dextrin, and Maltose Maltodextrin, β-cyclodextrin, Hydroxypropyl-β-cyclodextrin, Dextran, Hyaluronic acid, carboxymethyl fiber Sodium Carboxymethylcellulose, Methylcellulose (MC), Carboxymethylcellulose (CMC), Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (Hydroxypropylcellulose, HPC), gelatin (Gelatin), polyvinylpyrrolidone (PVP), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic acid-glycolic acid) copolymer (Poly(lactic acid) -co-glycolic acid), PLGA), Chitosan (Chitosan) or a combination thereof.

In one embodiment, relative to the total weight of the first forming solution, the carrier component of the first forming solution includes 1% to 10% by weight of carboxymethyl cellulose and 1% to 15% by weight of hyaluronic acid .

In one embodiment, relative to the total weight of the first forming solution, the carrier component of the first forming solution includes 5 wt% to 15 wt% of low molecular weight hyaluronic acid, and 1 wt% to 10 wt% of high molecular weight hyaluronic acid And 1 weight percent to 15 weight percent of hydroxypropyl-β-cyclodextrin.

In one embodiment, relative to the total weight of the second molding solution, the carrier component of the second molding solution includes 1 to 10 weight percent of carboxymethyl cellulose and 1 to 15 weight percent of hyaluronic acid .

In one embodiment, relative to the total weight of the second molding solution, the carrier component of the second molding solution includes 5 wt% to 15 wt% of low molecular weight hyaluronic acid, and 1 wt% to 10 weight percent of high molecular weight hyaluronic acid And 1 weight percent to 15 weight percent of hydroxypropyl-β-cyclodextrin.

In one embodiment, the needle tip layer contains an active ingredient. In one embodiment, the structure layer contains an active ingredient. In one embodiment, the structure layer and the needle tip layer contain substantially the same effective ingredient. In another embodiment, the structure layer and the needle tip layer may also contain an effective ingredient that is substantially different. Preferably, the active ingredients of the tip layer and the structural layer include but are not limited to glutathione, nicotinic acid, nicotine amide, cetyl tranexamate, vitamin C magnesium phosphate, kojic acid, Vitamin C glycosides, arbutin, vitamin C phosphate sodium salt, ellagic acid, chamomile extract, dipropyl biphenyldiol, tranexamic acid, potassium methoxysalicylate, 3-o-ethyl ascorbic acid, tetraiso ascorbic acid Palmitate or its composition. The active ingredients referred to in the present invention are active ingredients that achieve specific effects. The specific effects can be, for example, skin care or skin repair effects such as pigment lightening, anti-wrinkle, and moisturizing, and the present invention is not limited.

In one embodiment, relative to the total weight of the first forming solution, the first forming solution includes 1 wt% to 10 wt% of glutathione, 1 wt% to 10 wt% of nicotine amide, and 1 wt% Percent to 10% by weight of tranexamic acid.

In one embodiment, relative to the total weight of the second molding solution, the second molding solution includes 1 weight percent to 10 weight percent glutathione, 1 weight percent to 10 weight percent nicotine amide, and 1 weight percent Percent to 10% by weight of tranexamic acid.

In one embodiment, the needle tip layer includes a surfactant. In one embodiment, the structural layer includes a surfactant. Preferably, the surface active agent of the tip layer and the surface active agent of the structure layer include but not limited to polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, Polyoxyethylene sorbitan tristearate, polysorbate, polyoxyethylene sorbitan monolaurate or a combination thereof.

In one embodiment, based on 1 mg of the first molding solution, the first molding solution contains 0.000001 to 0.0001 ml of polyoxyethylene sorbitan monolaurate. In one embodiment, based on 1 mg of the second molding solution, the second molding solution contains 0.000001 to 0.0001 ml of polyoxyethylene sorbitan monolaurate.

In one embodiment, the base layer includes, but is not limited to, maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran, Amylose, hyaluronic acid, methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin , Polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan or a combination thereof.

In one embodiment, the total height of the needle body includes the needle tip layer, the structure layer and the base layer, and the height of the base layer accounts for 25% to 30% of the total height of the needle body.

In one embodiment, the total height of the needle body includes the needle tip layer, the structure layer and the base layer, and the height of the base layer is 145 μm to 190 μm.

To achieve the above objective, the present invention provides a method for manufacturing a microneedle device, which includes: filling a mold with a first molding solution; molding the first molding solution; filling the mold with a second molding solution, wherein The second forming solution and the first forming solution contain substantially the same carrier components; forming the second forming solution; filling the mold with a third forming solution; and forming the third forming solution.

In one embodiment, the first molding solution is filled into the mold to a first liquid level, the first molding solution has a first molding surface after molding, and the height of the first molding surface is lower than that of the first liquid. The height of the surface. In one embodiment, the first forming solution is formed into a needle tip layer.

In one embodiment, the second molding solution is filled into the mold to a second liquid level, the second molding solution has a second molding surface after molding, and the height of the second molding surface is lower than that of the second liquid. The height of the surface. In one embodiment, the second forming solution is formed into a structural layer.

In one embodiment, the third molding solution is filled into the mold to a third liquid level, the third molding solution has a third molding surface after molding, and the height of the third molding surface is lower than that of the third liquid. The height of the surface. In one embodiment, the third forming solution is formed into a base layer.

In one embodiment, the pH value of the first forming solution and the second forming solution is between 4-6.

In one embodiment, the above method further includes forming the first molding solution to make the water content less than 5 weight percent, and then filling the second molding solution into the mold.

In one embodiment, the above method further includes making the water content of the second molding solution less than 5 weight percent after molding, and then filling the third molding solution into the mold.

In one embodiment, the above method may further include: before filling the first molding solution, adding a surfactant to the first molding solution so that the surface tension of the first molding solution is less than the surface tension of the mold .

In one embodiment, the above method may further include: before filling the second molding solution, adding a surfactant to the second molding solution so that the surface tension of the second molding solution is less than the surface tension of the mold .

In one embodiment, the surface tension of the first molding solution is less than the surface tension of the mold.

In one embodiment, the surface tension of the second molding solution is less than the surface tension of the mold.

In one embodiment, the first molding solution, the second molding solution, and the third molding solution are molded at a temperature of minus 60°C to 40°C.

In one embodiment, the first molding solution and the second molding solution are filled into the mold by vacuum extraction. Preferably, the first molding solution and the second molding solution are filled into the mold by vacuum pumping to make the ambient pressure less than 1 atmosphere.

In one embodiment, the third molding solution is filled into the mold by centrifugation.

In one embodiment, the carrier component includes but is not limited to maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran, hyaluronic acid , Sodium carboxymethylcellulose, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, polylactic acid-hydroxy Acetic acid copolymer, chitosan or a combination thereof.

In one embodiment, relative to the total weight of the first forming solution, the first forming solution includes 1 wt% to 10 wt% of carboxymethyl cellulose and 1 wt% to 15 wt% of hyaluronic acid.

In one embodiment, relative to the total weight of the first forming solution, the first forming solution includes 5 wt% to 15 wt% of low molecular weight hyaluronic acid, 1 wt% to 10 wt% of high molecular weight hyaluronic acid, and 1 wt% To 15% by weight of hydroxypropyl-β-cyclodextrin.

In one embodiment, relative to the total weight of the second molding solution, the second molding solution includes 1 to 10 weight percent of carboxymethyl cellulose and 1 to 15 weight percent of hyaluronic acid.

In one embodiment, relative to the total weight of the second molding solution, the second molding solution includes 5 weight percent to 15 weight percent low molecular weight hyaluronic acid, 1 weight percent to 10 weight percent high molecular weight hyaluronic acid, and 1 weight percent To 15% by weight of hydroxypropyl-β-cyclodextrin.

In one embodiment, the first molding solution contains an active ingredient. In one embodiment, the second molding solution contains an active ingredient. In one embodiment, the second molding solution and the first molding solution contain substantially the same effective ingredient. In another embodiment, the second molding solution and the first molding solution may also contain an effective ingredient that is substantially different. Preferably, the effective ingredients of the first forming solution and the effective ingredients of the second forming solution include glutathione, nicotinic acid, nicotine amide, cetyl tranexamate, vitamin C magnesium phosphate, kojic acid , Vitamin C glycosides, arbutin, vitamin C phosphate sodium salt, ellagic acid, chamomile, dipropyl biphenyldiol, tranexamic acid, potassium methoxysalicylate, 3-o-ethyl ascorbic acid, ascorbic acid Isopalmitate or its composition.

In one embodiment, relative to the total weight of the first forming solution, the first forming solution includes: 1 weight percent to 10 weight percent glutathione, 1 weight percent to 10 weight percent nicotine amide, and 1 Tranexamic acid to 10% by weight.

In one embodiment, the first molding solution includes a surfactant. In one embodiment, the second molding solution includes a surfactant.

Preferably, the surfactant includes, but is not limited to, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polysorbate Esters, polyoxyethylene sorbitan monolaurate or combinations thereof.

In one embodiment, the third forming solution includes, but is not limited to, maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran , Pullulan, hyaluronic acid, methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose , Gelatin, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan or combinations thereof.

In order to achieve the above-mentioned object, the present invention provides a microneedle device for diminishing pigment, which comprises a plurality of needle bodies, each of the plurality of needle bodies includes a needle tip layer, which is made of a molding solution, and the molding solution includes a The active ingredient and a carrier ingredient, relative to the total weight of the forming solution, the active ingredient contains 1% to 10% by weight of peptides or derivatives thereof, 1% to 10% by weight of vitamins or derivatives thereof, and 1 To 10% by weight of acid or its derivative.

In one embodiment, the peptide or derivative thereof contains glutathione.

In one embodiment, the vitamin or its derivative comprises nicotinic acid, niacinamide, vitamin C phosphate magnesium salt, vitamin C glycoside, vitamin C phosphate sodium salt, 3-o-ethyl ascorbic acid, ascorbic acid tetraisopalmitate Esters or combinations thereof.

In one embodiment, the acid or its derivative comprises cetyl tranexamate, kojic acid, tranexamic acid, potassium methoxysalicylate or a combination thereof.

In one embodiment, the active ingredient includes 1% to 10% by weight of glutathione, 1% to 10% by weight of nicotine amide, and 1% to 10% by weight of tranexamic acid.

In one embodiment, the carrier component includes maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran, hyaluronic acid, carboxymethyl Sodium base cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer , Chitosan or a combination thereof.

In one embodiment, the carrier component includes 1% to 10% by weight of carboxymethyl cellulose and 1% to 15% by weight of hyaluronic acid.

In one embodiment, the carrier component includes 5 weight percent to 15 weight percent low molecular weight hyaluronic acid, 1 weight percent to 10 weight percent high molecular weight hyaluronic acid, and 1 weight percent to 15 weight percent hydroxypropyl-β-cyclopaste fine.

In one embodiment, based on 1 mg of the molding solution, the molding solution contains 0.000001 to 0.0001 ml of surfactant.

Preferably, the surfactant comprises polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polysorbate, and polyoxyethylene sorbitan monostearate. Oxyethylene sorbitan monolaurate or a combination thereof.

In an embodiment, each of the plurality of needle bodies further includes a structural layer, which is also made of the molding solution.

The stratum corneum itself has the function of resisting physical invasion, coupled with the elasticity of the subcutaneous tissue, past studies have shown that the microneedle body must have sufficient mechanical strength to enable the microneedle device to pierce the stratum corneum, but it will not cause inflammation in the human body. Natural ingredients generally have insufficient strength after curing and cannot meet this demand. Therefore, the past products have to add high content of synthetic material polyvinyl alcohol (PVA), and even PVA is used as the main material of the microneedle body. To make up. In some microneedle devices, the entire needle body is made of hyaluronic acid. Although this method can avoid inflammation, it sacrifices mechanical strength. For melanin located deep in the epidermis, the depth that can be reached is far from enough.

The microneedle device and its production method provided by the present invention and the microneedle device for diluting pigment are formed by forming the same carrier component into a two-stage or two-layer needle tip through a segmented process, thereby generating the effect of improving the structural strength and solving The need to add artificial materials to the tip of the needle, compared to the needle body with PVA added to the tip, can also reach the bottom layer of the epidermis.

Secondly, with the same material and dosage, the two-segment tip through the segmented process of the present invention has a higher height than the non-segmented tip, that is, the microneedle body of the same height is to be produced. Only a base layer with a relatively low height is required. Since the base layer is added with artificial materials to strengthen the mechanical structure, reducing the height of this layer can reduce the contact between artificial materials and the skin epidermis, and can even completely prevent artificial materials from entering the skin epidermis. Reduce inflammation problems. At the same time, although the height of the basal layer that strengthens the mechanical strength is reduced (the proportion of the needle body volume is reduced), the microneedle device made in this way still has enough mechanical strength to penetrate the stratum corneum of the skin. Finally, the microneedle device containing the effective ingredients for lightening the pigment can penetrate the stratum corneum of the skin and enter the epidermis through the microneedle device, and transfer the effective ingredients carried by it to the bottom layer of the epidermis for release, which can improve the use efficiency of the effective ingredients and Transfer efficiency to enhance the effect of lightening pigments.

Description of the drawings

Figure 1 is a schematic diagram of the microneedle device of the present invention.

Fig. 2 is a flow chart of the manufacturing method of the microneedle device.

3A is a comparison diagram of the height of the base layer in the microneedle devices of Example 1 and Comparative Example 1, and FIG. 3B is a diagram of the height comparison of the base layer in the microneedle devices of Example 2 and Comparative Example 2.

4A is a diagram of the stress-corresponding displacement of the two-stage microneedle device of Comparative Example 1 and the three-stage microneedle device of Example 1, FIG. 4B is an enlarged view of the area framed by the dotted line in FIG. 4A; FIG. 4C is the second of Comparative Example 2. The stress-corresponding displacement diagrams of the stage microneedle device and the three-stage microneedle device of Example 2. FIG. 4D is an enlarged view of the area framed by the dotted line in FIG. 4C.

Figure 5A is a diagram of a pig skin tissue section of the microneedle device of Example 1 with different needle lengths for a pigskin puncture depth test, and Figure 5B is a diagram of a pigskin puncture depth test performed with the microneedle device of Example 1 with different needle lengths Quantitative diagram of puncture depth of pigskin.

Fig. 6A is a diagram of a pig skin tissue section of a pig skin puncture depth test performed with the microneedle device of Example 2 with different needle lengths, and Fig. 6B is a pig skin puncture depth test performed with the microneedle device of Example 2 with different needle lengths Quantitative diagram of puncture depth of pigskin.

detailed description

The microneedle device, also called microneedle array or microneedle structure, has a basic structure with a substrate and multiple microneedles with a height of 50 to 900 microns on the substrate. This is a miniaturized invasive device that can cross the stratum corneum barrier to form a transdermal delivery pathway that is different from the traditional one. Several microneedle devices and their manufacturing methods are listed below as examples to illustrate the implementation of this creation. Those who are familiar with this technique can easily understand the advantages and effects of this creation through the content of this manual, and do not deviate from the original Various modifications and changes are made in the spirit of creation to implement or apply the content of this creation.

As shown in FIG. 1, the microneedle device 1 of the embodiment of the present invention has a plurality of needle bodies 11 and a substrate 12, and the needle bodies 11 are disposed on the substrate 12.

The size of the substrate 12 can be slightly larger than 1 cm2, and one side of the substrate 12 can be adhesive, so as to adhere to the needle body 11 and make the microneedle device 1 stick to the user's skin during use , To prevent the microneedle device 1 from falling off during use. In the present invention, materials such as non-woven fabrics, artificial skins, and medical hydrocolloid dressings can be used as the substrate 12, but are not limited to this. In a preferred embodiment, the substrate 12 may be a medical hydrocolloid dressing made of sodium carboxymethyl cellulose (CMC).

Each needle body 11 includes a needle tip layer 111, a structure layer 112, and a base layer 113, respectively. The configuration of the needle body 11 can be a cone, a flat-top cone (or frustum-cone shape) or a cone-cylinder shape, and the difference between the two is that the tip is a point structure or a plane structure. Among them, the cone can be conical, elliptical, triangular, quadrangular, pentagonal, hexagonal or polygonal. Similarly, flat-topped cones or cones can also have various shapes. However, the present invention does not limit the configuration of the needle body, and any configuration suitable for piercing the epidermis can be applied to this creation. The base layer 113 of each needle body 11 is connected to each other in a horizontal direction and extends to form an extended base layer 114, wherein the needle body 11 is connected to the base material 12 through the extended base layer 114.

In one embodiment, the size of the extended base layer 114 is 1 square centimeter. Considering that the number of needle bodies 11 included in the microneedle device 1 is too small, the physical puncture strength will be insufficient, while the number of needle bodies 11 will increase the difficulty of the process and the configuration and length of the needle body 11 are difficult to control, so the size of 1 cm2 Below, each microneedle device can have 100 to 289 needles, preferably 14 per side, 196 needles in total, but any number between 100 to 289 needles can make the micro The needle body 11 of the needle device 1 has a complete configuration and sufficient mechanical strength to penetrate the stratum corneum. In another embodiment, the size of the extended base layer 114 is 2 cm2, and each microneedle device may have 100 to 676 needles. Secondly, the length of the needle body 11 can be designed to be 300 μm to 600 μm. When the length of the needle body 11 is 300±10 microns, the needle body 11 can penetrate to a depth of 35 to 90 microns in the epidermal layer, which is deeper than the depth of the human stratum corneum (10 to 15 microns) but not more than the depth of the epidermal layer ( (Approximately 100 microns), it can penetrate the stratum corneum and deliver the active ingredients directly to the epidermis without touching the dermis layer full of nerves and blood vessels. When the length of the needle body 11 is 600±10 microns, the needle body 11 can penetrate to a depth of 55 to 130 microns in the epidermal layer. Due to the different depths of the human epidermal layer, this puncture depth may puncture the dermis layer. Causes pain during use. Therefore, the preferred length of the needle body 11 is 300±10 microns.

When using the microneedle device 1, the user can directly stick the microneedle device 1 to the skin by hand, or use an applicator to apply a fixed force at a precise position to stick the microneedle device 1 to the skin. In one embodiment, for the same skin area, the user can apply one piece of microneedle device 1 every day, and then let the microneedle device 1 fit the skin for 15 to 30 minutes before removing it. Preferably, the microneedle device 1 stays on the skin for 30 minutes before being removed, so that the active ingredients carried by the needle body 11 have enough time to dissolve in the epidermal layer.

In the needle body 11, the needle tip layer 111 is used to penetrate the stratum corneum of the skin and dissolve in the epidermal layer to release active ingredients. The structure layer 112 contains substantially the same carrier component as the needle tip layer 111, which can enhance the mechanical strength of the needle body 11. In one embodiment, the structural layer 112 does not contain active ingredients, but only has carrier ingredients. In another embodiment, the structural layer 112 also contains active ingredients, and the structural layer 112 releases the active ingredients after entering the skin layer. Wherein, the effective ingredients contained in the structure layer 112 may be the same as the effective ingredients contained in the needle tip layer 111, or the structure layer 112 may contain different effective ingredients from the needle tip layer 111. The structural layers 112 between the needle bodies 11 are not continuous with each other, and the needle tip layer 111 is also not continuous with each other, forming multiple units that independently release effective ingredients. The base layer 113 mainly provides the layers with the required structural strength of the needle bodies 11. The base layers 113 between the needle bodies 11 are not continuous with each other, but the base layers 113 are connected to each other in the horizontal direction and extend to form the extended base layer 114 , Connect multiple needle bodies 11 into one device.

In this creative embodiment, the carrier component of the tip layer 111 and the structural layer 112 can be a dissolvable, biocompatible or biodegradable polymer material, and the carrier component is a structure This carrier component forms the main part of the needle tip layer 111 and the structure layer 112 to support the configuration of the needle tip layer 111 and the structure layer 112. The carrier component may include maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran, hyaluronic acid, sodium carboxymethylcellulose, methyl cellulose Base cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan or The composition, but not limited to this. In an embodiment of the present invention, the tip layer 111 and the structure layer 112 have substantially the same carrier components, and carboxymethyl cellulose and hyaluronic acid are selected. In another embodiment of the present invention, the tip layer 111 and the structure layer 112 have substantially the same carrier components, and low molecular weight hyaluronic acid, high molecular weight hyaluronic acid and hydroxypropyl-β-cyclodextrin are selected.

Since the needle body 11 can pierce the skin layer to a depth of 35 μm to 90 μm, the needle tip layer 111 contains effective ingredients to deliver the effective ingredients to the bottom layer of the skin layer. Active ingredients can be selected as active ingredients that achieve specific effects according to different needs. The specific effects can be, for example, skin care or skin repair effects such as pigment lightening, anti-wrinkle, and moisturizing, but are not limited to this.

In the implementation aspect of this creation, the structural layer 112 may not have effective ingredients and only have carrier components, or the structural layer 112 may also contain effective ingredients. In this way, the structural layer 112 can not only enhance the mechanical strength of the needle body 11, but also can be used on the surface. Effective ingredients are released in the cortex. The tip layer 111 and the structure layer 112 may contain substantially the same effective ingredients or substantially different effective ingredients. In one embodiment, the active ingredient may be a lightening pigment ingredient, including glutathione (Glutathione, L-Glutathione, GSH for short), nicotinic acid (Niacin, Nicotinic Acid, also known as microbiotic B3), tobacco Alkali amide (Nicotinamide, Niacinamide), Cetyl Tranexamate HCl, Vitamin C and its derivatives (including: Magnesium Ascorbyl Phosphate, Ascorbyl Glucoside), Vitamin C phosphate sodium salt (Sodium Ascorbyl Phosphate), 3-O-Ethyl Ascorbic Acid (3-O-Ethyl Ascorbic Acid), Ascorbyl Tetraisopalmitate (Ascorbyl Tetraisopalmitate), Kojic Acid (Kojic Acid), Arbutin ), Ellagic Acid (Ellagic Acid), Chamomile ET, Dipropyl Biphenyldiol (5,5'-Dipropyl-Biphenyl-2,2'-diol), Tranexamic Acid (Tranexamic Acid), Potassium Methoxysalicylate (Potassium Methoxysalicylate) or its composition, but not limited to this. In a preferred embodiment, the effective ingredient may be a combination of glutathione (L-Glutathione), nicotinamide (Nicotinamide) and tranexamic acid (Tranexamic Acid).

The base layer 113 mainly provides the mechanical strength of the needle body 11. After the needle 11 enters the epidermal layer, although the probability of contact between the basal layer and the skin epidermal layer is low, in order to avoid inflammation and increase the safety of use, the material of the basal layer 113 can be selected to be soluble, biocompatible or biocompatible. Degradable polymer materials. In the embodiment of the present invention, the base layer 113 may include maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran, pullulan , Hyaluronic acid, methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, poly Vinyl alcohol (Poly(vinyl alcohol), PVA), polyvinylpyrrolidone, polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan or a combination thereof, but not limited to these . In a preferred embodiment, the base layer 113 may be a combination of polyvinyl alcohol, β-cyclodextrin and trehalose, wherein polyvinyl alcohol is the main component that provides the mechanical strength of the needle 11.

The embodiment of the present invention also provides a manufacturing method of the microneedle device. As shown in Figure 2, a mold 20 is prepared. The mold 20 is made of poly(dimethylsiloxane) (PDMS). The manufacturing method is to inject a poly(dimethylsiloxane) solution into the male mold and heat it. After the polydimethylsiloxane is cured at 100° C., the mold is released to obtain the mold 20. The mold 20 includes a molding part 21 that includes a plurality of tapered needle-point grooves 211. The configuration of the grooves 211 is designed according to the configuration of the needle body 11, and may have a tapered or flat top. Unlimited shapes such as cone (or frustum) or cone column. The cone can be a cone, an elliptical cone or a polygonal cone.

Fill the mold 20 with the first molding solution 31 with a volume of 1 to 3 ml. For the formula of the first molding solution 31, please refer to the following description. After the air pressure in the closed environment where the mold 20 is located is less than 1 atmosphere by vacuum pumping, the first molding solution 31 is completely filled into the molding part 21 of the mold 20 to form a first liquid level. Next, at a temperature of 30° C., the first molding solution 31 is dried to a moisture content of less than 5 weight percent, and the molding of the first molding solution 31 is completed. The moisture content is the weight percentage of the weight after drying of the first forming solution 31 to the weight before drying (the weight after drying is divided by the weight before drying, and then multiplied by 100%). Wherein, the formed first molding solution 31 is the needle tip layer 111 and has a first molding surface. The height of the first molding surface in the molding portion 21 is lower than the height of the first liquid surface.

After confirming that the water content of the needle tip layer 111 is less than 5 wt%, the second molding solution 32 with a volume of 1 to 3 ml is completely filled into the molding part 21 of the mold 20, and vacuum is also used in the process to make the closed environment where the mold 20 is located. The air pressure is maintained at less than 1 atmosphere, and the second molding solution 32 is completely filled into the molding part 21 of the mold 20 to form a second liquid level. For the formula of the second molding solution 32, please refer to the following description. Similarly, at a temperature of 30° C., the second molding solution 32 is dried until the water content is less than 5 weight percent, and the molding of the second molding solution 32 is completed. As mentioned above, the moisture content is the weight percentage of the weight of the second forming solution 32 after drying to the weight before drying. The second molding solution 32 to be molded is the structural layer 112 and has a second molding surface, and the height of the second molding surface in the molding portion 21 is lower than the height of the second liquid surface.

Next, fill the third molding solution 33 with a volume of 2 to 5 ml into the mold 20. For the formula of the third molding solution 33, please refer to the following description. The third molding solution 33 is completely filled into the molding part 21 of the mold 20 containing the tip layer 111 and the structure layer 112 by a centrifugal method to form a third liquid level. The third molding solution 33 is dried at a temperature of 30° C. until the water content is less than 5 weight percent, and the molding of the third molding solution 33 is completed.

After confirming that the water content of the needle tip layer 111, the structure layer 112, and the base layer 113 are all less than 5 wt%, the mold is turned over to obtain a plurality of needle bodies 11 connected by the extended base layer 114. When the water content is lower than 5 weight percent, the mold turning can reduce the sticking of the needle body 11 to the mold 20 and achieve the effect of smooth demolding. In other embodiments, the first forming solution 31, the second forming solution 32, and the third forming solution 33 can be dried at a temperature of minus 60°C to 40°C until the water content is less than 5 weight percent, so that the forming solution can be formed. Remove the membrane smoothly and keep the configuration of the needle 11 intact.

Here, the first molding solution 31 may include the aforementioned carrier component and effective ingredient, the second molding solution 32 may also include the aforementioned carrier component and effective ingredient, or only the carrier component without the effective ingredient, and the first The carrier component of the molding solution 31 is substantially the same as the carrier component of the second molding solution 32, and the effective components of the first molding solution 31 and the second molding solution 32 may be substantially the same or substantially different components. . The carrier component may include maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran, hyaluronic acid, sodium carboxymethylcellulose, methyl cellulose Base cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan or The composition, but not limited to this. In one embodiment, relative to the total weight of the first forming solution 31, the carrier component in the first forming solution 31 may include 1% to 10% by weight of carboxymethyl cellulose and 1% to 15% by weight. Hyaluronic acid, and the second molding solution 32 and the first molding solution 31 contain substantially the same carrier components. In another embodiment, relative to the total weight of the first forming solution 31, the carrier component in the first forming solution 31 may include 5 wt% to 15 wt% of low molecular weight hyaluronic acid, 1 wt% to 10 wt% of high The molecular weight hyaluronic acid and 1 to 15 weight percent of hydroxypropyl-β-cyclodextrin, the second molding solution 32 and the first molding solution 31 contain substantially the same carrier components. Specifically, the molecular weight of low molecular weight hyaluronic acid is between 1,000 and 100,000 daltons, and the molecular weight of high molecular weight hyaluronic acid is between 200,000 and 500,000 daltons.

Active ingredients can include glutathione, niacin, nicotine amide, cetyl tranexamate, vitamin C and its derivatives (including: vitamin C phosphate magnesium salt, vitamin C glycoside, vitamin C phosphate sodium salt , 3-o-ethyl ascorbic acid, ascorbyl tetraisopalmitate), kojic acid, arbutin, ellagic acid, chamomile, dipropyl biphenyldiol, tranexamic acid, potassium methoxysalicylate or The composition, but not limited to this. In one embodiment, relative to the total weight of the first forming solution 31, the first forming solution 31 may include 1 wt% to 10 wt% of glutathione, 1 wt% to 10 wt% of nicotine amide, and 1% to 10% by weight of tranexamic acid. In another embodiment, relative to the total weight of the second forming solution 32, the second forming solution 32 may contain 1% to 10% by weight of glutathione and 1% to 10% by weight of nicotine amide. And 1 weight percent to 10 weight percent of tranexamic acid.

In order to ensure the activity of the active ingredients and provide the effects of the active ingredients, the pH of the first forming solution 31 and the second forming solution 32 can be adjusted by using a pH adjuster. For example, a pH adjuster can be added to adjust the pH of the first forming solution 31 and the second forming solution 32 to pH 4 to 6, to ensure the activity of glutathione, so that it can provide better The effect of lightening the pigment. In one embodiment, the solution containing the carrier components can be adjusted to pH 4 to 6 with hydrochloric acid and sodium hydroxide, and then the active ingredients are added to make the final pH of the first forming solution 31 and the second forming solution 32 fall below The pH is between 4 and 6, to maintain the active ingredients in the forming solution. The aforementioned pH adjusting agent can be hydrochloric acid, acetic acid or sodium hydroxide.

Since the first molding solution and the second molding solution are filled into the mold by vacuum pumping, the viscosity of the solution will affect the difficulty of the operation. The inventor found that when the viscosity of the solution is controlled to less than 100,000 mPa·s (mPa·s), The molding solution can be easily filled into the mold. The viscosity of the solution is tested with a rheometer (Anton Parr MCR320) and a parallel plate (model: PP25 or PP43). The test conditions are at a temperature of 25°C and a shear rate setting range of 0.1 to 100 seconds. One (s ^-1 ). In one embodiment, the viscosity value of the first molding solution or the second molding solution falls within the range of 50 to 165 mPa based on the viscosity value of the temperature of 25°C and the shear rate of one part of a second (s ^-1 ). second. In a preferred embodiment, the viscosity of the first molding solution or the second molding solution is about 53.3 mPa·s; in another preferred embodiment, the viscosity of the first molding solution or the second molding solution is about It is 163.5 mPa·s.

When making the microneedle device 1, if the surface tension of the molding solution is greater than the surface tension of the mold 20, when the molding solution is filled into the mold 20 by vacuum, the molding solution cannot be completely spread on the surface of the mold 20 and cohesion is likely to occur (cohesion), the molding solution cannot be completely filled into the mold 20, and the produced microneedle device 1 has the problem that the needle body is incomplete and the needle tip is not sharp, making it difficult to penetrate the skin. To solve the aforementioned problems, a surfactant can be added to the molding solution to make the surface tension of the molding solution smaller than the surface tension of the mold, so that the molding solution can be flattened on the surface of the mold 20 and can be completely filled into the mold 20. The 1-needle type of the microneedle device is complete.

The above-mentioned surfactants (Surfactant) can be polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polysorbate, polyoxyethylene sorbitan Oxyethylene sorbitan monolaurate (Tween 20) or a combination thereof. Preferably, the surfactant can be polyoxyethylene sorbitan monolaurate. In order to reduce the amount of artificial materials added in the microneedle device 1, the amount of surfactant must be minimized. In one embodiment, based on each milligram of the first molding solution, the first molding solution may include 0.000001 to 0.0001 ml of polyoxyethylene sorbitan monolaurate. Preferably, each milligram of the first molding solution contains 0.00005 milliliters of polyoxyethylene sorbitan monolaurate. More preferably, each milligram of the first molding solution contains 0.00001 milliliters of polyoxyethylene sorbitan monolaurate. In another embodiment, based on each milligram of the second molding solution, the second molding solution may include 0.000001 to 0.0001 ml of polyoxyethylene sorbitan monolaurate. Preferably, each milligram of the second molding solution contains 0.00005 milliliters of polyoxyethylene sorbitan monolaurate. More preferably, each milligram of the second molding solution contains 0.00001 milliliters of polyoxyethylene sorbitan monolaurate.

The surface tension is tested with a surface tension meter (Kyowa Interface Science, model: CBVP-A3) and calibrated with deionized water. The normal range is 72 to 74 millinewtons/meter (mN/m). In the embodiment of the present invention, the surface tension of the mold 20 is about 22 to 23 millinewtons/meter. The inventor found that when the surface tension of the first molding solution 31 or the second molding solution 32 is less than 40 millinewtons/meter, it can be flat. Spread the surface of the mold 20. Preferably, after the surfactant is added, the surface tension of the first forming solution 31 or the second forming solution 32 is about 34.9 millinewtons/m. In another preferred embodiment, after the surfactant is added, the surface tension of the first forming solution 31 or the second forming solution 32 is about 33.6 millinewtons/m. During implementation, the surface tension of the first molding solution 31 or the second molding solution 32 can be adjusted according to the surface tension of the material of the mold 20, so that the molding solution can be flattened on the surface of the mold 20 to completely fill the mold 20, and a needle shape can be produced Complete microneedle device 1.

The third forming solution 33 may contain maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran, pullulan, hyaluronic acid, methyl alcohol, etc. Vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinyl alcohol, poly Vinylpyrrolidone, polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan or a combination thereof, but not limited to these.

The present invention also provides a microneedle device for diluting pigment, which has the same structure as the aforementioned microneedle device 1 and is manufactured by the aforementioned microneedle device manufacturing method. The microneedle device for diluting pigment comprises a plurality of needle bodies, and each needle body comprises a needle tip layer, which is made of a molding solution, and the molding solution includes an active ingredient and a carrier ingredient. Relative to the total weight of the molding solution, the active ingredient contains 1% to 10% by weight of peptides or derivatives thereof, 1% to 10% by weight of vitamins or derivatives thereof, and 1% to 10% by weight of Acid or its derivatives. In another embodiment, relative to the total weight of the molding solution, the active ingredient contains 1% to 10% by weight of amino acids or derivatives thereof, 1% to 10% by weight of vitamins or derivatives thereof, and 1% to 10% by weight of acid or its derivative. Wherein, the peptide or its derivative contains glutathione; the vitamin or its derivative contains nicotinic acid, nicotine amide, vitamin C phosphate magnesium salt, vitamin C glycoside, vitamin C phosphate sodium salt, 3-o-ethyl Ascorbic acid, ascorbyl tetraisopalmitate or a combination thereof; the acid or its derivative comprises cetyl tranexamate, kojic acid, tranexamic acid, potassium methoxysalicylate or a combination thereof. In one embodiment, the active ingredient may include 1% to 10% by weight of glutathione, 1% to 10% by weight of nicotine amide, and 1% to 10% by weight of tranexamic acid.

The molding solution may further include a surfactant, and the carrier components and the surfactant contained therein can be referred to the above content, and will not be repeated here. Each needle body further includes a structural layer, which is made of the same molding solution.

Preparation example: Molding solution for microneedle device

In order to prepare the microneedle device of the following embodiments, different molding solutions need to be prepared first. Table 1 is an example of possible formulations of the molding solution. The first forming solution and the second forming solution respectively contain carrier components, effective ingredients and surfactants, wherein the molecular weight of low molecular weight hyaluronic acid is 7kDa; the molecular weight of high molecular weight hyaluronic acid is 300kDa. The percentages shown in Table 1 are percentages by weight.

Table 1: Formulation solution formula one and formula two

Example 1 and Example 2: Three-stage microneedle device

In order to prepare the microneedle device of this embodiment, embodiments 1 and 2 are taken as examples to illustrate the manufacturing process of the microneedle device. Among them, the first forming solution, the second forming solution, and the third forming solution of Example 1 Is from formula one; the first molding solution, second molding solution, and third molding solution of example 2 are from formula two, respectively, embodiment 1 or embodiment 2 are applied to the aforementioned production process to prepare these implementations Example of microneedle device.

As shown in Table 1, the composition of the first molding solution and the second molding solution of formula 1 are the same, and the composition of the first molding solution and the second molding solution of formula 2 are the same. Embodiments 1 and 2 will still divide the production process. Completed in three stages.

Comparative example 1 and comparative example 2: Two-stage microneedle device

In order to illustrate the advantages of the three-stage microneedle device of Example 1 and Example 2, another two-stage microneedle device was made for comparison.

The two-stage microneedle device refers to a microneedle device made by filling twice the amount of the first molding solution into the mold at a time, and directly filling the third molding solution without filling the second molding solution. Comparative Example 1 is a two-stage microneedle device made using Formula One, and Comparative Example 2 is a two-stage microneedle device made using Formula Two.

With the total length of the needle body of the microneedle device set to 600±10 microns, the height of the base layer of the needle bodies of Examples 1 and 2 and Comparative Examples 1 and 2 were compared, and the experimental results are shown in FIG. 3A and FIG. 3B. Please refer to Figure 3A, the height of the base layer of the needle body in the two-stage microneedle device of Comparative Example 1 is 170±10 microns, which accounts for 28% of the height of the needle body, while the base layer of the needle body in the three-stage microneedle device of Example 1 The height of the bottom layer is 158±12 microns, accounting for 26% of the height of the needle body; please refer to Figure 3B again, the base layer height of the needle body in the two-stage microneedle device of Comparative Example 2 is 191±7 μm, which accounts for 32% of the needle body height %, the height of the base layer of the needle body of the three-stage microneedle device prepared in Example 2 is 181±9 microns, which accounts for 30% of the height of the needle body.

It can be seen from the above results that the manufacturing method of the three-stage microneedle device of Examples 1 and 2 uses a stepwise process to form two-stage or two-layer needle tips with the same carrier components in batches. With the same material and amount, the embodiment The height of the base layer of the needle body of the three-stage microneedle device 1 and 2 is smaller than the height of the base layer of the needle body of the two-stage microneedle device of Comparative Examples 1 and 2, respectively. It can be seen that, in order to make a microneedle device of the same height, the base layer two-section tip of the microneedle device of the invention only needs a base layer with a relatively low height. Since the base layer is designed to add artificial materials to strengthen the mechanical structure, reducing the height of the base layer can reduce the contact between artificial materials and the skin epidermis, and can even substantially prevent artificial materials from entering the skin epidermis, reducing the use of artificial materials. Inflammation problems.

Although the height of the base layer that provides mechanical strength in the three-stage microneedle device of Examples 1 and 2 is reduced, the three-stage microneedle device manufactured according to the manufacturing method of the embodiment of the present invention still has sufficient mechanical strength to penetrate the skin For the stratum corneum, this effect will be further illustrated in the following test examples.

The following test examples will illustrate the microneedle characteristics of the three-stage microneedle device of Example 1 and Example 2, including the mechanical strength of the microneedles and the pigskin penetration test.

Test 1: The mechanical strength of the microneedle device

In order to measure the mechanical strength of the needle body of the microneedle device, this experiment will use a compression jig to test the microneedle device with a total needle length of 600±10 microns. Set the upper plate of the compression jig to zero at a height of 10 mm from the lower plate, and set the upper plate to compress at a speed of 1.1 mm per second in the direction of the lower plate attached with the microneedle device, after touching the needle body Detect the value of load and displacement for the mechanical strength that the needle body can bear. According to research, the minimum stress required to pierce human skin is 0.058 Newton per needle. Based on this point of view, the mechanical strength of the needle body must be greater than 0.058 Newton per needle.

The test results are shown in Figure 4A to Figure 4D. 4A is a diagram of the stress-corresponding displacement of the two-stage microneedle device of Comparative Example 1 and the three-stage microneedle device of Example 1, FIG. 4B is an enlarged view of the area framed by the dotted line in FIG. 4A; FIG. 4C is the second of Comparative Example 2. The stress-corresponding displacement diagrams of the stage microneedle device and the three-stage microneedle device of Example 2. FIG. 4D is an enlarged view of the area framed by the dotted line in FIG. 4C.

As shown in Fig. 4A and Fig. 4C, under the condition of increased stress, no matter the curve of the two-stage microneedle device of Comparative Examples 1 and 2 or the three-stage microneedle device of Examples 1 and 2, there is no sudden drop in the curve. The dot indicates that the microneedle device did not break due to stress. When the load of each needle is 0.058 Newtons, the displacement is within one half of the needle length (ie 0.3 mm), which means that both the two-stage microneedle device or the three-stage microneedle device can withstand the minimum stress of piercing the skin. As shown in Figure 4B, the stress value under the displacement of 0.2 mm is compared. The average mechanical strength of the microneedle of the three-stage microneedle device of Example 1 is 0.16±0.04 Newton per needle, which is compared with the two-stage of Comparative Example 1. The average value of the microneedle mechanical strength of the microneedle device is 0.19±0.07 Newtons per needle, and there is no significant difference; as shown in Figure 4D, the stress value under a displacement of 0.2 mm is compared, and the three-stage microneedle device of Example 2 has The average mechanical strength of the microneedles is 0.26±0.21 Newton per needle, and there is no significant difference from the average of the two-stage microneedle device of Comparative Example 2 of 0.21±0.04 Newton per needle. It can be seen from the above results that although the height of the base layer of the three-stage microneedle device is reduced, it does not affect the mechanical strength of the microneedle. That is, the microneedle device manufactured according to the manufacturing method of the embodiment of the present invention still has sufficient mechanical strength to penetrate Cuticle of skin.

Test 2: Porcine skin puncture depth detection of microneedle device

In order to understand the depth that the needle body of the microneedle device of Example 1 or Example 2 of this case can penetrate when actually piercing the skin, the three-stage microneedle device of Example 1 and Example 2 was tested for the depth of pig skin puncture. In this test example, three different needle lengths are used for testing, namely 300 microns, 450 microns and 600 microns. Making microneedle devices with different needle lengths only needs to adjust the depth of the groove of the mold forming part, and correspondingly adjust the amount of the first molding solution, the second molding solution, and the third molding solution filled into the mold.

Attach the microneedle device to the displaceable upper plate of the universal material testing machine, fix the pigskin on the lower plate, and then move the upper plate down at a speed of 600 mm per minute until the induction force of the plate reaches 17 Newtons ( N) After stopping (it is calculated based on the minimum puncture skin stress of each needle of 0.058 Newton, multiplied by the total number of needles), after stopping, maintain the upper and lower plates for 5 minutes, then remove the plates to end the puncture. Remove the pig skin and use a tissue stain to confirm whether there are holes on the surface of the pig skin. After that, the pig skin is cut and soaked in formalin for fixation. The pigskin was fixed, embedded and sliced, stained with hematoxylin-eosin (H-E stain), and the penetration depth of the microneedles was observed under an optical microscope and quantified as shown in Figure 5B and Figure 6B.

Figure 5A is a diagram of a pig skin tissue section of the microneedle device of Example 1 with different needle lengths for a pigskin puncture depth test, and Figure 5B is a diagram of a pigskin puncture depth test performed with the microneedle device of Example 1 with different needle lengths Quantitative diagram of puncture depth of pigskin. Fig. 6A is a diagram of a pig skin tissue section of a pig skin puncture depth test performed with the microneedle device of Example 2 with different needle lengths, and Fig. 6B is a pig skin puncture depth test performed with the microneedle device of Example 2 with different needle lengths Quantitative diagram of puncture depth of pigskin. It can be seen from FIGS. 5A and 6A that the microneedle device of Example 1 with different needle lengths and the microneedle device of Example 2 with different needle lengths can pierce the stratum corneum to reach the epidermis. Figures 5B and 6B clearly show that the penetration depth of the microneedle device of Example 1 with different needle lengths and the microneedle device of Example 2 with different needle lengths can penetrate the stratum corneum to reach the epidermis.

Test 3: The effect of the microneedle device used in light shift

In order to understand the effect of the user using the microneedle device to lighten the pigment, a double-blind half-face control test of the microneedle device was conducted.

A total of 15 subjects over the age of 30 were recruited in this trial. Each subject has obvious dark spots (including freckles, sunburns or liver spots) on the subject’s face. Choose one on the subject’s left and right faces. Dark spots are used as test targets. Each subject is provided with two sets of microneedle devices, one of which (experimental group) contains the effective ingredient to lighten the pigment, and the other group (control group) does not contain the effective ingredient to lighten the pigment, the same group The microneedle device is used on the same test target. The microneedle device is applied once a day after facial cleansing, staying for 20 minutes each time, and using it continuously for 14 days.

In this test, a colorimeter (Konica Minolta CR-400 Chromameter) was used to measure the skin color of each subject on the first day (before the use of the microneedle device) and the fifteenth day of the test. . The color difference data measured by the color difference meter includes a value, b value and L value. a value means red and green, +a means reddish, -a means greenish; b value means yellowish blue, +b means yellowish, -b means blueish; L value means brightness, +L means whiter, -L Means darker. The changes in the values before and after the use of the microneedle patch are shown in Table 2.

Table 2: Test results of subjects using the microneedle patch

After the test is unblinded, the test target using the microneedle device containing no active ingredient is classified as the control group, and the test target using the microneedle device containing the active ingredient is classified as the experimental group. During the use of the microneedle device, the subjects did not experience skin breakage or bleeding. It can be seen that the microneedle patch did not penetrate the epidermis.

In Table 2, Δa is the change in a value after using the microneedle device, Δb is the change in b value after using the microneedle device, ΔL is the change in L value after using the microneedle device, and ΔITA° is the change in the value of L after using the microneedle device. ITA° value change value after installation. ITA° is an individual type angle (Individual Typological Angle), which can be used as an indicator of skin color or skin pigmentation. It is calculated according to the following formula: ITA°=(ArcTan((L-50)/b))× 180/3.14159. When ΔITA° is a positive value, it means that the skin of the test target becomes fairer; when ΔL is a positive value, it means that the skin of the test target becomes brighter.

As shown in Table 2, the ΔL and ΔITA° of the experimental group are both positive and statistically different from the ΔL and ΔITA° of the control group (p<0.05), indicating that the test target of the experimental group is using a microneedle device containing active ingredients After two weeks, the skin tone becomes brighter and fairer. It can be seen that when the microneedle device contains the effective ingredient to lighten the pigment, it can obviously make the skin white and brighten the skin of the subjects. On the contrary, the microneedle device of the control group does not have the effective ingredient to lighten the pigment. , It cannot achieve the aforementioned effects.

As mentioned above, by using the manufacturing method of the present invention, the molding solution can be flattened on the surface of the mold and can be completely filled into the mold, and the produced microneedle device has a complete needle body configuration. The microneedle device and its production method provided by the present invention and the microneedle device for diluting pigment form the same carrier component into a two-stage or two-layer tip through a segmented process, thereby generating the effect of improving the structural strength and solving the need Compared with the needle body with PVA added to the needle tip, the problem of adding artificial materials to the needle tip can also reach the bottom layer of the epidermis.

Claims

A microneedle device includes a plurality of needle bodies, and the plurality of needle bodies includes:

A pinpoint layer

A structure layer located on the needle tip layer, wherein the structure layer and the needle tip layer contain substantially the same carrier components; and

A base layer is located on the structure layer.
3. The microneedle device of claim 1, wherein the needle tip layer is formed by a first forming solution.
3. The microneedle device of claim 1, wherein the structure layer is formed by a second forming solution and formed on the formed needle tip layer.
The microneedle device of claim 1, wherein the carrier component comprises: maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, glucose Glycan, hyaluronic acid, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, Polylactic acid-glycolic acid copolymer, chitosan or a combination thereof.
3. The microneedle device of claim 2, wherein relative to the total weight of the first forming solution, the carrier component in the first forming solution comprises:

1 weight percent to 10 weight percent carboxymethyl cellulose and

1 weight percent to 15 weight percent hyaluronic acid.
3. The microneedle device of claim 2, wherein relative to the total weight of the first forming solution, the carrier component in the first forming solution comprises:

5 weight percent to 15 weight percent of low molecular weight hyaluronic acid,

1% to 10% by weight of high molecular weight hyaluronic acid and

1% to 15% by weight of hydroxypropyl-β-cyclodextrin.
3. The microneedle device of claim 3, wherein relative to the total weight of the second molding solution, the carrier component in the second molding solution comprises:

1 weight percent to 10 weight percent carboxymethyl cellulose and

1 weight percent to 15 weight percent hyaluronic acid.
3. The microneedle device of claim 3, wherein relative to the total weight of the second molding solution, the carrier component in the second molding solution comprises:

5 weight percent to 15 weight percent of low molecular weight hyaluronic acid,

1% to 10% by weight of high molecular weight hyaluronic acid and

1% to 15% by weight of hydroxypropyl-β-cyclodextrin.
3. The microneedle device of claim 1, wherein the structure layer and the needle tip layer contain substantially the same effective ingredient.
The microneedle device according to claim 9, wherein the active ingredient comprises: glutathione, nicotinic acid, nicotine amide, cetyl tranexamate, vitamin C magnesium phosphate, kojic acid, vitamin C Glycoside, arbutin, vitamin C phosphate sodium salt, ellagic acid, chamomile extract, dipropyl biphenyldiol, tranexamic acid, potassium methoxysalicylate, 3-o-ethyl ascorbic acid, ascorbic acid tetraisopalmitate Esters or combinations thereof.
3. The microneedle device of claim 2, wherein relative to the total weight of the first forming solution, the first forming solution comprises:

1 weight percent to 10 weight percent of glutathione,

1 weight percent to 10 weight percent nicotine amide and

1% to 10% by weight of tranexamic acid.
3. The microneedle device of claim 3, wherein relative to the total weight of the second forming solution, the second forming solution comprises:

1 weight percent to 10 weight percent of glutathione,

1 weight percent to 10 weight percent nicotine amide and

1% to 10% by weight of tranexamic acid.
The microneedle device of claim 1, wherein the base layer comprises: maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, glucose Polysaccharides, pullulan, hyaluronic acid, methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl Cellulose, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan or a combination thereof.
8. The microneedle device of claim 1, wherein the height of the base layer accounts for 25% to 30% of the total height of the plurality of needle bodies.
3. The microneedle device of claim 1, wherein the height of the base layer is 145 μm to 190 μm.
A method of making a microneedle device, including:

Fill a mold with a first molding solution;

Shaping the first shaping solution;

Filling the mold with a second molding solution, wherein the second molding solution and the first molding solution contain substantially the same carrier components;

Shaping the second shaping solution;

Fill the mold with a third molding solution; and

The third molding solution is molded.
16. The method of claim 16, wherein the first molding solution is filled into the mold to a first liquid level, the first molding solution has a first molding surface after molding, and the height of the first molding surface is lower than The height of the first liquid level.
16. The method of claim 16, wherein the first molding solution is molded into a needle tip layer.
16. The method of claim 16, wherein the second molding solution is filled into the mold to a second liquid level, the second molding solution has a second molding surface after molding, and the height of the second molding surface is lower than The height of the second liquid level.
15. The method of claim 16, wherein the second molding solution is molded into a structural layer.
15. The method of claim 16, wherein the third molding solution is filled into the mold to a third liquid level, the third molding solution has a third molding surface after molding, and the height of the third molding surface is lower than The height of the third liquid level.
The method of claim 16, wherein the third molding solution is molded into a base layer.
15. The method of claim 16, wherein the pH value of the first molding solution and the second molding solution is between 4-6.
16. The method of claim 16, wherein the method comprises making the water content of the first molding solution less than 5 weight percent after molding, and then filling the mold with the second molding solution.
16. The method of claim 16, wherein the method comprises making the water content of the second molding solution less than 5 weight percent after molding, and then filling the mold with the third molding solution.
The method of claim 16, wherein the method further comprises:

Before the first molding solution is filled into the mold, a surfactant is added to the first molding solution to make the surface tension of the first molding solution smaller than the surface tension of the mold.
The method of claim 16, wherein the method further comprises:

Before the second molding solution is filled into the mold, a surfactant is added to the second molding solution to make the surface tension of the second molding solution smaller than the surface tension of the mold.
16. The method of claim 16, wherein the method is to mold the first molding solution, the second molding solution, and the third molding solution at a temperature of minus 60°C to 40°C.
16. The method of claim 16, wherein the method comprises filling the first molding solution and the second molding solution into the mold by vacuum extraction.
29. The method according to claim 29, wherein the method comprises reducing the ambient pressure to less than 1 atmosphere through vacuum extraction, so that the first molding solution and the second molding solution are filled into the mold.
The method of claim 16, wherein the carrier component comprises: maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran , Hyaluronic acid, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, polylactic acid -Glycolic acid copolymer, chitosan or a combination thereof.
The method of claim 16, wherein the first molding solution comprises: relative to the total weight of the first molding solution:

1 weight percent to 10 weight percent carboxymethyl cellulose and

1 weight percent to 15 weight percent hyaluronic acid.
The method of claim 16, wherein relative to the total weight of the first molding solution, the first molding solution comprises:

5 weight percent to 15 weight percent of low molecular weight hyaluronic acid,

1% to 10% by weight of high molecular weight hyaluronic acid and

1% to 15% by weight of hydroxypropyl-β-cyclodextrin.
16. The method of claim 16, wherein the second molding solution comprises: relative to the total weight of the second molding solution:

1 weight percent to 10 weight percent carboxymethyl cellulose and

1 weight percent to 15 weight percent hyaluronic acid.
16. The method of claim 16, wherein the second molding solution comprises: relative to the total weight of the second molding solution:

5 weight percent to 15 weight percent of low molecular weight hyaluronic acid,

1% to 10% by weight of high molecular weight hyaluronic acid and

1% to 15% by weight of hydroxypropyl-β-cyclodextrin.
16. The method of claim 16, wherein the second molding solution and the first molding solution contain substantially the same effective ingredient.
The method of claim 36, wherein the active ingredient comprises glutathione, nicotinic acid, nicotine amide, cetyl tranexamate, vitamin C phosphate magnesium salt, kojic acid, vitamin C glycoside, arbutin , Vitamin C phosphate sodium salt, ellagic acid, chamomile extract, dipropyl biphenyldiol, tranexamic acid, potassium methoxysalicylate, 3-o-ethyl ascorbic acid, ascorbyl tetraisopalmitate or its combination.
The method of claim 16, wherein the first molding solution comprises: relative to the total weight of the first molding solution:

1 weight percent to 10 weight percent of glutathione,

1 weight percent to 10 weight percent nicotine amide and

1% to 10% by weight of tranexamic acid.
16. The method of claim 16, wherein the second molding solution comprises: relative to the total weight of the second molding solution:

1 weight percent to 10 weight percent of glutathione,

1 weight percent to 10 weight percent nicotine amide and

1% to 10% by weight of tranexamic acid.
The method of claim 16, wherein the third forming solution comprises maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran Sugar, pullulan, hyaluronic acid, methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl fiber Vegetarian, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan or a combination thereof.