TWI759712B - Microneedle device and method for making the same - Google Patents

Abstract

This creation relates to a microneedle device and a method for making the same. The microneedle device includes a plurality of needle bodies, and each of the plurality of needle bodies includes a needle tip layer, a structure layer and a base layer. Using the fabrication method of this creation, the need to increase the structure can be reduced. The amount of additional material required to increase the strength can also obtain a microneedle device with sufficient mechanical strength. The present invention also relates to a micro-needle device for lightening pigment obtained by using the above-mentioned manufacturing method of the micro-needle device. To achieve the effect of lightening pigment.

Description

Microneedle device and method of making the same

This creation relates to a percutaneous delivery device and a method for making the same, especially a microneedle device and a method for making the same.

If the pigmentation on the skin is caused by the deposition or uneven distribution of melanin (melanin), it is generally referred to as black spots or skin black spots. Melanin is produced by melanocytes located in the basal layer and transported to surrounding keratinocytes by being wrapped in melanosomes. Dark spots develop on the skin when melanin cannot be removed. In terms of depth, because melanocytes are located in the basal layer of the epidermis, the thickness of the epidermis on the face is about 100 microns. By the traditional transepidermal delivery route, the preparation containing the active ingredients of lightening pigment is directly applied to the skin On the other hand, the proportion of active ingredients for lightening pigments that penetrate the stratum corneum is limited, and only a very low proportion can reach the basal layer of melanocytes, so that the effect of lightening pigments or dark spots is limited. Therefore, how to improve the delivery and use efficiency of active ingredients has been the goal of continuous efforts in the field of dermatology and medical beauty in the past.

Microneedle device, also known as microneedle array (microneedle array), or microneedle structure (microneedle structure), has a plurality of microneedles with a height of 50 to 900 microns. The formation of the stratum corneum barrier is different from the traditional transdermal transmission pathway. 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 are not easy to 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 limited 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 administration or vaccines. The microneedle array is arranged on the substrate. The length of these microneedles is designed to penetrate the stratum corneum and enter the epidermis. But it does not touch the dermis, which is full of nerves and blood vessels. Therefore, the active ingredient can be delivered to the epidermis without causing pain.

In the field of medical cosmetology or skin repair and maintenance, dissolvable microneedles have also been developed, which are designed to penetrate the stratum corneum and release the microneedles by rapidly dissolving the needles in the epidermis by the tissue fluid in the body. out the active ingredients. At present, there is known a dissolvable microneedle that uses hyaluronic acid as a single material. It uses two sheets to pull the hyaluronic acid between the sheets apart by adhesion, and then dries to form microneedles in the process of pulling apart. 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, so it is generally unable to penetrate the stratum corneum. In order to make the microneedle have sufficient mechanical strength, there is another dissolvable microneedle made of polyvinyl alcohol (PVA) as the main material. Polyvinyl alcohol is a high molecular polymer with good biocompatibility, rapid dissolution and excellent mechanical strength after drying. It is generally considered to be suitable as a carrier component for dissolvable microneedles. The carrier component is a structural material, and its function is to form the main structure of the needle body after curing and molding. Using polyvinyl alcohol as the carrier component can enable the microneedle to 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, and it is not a component of the human body itself, and it still has the potential risk of causing skin inflammation. Therefore, how to provide a microneedle device with sufficient mechanical strength without adding artificial material to the needle tip is an urgent problem to be overcome.

In view of the above-mentioned problems, the present invention provides a microneedle device and a manufacturing method thereof. Such a 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 of the skin and enter the epidermis for release. Active ingredients without the concern of causing inflammation. Secondly, the present invention also provides a microneedle device containing an active ingredient for lightening pigments. The microneedle device can improve the use efficiency and delivery efficiency of the active ingredient, so as to enhance the effect of lightening pigments. Here, the improvement of the use efficiency of active ingredients means that the same effect of lightening pigment can be achieved with a smaller amount of active ingredients, and the improvement of delivery efficiency means that more active ingredients can be delivered to the target area (skin base) per unit time through the microneedle device. layer).

In order to achieve the above object, the present invention provides a microneedle device comprising a plurality of needle bodies, each of the plurality of needle bodies comprising a needle tip layer, a structural layer and a base layer, and the structural layer is located on the needle tip layer , the base layer is located on the structure layer, and the structure layer and the tip layer contain substantially the same carrier component. 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 structural layer to support the structure of the needle tip layer and the structural layer.

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

In one embodiment, the structural layer is formed from 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 structural layer and the tip layer include but are not limited to Maltose, Sucrose, Trehalose, Lactose, Dextrin, Maltose Maltodextrin, β-cyclodextrin, Hydroxypropyl-β-cyclodextrin, Dextran, Hyaluronic acid, Carboxymethyl Sodium Carboxymethylcellulose (Sodium Carboxymethylcellulose), Methylcellulose (MC), Carboxymethylcellulose (CMC), Hydroxypropylmethylcellulose (Hydroxypropylmethylcellulose, HPMC), Hydroxypropyl cellulose (Hydroxypropyl cellulose) , HPC), gelatin (Gelatin), polyvinylpyrrolidone (PVP), polylactic acid (PLA), poly(glycolic acid, PGA), poly(lactic acid-glycolic acid) copolymer (Poly( lactic-co-glycolic acid), PLGA), chitosan (Chitosan) or a combination thereof.

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

In one embodiment, relative to the total weight of the first molding solution, the carrier component of the first molding solution comprises 5 to 15 weight percent of low molecular weight hyaluronic acid and 1 to 10 weight percent of high molecular weight hyaluronic acid and 1 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 comprises 1 to 10 percent by weight of carboxymethyl cellulose and 1 to 15 percent by weight of hyaluronic acid .

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

In one embodiment, the tip layer contains an active ingredient. In one embodiment, the structural layer includes an active ingredient. In one embodiment, the structural layer and the needle tip layer contain substantially the same active ingredient. In another embodiment, the structural layer and the needle tip layer may also contain a substantially different active ingredient. Preferably, the active ingredients of the needle tip layer and the active ingredients of the structural layer include but are not limited to glutathione, nicotinic acid, nicotinamide, tranexamic acid cetyl ester, vitamin C magnesium phosphate, koji acid. , Vitamin C Glycoside, Arbutin, Vitamin C Phosphate Sodium Salt, Ellagic Acid, Chamomile Extract, Dipropyl Biphenyl Diol, Tranexamic Acid, Potassium Methoxysalicylate, 3-O-Ethyl Ascorbic Acid, Ascorbic Acid Tetra Isopalmitate or a combination thereof. The active ingredient referred to in the present invention is an active ingredient that achieves a specific effect. The specific effect can be, for example, skin care or skin repair effects such as lightening pigment, anti-wrinkle, moisturizing, etc., which is not limited in the present invention.

In one embodiment, with respect to the total weight of the first forming solution, the first forming solution comprises 1 to 10 weight percent glutathione, 1 to 10 weight percent nicotinamide, and 1 wt% to 10 wt% tranexamic acid.

In one embodiment, relative to the total weight of the second forming solution, the second forming solution comprises 1-10 wt% glutathione, 1-10 wt% nicotinamide and 1 wt% to 10 wt% tranexamic acid.

In one embodiment, the tip layer includes a surfactant. In one embodiment, the structural layer includes a surfactant. Preferably, the surfactant of the needle tip layer and the surfactant of the structural layer include but are 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, the first forming solution contains 0.000001 to 0.0001 milliliters of polyoxyethylene sorbitan monolaurate per 1 mg of the first forming solution. In one embodiment, the second forming solution comprises 0.000001 to 0.0001 ml of polyoxyethylene sorbitan monolaurate per 1 mg of the second forming solution.

In one embodiment, the base layer 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-co-glycolic acid, chitosan, or a combination thereof.

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

In order to achieve the above object, the present invention provides a method for manufacturing a microneedle device, comprising: filling a mold with a first molding solution; molding the first molding solution; filling the mold with a second molding solution, wherein the The second molding solution contains substantially the same carrier components as the first molding solution; molding the second molding solution; filling the mold with a third molding solution; and molding the third molding solution.

In one embodiment, the first molding solution fills 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 face height. In one embodiment, the first forming solution is formed into a tip layer.

In one embodiment, the second molding solution fills 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 second liquid surface. face height. In one embodiment, the second forming solution is formed into a structural layer.

In one embodiment, the third molding solution fills 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 face height. 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 and 6.

In one embodiment, the above-mentioned method further includes forming the first forming solution so that the water content thereof is less than 5 weight percent, and then filling the second forming solution into the mold.

In one embodiment, the above-mentioned method further includes filling the third molding solution into the mold after the moisture content of the second molding solution is less than 5 weight percent after molding.

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 smaller than the surface tension of the mold .

In one embodiment, the above-mentioned method may further comprise: 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 smaller 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 evacuation. Preferably, the first molding solution and the second molding solution are filled into the mold by vacuum evacuation to make the ambient pressure less than 1 atm.

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 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.

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

In one embodiment, relative to the total weight of the first molding solution, the first molding solution comprises 5 to 15 weight percent of low molecular weight hyaluronic acid, 1 to 10 weight percent of high molecular weight hyaluronic acid, and 1 weight percent to 15 weight percent hydroxypropyl-beta-cyclodextrin.

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

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

In one embodiment, the first forming solution contains an active ingredient. In one embodiment, the second molding solution includes an active ingredient. In one embodiment, the second molding solution and the first molding solution contain substantially the same active ingredient. In another embodiment, the second forming solution and the first forming solution may also contain a substantially different active ingredient. Preferably, the active ingredients of the first forming solution and the active ingredients of the second forming solution include glutathione, nicotinic acid, nicotinamide, tranexamic acid cetyl ester, vitamin C magnesium phosphate, koji. Acid, Vitamin C Glycoside, Arbutin, Vitamin C Phosphate Sodium Salt, Ellagic Acid, Chamomile Extract, Dipropyl Biphenyl Diol, Tranexamic Acid, Potassium Methoxysalicylate, 3-o-Ethyl Ascorbic Acid, Ascorbic Acid Tetraisopalmitate or a combination thereof.

In one embodiment, relative to the total weight of the first molding solution, the first molding solution comprises: 1-10 wt% glutathione, 1-10 wt% nicotinamide, and 1 wt% to 10 wt% tranexamic acid.

In one embodiment, relative to the total weight of the second forming solution, the second forming solution comprises 1-10 wt% glutathione, 1-10 wt% nicotinamide and 1 wt% to 10 wt% tranexamic acid.

In one embodiment, the first forming solution includes a surfactant. In one embodiment, the second forming 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, and polysorbate. ester, polyoxyethylene sorbitan monolaurate, or a combination thereof.

In one embodiment, the first forming solution contains 0.000001 to 0.0001 ml of polyoxyethylene sorbitan monolaurate per 1 mg of the first forming solution. In one embodiment, the second forming solution comprises 0.000001 to 0.0001 ml of polyoxyethylene sorbitan monolaurate per 1 mg of the second forming solution.

In one embodiment, the third forming solution includes but is not limited to maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dextran Sugar, pullulan, hyaluronic acid, methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose Vinegar, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, chitosan, or a combination thereof.

In order to achieve the above object, the present invention provides a microneedle device for lightening pigment, which includes a plurality of needle bodies, each of which includes a needle tip layer, which is made of a molding solution, and the molding solution contains an effective Component and a carrier component, relative to the total weight of the molding solution, the active ingredient comprises 1 to 10 weight percent of a peptide or its derivative, 1 to 10 weight percent of a vitamin or its derivative and 1 weight percent percent to 10 percent by weight of acid or its derivatives.

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

In one embodiment, the vitamin or derivative thereof comprises nicotinic acid, nicotinamide, vitamin C magnesium phosphate, vitamin C glycoside, vitamin C sodium phosphate, 3-o-ethylascorbic acid, ascorbyl tetraisopalmitate acid or a combination thereof.

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

In one embodiment, the active ingredient comprises 1-10 wt% glutathione, 1-10 wt% nicotinamide and 1-10 wt% tranexamic acid.

In one embodiment, the carrier component comprises maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, glucan, hyaluronic acid, carboxylate Sodium methyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer substance, chitosan or a combination thereof.

In one embodiment, the carrier component comprises 1 to 10 weight percent of carboxymethyl cellulose and 1 to 15 weight percent of hyaluronic acid.

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

In one embodiment, the forming solution contains 0.000001 to 0.0001 ml of surfactant per 1 mg of the forming solution.

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

In one 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 allow the microneedle device to penetrate the stratum corneum, but it will not cause an inflammatory response in the human body. Natural ingredients generally have insufficient strength after curing, which cannot meet this demand. Therefore, in the past, high content of synthetic material polyvinyl alcohol (PVA) was added to the products, and even PVA was used as the main material of the microneedle needle. to make up for it. The entire needle body of some microneedle devices is composed of hyaluronic acid. Although this method can avoid the problem of inflammation, it sacrifices mechanical strength. For the inhibition of melanin located deep in the epidermis, the depth that can be reached is far from enough.

The microneedle device and its manufacturing method and the microneedle device for lightening pigments provided by the present invention form the same carrier component into a two-stage or two-layer needle tip through a segmented manufacturing process, so as to improve the structural strength and solve the problem. In order to solve the problem of adding artificial materials to the needle tip, compared with the needle body with PVA added to the needle tip, it can also reach the bottom layer of the epidermis.

Secondly, on the same material and dosage, the height of the two-segment needle tip through the segmented process of the present invention is higher than that of the non-segmented needle tip, that is, to make a microneedle body of the same height, the two-segment needle tip only has a higher height. A base layer with a relatively low height is required. Since artificial materials are added to the base layer to strengthen the mechanical structure, reducing the height of this layer can reduce the contact between the artificial material and the skin epidermis, and even completely avoid the artificial material entering the skin epidermis, reducing the Inflammation problems arise. At the same time, the microneedle device fabricated in this way still has sufficient mechanical strength to penetrate the stratum corneum of the skin, although the height of the basal layer that enhances the mechanical strength is reduced (the proportion of the needle body volume is reduced). Finally, the microneedle device containing the active ingredients to lighten pigments can penetrate the stratum corneum of the skin and enter the epidermis through the characteristics of the microneedle device, and transfer the active ingredients carried by the microneedle device to the bottom layer of the epidermis for release, which can improve the use efficiency of the active ingredients. and transfer efficiency to enhance the effect of lightening pigments.

Microneedle device, also known as microneedle array or microneedle structure, its basic structure is a substrate and a plurality of microneedles with a height of 50 to 900 microns on the substrate. Miniaturized invasive devices that can cross the stratum corneum barrier and form a different route than traditional transdermal delivery. Several microneedle devices and their manufacturing methods are listed below as examples to illustrate the implementation of the present invention. Those skilled in the art can easily understand the advantages and effects of the present invention through the contents of this specification, and do not deviate from the present invention. 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 according to the embodiment of the present invention has a plurality of needle bodies 11 and a base material 12 , and the needle bodies 11 are arranged on the base material 12 .

The size of the base material 12 may be slightly larger than 1 square centimeter, and one side of the base material 12 may be adhesive, thereby adhering to the needle body 11 and enabling the microneedle device 1 to stick to the user's skin during use. Avoid falling off of the microneedle device 1 during use. Materials such as non-woven fabrics, artificial skins, medical hydrocolloid dressings, etc. can be selected as the base material 12 in this creation, but are not limited to this. In a preferred embodiment, the substrate 12 can 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 a frustum shape) or a cone cylinder, and the difference between the former two is that the tip is a point-like structure or a plane structure. Wherein, the cone can be conical, elliptical, triangular, quadrangular, pentagonal, hexagonal or polygonal. Similarly, the flat-topped cone or cone can also have various different 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 the present invention. The base layers 113 of each needle body 11 are connected to each other along the horizontal direction and extend to form an extended base layer 114 , wherein the needle bodies 11 are 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 contained in the microneedle device 1 is too small, the physical puncture strength will be insufficient, and the number of needle bodies 11 will increase the difficulty of the manufacturing process and the configuration and length of the needle bodies 11 are difficult to control. Therefore, under the size of 1 square centimeter, Each microneedle device can have 100 to 289 needles, preferably 14 per side, for a total of 196 needles, but any number between 100 and 289 needles can make the microneedle device The needle body 11 of 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 square centimeters, and each microneedle device may have 100 to 676 needles. Secondly, the length of the needle body 11 can be designed to be 300 microns to 600 microns. When the length of the needle body 11 is 300±10 microns, the needle body 11 can penetrate to a depth of 35 microns to 90 microns of the epidermis, which is deeper than the depth of the human stratum corneum (10 to 15 microns) but not more than the depth of the epidermis ( About 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 microns to 130 microns of the epidermis. Causes pain when using it. Therefore, the preferred length of the needle body 11 is 300±10 μm.

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, the user may apply one piece of the microneedle device 1 to the same skin part every day, and then take it off after the microneedle device 1 is adhered to the skin for 15 to 30 minutes. Preferably, the microneedle device 1 stays on the skin for 30 minutes before taking it off, so that the active ingredient carried by the needle body 11 has enough time to dissolve in the epidermis.

In the needle body 11, the needle tip layer 111 is used to penetrate the stratum corneum of the skin and dissolve in the epidermis to release the active ingredient. The structural 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 any active ingredient, but only has a carrier ingredient. In another embodiment, the structural layer 112 also contains an active ingredient, and the active ingredient is released after the structural layer 112 enters the epidermis layer. The active ingredient contained in the structural layer 112 may be the same as the active ingredient contained in the needle tip layer 111 , or the structural layer 112 may contain different active 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 layers 111 are also discontinuous with each other, forming a plurality of units that independently release active ingredients. The base layer 113 is a layer that mainly provides the needle bodies 11 with the required structural strength. 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 an extended base layer 114 , connecting a plurality of needle bodies 11 into a device.

In this creative embodiment, the carrier components of the needle tip layer 111 and the structural layer 112 can be selected from dissolvable, biocompatible or biodegradable polymer materials, and the carrier components are Being a structural material, the carrier component forms a major portion of the tip layer 111 and the structure layer 112 to support the configuration of the tip layer 111 and the structure layer 112 . Carrier ingredients may include maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dextran, hyaluronic acid, sodium carboxymethylcellulose, 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, but not limited thereto. In an embodiment of the present invention, the needle tip layer 111 and the structure layer 112 have substantially the same carrier components, which are selected from carboxymethyl cellulose and hyaluronic acid. In another embodiment of the present invention, the needle tip layer 111 and the structure layer 112 have substantially the same carrier components, which are selected from low molecular weight hyaluronic acid, high molecular weight hyaluronic acid and hydroxypropyl-β-cyclodextrin.

Since the needle body 11 can penetrate to a depth of 35 micrometers to 90 micrometers in the epidermis layer, the needle tip layer 111 contains an active ingredient to deliver the active ingredient to the bottom layer of the epidermis layer. Active ingredients can be selected to achieve specific effects according to different needs. The specific effects can be, for example, skin care or skin repair effects such as lightening pigment, anti-wrinkle, moisturizing, etc., but not limited to this.

In the embodiment of the present invention, the structural layer 112 may not have an active ingredient, but only a carrier ingredient, or the structural layer 112 may also include an active ingredient. In this way, the structural layer 112 can not only enhance the mechanical strength of the needle body 11, but also can be used in the epidermis. The active ingredient is released in the layer. The needle tip layer 111 and the structure layer 112 may contain substantially the same active ingredients or substantially different active 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 Niacinamide (Nicotinamide, Niacinamide), Cetyl Tranexamate HCl, Vitamin C and its derivatives (including: Magnesium Ascorbyl Phosphate, Ascorbyl Glucoside) , Sodium Ascorbyl Phosphate, 3-O-Ethyl Ascorbic Acid, Ascorbyl Tetraisopalmitate), Kojic Acid, Arbutin ( Arbutin), Ellagic Acid, Chamomile ET, Dipropyl Biphenyl Diol (5,5'-Dipropyl-Biphenyl-2,2'-diol), Tranexamic Acid , Potassium Methoxysalicylate or a combination thereof, but not limited thereto. In a preferred embodiment, the active ingredient can be a combination of L-Glutathione, Nicotinamide and Tranexamic Acid.

The base layer 113 mainly provides the mechanical strength of the needle body 11 . After the needle body 11 enters the epidermis, although the probability of contact between the base layer and the skin epidermis is relatively low, in order to avoid inflammatory reaction and increase the safety of use, the material of the base layer 113 can be selected to be soluble, biocompatible or Biodegradable polymer materials. In the embodiment of the present invention, the base layer 113 may comprise maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dextran, branched chain Starch, hyaluronic acid, methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, Polyvinyl 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 this. 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 for providing the mechanical strength of the needle body 11 .

Embodiments of the present invention also provide a method for fabricating a microneedle device. As shown in FIG. 2 , a mold 20 is prepared. The mold 20 is made of poly(dimethylsiloxane) (PDMS). The manufacturing method is to inject the polydimethylsiloxane solution into the male mold and heat it. The polydimethylsiloxane is cured at 100° C. and then demolded to obtain a mold 20 . The mold 20 includes a molding portion 21, and the molding portion 21 includes a plurality of conical needle-point-shaped grooves 211. The configuration of the grooves 211 is designed according to the required configuration of the needle body 11, and may have conical, flat tops Unrestricted shapes such as cone (or frustum) or cone and cylinder. 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. Please refer to the following description for the formula of the first molding solution 31 . After the air pressure of the closed environment where the mold 20 is located is less than 1 atmosphere by vacuum evacuation, the first molding solution 31 is completely filled into the molding portion 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 to complete the molding of the first molding solution 31 . The moisture content is the weight percentage of the weight of the first forming solution 31 after drying to the weight before drying (the weight after drying is divided by the weight before drying, and then multiplied by 100%). The first molding solution 31 after molding is the tip layer 111 and has a first molding surface, and the height of the first molding surface in the molding part 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 weight percent, the second molding solution 32 with a volume of 1 to 3 ml is completely filled into the molding portion 21 of the mold 20, and the mold 20 is closed by vacuuming during the process. The ambient air pressure is maintained below 1 atmosphere, and the second molding solution 32 is completely filled into the molding portion 21 of the mold 20 to form the second liquid level. Please refer to the following description for the formulation of the second molding solution 32 . Also at a temperature of 30°C, the second molding solution 32 is dried to a moisture content of less than 5 weight percent to complete the molding of the second molding solution 32 . 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 molded second molding solution 32 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, the third molding solution 33 with a volume of 2 to 5 ml is filled into the mold 20 . Please refer to the following description for the formulation of the third molding solution 33 . The third molding solution 33 is completely filled into the molding portion 21 of the mold 20 containing the needle tip layer 111 and the structural layer 112 by centrifugation to form a third liquid level. The third molding solution 33 is dried at a temperature of 30°C to a moisture content of less than 5 weight percent, and the molding of the third molding solution 33 is completed.

After confirming that the moisture content of the needle tip layer 111 , the structural layer 112 and the base layer 113 is all less than 5 wt %, the mold is turned over to obtain a plurality of needle bodies 11 connected by extending the base layer 114 . Turning the mold under the condition that the moisture content is lower than 5% by weight can reduce the sticking of the needle body 11 to the mold 20 and achieve the effect of smooth demoulding. In other embodiments, the first molding solution 31 , the second molding solution 32 and the third molding solution 33 can be dried at a temperature of minus 60ºC to 40ºC to a moisture content of less than 5 wt %, so that the molding solution can be shaped, which can also be removed smoothly. membrane and keep the needle 11 configuration intact.

Here, the first molding solution 31 may include the aforementioned carrier component and active ingredient, the second molding solution 32 may also include the aforementioned carrier component and active ingredient, or only the carrier component without the active ingredient, and the first The carrier components of the molding solution 31 and the carrier components of the second molding solution 32 are substantially the same, and the active components of the first molding solution 31 and the active components of the second molding solution 32 may be substantially the same or substantially different components . Carrier ingredients may include maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dextran, hyaluronic acid, sodium carboxymethylcellulose, 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, but not limited thereto. In one embodiment, relative to the total weight of the first molding solution 31, the carrier component in the first molding solution 31 may include 1 to 10 weight percent of carboxymethyl cellulose and 1 to 15 weight percent of carboxymethyl cellulose. hyaluronic acid, and the second molding solution 32 and the first molding solution 31 contain substantially the same carrier component. In another embodiment, relative to the total weight of the first molding solution 31 , the carrier component in the first molding solution 31 may include 5 to 15 weight percent of low molecular weight hyaluronic acid, 1 to 10 weight percent of high Molecular weight of 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 the low molecular weight hyaluronic acid is between 1,000 and 100,000 Daltons, and the molecular weight of the high molecular weight hyaluronic acid is between 200,000 and 500,000 Daltons.

Active ingredients can include glutathione, nicotinic acid, nicotinamide, cetyl tranexamic acid, vitamin C and its derivatives (including: vitamin C magnesium phosphate, vitamin C glycoside, vitamin C sodium phosphate salt, 3-o-ethylascorbic acid, ascorbyl tetraisopalmitate), koji acid, arbutin, ellagic acid, chamomile, dipropylbiphenyldiol, tranexamic acid, potassium methoxysalicylate or its composition, but not limited thereto. In one embodiment, relative to the total weight of the first molding solution 31 , the first molding solution 31 may contain 1-10 wt% glutathione and 1-10 wt% nicotinamide And 1 to 10 weight percent of tranexamic acid. In another embodiment, relative to the total weight of the second molding solution 32 , the second molding solution 32 may include 1 to 10 wt % of glutathione and 1 to 10 wt % of nicotine Amine and 1 to 10 weight percent of tranexamic acid.

In order to ensure the activity of the active ingredient and enable the active ingredient to provide efficacy, the pH of the first molding solution 31 and the second molding 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 molding solution 31 and the second molding solution 32 to be between pH 4 and 6, so as to ensure the activity of glutathione, so that it can provide better The lightening effect of pigment. In one embodiment, the solution containing the carrier component 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 value of the first molding solution 31 and the second molding solution 32 fall within The pH is between 4 and 6 to maintain the active ingredient activity in the molding solution. The aforementioned pH adjuster 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 evacuation, the viscosity of the solution will affect the difficulty of operation. The inventor found that the viscosity of the solution is controlled to be less than 100,000 milliPascal·seconds (mPa·s) , the molding solution can be easily filled into the mold. The solution viscosity value is tested by a rheometer (Anton Parr MCR320) with a parallel plate (model: PP25 or PP43), the test conditions are the temperature 25ºC, the shear rate setting range is 0.1 to 1/100 seconds ( 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·s based on the viscosity value of the temperature at 25°C and the shear rate in one part of a second (s ^-1 ) . 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 53.3 mPa·s. 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 evacuation, the molding solution cannot be completely spread on the surface of the mold 20 and cohesion is likely to occur The phenomenon (cohesion) may cause the situation that the molding solution cannot be completely filled into the mold 20, and the microneedle device 1 produced has the problems that the needle shape of the needle body is incomplete and the needle tip is not sharp, so that it is difficult to pierce the skin. In order to solve the aforementioned problems, a surfactant can be added to the molding solution, so that the surface tension of the molding solution is smaller than that of the mold, so that the molding solution can be flat on the surface of the mold 20 and can be completely filled into the mold 20. The needle shape of the microneedle device 1 is complete.

The above-mentioned surfactant (Surfactant) can be polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polysorbate, polyoxyethylene Oxyethylene sorbitan monolaurate (Tween 20) or a combination thereof. Preferably, the surfactant can be selected from polyoxyethylene sorbitan monolaurate. In order to reduce the amount of artificial materials added in the microneedle device 1, the amount of surfactant must be reduced as much as possible. In one embodiment, the first forming solution may contain 0.000001 to 0.0001 milliliters of polyoxyethylene sorbitan monolaurate per milligram of the first forming solution. Preferably, each milligram of the first forming solution contains 0.00005 milliliters of polyoxyethylene sorbitan monolaurate. More preferably, each milligram of the first forming solution contains 0.00001 milliliters of polyoxyethylene sorbitan monolaurate. In another embodiment, the second forming solution may comprise 0.000001 to 0.0001 milliliters of polyoxyethylene sorbitan monolaurate per milligram of the second forming solution. Preferably, each milligram of the second forming solution contains 0.00005 milliliters of polyoxyethylene sorbitan monolaurate. More preferably, each milligram of the second forming solution contains 0.00001 milliliter of polyoxyethylene sorbitan monolaurate.

Surface tension was measured with a surface tensiometer (Kyowa Interface Science, model: CBVP-A3) and calibrated with deionized water, with a normal range of 72 to 74 millinewtons per meter (mN/m). In the embodiment of the present invention, the surface tension of the mold 20 is about 22 to 23 mN/m. The inventors found that when the surface tension of the first molding solution 31 or the second molding solution 32 is less than 40 mN/m, the Spread the surface of the mold 20 . Preferably, after adding the surfactant, the surface tension of the first forming solution 31 or the second forming solution 32 is about 34.9 mN/m. In another preferred embodiment, after adding the surfactant, the surface tension of the first forming solution 31 or the second forming solution 32 is about 33.6 mN/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 flat on the surface of the mold 20 to completely fill the mold 20 , and the needle shape can be produced. Complete Microneedle Device 1.

The third molding solution 33 may contain 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-co-glycolic acid, chitosan or a combination thereof, but not limited thereto.

The present invention also provides a microneedle device for lightening pigment, the structure of which is the same as that of the aforementioned microneedle device 1 and is manufactured by the aforementioned microneedle device manufacturing method. The microneedle device for lightening pigment comprises a plurality of needle bodies, each needle body comprises a needle tip layer, which is made from a molding solution, and the molding solution includes an active ingredient and a carrier ingredient. With respect to the total weight of the molding solution, the active ingredient comprises 1 to 10 percent by weight of a peptide or its derivative, 1 to 10 percent by weight of a vitamin or its derivative, and 1 to 10 percent by weight of a acid or its derivatives. In another embodiment, relative to the total weight of the molding solution, the active ingredient comprises 1 to 10 weight percent of amino acids or derivatives thereof, 1 to 10 weight percent of vitamins or derivatives thereof, and 1 to 10 weight percent of acid or derivative thereof. Wherein, the peptide or its derivative includes glutathione; the vitamin or its derivative includes nicotinic acid, nicotinamide, vitamin C magnesium phosphate, vitamin C glycoside, vitamin C sodium phosphate, 3-o-ethyl ascorbic acid, ascorbyl tetraisopalmitate or a combination thereof; the acid or a derivative thereof comprises cetyl tranexamate, koji acid, tranexamic acid, potassium methoxysalicylate or a combination thereof. In one embodiment, the active ingredient may comprise 1-10 wt% glutathione, 1-10 wt% nicotinamide and 1-10 wt% tranexamic acid.

The molding solution may further contain a surfactant, and the carrier components and surfactants contained therein can refer to the above-mentioned contents, which will not be repeated here. Each needle body further includes a structural layer, which is made from the same molding solution.

Preparation Example: Forming Solution for Microneedle Device

In order to prepare the microneedle devices of the following examples, different molding solutions were prepared first. Table 1 is an example of a possible formulation of the molding solution. The first molding solution and the second molding solution respectively comprise a carrier component, an active ingredient and a surfactant, wherein the molecular weight of the low molecular weight hyaluronic acid is 7 kDa; the molecular weight of the high molecular weight hyaluronic acid is 300 kDa. The percentages shown in Table 1 are weight percentages. Table 1: Formulation Solution 1 and Formulation 2 recipe one first forming solution carrier component Active ingredients Surfactant 2% carboxymethyl cellulose, 6% low molecular weight hyaluronic acid 2% Grainathione 2% Nicotinamide 2% Tranexamic Acid 0.001% (v/w) polyoxyethylene sorbitan monolaurate Second molding solution carrier component Active ingredients Surfactant 2% carboxymethyl cellulose, 6% low molecular weight hyaluronic acid 2% Grainathione 2% Nicotinamide 2% Tranexamic Acid 0.001% (v/w) polyoxyethylene sorbitan monolaurate third molding solution 20% polyvinyl alcohol, 10% beta-cyclodextrin, 20% trehalose Recipe two first forming solution carrier component Active ingredients Surfactant 9.33% Low Molecular Weight Hyaluronic Acid 1.33% High Molecular Weight Hyaluronic Acid 5.33% Hydroxypropyl Beta-Cyclodextrin 2% Grainathione 2% Nicotinamide 2% Tranexamic Acid 0.005% (v/w) polyoxyethylene sorbitan monolaurate Second molding solution carrier component Active ingredients Surfactant 9.33% Low Molecular Weight Hyaluronic Acid 1.33% High Molecular Weight Hyaluronic Acid 5.33% Hydroxypropyl Beta-Cyclodextrin 2% Grainathione 2% Nicotinamide 2% Tranexamic Acid 0.005% (v/w) polyoxyethylene sorbitan monolaurate third molding solution 20% polyvinyl alcohol, 10% beta-cyclodextrin, 20% trehalose

Example 1 and Example 2: Three-stage Microneedle Device

In order to prepare the microneedle device of this embodiment, Example 1 and Example 2 are used as examples to illustrate the manufacturing process of the microneedle device, wherein the first molding solution, the second molding solution and the third molding solution of Example 1 are It comes from formula 1; the first molding solution, the second molding solution and the third molding solution of Example 2 are from formula 2, respectively, Example 1 or Example 2 are subjected to the above-mentioned production process to obtain these implementations. Example of a 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, and the production process of Example 1 and Example 2 is still divided into 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 in Example 1 and Example 2, another two-stage microneedle device was fabricated 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 one time, without filling the second molding solution but directly filling the third molding solution. Comparative example 1 is a two-stage microneedle device prepared by formula 1, and comparative example 2 is a two-stage microneedle device prepared by formula two.

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

From the above results, it can be seen that the manufacturing method of the three-stage microneedle device in Examples 1 and 2 uses the same carrier component to form a two-stage or two-layer needle tip in batches through a segmented process. The heights of the base layer of the needle bodies of the three-stage microneedle devices of Examples 1 and 2 are both smaller than the base layer heights of the needle bodies of the two-stage microneedle devices of Comparative Examples 1 and 2, respectively. It can be seen that, in order to manufacture a microneedle device of the same height, the two-stage needle tip of the base layer of the microneedle device of the present invention only needs a base layer with a lower height. Since the basal layer is designed to add artificial materials to strengthen the mechanical structure, reducing the height of the basal layer can reduce the contact between artificial materials and the skin epidermis, and can even substantially completely prevent artificial materials from entering the skin epidermis, reducing the use of artificial materials. Inflammation problems.

Although the height of the base layer providing mechanical strength in the three-stage microneedle device of Examples 1 and 2 is reduced, the three-stage microneedle device produced according to the manufacturing method of the embodiment of the present invention still has sufficient mechanical strength to penetrate the skin 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 microneedle and the penetration test of pigskin.

test one : Mechanical strength of the microneedle device

In order to measure the mechanical strength of the needle body of the microneedle device, this test will use a compression fixture to test the microneedle device with a total length of the needle body of 600±10 microns. Set the upper plate of the compression fixture 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 towards the lower plate attached to the microneedle device. Measure the value of load and displacement to find out the mechanical strength that the needle body can bear. According to research, the minimum stress for piercing human skin is 0.058 Newton per needle, so based on this point of view, the mechanical strength that the needle body can withstand must be greater than 0.058 Newton per needle.

The test results are shown in Figures 4A to 4D. FIG. 4A is a stress-corresponding displacement diagram 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 staged 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 increasing stress, the curves of the two-stage microneedle devices of Comparative Examples 1 and 2 or the three-stage microneedle devices of Examples 1 and 2 have no inflection of sudden sudden drop. The dots indicate that the microneedle device did not break due to stress. When each needle is loaded with 0.058 N, the displacement is within one-half of the needle length (ie, 0.3 mm), indicating that both the two-stage microneedle device or the three-stage microneedle device can withstand the minimum stress of puncturing the skin. As shown in FIG. 4B , compared with the stress value under the displacement of 0.2 mm, the average value of the microneedle mechanical strength of the three-stage microneedle device of Example 1 is 0.16±0.04 N per needle, which is comparable to that of the second stage of Comparative Example 1. The average value of the microneedle mechanical strength of the microneedle device was 0.19±0.07 Newton per needle, and there was no significant difference; as shown in Figure 4D, the stress value under the displacement of 0.2 mm was compared. The average mechanical strength of the microneedles was 0.26±0.21 Newton per needle, which was not significantly different from the average value of the microneedle mechanical strength of the two-stage microneedle device in Comparative Example 2, which was 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 prepared according to the manufacturing method of the embodiment of the present invention still has sufficient mechanical strength to penetrate Cuticle of skin.

Test two : Pig skin puncture depth detection by microneedle device

In order to know the depth that the needle body of the microneedle device of Example 1 or Example 2 can penetrate when actually piercing the skin, the pigskin puncture depth was detected on the three-stage microneedle device of Example 1 and Example 2. This test example was tested with three different needle lengths, namely 300 microns, 450 microns and 600 microns. To manufacture microneedle devices with different needle lengths, it is only necessary to adjust the depth of the groove of the molding part of the mold, 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 to the lower plate, and then move the upper plate downward at a speed of 600 mm per minute until the induction force of the plate reaches 17 Newtons ( N) and then stop (calculated based on the minimum skin piercing stress of each needle is 0.058 Newton, multiplied by the total number of needles), after stopping, maintain the state of the upper plate and the lower plate for 5 minutes, remove the plate, and end the puncture. The pigskin was removed, and the presence or absence of pores on the surface of the pigskin was confirmed with tissue stain. After that, the pigskin was cut and immersed in formalin for fixation. The pigskin was fixed and then embedded and sectioned, stained with hematoxylin-eosin (H-E stain), and the penetration depth of the microneedles was observed and quantified under an optical microscope, as shown in Figure 5B and Figure 6B.

Fig. 5A is a view of a pigskin tissue section using the microneedle device of Example 1 with different needle lengths to perform a pigskin puncture depth test, and Fig. 5B is a diagram of a pigskin puncture depth test performed with the microneedle device of Example 1 with different needle lengths. Pig skin puncture depth quantification map. Fig. 6A is a view of a pigskin tissue section using the microneedle device of Example 2 with different needle lengths to perform a pigskin puncture depth test, and Fig. 6B is a diagram of a pigskin puncture depth test performed with the microneedle device of Example 2 with different needle lengths Pig skin puncture depth quantification map. It can be seen from FIG. 5A and FIG. 6A that the microneedle device of Example 1 with different needle lengths and the microneedle device of Example 2 with different needle lengths can both penetrate the stratum corneum to the epidermis. 5B and 6B more clearly show that the penetration depths of the microneedle devices of Example 1 with different needle lengths and the microneedle devices of Example 2 with different needle lengths can penetrate the stratum corneum to the epidermis.

Experiment 3: The effect of microneedle device used in light shifts

In order to understand the effect of the user's use of the microneedle device to lighten the pigment, a double-blind half-face control experiment of the microneedle device was carried out.

A total of 15 subjects over the age of 30 were recruited in this trial. Each subject has obvious dark spots (including freckles, sunburn or liver spots) on the face, and choose one on the left and right faces of the subject. Dark spots are used as test targets. Each subject was provided with two groups of microneedle devices, one of which (experimental group) microneedle devices contained active ingredients for lightening pigments, and the other group (control group) microneedle devices did not contain active ingredients for lightening pigments. The microneedle device is used on the same test target. The microneedle device was applied once a day after facial cleansing, and stayed for 20 minutes each time for 14 consecutive days.

In this experiment, a colorimeter (brand model: Konica Minolta CR-400 Chroma meter) was used to measure the difference between the subjects on the first day of the experiment (before the use of the microneedle device) and on the fifteenth day. color. The color difference data measured by the colorimeter includes a value, b value and L value. a value means red and green, +a means reddish, -a means greenish; b value means yellow-blue, +b means yellowish, -b means blueish; L value means brightness, +L means whiteish, -L Indicates dark. Table 2 shows the change of each numerical value before and after the use of the microneedle patch. Table 2: Test results of subjects using the microneedle patch group Δa Δb ΔL ΔITA° control group 0.21 -0.80 -1.22 -2.17 test group -0.43 -0.57 2.61 6.99

After the experiment was unblinded, the test subjects using the microneedle device without active ingredients were classified as the control group, and the test subjects using the microneedle device containing active ingredients were classified as the experimental group. During the use of the microneedle device, the subjects did not experience skin damage or bleeding, and it can be seen that the microneedle patch did not pierce the epidermis.

。當ΔITA°為正值時，表示測試標的膚色變白皙；ΔL為正值時，表示測試標的膚色變亮。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, ΔITA° is the change in the value of L after using the microneedle device The change in ITA° 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 degree. It is calculated according to the following formula:

. When ΔITA° is a positive value, it means that the skin color of the test object becomes fair; when ΔL is a positive value, it means that the skin color of the test object becomes brighter.

As shown in Table 2, the ΔL and ΔITA° of the experimental group are both positive and there is a statistical difference with the ΔL and ΔITA° of the control group (p>0.05), indicating that the test target of the experimental group is using the microneedle device containing active ingredients The complexion is brightened and fairer after two weeks. It can be seen that when the microneedle device contains the active ingredient for lightening pigment, the subjects can obviously obtain the effect of fair skin and skin tone. , so the aforementioned effect cannot be achieved.

Based on the above, 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 needle body of the manufactured microneedle device has a complete configuration. The microneedle device and its manufacturing method provided by the present invention and the microneedle device for lightening pigments form two-stage or two-layer needle tips from the same carrier component through a segmented manufacturing process, so as to improve the structural strength and solve the problem. The problem of adding artificial materials to the needle tip can also reach the bottom layer of the epidermis compared to the needle body with PVA added to the needle tip.

Secondly, on the same material and dosage, the height of the two-segment needle tip through the segmented process of the present invention is higher than that of the non-segmented needle tip, that is, to make a microneedle body of the same height, the two-segment needle tip only has a higher height. A base layer with a relatively low height is required. Since artificial materials are added to the base layer to strengthen the mechanical structure, reducing the height of this layer can reduce the contact between the artificial material and the skin epidermis, and even completely prevent the artificial material from entering the skin epidermis, reducing the Inflammation problems arise. At the same time, the microneedle device fabricated in this way still has sufficient mechanical strength to penetrate the stratum corneum of the skin, although the height of the basal layer that enhances the mechanical strength is reduced (the proportion of the needle body volume is reduced). Finally, the microneedle device containing the active ingredients for lightening pigments can penetrate the stratum corneum of the skin and enter the epidermis through the characteristics of the microneedle device, and transfer the active ingredients carried by the microneedle device to the bottom layer of the epidermis for release, which can improve the use efficiency of the active ingredients. and transfer efficiency to enhance the effect of lightening pigments.

1: Microneedle device 11: Needle body 111: Needle tip layer 112: Structural Layer 113: basal layer 114: Extend the base layer 12: Substrate 20: Mold 21: Forming Department 211: Groove 31: First molding solution 32: Second molding solution 33: Third molding solution

FIG. 1 is a schematic diagram of the microneedle device of the present invention. FIG. 2 is a flow chart of a method of fabricating a microneedle device. 3A is a height comparison diagram of the base layer in the microneedle devices of Example 1 and Comparative Example 1, and FIG. 3B is a height comparison diagram of the base layer in the microneedle devices of Example 2 and Comparative Example 2. FIG. 4A is the stress-corresponding displacement diagram 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 staged 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 . Fig. 5A is a view of a pigskin tissue slice using the microneedle device of Example 1 with different needle lengths to perform a pigskin puncture depth test, and Fig. 5B is a diagram of a pigskin puncture depth test performed with the microneedle device of Example 1 with different needle lengths. Pig skin puncture depth quantification map. Fig. 6A is a view of a pigskin tissue section using the microneedle device of Example 2 with different needle lengths to perform a pigskin puncture depth test, and Fig. 6B is a diagram of a pigskin puncture depth test performed with the microneedle device of Example 2 with different needle lengths Pig skin puncture depth quantification map.

none.

1: Microneedle device

11: Needle body

111: Needle tip layer

112: Structural Layer

113: basal layer

114: Extend the base layer

12: Substrate

Claims (36)

A microneedle device comprising a plurality of needle bodies, the plurality of needle bodies comprising: a needle tip layer; a structural layer on the needle tip layer, wherein the structural layer and the needle tip layer contain substantially the same carrier component; and a The base layer is located on the structure layer, wherein the height of the base layer accounts for 25% to 30% of the total height of the plurality of needle bodies. The microneedle device according to claim 1, wherein the needle tip layer is formed from a first forming solution. The microneedle device according to claim 1, wherein the structural layer is formed from a second forming solution. The microneedle device according to claim 1, 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 microneedle device according to claim 2, wherein relative to the total weight of the first forming solution, the carrier component in the first forming solution comprises: 1 to 10 weight percent of carboxymethyl cellulose and 1 Weight percent to 15 weight percent hyaluronic acid. The microneedle device according to claim 2, wherein relative to the total weight of the first molding solution, the carrier component in the first molding solution comprises: 5 to 15 wt% of low molecular weight hyaluronic acid, 1 wt% to 10% by weight of high molecular weight hyaluronic acid and 1 to 15 weight percent hydroxypropyl-beta-cyclodextrin. The microneedle device of claim 3, wherein relative to the total weight of the second forming solution, the carrier component in the second forming solution comprises: 1 to 10 weight percent of carboxymethyl cellulose and 1 Weight percent to 15 weight percent hyaluronic acid. The microneedle device according to claim 3, wherein relative to the total weight of the second molding solution, the carrier component in the second molding solution comprises: 5 to 15 wt% of low molecular weight hyaluronic acid, 1 wt% To 10 weight percent of high molecular weight hyaluronic acid and 1 to 15 weight percent of hydroxypropyl-beta-cyclodextrin. The microneedle device as claimed in claim 1, wherein the structure layer and the needle tip layer contain substantially the same active ingredient. The microneedle device according to claim 9, wherein the active ingredients comprise: glutathione, nicotinic acid, nicotinamide, cetyl tranexamic acid, vitamin C magnesium phosphate, kosic acid, vitamin C glycoside, arbutin, sodium vitamin C phosphate, ellagic acid, chamomile, dipropyl biphenyl diol, tranexamic acid, potassium methoxysalicylate, 3-o-ethyl ascorbic acid, ascorbyl tetraisopalmitate acid or a combination thereof. The microneedle device according to claim 2, wherein relative to the total weight of the first molding solution, the first molding solution comprises: 1-10 wt% glutathione, 1-10 wt% of nicotinamide and 1 to 10 weight percent of tranexamic acid. The microneedle device of claim 3, wherein relative to the total weight of the second forming solution, the second forming solution comprises: 1 to 10 weight percent of glutathione, 1 to 10 weight percent of nicotinamide, and 1 to 10 weight percent 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, 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-co-glycolic acid, chitosan, or a combination thereof. The microneedle device of claim 1, wherein the base layer has a height of 145 to 190 microns. A method of manufacturing a microneedle device, comprising: filling a mold with a first molding solution; molding the first molding solution into a tip layer; filling the mold with a second molding solution, wherein the second molding solution containing substantially the same carrier component as the first molding solution; molding the second molding solution into a structural layer; filling the mold with a third molding solution; and molding the third molding solution into a base layer, The height of the base layer accounts for 25% to 30% of the total height of the tip layer, the structure layer and the base layer. The method of claim 15, wherein the first molding solution fills 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. The method of claim 15, wherein the second molding solution fills 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. The method of claim 15, wherein the third molding solution fills 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 15, wherein the pH values of the first forming solution and the second forming solution are between 4 and 6. The method of claim 15, 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. The method of claim 15, 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 15, wherein the method further comprises: before the first molding solution is filled into the mold, adding a surfactant to the first molding solution to make the surface tension of the first molding solution less than Surface tension of the mold. The method of claim 15, wherein the method further comprises: before the second molding solution is filled into the mold, adding a surfactant to the second molding solution to make the surface tension of the second molding solution less than Surface tension of the mold. The method of claim 15, wherein the method forms the first forming solution, the second forming solution and the third forming solution at a temperature of minus 60°C to 40°C. 16. The method of claim 15, wherein the method includes filling the mold with the first molding solution and the second molding solution by vacuum evacuation. The method of claim 25, wherein the method includes filling the mold with the first molding solution and the second molding solution by making the ambient pressure less than 1 atmosphere by vacuum evacuation. The method of claim 15, wherein the carrier component comprises: maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dextran Sugar, hyaluronic acid, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, poly Lactic acid-glycolic acid copolymer, chitosan or a combination thereof. The method of claim 15, wherein relative to the total weight of the first forming solution, the first forming solution comprises: 1 to 10 weight percent carboxymethyl cellulose and 1 to 15 weight percent Hyaluronic acid. The method of claim 15, wherein relative to the total weight of the first molding solution, the first molding solution comprises: 5 to 15 weight percent of low molecular weight hyaluronic acid, and 1 to 10 weight percent of high molecular weight Hyaluronic acid and 1 to 15 weight percent of hydroxypropyl-beta-cyclodextrin. The method of claim 15, wherein relative to the total weight of the second forming solution, the second forming solution comprises: 1 to 10 weight percent carboxymethyl cellulose and 1 to 15 weight percent Hyaluronic acid. The method of claim 15, wherein relative to the total weight of the second molding solution, the second molding solution comprises: 5 to 15 weight percent of low molecular weight hyaluronic acid, 1 to 10 weight percent of high molecular weight hyaluronic acid and 1 to 15 weight percent of hydroxypropyl-beta-cyclodextrin. The method of claim 15, wherein the second forming solution and the first forming solution contain substantially the same active ingredient. The method according to claim 32, wherein the active ingredient comprises glutathione, nicotinic acid, nicotinamide, cetyl tranexamic acid, vitamin C magnesium phosphate, koji acid, vitamin C glycoside, Arbutin, Vitamin C Sodium Phosphate, Ellagic Acid, Chamomile Extract, Dipropyl Biphenyl Diol, Tranexamic Acid, Potassium Methoxysalicylate, 3-O-Ethyl Ascorbic Acid, Ascorbyl Tetraisopalmitate or its composition. The method of claim 15, wherein relative to the total weight of the first molding solution, the first molding solution comprises: 1-10 wt% glutathione, 1-10 wt% cigarette smoke Alkaline amide and 1 to 10 weight percent of tranexamic acid. The method of claim 15, wherein relative to the total weight of the second molding solution, the second molding solution comprises: 1-10 wt% glutathione, 1-10 wt% cigarette smoke Alkaline amide and 1 to 10 weight percent of tranexamic acid. The method of claim 15, wherein the third forming solution comprises maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, glucose Polysaccharide, pullulan, hyaluronic acid, methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl Cellulose, gelatin, polyethylene Enol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, chitosan, or a combination thereof.

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