TWI633901B - Medical beauty microneedle patch manufacturing method - Google Patents

Abstract

This creation relates to a method for making a medical microneedle patch, which first forms a needle tip mixed solution containing medical active ingredients in multiple holes in a master mold, dries it into a needle tip layer, and then mixes the needle base The liquid is formed on the needle tip layer and in the above-mentioned multiple holes, and then the needle bottom mixed liquid is dried into the needle bottom layer, so that the needle bottom layer is adhered to the needle tip layer, and finally the bonded needle tip layer and needle are removed from the mother mold. On the bottom layer, a medical microneedle patch is obtained. The method of this creation can not only overcome the problems of adhesion, machine alignment and production cost faced in the past in the production of microneedle patches, but also can specifically save process time and improve mass production efficiency, and provide a microneedle suitable for mass production of medical beauty How to make a patch.

Description

Medical beauty microneedle patch manufacturing method

This creation is about the production technology of a medical product, especially a method of making a medical microneedle patch.

Transdermal drug delivery is a drug delivery method that has attracted much attention in recent years. It can utilize non-invasive drug delivery methods to allow drugs to be absorbed through the skin to exert their effects. Although transdermal infusion can prevent oral administration from effectively controlling the effect of the digestive system, and at the same time avoid the fear and pain caused by subcutaneous injection, but because the stratum corneum of the skin is both hydrophobic and negatively charged, It is not suitable for delivery of water-soluble drugs through a transdermal drug delivery system.

In response to the above problems, the prior art has developed a microneedle patch, the substrate of which is covered with a plurality of micron-scale microneedle structures. These microneedle structures can pierce the stratum corneum of the skin and deliver the drug to the epidermal layer for release. . The use of microneedle patch can not only solve many problems in the past oral administration or subcutaneous injection, but also expand the types of drugs to be delivered into fat-soluble drugs and water-soluble drugs, so that the aforementioned different types of drugs can pass through the microneedle The microneedle structure on the patch is directly delivered to the epidermal layer to release the drug effect without pain.

Based on the many advantages of microneedle patches, the industry has actively invested in the development of microneedle patches. For example, Taiwan Invention Patent No. 201400140A discloses a method for manufacturing a mosaic transdermal drug release patch. On the one hand, a biodegradable polymer colloid containing a drug is firstly perfused to obtain a plurality of biodegradable carriers, and the other On the one hand, it is necessary to first prepare a support substrate having a plurality of protruding support shafts, and apply an adhesive to the support substrate in advance; then, try to align the protruding support shafts on the surface of the support substrate with the aforementioned biodegradable carrier. In order to obtain a mosaic transdermal drug release patch, they can be adhered to each other.

However, the above manufacturing method must additionally consider the spacing and alignment between the plurality of protruding support shafts on the supporting substrate and the plurality of carriers, which increases the difficulty of the process; and in the manufacturing process, an additional step of applying an adhesive is required in advance. In order to adhere the supporting substrate and the carrier, it will increase the complexity of the process and the production cost.

In view of the above technical problems, the purpose of this creation is to solve the technical defects and inconveniences of microneedle patches in the prior art, and to provide a manufacturing method that is beneficial to mass production of microneedle patches.

In order to achieve the foregoing objective, the present invention provides a method for manufacturing a medical microneedle patch, which includes the following steps: (a) providing a master mold having a reference surface and a plurality of holes, and the plurality of holes are faced by the reference Set down to shape; (b) Form a needle tip mixture into the holes of the master mold, so that the needle tip mixture fills the holes in the master mold to obtain a master mold filled with the needle tip mixture. The liquid level of the needle-point mixed liquid is flush with the reference surface of the master mold, and the needle-point mixed liquid contains medicinal active ingredients; (c) drying the needle-point mixed liquid into a needle-point layer to obtain a mother mold having a needle-point layer, The surface of the needle tip layer is lower than the reference surface of the master mold; (d) forming a needle bottom mixed solution on the needle tip layer and the aforementioned multiple holes, so that the needle bottom mixed solution covers the needle tip layer and the reference of the mother mold And a plurality of holes to obtain a master mold filled with the needle bottom mixed liquid; (e) drying the needle bottom mixed liquid to the bottom layer of the needle, thereby making the bottom layer of the needle adhere to the needle tip layer; and (f) from the master mold The needle tip layer and the needle bottom layer which are adhered to each other are removed to obtain the medical beauty microneedle patch. .

According to the production method of this creative medical beauty microneedle patch, the creation can complete the production of the needle tip layer and the needle bottom layer in the same master mold without additional adhesive. Because the method of making this medical and aesthetic microneedle patch is to dry the needle tip mixture into a needle tip layer, and then form the needle bottom mixture and let it dry, it can use the polymer materials in the needle tip mixture and the needle bottom mixture. The polymer force causes the dried needle tip layer and the needle bottom layer to adhere to each other, and specifically overcomes the problems of adhesion, machine alignment and production costs derived from previous manufacturing methods, thereby saving process time and improving mass production efficiency, providing a It is suitable for the manufacturing method of medical micro-needle patch.

In one embodiment, the water solubility of the needle-point mixed solution is greater than that of the needle-bottom mixed solution, so that the water-solubility of the tip layer of the medical beauty microneedle patch is greater than that of the bottom layer of the needle. According to this, when the medical beauty microneedle patch of this creation is used to pierce the skin, the needle layer of the medical beauty microneedle patch will quickly dissolve and detach from the needle bottom layer, thereby quickly releasing the medical beauty active ingredients in the epidermal layer. In another embodiment, the water-solubility of the needle-point mixed solution is lower than that of the needle-bottom mixed solution, so that the water-solubility of the tip layer of the medical beauty microneedle patch is less than that of the bottom layer of the needle. According to this, when the medical beauty microneedle patch used in this creation pierces the skin, the needle bottom layer of the medical beauty microneedle patch will dissolve earlier than the needle tip layer, so that the needle tip layer will remain in the body and will be slowly released in the epidermal layer. Medical beauty active ingredients. Therefore, the method for producing the medical micro-needle patch can create the medical micro-needle patch and the slow-release medical micro-needle patch according to different needs by controlling the water solubility of both the needle tip mixed solution and the needle bottom mixed solution. Beautiful micro needle patch.

In the production method of the creative medical beauty microneedle patch, the above steps (b) and (d) can use wet coating method or printing method to form the needle tip mixed solution or the needle bottom mixed solution into a plurality of the master mold. Inside the hole. The wet tip coating method is used to coat the needle tip mixture and the needle bottom mixture, which can help to control the distribution range of the active ingredients of TCM beauty in each microneedle structure, and then specifically control the dose of the active ingredients of the microneedle patch.

Preferably, the aforementioned steps (b) and (d) can be performed independently using a slit or slot die coating method, a blade coating method, or a slid coating method. The dip coating, inkjet printing, or nozzle printing method forms the needle tip mixture or the needle bottom mixture into the multiple holes of the master mold, but it is not limited to The above method. The method of forming the needle tip mixed liquid in the multiple holes in the step (b) may be the same as or different from the method of forming the needle bottom mixed liquid in the multiple holes in the step (d). Preferably, the production method of the creative medical beauty microneedle patch can adopt a slit coating method or a doctor blade coating method, and the needle tip mixed liquid and the needle bottom mixed liquid are formed in a plurality of holes of the master mold.

When the needle tip mixture is applied by the slit coating method in step (b), the coating gap can be controlled from 1 μm to 5000 μm, and the coating speed can be controlled from 1 m / min to 100 m / min; the above process The parameters can be adjusted according to the characteristics of the selected needle tip mixture and the specifications of the medical beauty microneedle patch. In addition, when the needle base mixed solution is applied by the slit coating method in step (d), the coating gap can be controlled from 1 μm to 3000 μm, and the coating speed can be controlled from 1 m / min to 100 m / min. The above-mentioned process parameters can be adjusted according to the characteristics of the selected needle-bottom mixture and the specifications of Yimei microneedle patch.

Preferably, in the step (b), the coating gap can be controlled from 100 μm to 5000 μm, and the coating speed can be controlled from 1 m / min to 100 m / min; in the step (d), the coating The gap can be controlled from 100 μm to 3000 μm, and the coating speed can be controlled from 1 m / min to 100 m / min.

Preferably, the step (b) may further include: forming the needle-point mixed liquid on the mother mold, and then allowing the needle-point mixed liquid to flow into a plurality of holes, so that the needle-point mixed liquid covers the reference surface of the mother mold. And a plurality of holes; and removing the tip liquid mixture on the reference surface, so that the liquid level of the needle tip liquid is flush with the reference surface of the master mold.

In the aforementioned step of causing the needle tip mixed liquid to flow into the plurality of holes, the method adopted may be a vacuum suction method or a centrifugation method. In one of the embodiments, the creation can place the needle-point mixture and the master mold in an oven to extract air, so that the needle-point mixture covers the reference surface and multiple holes of the master mold; in the other embodiment, In this creation, the needle tip mixed liquid and the mother mold are centrifuged together, so that the needle tip mixed liquid covers the reference surface and multiple holes of the mother mold. Here, the pressure in the oven can be controlled from 0.001 to 90 torr, preferably from 0.009 to 90 torr. The speed of the centrifugation step can be controlled from 100 rpm to 10000 rpm, preferably from 100 rpm to 8000 rpm.

Preferably, the step (d) may further include: forming a needle base mixed liquid on the master mold, and then allowing the needle base mixed liquid to flow into a plurality of holes, so that the needle base mixed liquid covers the needle tip layer and the In the reference plane of the master mold and in a plurality of holes, a master mold containing a mixture of needle bottoms was obtained.

In the aforementioned step of causing the needle-bottom mixed solution to flow into the plurality of holes, the method adopted may be a vacuum extraction method or a centrifugation method. In one of the implementations, the creation can place the needle bottom mixture and the master mold in an oven to extract air, so that the needle bottom mixture can cover the reference surface and multiple holes of the master mold; in the other implementation In this way, in this creation, the needle base mixed liquid and the female mold are centrifuged together, so that the needle base mixed liquid covers the reference surface of the female mold and a plurality of holes. Here, the pressure in the oven can be controlled from 0.001 to 90 torr, preferably from 0.009 to 90 torr. The speed of the centrifugation step can be controlled from 100 rpm to 10000 rpm, preferably from 100 rpm to 5000 rpm.

The steps (c) and (e) can be performed by freeze drying or drying at room temperature. Preferably, the drying temperature in the steps (c) and (e) can be controlled between -80 ° C and 160 ° C; more preferably between -80 ° C and 80 ° C; even more preferably -80 ° C To 50 ° C.

Preferably, the aforementioned step (e) includes: drying the needle bottom mixed liquid at -80 ° C to 0 ° C to dry the needle bottom layer to obtain a first dried needle bottom layer and the needle tip layer; and drying the first dried needle bottom layer and the needle tip. The layer is placed at 2 ° C to 10 ° C to obtain the dried needle bottom layer and the needle tip layer. The dried needle bottom layer and the needle tip layer are dried at room temperature to make the needle bottom adhere to The tip layer.

More preferably, the aforementioned step (e) includes: drying the needle bottom mixed liquid at -80 ° C to 0 ° C to dry the needle bottom layer to obtain an initial dried needle bottom layer and a needle tip layer; The needle tip layer is dried at 2 ° C to 10 ° C to obtain the dried needle bottom layer and the needle tip layer. The secondary dried needle bottom layer and the needle tip layer are dried at -80 ° C to 0 ° C. To obtain the dried needle bottom layer and the needle point layer once or three times; then dry the dried needle bottom layer and the needle point layer three times at 2 ° C to 10 ° C to obtain the dried needle bottom layer and the needle point layer one or four times; The four-dried needle bottom layer and the needle tip layer are dried at room temperature, so that the needle bottom layer is adhered to the needle tip layer.

According to this, through the foregoing steps of repeated freeze-crosslinking, the mechanical strength of the medical microneedle patch can be improved, and the Young's modulus of the microneedle structure of the medical microneedle patch can be increased by 3 times. the above.

Preferably, the temperature of the foregoing first and third drying steps may be -40 ° C to 0 ° C, more preferably -30 ° C to -10 ° C; and the temperature of the foregoing second and fourth drying steps may be 2 ° C to 6 ° C.

Preferably, after step (e), the step (f) may further include: first forming a back layer on the mother mold and the needle bottom layer, so that the needle tip layer and the needle bottom layer are sandwiched between the mother mold and the needle bottom layer. Between the layers; the needle tip layer, the needle bottom layer and the back layer are simultaneously removed from the mother mold having the needle tip layer and the needle bottom layer to obtain the medical beauty microneedle patch.

In the aforementioned step of forming the back layer on the mother mold and the needle base layer, the back layer has adhesiveness, which may be an adhesive tape, but it is not limited thereto.

Preferably, the viscosity of the needle tip mixture is lower than the viscosity of the needle bottom mixture. The viscosity of the needle tip mixture at 25 ° C and a shear rate of 1 S ^-1 is preferably 3 centipoise (cP) to 500,000 cP, and more preferably 5 cP to 100000 cP; and the viscosity measured at 25 ° C and a shear rate of 1 S ^-1 is preferably 100 cP to 5000000 cP, and more preferably 10,000 cP to 500,000 cP. When the viscosity of the needle tip mixture is too high, the needle tip mixture will not flow to the bottom of the hole as scheduled, resulting in structural defects in the medical microneedle patch, and the required needle height and complete microneedle structure cannot be obtained; When the viscosity of the bottom mixed solution exceeds the above range, it cannot provide sufficient support, and even deteriorate the quality of the medical beauty microneedle patch. In addition, by controlling the viscosity range of the needle tip mixed solution and the needle bottom mixed solution, it is more conducive to shortening the process time of the aforementioned steps (b) and (d) and improve mass production efficiency.

Preferably, the surface tension of the needle tip mixture is less than or equal to 70 dyne / cm; more preferably, the surface tension of the needle tip mixture is greater than or equal to 1 dyne / cm and less than or equal to 60 dyne / cm. When the surface tension of the needle tip mixed solution is too high, the needle tip mixed solution cannot flow to the bottom of the hole as scheduled, resulting in structural defects in the medical beauty microneedle patch. Preferably, the surface tension of the needle bottom mixture is less than or equal to 50 dyne / cm; more preferably, the surface tension of the needle bottom mixture is greater than or equal to 1 dyne / cm and less than or equal to 40 dyne / cm. cm. When the surface tension of the mixture at the bottom of the needle is too high, the underlying structure of the needle in the medical beauty microneedle patch is incomplete, the needle tip layer and the needle bottom layer cannot be firmly adhered, and the back layer structure is defective (such as unevenness, air bubbles, or Uneven surface)).

According to this creation, both the needle-point mixed solution and the needle-bottom mixed solution may be a polymer aqueous solution, and the needle-point mixed solution is a polymer aqueous solution containing active medical ingredients. Preferably, the concentration of the needle-point mixed solution is smaller than the concentration of the needle-bottom mixed solution. Preferably, the concentration of the needle tip mixed solution is 5 wt% to 50 wt%, and the concentration of the needle bottom mixed solution is 10 wt% to 95 wt%; more preferably, the concentration of the needle tip mixed solution is 10 wt% to 50 wt%, and the concentration of the needle bottom mixed solution is 15 wt% to 95 wt%. By controlling the concentration range of the needle tip mixed solution and the needle bottom mixed solution, it can be beneficial to ensure the mechanical strength of the needle tip layer and the needle bottom layer in the prepared medical beauty microneedle patch, so that it can smoothly pass through the stripping step and obtain Medical microneedle patch with complete microneedle structure.

According to this creation, the medically active ingredients can be whitening ingredients, moisturizing ingredients, antioxidants, and anti-wrinkle ingredients, but it is not limited to this. The whitening ingredients that can be used in this creation are: kojic acid, arbutin, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl glycoside ), Ellagic acid, chamomile ET, cetyltranexamate HCl, potassium 4-methoxysalicylate, 3 -O-ethyl ascorbic acid, nonapeptide, but not limited to this. Moisturizing ingredients that can be used in this creation, such as: ceramide, lecithin, glycerol, polysaccharides, hyaluronic acid, sodium hyaluronate, protein ), Collagen, elastin, peptide, amino acid, citrate, uric acid, urea, glucose, sucrose ( sucrose, fructose, glycogen, glucosamine, mucopolysaccharides, lactate, phosphate, pyrrolidone-5-carboxylic acid ethyl ester -dl-2-pyrrolidone-5-carboxylate), but it is not limited to this. Antioxidants such as grape extract, green tea extract, ginkgo extract, soy extract, pomegranate extract , Ginger extract, yeast extract, coix extract, R-alpha-lipoic Acid, glucan, coenzyme Q10 ), Superoxide dismutase (SOD), vitamin C (vitamine C) and its derivatives, vitamin E (Vitamine E) and its derivatives, but it is not limited to this. Anti-wrinkle ingredients that can be used in this creation, such as: Vitamin A (retinol) and its derivatives, copper peptide (GHK-Cu), pentapeptide, hexapeptide, but not limited to this.

According to this creation, the polymer materials contained in the needle tip mixed liquid and the needle bottom mixed liquid may be dissolvable or swellable materials. More specifically, the polymer material may be a biocompatible material or a biodegradable material. The needle tip mixture and the needle base mixture each independently comprise a polymer material, and the polymer material contained in the needle tip mixture may be the same as or different from the polymer material contained in the needle base mixture. For example, the aforementioned polymer material may be maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, b-cyclodextrin (b-cyclodextrin), 2-hydroxypropyl-b-cyclodextrin, dextran, amylopectin, starch, sodium hyaluronate (sodium hyaluronate), poly (methyl vinyl ether-alt-maleic anhydride) (PMVE / MA), sodium carboxymethylcellulose (CMC), methyl cellulose ( methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, poly (vinyl alcohol, PVA), polyethylene Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polylactic acid (PLA), poly (glycolic acid, PGA), polylactic acid-glycolic acid copolymer (poly ( lactic-co-glycolic acid), PLGA), chitosan Or a combination thereof, but it is not limited to this.

In one embodiment, the needle-bottom mixed solution may contain an aqueous solution of polyvinyl alcohol, b-cyclodextrin and trehalose, and the concentration of the needle-bottom mixed solution is a polymer aqueous solution of 20 wt% to 50 wt%. That is, the water content of the needle bottom mixed liquid is 50% to 80%. Based on the polymer material, the weight ratio of polyvinyl alcohol is 30 wt% to 80 wt%, and the weight ratio of b-cyclodextrin is less than or equal to 50 wt%. Here, the viscosity measured at 25 ° C and a shear rate of 1 S ^-1 of the needle bottom mixed liquid is preferably 100,000 cP to 300,000 cP.

In another embodiment, the needle-bottom mixed solution may contain an aqueous solution of polyvinyl alcohol and polyvinylpyrrolidone, and the concentration of the needle-bottom mixed solution is a polymer aqueous solution of 20 wt% to 50 wt%. Based on the polymer material, the weight ratio of polyvinylpyrrolidone is 50 wt% or less. Here, the measured viscosity of the needle bottom mixed liquid at 25 ° C and a shear rate of 1 S ^-1 is preferably 10,000 cP to 30,000 cP.

In one embodiment, the master mold may be a hard master mold, and the material of the hard master mold may be glass, quartz, silicon wafer, metal, metal oxide, metal alloy; the metal material may be aluminum, Copper or nickel, but not limited to this. In another embodiment, the master mold may be a soft master mold, and the material of the soft master mold may be a polymer, metal foil or flexible glass; the polymer is polydimethyl silicon Poly (dimethylsiloxane) (PDMS), poly (methyl methacrylate, PMMA), polycarbonate (PC), polyethersulfone (PES), etc., but not limited to this.

According to this creation, the shape of the holes in the master mold may be conical, square, or spire, but it is not limited to this. In the master mold, the master mold has a reference surface and a plurality of holes, and each hole is concavely formed from the reference surface. The depth of each hole is between 75 μm and 1500 μm, preferably between 150 μm and 1200 μm, more preferably between 175 μm and 1000 μm, and even more preferably between 200 μm and 950 μm. The maximum width of each hole is 50 μm to 600 μm, preferably between 75 μm and 550 μm, more preferably between 100 μm and 500 μm, and even more preferably between 100 μm and 450 μm.

In the medical beauty microneedle patch, the needle shape of each microneedle structure may be a cone shape, a square cone shape, or a spire type, but it is not limited thereto.

In the medical beauty microneedle patch, the needle length of each microneedle structure may be less than 1500 μm; preferably, it is less than 1000 μm; even more preferably, it is between 200 μm and 950 μm.

In the medical beauty microneedle patch, the tip radius of each microneedle structure may be less than 15 μm; preferably, it is less than 11 μm; even more preferably, it may be between 5 μm and 10 μm. In addition, the apex angle of the needle tip of the medical beauty microneedle patch may be less than 30 °.

In the medical beauty microneedle patch, the density of the microneedle structure may be between 100 needles / cm ² and 1000 needles / cm ² ; preferably 150 needles / cm ² to 750 needles / cm ² .

In application, by controlling the needle length of the medical beauty microneedle patch, the medical beauty microneedle patch can prevent the nervous system under the dermal layer from being used, so it can reduce the fear of the user and avoid its pain. sense. In addition, the medical beauty microneedle patch produced by this creation has the advantages of convenient operation, and it is more conducive to avoiding the effect of active ingredients due to gastric acid effect during oral administration.

The following is a list of several methods of making medical microneedle patches as examples to explain the implementation of this creation; those skilled in this art can easily understand the advantages and effects that this creation can achieve through the content of this manual, and it is not inconsistent Various modifications and changes are made in the spirit of this creation to implement or apply the content of this creation.

Examples 1

Please refer to FIG. 1 and FIG. 2. The medical beauty microneedle patch of this embodiment is prepared by the following method.

First, as shown in step (a) of FIG. 1 and FIG. 2, a master mold 10 is prepared. The master mold 10 has a reference surface 11 and a plurality of holes 12. The concave mold is formed, and the plurality of holes 12 are concavely arranged on the mother mold 10 in a matrix arrangement. In this embodiment, the material of the master mold 10 is PDMS. The hole density on the master mold 10 is 289 holes / cm ^{2. The} hole array range is 1.5 cm × 1.5 cm. The shape of each hole 12 is a square cone. The depth (the vertical distance between the end of the hole 12 and the reference plane 11) is 750 μm, and the maximum width (the maximum inner diameter of the horizontal plane where the hole 12 is flush with the reference plane 11) is 300 μm.

Then, as shown in step (b) of FIG. 1, the needle tip mixed solution 21 ′ is applied to the plurality of holes 12 of the master mold 10 by using a slit coating method to fill the needle tip mixed solution 21 ′. The plurality of holes 12 of the master mold 10 is until the liquid level of the needle tip mixed liquid 21 'is flush with the reference surface 11, and a master mold 10A containing the needle tip mixed liquid is obtained. Specifically, the step (b) can be completed by performing steps (b1) to (b4) in sequence. As shown in step (b1) of FIG. 2, the slit-type coating method is used to make the needle tip mixed liquid 21 ′ from the slit-type coating head S1 at a coating gap of 1000 μm and a coating speed of 3 m / min. A slit nozzle is extruded and coated on the master mold 10. The needle tip mixed solution 21 ′ is a 20 wt% aqueous solution containing blue copper peptide and methyl vinyl ether-maleic anhydride copolymer, that is, the needle tip mixed solution 21 ′ contains 80 wt% water and 20 wt% blue A mixture of copper peptide and methyl vinyl ether-maleic anhydride copolymer. The viscosity of the needle tip mixture 21 ′ at 25 ° C and 1 S ^-1 is 40 cP, and its surface tension is 30 dyne. / cm. Next, as shown in step (b2) of FIG. 2, the needle tip mixed solution 21 ′ and the master mold 10 are put together in a vacuum oven with a pressure of 20 torr to evacuate, so that the needle tip mixed solution 21 ′ can be drawn from the reference surface 11. The upper part flows into the plurality of holes 12 of the mother mold 10 through air extraction, and covers the reference surface 11 and all the holes 12 of the mother mold 10. Then, as shown in step (b3) of FIG. 2, use the scraper S2 to scrape the needle tip mixed solution 21 ′ on the reference surface 11 until the liquid level of the needle tip mixed solution 21 ′ is flush with the reference surface 11 to obtain a package. The mother mold 10A having the needle tip mixed liquid is in a state of step (b4) shown in FIG. 2. In another embodiment, the step (b2) can also be completed by centrifugation; for example, the mother mold containing the needle tip mixture is placed in a centrifuge, and the centrifuge is continuously centrifuged at 3600 rpm for 20 minutes, so that The needle tip mixture can flow downward from the reference surface and be fixed in multiple holes of the master mold, and cover the reference surface and all holes.

Next, as shown in step (c) in FIG. 1 and FIG. 2, the master mold 10A containing the needle-point mixed solution is continuously dried at a temperature of 30 ° C. for 1 hour, thereby making the aforementioned needle-point mixed solution 21 ′ Dried into the needle tip layer 21 and making the surface of the needle tip layer 21 lower than the reference surface 11 to obtain a female mold 10B having the needle tip layer.

Thereafter, as shown in step (d) of FIG. 1, a needle-bottom mixed solution 22 ′ is formed on the needle-point layer 21 and in the plurality of holes 12, so that the needle-bottom mixed solution 22 ′ covers the needle-point layer 21 and the reference. The surface 11 and the plurality of holes 12 obtain a female mold 10C filled with a needle bottom mixed liquid. Specifically, the step (d) may be completed by performing the steps (d1) to (d4) in sequence. As shown in step (d1) shown in FIG. 2, the slit-type coating method is used to make the needle bottom mixed solution 22 ′ from the slit-type coating head at a coating gap of 1600 μm and a coating speed of 3 m / min. The slit nozzle of S1 is extruded to apply on a mother die 10B having a needle tip layer. The needle bottom mixed solution 22 ′ is a 50 wt% polyvinyl alcohol aqueous solution, that is, the needle bottom mixed solution 22 ′ contains 50 wt% of water and 50 wt% of polyvinyl alcohol, and the needle bottom mixed solution 22 ′ is at 25%. The measured viscosity at ° C, 1 S ^-1 is 200,000 cP, and its surface tension is 37 dyne / cm. Next, as shown in step (d2) of FIG. 2, the needle bottom mixed liquid 22 ′ and the female mold 10B having the needle tip layer are put together in a vacuum oven with a pressure of 35 torr to evacuate, so that the needle bottom mixed liquid 22 ′ Can flow from the reference surface 11 into the plurality of holes 12 of the master mold 10 through air extraction, and cover the tip layer 21, the reference surface 11 and all the holes 12. Then, as shown in step (d3) of FIG. 2, the needle-bottom mixed solution 22 ′ on the reference surface 11 is scraped off with a scraper S2 until the liquid level of the needle-bottom mixed solution 22 ′ is flush with the reference surface 11 to obtain A master mold 10C containing a mixture of needle bottoms is shown in step (d4) in FIG. 2. In another embodiment, the step (d2) can also be completed by centrifugation; for example, the mother mold containing the needle bottom mixed solution is placed in a centrifuge and centrifuged at 3600 rpm for 15 minutes, The needle bottom mixed liquid can flow downward from the reference surface and be fixed in a plurality of holes of the master mold, and covers the needle tip layer, the reference surface and all holes.

Next, as shown in step (e) in FIG. 1 and FIG. 2, the female mold with the needle bottom mixed liquid 10C is continuously dried at a temperature of 30 ° C. for 48 hours, thereby making the needle bottom mixed liquid 22 ′ Is dried to the needle base layer 22 and adhered to the needle tip layer 21 to obtain a female mold 10D having the needle tip layer and the needle base layer.

Finally, as shown in step (f) of FIG. 1, the needle tip layer 21 and the needle bottom layer 22 are removed from the mother mold 10D having the needle tip layer and the needle bottom layer to obtain the medical beauty microneedle patch 20. Specifically, the step (f) can be completed by performing the steps (f1) to (f2) in sequence. As shown in the step (f1) in FIG. 2, a back layer 23 is formed on the mother mold 10D having the needle tip layer and the needle bottom layer, so that the needle tip layer 21 and the needle bottom layer 22 are sandwiched between the mother mold 10D and the back layer 23. between. In this embodiment, the back layer 23 is a breathable tape. Finally, as shown in step (f2) of FIG. 2, the needle tip layer 21, the needle bottom layer 22, and the back layer 23 are simultaneously removed from the mother mold 10D having the needle tip layer and the needle bottom layer, and the medical microneedles of this embodiment are completed. Manufacturing process of the patch 20.

According to the above manufacturing method, in this embodiment, the needle tip mixed solution is first formed on the master mold by using the slit coating method, and then the needle bottom mixed solution is formed on the dried needle tip layer by using the slit coating method, so that the needle bottom mixed solution can be formed. Through the polymer force of the needle tip mixed liquid and the needle bottom mixed liquid, the dried needle tip layer and the needle bottom layer are adhered to each other, thereby achieving the effects of saving process time and cost, and improving mass production efficiency. In addition, the use of wet coating technology to make the medical beauty microneedle patch is more conducive to controlling the dose of the active ingredients of traditional Chinese medicine beauty in each microneedle structure, and to achieve the purpose of effective dose control.

As shown in FIG. 3, through the above-mentioned manufacturing method, the medical beauty microneedle patch 20 of this embodiment is sequentially bonded from bottom to top to form a back layer 23, a needle bottom layer 22, and a needle tip layer 21, each of which is bonded to each other. The needle tip layer 21 collectively constitutes a one-sided tapered structure, and the needle bottom layers 22 are spaced from each other and arranged in a matrix on the back layer 23.

Examples 2

This embodiment uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that this embodiment uses a doctor blade coating method to coat the tip mixture with the bottom of the needle. The mixture of the needle bottom is fixed in a plurality of holes by centrifugation, and the step of scraping the mixture of the needle bottom is omitted.

Specifically, after step (a), step (b1) is performed by a doctor blade coating method, and a needle tip mixed solution is applied to the master mold at a coating gap of 1000 μm and a coating speed of 3 m / min. Up; and then sequentially through steps (b2) to (b4) and (c) as described in Example 1, to obtain a master mold with a needle tip layer. The tip mixture was an aqueous solution of 20 wt% blue copper peptide and methyl vinyl ether-maleic anhydride copolymer, and the viscosity measured at 25 ° C and 1 S ^-1 of the tip mixture was 40. cP, with a surface tension of 30 dyne / cm. Based on the total weight of the entire needle-point mixture, the needle-point mixture contains 80 wt% of water and 20 wt% of a mixture of blue copper peptide and methyl vinyl ether-maleic anhydride copolymer.

After that, the step (d1) is performed by a doctor blade coating method to apply the needle-bottom mixture to the master mold at a coating gap of 1600 μm and a coating speed of 3 m / min; The mother mold of the bottom mixed liquid is placed in a centrifuge, and the centrifugation is continued at 3600 rpm for 15 minutes, so that the needle bottom mixed liquid can flow downward from the reference surface and fixed in a plurality of holes of the mother mold, and is covered in the needle tip layer, The reference plane and all holes; and then sequentially through step (e) as described in Example 1, a master mold having a needle tip layer and a needle bottom layer is obtained. The needle bottom mixture is a 50 wt% polyvinyl alcohol / b-cyclodextrin / trehalose aqueous solution, and the viscosity measured at 25 ° C and 1 S ^-1 of the needle bottom mixture is 230,000 cP. The surface tension was 37 dyne / cm. Based on the total weight of the entire needle base mixed liquid, the needle base mixed liquid contains 50 wt% of water and 50 wt% of a mixture of polyvinyl alcohol, b-cyclodextrin and trehalose. Based on the total weight of polyvinyl alcohol, b-cyclodextrin and trehalose, the content of polyvinyl alcohol is 40 wt%, and the content of b-cyclodextrin is not more than 50 wt%.

In this embodiment, the needle bottom layer can be adhered to the needle tip layer by the high polymer force of the material itself; therefore, after step (e), the needle bottom layer can be directly removed from the mother mold having the needle tip layer and the needle bottom layer simultaneously. The needle tip layer and the needle bottom layer which are adhered to each other are completed, and step (f) is completed to obtain the medical beauty microneedle patch of this embodiment.

Examples 3

This embodiment uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that this embodiment uses a doctor blade coating method to coat the tip mixture with the bottom of the needle. In addition, the structure of the master mold is changed and the step of scraping off the mixed liquid at the bottom of the needle is omitted. In addition, the composition of the needle-point mixture used in this embodiment is also different from the composition of the needle-point mixture in Example 1. Please refer to FIG. 4 for the detailed manufacturing process of this embodiment. The manufacturing method of this embodiment will be described below with reference to FIGS. 1 and 4.

First, as shown in step (a) of FIGS. 1 and 4, a master mold 10 is prepared. The master mold 10 has a reference surface 11 and a plurality of holes 12. In this embodiment, the material of the master mold 10 is PDMS, the hole density on the master mold 10 is 289 holes / cm ² , the hole array range is 1.0 cm × 1.0 cm, and the shape of each hole 12 is conical and its depth (That is, the vertical distance between the end of the hole 12 and the reference surface 11) is 600 μm, and the diameter (that is, the maximum inner diameter of the horizontal plane where the hole 12 is flush with the reference surface 11) is 300 μm.

Then, as shown in step (b) of FIG. 1, the needle tip mixed solution 21 ′ is applied to the plurality of holes 12 of the master mold 10 by a doctor blade coating method, so that the needle tip mixed solution 21 ′ fills the mother. A plurality of holes 12 of the mold 10 is used until the liquid level of the needle tip mixed liquid 21 'is flush with the reference surface 11 to obtain a female mold 10A filled with the needle tip mixed liquid. Specifically, as shown in step (b1) shown in FIG. 4, step (b1) of this embodiment uses a doctor blade coating method with a coating gap of 800 μm and a coating speed of 3 m / min, using a doctor blade. S1A applies the needle tip mixed solution 21 'on the master mold 10, and then sequentially proceeds through steps (b2) to (b4) and (c) as described in Example 1 to obtain a master mold 10B having a needle tip layer. Here, the tip mixture 21 ′ is a 10 wt% aqueous solution containing sodium carboxymethylcellulose / hyaluronic acid / polyoxyethylene monolaurate desorbate (polyoxyethylene sorbitan monolaurate, polysorbate 20, tween 20), and the tip The viscosity of the mixed solution 21 ′ measured at 25 ° C and 1 S ^-1 was 45 cP, and its surface tension was 35 dyne / cm. Based on the total weight of the needle tip mixture, the needle tip mixture contains 90 wt% water and 10 wt% sodium carboxymethyl cellulose, a mixture of hyaluronic acid and polyoxyethylene monolaurate desorbate. Based on the total weight of sodium carboxymethylcellulose, hyaluronic acid, and polyoxyethylene monolaurate sorbitan, the content of sodium carboxymethylcellulose is not more than 50 wt%, and polyoxyethylene monolaurate sorbitan Its content is 0.5 wt%.

Thereafter, as shown in step (d) of FIG. 1, a needle-bottom mixed solution 22 ′ is formed on the needle-point layer 21 and in the plurality of holes 12, so that the needle-bottom mixed solution 22 ′ covers the needle-point layer 21 and the reference. The surface 11 and the plurality of holes 12 obtain a female mold 10C filled with a needle bottom mixed liquid. Specifically, as shown in step (d1) shown in FIG. 4, step (d1) of this embodiment also uses a doctor blade coating method, with a coating gap of 1000 μm and a coating speed of 3 m / min, using a doctor blade. In S1A, the needle bottom mixed solution 22 'is applied on a mother mold 10B having a needle tip layer. Next, as shown in step (d2) of FIG. 4, the needle bottom mixed liquid 22 ′ and the female mold 10B having the needle tip layer are put together in a vacuum oven at a pressure of 30 torr to evacuate the needle bottom mixed liquid 22. ′ Can be flowed from the reference surface 11 into a plurality of holes 12 through suction to obtain a female mold 10C filled with a needle bottom mixed liquid. Here, the needle bottom mixed solution is a 50 wt% polyvinyl alcohol / b-cyclodextrin / trehalose aqueous solution, and the viscosity measured at 25 ° C and 1 S ^-1 of the needle bottom mixed solution is 230,000 cP. , Its surface tension is 37 dyne / cm. Based on the total weight of the needle-bottom mixture, the needle-bottom mixture contains 50 wt% of water and 50 wt% of a mixture of polyvinyl alcohol, b-cyclodextrin and trehalose; based on polyvinyl alcohol, b- Based on the total weight of cyclodextrin and trehalose, the content of polyvinyl alcohol is 40 wt%, and the content of b-cyclodextrin is not more than 50 wt%.

Next, as shown in step (e) in FIG. 1 and FIG. 4, the female mold with the needle bottom mixed liquid 10C is continuously dried at a temperature of 30 ° C. for 12 to 16 hours, so that the needle bottom is mixed. The liquid 22 ′ is dried into a needle base layer 22A and adhered to the needle tip layer 21 to obtain a female mold 10D having a needle tip layer and a needle base layer. The needle base layer 22A is simultaneously adhered to the needle tip layer 21 and covers the reference surface. 11; Finally, the steps (f1) and (f2) as described in Example 1 are sequentially performed to complete the manufacturing process of the medical beauty microneedle patch 20A of this embodiment.

Please refer to FIG. 5, the medical beauty microneedle patch 20A is sequentially bonded from bottom to top to form a back layer 23, a needle bottom layer 22A, and a needle tip layer 21, and each of the needle bottom layers 22A and the needle tip layer 21 bonded together form a In the conical structure, the needle bottom layers 22 are connected to each other and formed on the back layer 23, and the conical structures are arranged in a spaced and matrix manner.

Examples 4

This embodiment uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that in this embodiment, the structure of the master mold is changed and the needle tip is coated by a doctor blade coating method. Mixing the liquid with the needle bottom and omitting the step of scraping the needle bottom mixed liquid.

Specifically, in step (a), the selected master mold has a reference plane and a plurality of holes. The hole density on the master mold is 289 holes / cm ² , and the hole array range is 1 cm × 1 cm. The shape is a square cone with a depth of 600 μm and a maximum width of 300 μm.

In (b1) step, a coating gap of 400 μm, 3 m / min the coating speed, using a doctor knife coating mixture is applied to the needle tip on the master mold; and then sequentially through as in Example 1 In the steps (b2) to (b4), and in step (c), the master mold with the needle tip mixed liquid is continuously dried at a temperature of 30 ° C for 3 hours to obtain a master mold having a needle tip layer. The tip of mixture containing 20 wt% of the hyaluronic acid / 2-hydroxypropyl cyclodextrin -b- / monolaurate polyoxyethylene polysorbate solution to water mountains, and the mixed solution at the needle tip 25 ° C, 1 S ^- The viscosity measured at ¹ was 13,500 cP and its surface tension was 30 dyne / cm. Based on the total weight of the needle tip mixture, the needle tip mixture contains 80 wt% water and 20 wt% hyaluronic acid, 2-hydroxypropyl-b-cyclodextrin, polyoxyethylene monolaurate desorbate Of a mixture. Based on the total weight of hyaluronic acid, 2-hydroxypropyl-b-cyclodextrin and polyoxyethylene monolaurate desorbate, the content of 2-hydroxypropyl-b-cyclodextrin is not more than 50 wt%, The content of polyoxyethylene monolaurate desorbate was 0.5 wt%.

In step (d1), a needle-bottom coating method is applied to the master mold at a coating gap of 1000 μm and a coating speed of 3 m / min by a doctor blade coating method. Next, in step (d2), the needle bottom mixed liquid and the mother mold are put together in a vacuum oven with a pressure of 50 torr to evacuate, so that the needle bottom mixed liquid can flow from the reference plane to the mother mold through suction. Among the plurality of holes, a master mold containing a mixture of needle bottoms was obtained. The needle bottom mixed solution is a 50 wt% polyvinyl alcohol / polyvinylpyrrolidone aqueous solution, and the measured viscosity of the needle bottom mixed solution at 25 ° C and 1 S ^-1 is 18000 cP, and its surface tension is 37 dyne / cm. Based on the total weight of the needle bottom mixed solution, the needle bottom mixed solution contains 50 wt% of water and 50 wt% of a mixture of polyvinyl alcohol and polyvinylpyrrolidone. Based on the total weight of polyvinyl alcohol and polyvinylpyrrolidone, the content of polyvinylpyrrolidone is not more than 50 wt%.

In step (e), at 30 ° C, the female mold with the needle bottom mixed liquid is continuously dried for 48 hours, so that the needle bottom mixed liquid is dried to the bottom of the needle and adhered to the needle tip layer. Thus, a female mold having a needle tip layer and a needle bottom layer was obtained.

In this embodiment, the needle bottom layer can be adhered to the needle tip layer by the high polymer force of the material itself; therefore, after step (e), the needle bottom layer can be directly removed from the mother mold having the needle tip layer and the needle bottom layer simultaneously. The needle tip layer and the needle bottom layer which are adhered to each other are completed, and step (f) is completed to obtain the medical beauty microneedle patch of this embodiment.

Examples 5

This embodiment uses the method described in the previous Example 4 to prepare a medical microneedle patch. The main difference is that the method of step (e) dries the needle base mixed solution and the composition of the needle base mixed solution.

Here, the needle-bottom mixed solution is 15% by weight of polyvinyl alcohol and polyvinylpyrrolidone, the weight ratio of the polyvinyl alcohol to the polyvinylpyrrolidone is 4: 1, and the needle-bottom mixed solution is at 25 ° C, 1 The measured viscosity at S ^-1 was 11,000 cP, and its surface tension was 37 dyne / cm.

In step (e), the embodiment is dried at room temperature for 24 hours, so that the needle bottom layer is adhered to the needle tip layer. Finally, through the steps (f1) and (f2) described in Example 4, the medical beauty microneedle patch is prepared.

Examples 6

This embodiment uses the method described in the previous Example 4 to prepare a medical microneedle patch. The main difference is that the method of step (e) dries the needle base mixed solution and the composition of the needle base mixed solution.

Specifically, the needle-bottom mixed solution is 15% by weight of polyvinyl alcohol and polyvinylpyrrolidone. The weight ratio of the polyvinyl alcohol to the polyvinylpyrrolidone is 4: 1, and the needle-bottom mixed solution is at 25 ° C. The measured viscosity at 1 S ^-1 is 11000 cP, and its surface tension is 37 dyne / cm.

In step (e), this example is to continuously dry the mother mold with the needle bottom mixed liquid at a temperature of -20 ° C for 15 minutes, and obtain the needle bottom layer and the needle tip layer which are dried for the first time; It is dried at 4 ° C for 15 minutes to obtain the secondary dried needle bottom and needle tip layer; then it is returned to the -20 ° C environment and dried for 15 minutes to obtain the three dried needle bottom and needle tip layer; Dry at 4 ° C for 15 minutes to obtain four dried needle bottoms and needle tip layers. Finally, dry the four dried needle bottoms and needle tip layers at room temperature for 24 hours to complete step (e). So that the bottom of the needle is adhered to the tip layer. Finally, through the steps (f1) and (f2) described in Example 4, the medical beauty microneedle patch is prepared.

Examples 7

This example uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that the needle tip mixture is 25 wt% of blue copper peptide / carboxymethyl cellulose. An aqueous solution of sodium / maltose / polyoxyethylene monolaurate desorbate, and the measured viscosity of the needle tip mixture at 25 ° C, 1 S ^-1 was 1500 cP, and its surface tension was 35 dyne / cm.

Comparative example 1

This comparative example uses the method described in Example 1 to prepare a medical microneedle patch. The main difference is that the needle tip mixture is 3 wt% of blue copper peptide / carboxymethyl cellulose. An aqueous solution of sodium / polyoxyethylene monolaurate dehydrated sorbate, and the measured viscosity of the needle tip mixture at 25 ° C, 1 S ^-1 was 31 cP, and its surface tension was 35 dyne / cm.

Test example 1

In order to analyze the mechanical strength of the medical beauty microneedle patches of Examples 5 and 6, two types of flat films of the same thickness were made in this test example. Among them, the flat film 1 (simulating the medical beauty microneedle patch of Example 5) and the flat film 2 (simulating the medical beauty microneedle patch of Example 6) are both coated with a 15 wt% aqueous solution of polyvinyl alcohol / polyvinylpyrrolidone. The weight ratio of the polyvinyl alcohol to the polyvinylpyrrolidone obtained by the cloth liquid is 4: 1.

In the drying process, the flat film 1 is dried at room temperature for 24 hours, and the drying step of the flat film 1 is completed; the flat film 2 is first dried at -20 ° C for 15 minutes, and then dried at 4 ° Dry at 15 ° C for 15 minutes, then return to -20 ° C for 15 minutes, then dry at 4 ° C for 15 minutes, and finally dry at room temperature for 24 hours to complete the drying step of flat film 2.

For the aforementioned flat film 1 and flat film 2, the test examples are analyzed by the ASTM D882 test method. The Young's modulus of the flat film 1 is 32.8 MPa, and the Young's modulus of the flat film 2 is significantly increased to 81.5 MPa. About 3.2 times.

It can be seen that, through a specific drying step, the medical beauty microneedle patch of Example 6 can have higher mechanical strength and obtain better microneedle patch quality.

Test example 2

In order to analyze the needle tip solubility of the medical beauty microneedle patch of Example 7 and Comparative Example 1, two kinds of flat films of the same thickness were made in this test example. The flat film 3 (a medical microneedle patch of Example 7) is a 25 wt% aqueous solution containing blue copper peptide / sodium carboxymethyl cellulose / maltose / polyoxyethylene monolaurate desorbate Coated as a coating liquid, the flat film 4 (simulating the medical beauty microneedle patch of Comparative Example 1) is made of 3 wt% blue copper peptide / sodium carboxymethyl cellulose / polyoxyethylene monolaurate Coated with an aqueous solution of sorbitan, the thickness of the flat film 3 and the flat film 4 are equal, and both materials are cut to a size of 2 cm × 2 cm.

In order to analyze the dissolution characteristics of the aforementioned planar film 3 and planar film 4, the same method is used to analyze the planar film 3 and the planar film 4 in this test example. Specifically, the PBS buffer solution was used to simulate the human body fluid environment, and the flat films 3 and 4 of the same size were immersed in a petri dish containing a known weight of PBS buffer solution at 37 ° C for 15 minutes. Next, the filter paper was placed on a Buchner funnel connected to a suction device, and the buffer solution impregnated with the flat membrane 3 and the buffer solution impregnated with the flat membrane 4 in the aforementioned petri dishes were suction-filtered, and then dried at 103 ° C. Dry the flat film remaining on the filter paper until the weight does not change any more to obtain the weight of the remaining flat film. Then calculate the weight difference between the flat film before immersion and the remaining flat film after immersion. The difference in weight is the dissolved weight of the flat film. Divide the dissolved weight of the flat film by the weight of the initial PBS buffer solution. Dissolution characteristics of the flat film 4.

The experimental results show that the solubility of Planar Film 3 measured by the aforementioned test method is 0.41 wt%, and the solubility of Planar Film 4 measured by the aforementioned test method is 0.026 wt%; it can be seen that the use of 25 wt% blue copper peptide / The medical beauty microneedle patch (Example 7) prepared by the aqueous solution of carboxymethylcellulose sodium / maltose / polyoxyethylene monolaurate desorbate as a needle-point mixture was more soluble than the medical beauty of Comparative Example 1. The microneedle patch has good solubility.

In addition, it can be seen from the manufacturing process of the medical beauty microneedle patch of Comparative Example 7 and Comparative Example 1 that the use of a suitable needle tip mixture to make the medical beauty microneedle patch can ensure that the medical beauty microneedle patch of Example 7 can obtain a better quality. Good solubility, so it can pass a sufficient amount of medical beauty active ingredients; in contrast, due to the poor solubility of the needle tip layer of the medical beauty microneedle patch of Comparative Example 1, the finished product can not ensure that the needle tip layer is dissolved and enough medicine is delivered. Beauty active ingredients or achieve their effect.

Test example 3

In order to confirm that the finished product made by the method of creating the medical beauty microneedle patch can indeed be used for medical beauty, this test example selects the depilated pigskin as the puncture object and conducts an in vitro puncture test to observe the medical beauty The depth of puncture of the needle patch.

In this test example, the medical beauty microneedle patch of the aforementioned Example 2 is selected as a representative example. The medical beauty microneedle patch is attached to a self-made jig, and pressed against the depilated pigskin for about 5 minutes. , Stain the punctured pig skin and observe whether the puncture point of the medical beauty microneedle patch appears on the pig skin.

Next, the punctured pig skin was immersed in formalin, and the tissue was fixed, sliced, and stained. The depth of the puncture point in the punctured pig skin was observed with an optical microscope. The results are shown in FIG. 6.

As shown in FIG. 6, the puncture depth of the medical beauty microneedle patch of Example 2 is about 100 μm; it can be seen that the medical beauty microneedle patch prepared by the foregoing manufacturing method can indeed penetrate the stratum corneum with an isolation barrier. And it reaches above the epidermal layer and the dermal layer, so that the medical beauty active ingredients in the medical beauty microneedle patch can exhibit desired effects in the body.

Test example 4

In order to confirm that the finished product produced by the method of creating the medical beauty microneedle patch can indeed be used for medical beauty, this test example uses a 6-week-old mouse (strain Balb / C) as the puncture object for living body Puncture test to observe the puncture situation of Yimei microneedle patch.

In this test example, the medical beauty microneedle patch as in the foregoing Example 2 is selected as a representative example, and the medical beauty microneedle patch is attached to a self-made jig.

Two days before the biopsy test, the hair was removed from the area intended for the biopsy test on the mouse by using a hair removal cream, as the observation object of the medical beauty microneedle patch. During the biopsy test, the mice were anesthetized, and the medical beauty microneedle patch of Example 2 was pressed against the hair-removed area of the mouse for about 1 minute, and then the medical beauty microneedle patch was continuously attached to the mouse skin. After 1 hour, observe whether the puncture point of the medical beauty microneedle patch appears on the rat skin; as shown in FIG. 7, the medical beauty microneedle patch of Example 2 has indeed produced a microneedle hole array on the mouse skin as expected. .

In addition, in this test example, an optical microscope was used to observe the change in the height of the microneedle structure on the medical microneedle patch before and after the puncture. Please refer to FIG. 8A. Before the puncture, the needle height of the medical beauty microneedle patch is 750 μm. Please refer to FIG. 8B. After the puncture, the needle height of the medical beauty microneedle patch is 260 μm.

As the needle tip layer of the medical beauty microneedle patch of Example 2 contains the medical beauty active ingredient, it can be seen that the medical beauty active ingredient of the medical beauty microneedle patch has been passed into mice as expected, and dissolved in it to exert the desired effect. Medical beauty effect.

10‧‧‧master

10A‧‧‧Master with mixed tip

10B‧‧‧Master with needle tip layer

10C‧‧‧Master with mixed liquid at the bottom of the needle

10D‧‧‧Master with needle tip layer and needle bottom layer

11‧‧‧ datum

12‧‧‧ Hole

20, 20A‧‧‧Medical Microneedle Patch

21‧‧‧ Needle Tip Layer

21′‧‧‧ Needle tip mixture

22, 22A‧‧‧ Needle bottom

22′‧‧‧ Needle tip mixture

23‧‧‧Back layer

S1‧‧‧Slit-type coating head

S1A‧‧‧Scraper

S2‧‧‧Scraper

FIG. 1 is a flowchart of a method for creating a medical microneedle patch. FIG. 2 is a schematic diagram illustrating a method for manufacturing a medical microneedle patch of Example 1. FIG. FIG. 3 is a schematic diagram of a medical beauty microneedle patch prepared by the manufacturing method of Example 1. FIG. FIG. 4 is a schematic diagram illustrating a method for manufacturing the medical beauty microneedle patch of Embodiment 3. FIG. FIG. 5 is a schematic diagram of a medical beauty microneedle patch prepared by the manufacturing method of Embodiment 3. FIG. FIG. 6 is a photograph of the medical beauty microneedle patch of Example 2 after puncturing pig skin. FIG. 7 is a photograph of the medical beauty microneedle patch of Example 2 after puncturing mouse skin. 8A and 8B are photographs of the medical beauty microneedle patch of Example 2 before and after puncturing the mice.

no.

Claims (19)

A method for manufacturing a medical microneedle patch includes the following steps: (a) providing a master mold having a reference surface and a plurality of holes, the plurality of holes are concavely formed from the reference surface; (b) ) Forming a needle-point mixed liquid in a plurality of holes in the master mold, thereby filling the needle-point mixed liquid in the holes in the master mold to obtain a master mold containing the needle-point mixed liquid, and the liquid level of the needle-point mixed liquid It is flush with the reference plane of the master mold, and the needle tip mixture contains medicinal active ingredients; (c) The needle tip mixture is dried into a needle tip layer to obtain a master mold with a needle tip layer, the surface of the needle tip layer is lower than that of the mother die. (D) forming a needle base mixed liquid on the needle tip layer and the plurality of holes, so that the needle base mixed liquid covers the needle tip layer and the reference surface and multiple holes of the master mold to obtain A female mold containing the needle bottom mixed liquid; (e) drying the needle bottom mixed liquid into the needle bottom layer, thereby making the needle bottom layer adhere to the needle tip layer; and (f) removing the adhesive needle point layer from the mother mold. And the needle bottom layer to obtain the medical beauty microneedle patch. The manufacturing method according to claim 1, wherein the viscosity of the needle tip mixed liquid is lower than the viscosity of the needle bottom mixed liquid. The manufacturing method as described in claim 2, wherein the viscosity of the needle tip mixed liquid is 3 centipoise to 500,000 centipoise. The manufacturing method as described in claim 2, wherein the viscosity of the needle base mixed liquid is 100 centipoise to 5000000 centipoise. The manufacturing method according to claim 1, wherein the concentration of the needle tip mixed solution is 5 wt% to 50 wt%. The manufacturing method according to claim 1, wherein the concentration of the needle bottom mixed liquid is 10 wt% to 95 wt%. The manufacturing method according to claim 1, wherein the surface tension of the needle tip mixed liquid is less than or equal to 70 dyne / cm. The manufacturing method according to claim 1, wherein the surface tension of the needle bottom mixed liquid is less than or equal to 50 dyne / cm. The production method according to claim 1, wherein the steps (c) and (e) are performed by freeze-drying or drying at room temperature. The method according to claim 1, wherein the drying temperature in the steps (c) and (e) is -80 ° C to 160 ° C. The manufacturing method according to claim 1, wherein the step (e) includes: drying the needle bottom mixed liquid at -80 ° C to 0 ° C to dry the needle bottom layer to obtain an initial dried needle bottom layer and the needle tip layer; The first dried needle bottom layer and the needle tip layer are placed at 2 ° C to 10 ° C to obtain the secondary dried needle bottom layer and the needle tip layer; and the second dried needle bottom layer and the needle tip layer are dried at room temperature. In this way, the bottom of the needle is adhered to the needle tip layer. The manufacturing method according to claim 1, wherein after step (e), the step (f) includes: forming a back layer on the master mold and the needle bottom layer, thereby making the needle tip layer and the needle The bottom layer is sandwiched between the mother mold and the back layer; and the needle tip layer, the needle bottom layer and the back layer are simultaneously removed from a mother mold having the needle tip layer and the needle bottom layer to obtain the medical beauty microneedle patch sheet. The manufacturing method according to claim 1, wherein the step (b) comprises: forming the needle-point mixed liquid on the mother mold, and then flowing the needle-point mixed liquid into a plurality of holes, thereby covering the needle-point mixed liquid on the mother. The reference surface of the mold and a plurality of holes; and removing the needle tip mixed liquid on the reference surface, so that the liquid level of the needle tip mixed liquid is flush with the reference surface of the mother mold. The production method according to claim 13, wherein the method for causing the needle tip mixed liquid to flow into the plurality of holes includes a vacuum evacuation method and a centrifugation method. The manufacturing method according to claim 1, wherein the step (d) includes forming the needle base mixed liquid on the master mold, and then allowing the needle base mixed liquid to flow into a plurality of holes, thereby covering the needle tip mixed liquid on the master mold. The needle tip layer and the reference plane of the mother mold and a plurality of holes obtain the mother mold filled with the needle bottom mixed liquid. The manufacturing method according to claim 15, wherein the method of causing the needle bottom mixed liquid to flow into the plurality of holes includes a vacuum evacuation method and a centrifugation method. The production method according to any one of claims 1 to 16, wherein the method of forming the needle tip mixed liquid in the plurality of holes of the master mold in the step (b) includes a slit coating method and a doctor blade method Coating method, swash plate coating method, dip coating method, inkjet printing method or nozzle printing method; the method of forming the needle bottom mixed liquid on the needle tip layer in the step (d) and the plurality of holes includes a slit Coating method, doctor blade coating method, swash plate coating method, dip coating method, inkjet printing method, or nozzle printing method. The manufacturing method according to any one of claims 1 to 16, wherein the medical beauty active ingredient comprises gallic acid, arbutin, vitamin C phosphate sodium salt, vitamin C magnesium phosphate salt, vitamin C glucoside, vitamin C, and Derivatives, Vitamin E and its derivatives, Vitamin A and its derivatives, ellagic acid, camomile extract, cetyl tranexamate, potassium 4-methoxysalicylate, 3-O- Ethyl ascorbic acid, neuraminamine, lecithin, glycerin, polysaccharides, hyaluronic acid, sodium hyaluronate, protein, collagen, elastin, blue copper peptide, pentapeptide, hexapeptide, nonapeptide, amino acid, lemon Acid, uric acid, urea, glucose, sucrose, fructose, liver sugar, glucosaminoglycan, mucopolysaccharide, lactate, phosphate, ethyl pyrrolidone-5-carboxylate, grape extract, green tea extract, ginkgo extract, Soy extract, pomegranate extract, ginger extract, yeast extract, coix seed extract, lipoic acid, dextran, cocoid Q10, superoxide dismutase or a combination thereof. The manufacturing method according to any one of claims 1 to 16, wherein the needle tip mixture and the needle bottom mixture each independently comprise a polymer material selected from the group consisting of maltose , Sucrose, trehalose, lactose, dextrin, maltodextrin, b-cyclodextrin, 2-hydroxypropyl-b-cyclodextrin, dextran, amylopectin, sodium hyaluronate, methyl vinyl ether -Maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, polylactic acid , Polyglycolic acid, polylactic-co-glycolic acid copolymer, chitosan and combinations thereof.