TWI629073B - Microneedle patch manufacturing method - Google Patents

Abstract

The present invention relates to a method for manufacturing a microneedle patch, which firstly forms a mixture of a tip containing an active ingredient in a plurality of holes of a master mold, and after drying it into a tip layer, a barrier layer is formed on the tip layer. Then, the needle bottom liquid is formed on the barrier layer and the plurality of holes, and then the needle bottom liquid is dried to the needle bottom layer, thereby bonding the needle bottom layer to the needle tip layer, and finally unbonding from the master mold to each other. The needle tip layer, the barrier layer and the bottom layer of the needle form a microneedle patch. The method of the present invention can not only overcome the problems of bonding, machine alignment and production cost faced by the conventional microneedle patch, but also can save the process time, improve the mass production efficiency, and control the carrying amount of the active ingredient, and provide a suitable application. For the mass production of pharmaceutical or vaccine microneedle patches.

Description

Microneedle patch manufacturing method

This creation relates to the production technology of a medical product, especially a method for manufacturing a microneedle patch.

Transdermal drug delivery is a mode of administration that has attracted attention in recent years, and it can utilize non-invasive methods of administration to allow drugs or vaccines to be absorbed through the skin to exert their effects. Although transdermal drug delivery can avoid oral administration due to the action of the digestive system, it can not effectively control the efficacy, while avoiding the fear and pain caused by subcutaneous injection, but because the stratum corneum of the skin is both hydrophobic and negatively charged, Therefore, it is not suitable for delivering water-soluble drugs or water-soluble vaccines through the transdermal drug delivery system.

In view of the above problems, the prior art has developed a microneedle patch whose substrate is covered with a plurality of micron-sized microneedle structures that pierce the stratum corneum of the skin and deliver the drug or vaccine to the epidermal layer. And released. 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 or vaccines to be delivered into the range of fat-soluble and water-soluble, so that the above different types of drugs and vaccines It can be directly delivered to the epidermis layer through the microneedle structure on the microneedle patch to release the drug without any 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, which is required to firstly incorporate a biodegradable polymer colloid containing a drug to obtain a plurality of biodegradable carriers, and another It is necessary to first form a support substrate formed with a plurality of protruding support shafts, and pre-coat the adhesive on the support substrate; then, try to align the protruding support shaft on the surface of the support substrate. The above-mentioned biodegradable carrier is adhered to each other to obtain a mosaic transdermal drug release patch.

However, the above process method must additionally consider the spacing and alignment between the plurality of protruding support shafts on the supporting substrate and the plurality of carriers, and increase the difficulty of the process; and the step of applying the adhesive beforehand in the manufacturing process In order to bond the supporting substrate and the carrier, the complexity of the process and the production cost are increased.

In addition, when the microneedle patch is particularly used for the delivery of a pharmaceutically active ingredient or a vaccine active ingredient, how to control the carrying amount of the pharmaceutically active ingredient or the active ingredient of the vaccine becomes quite important. However, the above process method also does not teach or suggest how to effectively control the carrying amount of the medicinal active ingredient or the active ingredient of the vaccine in the microneedle patch, so the existing process method still needs to be improved.

In view of the above technical problems, one of the purposes of the present invention is to solve the technical defects and inconveniences in the prior art for manufacturing microneedle patches, and to provide a method for manufacturing a microneedle patch.

Another object of the present invention is to effectively control the carrying amount of the active ingredient in the microneedle patch, so that it can be used for making a medical microneedle patch or a vaccine microneedle patch.

In order to achieve the foregoing object, the present invention provides a method for fabricating a microneedle patch, comprising the steps of: (a) providing a master mold having a reference surface and a plurality of holes, the plurality of holes being recessed from the reference surface Forming a molding; (b) forming a tip mixture in the plurality of holes of the master mold, thereby filling the plurality of holes of the master mold with the tip mixture to obtain a master mold containing the needle tip mixture, The liquid level of the tip mixture is flush with the reference surface of the master mold, and the needle tip mixture contains the active ingredient; (c) drying the tip mixture to a tip layer to obtain a master having a tip layer, the surface of the tip layer being lower than the reference surface of the master; (d) forming a barrier solution on the tip layer and the plurality of holes, thereby allowing the barrier solution to cover the tip layer and the reference surface of the master mold and the plurality of holes to obtain a master mold containing the barrier solution; (e) drying the barrier solution as a barrier layer to obtain a master mold having a tip layer and a barrier layer, the surface of the barrier layer being lower than the surface of the tip layer than the reference surface of the master mold; (f) forming a mixture of a needle bottom And a plurality of holes in the barrier layer, thereby covering the barrier layer and the reference surface of the master mold and the plurality of holes to obtain a master mold containing the bottom liquid mixture; (g) The needle bottom liquid is dried as a needle bottom layer, whereby the barrier layer is adhered between the needle tip layer and the needle bottom layer; and (h) the mutually adhered needle tip layer, the barrier layer and the needle bottom layer are removed from the master mold to obtain the micro Needle patch.

According to the manufacturing method of the micro-needle patch of the present invention, the creation can complete the preparation of the needle tip layer, the barrier layer and the needle bottom layer in the same master mold without using an additional adhesive. Since the microneedle patch is produced by first drying the tip mixture to a tip layer, forming a barrier solution and drying it into a barrier layer, then forming a mixture of the needle bottom and drying it, so that the needle tip can be mixed. The polymer force of the polymer material in the liquid, the blocking solution and the needle bottom liquid mixture causes the dried needle tip layer, the barrier layer and the needle bottom layer to adhere to each other, specifically overcoming the bonding and machine alignment and the derivative of the previous manufacturing method. The production cost problem, thereby saving process time and improving mass production efficiency, and providing a manufacturing method suitable for mass production of microneedle patches. In addition, by providing a barrier layer between the tip layer and the underlayer of the needle, the active ingredient can be more retained in the tip layer, and the active ingredient in the tip layer can be prevented from diffusing to the bottom layer of the needle, thereby facilitating the control of micro The amount of active ingredient carried in the needle patch.

In one embodiment, the water solubility of the tip mixture is greater than the water solubility of the needle bottom mixture, so that the water solubility of the needle tip layer of the microneedle patch is greater than the water solubility of the needle bottom layer. according to Thus, when the microneedle patch of the present invention is used to pierce the skin, the tip layer of the microneedle patch will rapidly dissolve and detach from the barrier layer and the underlayer of the needle, thereby rapidly releasing the active ingredient in the epidermal layer. In another embodiment, the water solubility of the tip mixture is less than the water solubility of the needle bottom mixture, so that the water tip of the needle tip layer of the microneedle patch is less than the water solubility of the needle bottom layer. Accordingly, when the microneedle patch of the present invention is used to pierce the skin, the bottom layer of the needle of the microneedle patch dissolves earlier than the tip layer, so that the tip layer and the barrier layer remain in the body, and the activity is slowly released in the epidermis layer. ingredient. Therefore, the method for manufacturing the microneedle patch can produce an instant microneedle patch and a sustained release microneedle patch according to different requirements by controlling the water solubility of the needle tip mixture and the needle bottom mixture.

In the method for producing the microneedle patch of the present invention, the steps (b), (d) and/or (f) may be carried out by wet coating or printing to mix the tip mixture, the blocking solution and/or the needle bottom. The liquid is formed in a plurality of holes of the master mold. Applying the wet coating method to the tip mixture, the blocking solution and/or the needle bottom mixture can help control the distribution range of the active ingredients in each microneedle structure, and then specifically control the carrying amount of the active ingredients of the microneedle patch. .

Preferably, the steps (b), (d), and (f) can be independently applied by slit or slot die coating, blade coating, and slant coating. (slide coating), dip coating, inkjet printing, or nozzle printing, forming a mixture of a tip mixture, a barrier solution, and a needle-bottom mixture in the master mold Inside the hole, but not limited to the above method. The step (b) of forming the tip mixture in the plurality of holes may be performed by the method of forming the barrier solution in the plurality of holes in the step (d), and forming the mixture of the needle bottom in the plurality of holes in the step (f). The methods within are the same or different. Preferably, the method for preparing the microneedle patch can be formed by sequentially applying a tip coating solution, a barrier solution and a needle bottom mixture to the master mold by a slit coating method or a doctor blade coating method. Multiple holes inside.

When the (b) step is applied to the tip mixture by the slit coating method, 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 number can be adjusted depending on the characteristics of the tip mixture selected and the size of the microneedle patch. When the barrier solution is applied by the slit coating method in the 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. In addition, when the needle bottom mixed solution is applied by the slit coating method in the step (f), 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; It can be adjusted according to the characteristics of the selected barrier solution, the mixture of the needle bottom and the specifications of the 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 foregoing step (d), the coating gap can be controlled The coating speed can be controlled from 1 m/min to 100 m/min in the step (f), the coating 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: first forming a tip mixture on the master mold, and flowing the tip mixture into the plurality of holes, thereby covering the tip mixture with the reference surface of the master mold. And a plurality of holes; and removing the tip mixture on the reference surface, so that the liquid level of the tip mixture is flush with the reference surface of the master.

In the foregoing step of flowing the tip mixture into a plurality of holes, the method may be vacuum evacuation or centrifugation. In one embodiment, the present invention can place the tip mixture and the master mold in an oven for pumping, thereby covering the needle tip mixture with the reference surface and the plurality of holes of the master mold; In this creation, the tip mixture and the master mold can be centrifuged together, so that the tip mixture is covered on the reference surface of the master mold and a plurality of holes. Here, the pressure in the oven can be controlled from 0.001 torr to 90 torr, preferably from 0.009 to 90 torr. The rotation speed of the centrifugation step can be controlled from 100 rpm to 10,000 rpm, preferably from 100 rpm to 8000 rpm.

Preferably, the step (d) may further include: forming a barrier solution on the tip layer and the plurality of holes, and then flowing the barrier solution into the plurality of holes, thereby allowing the barrier solution to cover the tip layer and the barrier layer A master mold containing a barrier solution is obtained from the reference surface of the master mold and a plurality of holes.

In the foregoing step of flowing the barrier solution into a plurality of pores, the method may be vacuum evacuation or centrifugation. In one embodiment, the creation of the barrier solution and the master mold can be evacuated in an oven, thereby allowing the barrier solution to cover the tip layer and the reference surface of the master mold and the plurality of holes; In this case, the creation solution can centrifuge the barrier solution and the master mold together, thereby allowing the barrier solution to cover the reference surface of the master mold and a plurality of holes. Here, the pressure in the oven can be controlled from 0.001 torr to 90 torr, preferably from 0.009 to 90 torr. The rotation speed of the centrifugation step can be controlled from 100 rpm to 10,000 rpm, preferably from 100 rpm to 8000 rpm.

Preferably, the step (f) may further include: forming a needle bottom liquid on the master mold, and flowing the needle bottom liquid into the plurality of holes, thereby covering the needle bottom liquid to the barrier layer and the In the reference surface of the master mold and a plurality of holes, a master mold with a mixture of needle bottoms is obtained.

In the above step of flowing the needle bottom liquid into a plurality of holes, the method may be vacuum evacuation or centrifugation. In one embodiment, the present invention can place the needle bottom liquid mixture and the master mold in an oven for pumping, thereby covering the needle bottom liquid mixture with the barrier layer, the reference surface of the master mold, and a plurality of holes; In another embodiment, the present invention can perform centrifugation of the needle bottom mixture and the master mold, thereby allowing the needle bottom liquid to cover the reference surface of the master mold and a plurality of holes. Here, the pressure in the oven can be controlled from 0.001 torr to 90 torr, preferably from 0.009 to 90 torr. The rotation speed of the centrifugation step can be controlled from 100 rpm to 10,000 rpm, preferably from 100 rpm to 5000 rpm.

The above steps (c), (e) and (g) may be carried out by freeze drying or room temperature drying. Preferably, the drying temperatures of the aforementioned steps (c), (e) and (g) are controlled at -80 ° C to 100 ° C. More specifically, when the medical microneedle patch is to be prepared, the drying temperatures of the above steps (c), (e) and (g) can be controlled at -80 ° C to 100 ° C to avoid drying temperature deterioration above 100 ° C. Molecular junction of medicinal active ingredients Structure, and the problem of deriving active ingredients is ineffective. On the other hand, when the vaccine microneedle patch is to be prepared, the drying temperature of the above steps (c), (e) and (g) can be controlled at -80 ° C to 40 ° C to avoid the drying temperature above 40 ° C. Lost activity.

Preferably, the step (g) comprises: drying the needle bottom mixture to a bottom layer of the needle at -80 ° C to 0 ° C to obtain a first dry needle bottom layer, a barrier layer and a needle tip layer; The barrier layer and the tip layer are placed at 2 ° C to 10 ° C to obtain a second dry needle bottom layer, a barrier layer and a needle tip layer; and the secondary dried needle bottom layer, the barrier layer and the needle tip layer are dried at room temperature. Thereby, the barrier layer is adhered between the tip layer and the bottom layer of the needle.

More preferably, the step (g) comprises: drying the needle bottom mixture to a bottom layer of the needle at -60 ° C to 0 ° C to obtain a first dry needle bottom layer, a barrier layer and a needle tip layer; the first dry needle bottom layer And the tip layer is dried at 2 ° C to 10 ° C to obtain a second dry needle bottom layer, a barrier layer and a needle tip layer; and the secondary dried needle bottom layer and the needle tip layer are dried at -60 ° C to 0 ° C. Obtaining the bottom layer, the barrier layer and the tip layer of the dry needle one or three times; then drying the bottom layer of the three dried needles and the tip layer at 2 ° C to 10 ° C to obtain a four-time dry needle bottom layer, a barrier layer and a needle tip The layer is then dried at room temperature, thereby allowing the barrier layer to adhere between the tip layer and the bottom layer of the needle.

Accordingly, by the step of repeatedly freezing and cross-linking, it is possible to improve the mechanical strength of the microneedle patch and to increase the Young's modulus of the microneedle structure of the microneedle patch by more than three times.

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

In one embodiment, the pH of the tip mixture may be between 4 and 8, to ensure the activity of the pharmaceutically active ingredient, so that the pharmaceutical microneedle patch can be advantageously produced. In another embodiment, the pH of the needle tip mixture may be between 5 and 9 to avoid inactivation of the vaccine active ingredient, thereby facilitating the preparation of the vaccine microneedle patch.

Preferably, after the step (g), the step (h) may further comprise: first forming a back layer on the master mold and the bottom layer of the needle, thereby placing the needle tip layer, the barrier layer and the needle bottom layer on the mother The microneedle patch is obtained by simultaneously removing the tip layer, the barrier layer, the needle bottom layer and the back layer from the mold having the tip layer, the barrier layer and the needle bottom layer.

In the foregoing step of forming the back layer on the master mold and the needle bottom layer, the back layer has adhesiveness, which may be a tape, but is not limited thereto.

Preferably, the viscosity of the tip mixture is lower than the viscosity of the needle bottom mixture. The viscosity of the tip mixture at a shear rate of ¹ S ^-1 at 25 ° C is preferably 3 centipoise (cP) to 500,000 cP, more preferably 5 cP to 100,000 cP; The viscosity of the needle bottom mixture measured at 25 ° C and a shear rate of 1 S-1 is preferably from 100 cP to 600,000 cP, more preferably from 10,000 cP to 500,000 cP. When the viscosity of the tip mixture is too high, the tip mixture will not flow to the bottom of the hole as expected, resulting in structural defects in the microneedle patch, and the desired needle height and complete microneedle structure cannot be obtained; when the needle bottom is mixed When the viscosity of the liquid exceeds the above range, it does not provide sufficient support, and even deteriorates the quality of the microneedle patch. In addition, by controlling the viscosity range of the needle tip mixture and the needle bottom mixture, it is more advantageous to shorten the process time of the above steps (b) and (d) and improve the mass production efficiency.

Preferably, the surface tension of the tip mixture is less than or equal to 70 dyne/cm; more preferably, the surface tension of the tip mixture is greater than or equal to 1 dyne/cm and less than Or equal to 60 dyne/cm; even more preferably, the surface tension of the 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 tip mixture is too high, the tip mixture will not flow to the bottom of the hole as expected, resulting in structural defects in the microneedle patch. Preferably, the surface tension of the bottom liquid mixture is less than or equal to 50 dyne/cm; more preferably, the surface tension of the needle bottom liquid is greater than or equal to 1 dyne/cm and less than or equal to 40 dyne/cm. When the surface tension of the needle-bottom mixture is too high, the under-needle structure of the microneedle patch may be incomplete, the needle tip layer and the needle bottom layer may not be surely bonded, and the back layer structure may be defective (such as unevenness, bubbles or uneven surface). Generated) and other issues.

According to the present invention, the concentration of the barrier solution is from 10% by weight to 70% by weight; preferably, the concentration of the barrier solution is less than or equal to 10% by weight to 40% by weight. By controlling the concentration range of the barrier solution, it is advantageous to ensure that the barrier solution is dried to form a uniform polymer barrier layer, and the barrier layer is slowly dissolved in the solvent of the mixture in the step (f), thereby avoiding the needle in the step (f) The solvent of the bottom mixture penetrates into the tip layer, causing the tip layer to reconstitute so that the active ingredient of the tip layer diffuses to the under layer of the needle.

According to the present invention, the mixture of the tip and the bottom of the needle may be a polymer aqueous solution, and the mixture of the tip is a polymer aqueous solution containing the active ingredient. Preferably, the concentration of the tip mixture is less than the concentration of the bottom mixture. Preferably, the concentration of the tip mixture is 5 wt% to 50 wt%, the concentration of the needle bottom mixture is 10 wt% to 95 wt%; more preferably, the concentration of the tip mix is 10 wt% to 50 wt%, the needle The concentration of the bottom liquid mixture is from 15% by weight to 95% by weight. By controlling the concentration range of the needle tip mixture and the needle bottom mixture, it is advantageous to ensure the mechanical strength of the needle tip layer and the needle bottom layer in the prepared microneedle patch, so that it can smoothly pass through the stripping step to obtain a complete micro Microneedle patch for needle structure.

According to the present invention, the active ingredient may be a pharmaceutically active ingredient or a vaccine active ingredient. Specifically, the pharmaceutically active ingredient may be a small molecule compound, a protein drug, a botanical drug or the like. Specifically, the vaccine active ingredient may be an attenuated vaccine, an inactivated vaccine, a virus-like particle (VLP), a purified subunit antibody. Purified subunit antigen, recombinant antigen, synthetic peptide, recombinant vector, DNA vaccine, nucleic acid vaccine, mucosal immunity (mucosal immunization), combined vaccine (combined vaccine) and other vaccines.

According to the present invention, the polymer material contained in the tip mixture and the needle bottom mixture may be a material that is dissolvable or swellable. More specifically, the polymeric material can be a biocompatible material or a biodegradable material. The tip mixture and the needle bottom mixture each independently comprise a polymer material, and the polymer material contained in the tip mixture may be the same as or different from the polymer material contained in the needle bottom mixture. For example, the aforementioned polymer material may be maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, β-cyclodextrin. (β-cyclodextrin), 2-hydroxypropyl-β-cyclodextrin, dextran, amylopectin, starch, sodium hyaluronate Hyaluronate), poly(methyl vinyl ether-alt-maleic anhydride, PMVE/MA), sodium carboxymethylcellulose (CMC), methylcellulose ( Methylcellulose, MC), hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, polyvinyl alcohol (PVA), polyethylene Polypyrrolidone (PVP), polyethylene glycol (PEG), polylactic acid (PLA), poly(glycolic acid, PGA), polylactic acid-glycolic acid copolymer (poly(poly) Lactic-co-glycolic acid), PLGA), chitosan (chito San) or a combination of these, but not limited to this. Here, when the polymer material contains trehalose, sucrose, heptagluconic acid, arginine, maltodextrin or cyclodextrin, it is advantageous to enhance the mechanical strength of the microneedle patch. In addition, when making vaccine microneedle patches, before Such as trehalose, sucrose, heptagluconate, arginine, maltodextrin or cyclodextrin can also be used as an immunoadjuvant.

According to the present invention, the barrier material of the barrier solution may comprise trehalose, dextrin, maltodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, dextran, amylopectin, Methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, polyethyl a diol, a polylactic acid, a polyglycolic acid, a polylactic acid-glycolic acid copolymer, a chitosan or a combination thereof; preferably, the barrier material of the barrier solution is gelatin, chitosan, polyvinyl alcohol or combination. Specifically, the barrier material has a molecular weight of more than 1000 Da, preferably from 1000 Da to 1,000,000 Da, more preferably from 3,000 Da to 800,000 Da. According to the present invention, the viscosity of the barrier solution measured at 25 ° C and a shear rate of 1 S-1 is greater than 10,000 cP, preferably from 10,000 cP to 2,000,000 cP, more preferably from 40,000 cP to 700,000 cP. Preferably, the viscosity of the barrier solution is greater than the viscosity of the tip mixture and greater than the viscosity of the mixture of the needle bottom; more preferably, the viscosity of the barrier solution is more than 1.1 times the viscosity of the mixture of the needle bottom; and even more preferably, The viscosity of the barrier solution is more than 1.2 times the viscosity of the needle bottom mixture. Accordingly, by using a high molecular weight and low solubility barrier material, the barrier layer can specifically prevent the active ingredient from diffusing from the needle tip layer to the underlayer of the needle, thereby effectively controlling the carrying amount of the active ingredient in the microneedle patch.

Preferably, the barrier layer has a thickness of from 1 micrometer to 200 micrometers, preferably from 20 micrometers to 200 micrometers.

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

In another embodiment, the bottom liquid mixture may contain an aqueous solution of polyvinyl alcohol and polyvinylpyrrolidone, and the concentration of the bottom liquid mixture is 20% by weight to 50% by weight of the aqueous polymer solution. The weight ratio of polyvinylpyrrolidone is less than or equal to 50% by weight based on the polymer material. Here, the viscosity of the needle bottom mixture measured 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, germanium 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, a metal foil or a flexible glass; the polymer is polydimethyl hydrazine. Oxygen (poly(dimethylsiloxane), PDMS), poly(methyl methacrylate), PMMA, polycarbonate (PC), polyethersulfone (PES), etc., but not limited to this.

According to the present invention, the shape of the hole in the female mold may be a conical shape, a square conical shape or a spire type, but is not limited thereto. In the master mold, the master mold has a reference surface and a plurality of holes, and the holes are recessed from the reference surface. The depth of each of the holes is from 75 μm to 1500 μm, preferably from 150 μm to 1200 μm, more preferably from 175 μm to 1000 μm, and even more preferably from 200 μm to 950 μm. The maximum width of each of the holes is from 50 μm to 600 μm, preferably from 75 μm to 550 μm, more preferably from 100 μm to 500 μm, still more preferably from 100 μm to 450 μm.

In the microneedle patch, the needle shape of each microneedle structure may be a conical shape, a square pyramid shape or a spire type, but is not limited thereto.

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

In the microneedle patch, the tip radius of each microneedle structure may be less than 15 μm; preferably less than 11 μm; more preferably between 5 μm and 10 μm. In addition, the microneedle patch may have a tip angle of less than 30°.

In the microneedle patch, the density of the microneedle structure may range from 1 needle (cm/cm ² ) to 1000 neodles/cm ² per square centimeter; preferably 1 needle/cm ² to 500 neodles/cm ² .

In application, by controlling the needle length of the microneedle patch, the microneedle patch can be protected from the nervous system under the dermis layer during use, thereby reducing the user's fear and eliminating the pain. In addition, the microneedle patch prepared by the present invention has the advantages of convenient operation, and is more beneficial for avoiding the effect of the active ingredient due to gastric acid action or liver first effect when orally administered.

10‧‧‧Female model

10A‧‧‧Female mold with tip mixture

10B‧‧‧The mother model with the tip layer

10C‧‧‧Female mold with barrier solution

10D‧‧‧Female model with tip layer and barrier layer

10E‧‧‧Female mold with needle bottom liquid

10F‧‧‧The master of the finished product

11‧‧‧Datum

12‧‧‧ holes

20, 20A‧‧‧medical microneedle patch

21‧‧‧needle layer

21'‧‧‧Needle Mix

22‧‧‧Barrier

22'‧‧‧ Barrier solution

23, 23A‧‧‧ needle bottom layer

23'‧‧‧Needle Mix

24‧‧‧ Back layer

S1‧‧‧Slit coating head

S1A‧‧‧ scraper

S2‧‧‧Scraper

FIG. 1 is a flow chart of a method for fabricating a microneedle patch.

Fig. 2 is a schematic view showing a method of producing the medical microneedle patch of the first embodiment.

3 is a schematic view of a medical microneedle patch prepared by the method of the first embodiment.

4 is a schematic view showing a method of producing a medical microneedle patch of Example 2.

Fig. 5 is a schematic view showing a medical microneedle patch prepared by the production method of the second embodiment.

6A and 6B are photographs of the medical microneedle patch of Example 1 in Test Example 2 before and after puncture of the mouse.

7A and 7B are fluorescence microscope images of the experimental group and the control group in Test Example 3, respectively.

The following describes a method for manufacturing a plurality of micro-needle patches as an example 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 the present specification, and do not deviate from the present. Various modifications and changes are made in the spirit of creation to implement or apply the content of this creation.

Preparation example: polymer material

In this experiment, five kinds of polymer materials of different compositions were prepared, and the dissolution rates of the polymer materials of the respective preparation examples were compared according to the method described below to simulate the release rate of the active ingredients in the microneedle patch. Here, the composition of the polymer material of each preparation example is shown in Table 1 below.

In order to analyze the dissolution rates of the polymer materials of the above Preparation Examples 1 to 5, in the present experiment, the above respective polymer materials are separately coated on a substrate by the same coating method to form a planar film 1 to a planar film 5 of equal thickness. For subsequent analysis of dissolution rates. Next, the human body fluid environment was simulated using a PBS buffer solution, and the planar membranes 1 to 5 of the same size were each immersed in a petri dish containing a known weight of PBS buffer solution at 37 ° C for 15 minutes. Next, the filter paper is placed on a Buchner funnel connected with an air suction device, and the buffer solution in which the flat membrane 1 is immersed in the culture dish is separately suction-filtered to the buffer solution immersed in the planar film 5, and then dried at 103 ° C. Each of the planar films remaining on the filter paper has a weight of the remaining planar film until the weight is no longer changed. Calculate the difference between the weight of each flat film before immersion and the residual flat film after immersion. The weight difference is the dissolved weight of the flat film. The plane film dissolved weight is divided by the solvent weight of the starting PBS buffer solution. 1 to the dissolution characteristics of the planar film 5.

As shown in Table 1 above, the solubility of the planar films 2, 4 and 5 was greater than the solubility of the planar films 1 and 3 at the same dissolution time. It can be seen that at the same time, the high scores of Preparation Examples 2, 4 and 5 The dissolution release rates of the planar films 2, 4, and 5 prepared from the sub-materials were significantly faster than the dissolution release rates of the planar films 1 and 3 prepared from the polymer materials of Preparation Examples 1 and 3. That is to say, by controlling the composition of the polymer material, the polymer materials of Preparation Examples 2, 4 and 5 can be used to form a tip mixture of the immediate release type microneedle patch, and the polymer materials of Preparation Examples 1 and 3 are It can be used to form a tip-tip mixture of sustained-release microneedle patches.

Example 1: Medical microneedle patch

Referring to FIG. 1 and FIG. 2 together, the medical microneedle patch of the present embodiment is obtained by the method described below.

First, as shown in FIG. 1 and FIG. 2 (a), a master 10 is prepared. The master 10 has a reference surface 11 and a plurality of holes 12, and the plurality of holes 12 are oriented by the reference plane 11 The recessed portion is formed, and the plurality of holes 12 are recessed in a matrix arrangement on the master mold 10. 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 array of holes is 1.5 cm×1.5 cm, and the shape of each hole 12 is a square cone, and the depth thereof is (i.e., the vertical distance between the end of the hole 12 and the reference surface 11) is 750 μm, and the maximum width (i.e., the maximum inner diameter of the horizontal plane in which the hole 12 is flush with the reference surface 11) is 300 μm.

Then, as shown in step (b) of FIG. 1, the tip mixture 21' is applied to the plurality of holes 12 of the master 10 by a slit coating method to fill the tip mixture 21'. The plurality of holes 12 of the master mold 10 are until the liquid level of the tip mixture 21' is flush with the reference surface 11, i.e., a master 10A containing the tip mixture is obtained. Specifically, the step (b) can be performed by the steps (b1) to (b4) which are sequentially performed. As shown in the step (b1) of FIG. 2, the tip coating liquid 21' is narrowed from the slit coating head S1 by a slit coating method at a coating gap of 1000 μm and a coating speed of 3 m/min. The slit nozzle is extruded and coated on the master mold 10. The tip mixture 21' is a 20% by weight aqueous solution containing insulin and a methyl vinyl ether-maleic anhydride copolymer, that is, the tip mixture 21' contains 80% by weight of water and 20% by weight of insulin (medicinal active ingredient) and a mixture of methyl vinyl ether-maleic anhydride copolymer, and the viscosity of the tip mixture 21' measured at 25 ° C, ¹ S ^-1 is 45 cP, the surface tension is 29 dyne / cm, and the pH is adjusted to Between 6 and 7. Next, as shown in step (b2) of FIG. 2, the tip mixture 21' and the master 10 are simultaneously pumped in a vacuum oven having a pressure of 20 torr, whereby the tip mixture 21' can be self-referenced on the reference surface 11. It flows through the plurality of holes 12 of the master mold 10 through the pumping, and covers the reference faces 11 of the master mold 10 and all the holes 12. Then, as shown in step (b3) of FIG. 2, the tip mixture 21' on the reference surface 11 is scraped off using the squeegee S2 until the liquid level of the tip mixture 21' is flush with the reference surface 11 to obtain a package. The master mold 10A having the tip mixture is in the state of the step (b4) shown in Fig. 2. In another embodiment, the step (b2) can also be performed by centrifugation; for example, placing the master mold with the tip mixture in a centrifuge and continuously centrifuging at 3600 rpm for 20 minutes to make the needle tip The mixed liquid can flow downward from the reference surface and be fixed in a plurality of holes of the master mold, and cover the reference surface and all the holes.

Next, as shown in step (c) of FIG. 1 and FIG. 2, the master mold 10A containing the tip mixture is continuously dried at a temperature of 30 ° C for 1 hour, thereby allowing the aforementioned tip mixture 21'. Drying is the tip layer 21, and the surface of the tip layer 21 is lower than the reference surface 11, and a master 10B having a tip layer is obtained.

Thereafter, as shown in step (d) of FIG. 1, a barrier solution 22' is formed on the tip layer 21 and the plurality of holes 12, thereby allowing the barrier solution 22' to cover the tip layer 21, the reference surface 11, and more. The holes 12 are obtained as a master 10C containing a barrier solution. Specifically, the step (d) can be performed by the steps (d1) to (d4) performed in sequence. As shown in step (d1) of FIG. 2, the slit solution coating method was used to make the barrier solution 22' from the slit of the slit coating head S1 at a coating gap of 800 μm and a coating speed of 3 m/min. The nozzle is extruded to be applied to a master 10B having a tip layer. The barrier solution 22' is a 30% by weight aqueous solution of polyvinyl alcohol, that is, the barrier solution 22' contains 70% by weight of water and 30% by weight of polyvinyl alcohol, and the blocking solution 22' is measured at 25 ° C, ¹ S ^-1 . The viscosity is 270,000 cP, the pH is 6-7, and the molecular weight of the polyvinyl alcohol is 90,000 Da. Next, as shown in step (d2) of FIG. 2, the barrier solution 22' and the master mold 10B having the tip layer are pumped together in a vacuum oven having a pressure of 35 torr, thereby allowing the barrier solution 22' to be self-referenced. 11 flows through the plurality of holes 12 of the master mold 10 through the pumping, and covers the needle tip layer 21, the reference surface 11, and all the holes 12. Then, as shown in step (d3) of FIG. 2, the barrier solution 22' on the reference surface 11 is scraped off using the squeegee S2 until the liquid level of the blocking solution 22' is flush with the reference surface 11, and a barrier is obtained. The master mold 10C of the solution is in the state of the step (d4) shown in Fig. 2 . In another embodiment, the step (d2) can also be performed by centrifugation; for example, placing a master mold containing a barrier solution in a centrifuge and continuously centrifuging at 3600 rpm for 15 minutes to form a blocking solution. It can flow from the reference face down and be fixed in the holes of the master mold and cover the tip layer, the reference surface and all the holes.

Then, as shown in step (e) of FIG. 1 and FIG. 2, the master mold 10C containing the barrier solution is continuously dried at a temperature of 30 ° C for 48 hours, thereby drying the barrier solution 22' into a barrier layer. 22 and bonded to the tip layer 21, thereby obtaining a master 10D having a tip layer and a barrier layer.

Thereafter, as shown in step (f) of FIG. 1, a needle bottom liquid mixture 23' is formed on the barrier layer 22 and the plurality of holes 12, thereby covering the barrier layer 22 with the needle bottom liquid mixture 23'. The face 11 and the plurality of holes 12 obtain a master 10E equipped with a mixture of needle bottoms. Specifically, the step (f) can be performed by the steps (f1) to (f4) which are sequentially performed. In the step (f1) shown in FIG. 2, the needle bottom mixed liquid 23' is applied from the slit coating head S1 by a slit coating method at a coating gap of 1600 μm and a coating speed of 3 m/min. The slit nozzle is extruded to be applied to the master 10D having the barrier layer. The needle bottom liquid mixture 23' is a 50% by weight aqueous solution of polyvinyl alcohol, that is, the needle bottom liquid mixture 23' contains 50% by weight of water and 50% by weight of polyvinyl alcohol, and the needle bottom liquid mixture 23' is at 25 ° C, 1 S. The viscosity measured under ^-1 is 200000 cP. Next, as shown in step (f2) of FIG. 2, the needle bottom liquid mixture 23' and the mother mold 10D having the barrier layer are simultaneously pumped in a vacuum oven having a pressure of 35 torr, thereby making the needle bottom liquid mixture 23' The plurality of holes 12 of the master mold 10 may be flowed from the reference surface 11 via suction, and covered in the barrier layer 22, the reference surface 11, and all the holes 12. Then, as shown in step (f3) of FIG. 2, the needle bottom liquid mixture 22' on the reference surface 11 is scraped off using the squeegee S2 until the liquid level of the needle bottom mixed liquid 23' is flush with the reference surface 11 to obtain A master mold 10E equipped with a needle bottom mixed liquid, as shown in Fig. 2 (f4). In another embodiment, the step (f2) can also be performed by centrifugation; for example, placing a master mold containing a needle bottom liquid in a centrifuge and continuously centrifuging at 3600 rpm for 15 minutes, so that The needle bottom mixture can flow downward from the reference surface and be fixed in a plurality of holes of the master mold, and cover the barrier layer, the reference surface and all the holes.

Next, as shown in step (g) of FIG. 1 and FIG. 2, the master mold 10E containing the needle bottom liquid mixture is continuously dried at a temperature of 30 ° C for 48 hours, thereby making the needle bottom liquid mixture 23' The needle bottom layer 23 is dried, and the barrier layer 22 is adhered between the needle tip layer 21 and the needle bottom layer 23, thereby obtaining a master mold 10F having a finished product.

Finally, as shown in step (h) of FIG. 1, the finished product (i.e., the structure including the tip layer 21, the barrier layer 22, and the needle underlayer 23) is removed from the master mold 10F having the finished product, that is, the microneedle patch 20 is obtained. . Specifically, the step (h) can be performed by the steps (h1) to (h2) performed in sequence. As shown in step (h1) of FIG. 2, a back layer 24 is formed on the master mold 10F having the finished product, whereby the needle tip layer 21, the barrier layer 22 and the needle bottom layer 23 are sandwiched between the aforementioned mother mold 10F and the back layer 24. between. In this embodiment, the backing layer 24 is a gas permeable tape. Finally, as shown in FIG. 2 (h2), the needle tip layer 21, the barrier layer 22, the needle bottom layer 23 and the back layer 24 are simultaneously removed from the master mold 10F having the finished product, that is, the microneedle patch of the embodiment is completed. 20 process.

According to the above manufacturing method, the present embodiment first forms a tip mixture on the master mold by a slit coating method, and then forms a barrier solution on the dried needle tip layer by a slit coating method, so that it can pass through the needle tip. The polymer force of the mixed solution and the blocking solution bonds the dried tip layer and the barrier layer to each other; similarly, the needle-bottom mixture is applied to the dried barrier layer by a slit coating method, and is also transparent. The polymer force of the needle bottom mixture and the barrier solution causes the dried barrier layer and the needle bottom layer to adhere to each other. Accordingly, the microneedle patch provided by the present invention can not only achieve the process time and cost saving, but also improve the mass production efficiency, and the medical activity can be achieved as scheduled by providing a barrier layer between the needle tip layer and the needle bottom layer. The component stays in the needle tip layer, and the medicinal active ingredient in the tip layer is blocked from diffusing to the bottom layer of the needle, so that the dosage of the medicinal active ingredient in each microneedle structure can be controlled, and the purpose of controlling the carrying amount of the medical microneedle patch can be achieved.

As shown in FIG. 3, the medical microneedle patch 20 of the present embodiment is formed by sequentially bonding the back layer 24, the needle bottom layer 23, the barrier layer 22 and the needle tip layer 21 from bottom to top, that is, the barrier layer 22 is bonded. Between the tip layer 21 and the needle bottom layer 23. The mutually adhered needle bottom layer 23, the barrier layer 22 and the needle tip layer 21 together form a one-sided tapered structure, and the needle bottom layers 23 are spaced apart from each other and arranged in a matrix on the back layer 24. In the medical microneedle patch of the present embodiment, the thickness of the tip layer 21, the barrier layer 22 and the needle underlayer 23 are sequentially 450±50 μm, 150±50 μm, and 150±50 μm.

It should be noted that the preparation method of Example 1 is not limited to the production of a medical microneedle patch, and those skilled in the art can replace the pharmaceutically active ingredient in the tip mixture with the vaccine active ingredient, as described above. Other methods of making microneedle patches (eg, vaccine microneedle patches).

Example 2: Medical microneedle patch

In this embodiment, the medical microneedle patch is prepared by the method as described in the foregoing Embodiment 1, and the difference mainly lies in that the present embodiment is applied by a doctor blade coating method to apply a needle tip mixture and a needle bottom liquid mixture. Further, the structure of the master mold is changed and the step of scraping the mixture of the needle bottom is omitted. Further, the composition of the tip mixture selected in the present embodiment is also different from the composition of the tip mixture of Example 1. For the detailed production process of this embodiment, please refer to FIG. 4, and the manufacturing method of this embodiment will be described below with reference to FIG. 1 and FIG.

First, as shown in (a) of FIG. 1 and FIG. 4, a master 10 having a reference surface 11 and a plurality of holes 12 is prepared. 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 array of holes is 1.0 cm×1.0 cm, and the shape of each hole 12 is conical, and the depth thereof is 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 in which the hole 12 is flush with the reference surface 11) is 300 μm.

Then, as shown in step (b) of FIG. 1, the tip mixture 21' is applied to the plurality of holes 12 of the master 10 by a doctor blade coating method to fill the tip mixture 21'. The plurality of holes 12 of the die 10 are until the liquid level of the tip mixture 21' is flush with the reference surface 11, i.e., a master 10A equipped with a tip mixture is obtained. Specifically, as shown in step (b1) of FIG. 4, the step (b1) of the present embodiment is carried out by a doctor blade coating method at a coating gap of 800 μm and a coating speed of 3 m/min using a doctor blade S1A. The tip mixture 21' is applied to the master mold 10, and sequentially 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 20% by weight aqueous solution containing insulin and methyl vinyl ether-maleic anhydride copolymer/maltose, and the tip mixture 21' is measured at 25 ° C, ¹ S ^-1 . The viscosity is 50 cP, the surface tension is 30 dyne/cm, and the pH is adjusted to 6-7. Based on the total weight of the tip mixture, the tip mixture contained 80% by weight of water and 20% by weight of a mixture of insulin and methyl vinyl ether-maleic anhydride copolymer and maltose.

Thereafter, as shown in step (d) of FIG. 1, a barrier solution 22' is formed on the tip layer 21 and the plurality of holes 12, thereby allowing the barrier solution 22' to cover the tip layer 21, the reference surface 11, and more. The holes 12 are obtained as a master 10C containing a barrier solution. Specifically, the step (d) can be performed by the steps (d1) to (d4) performed in sequence. As shown in step (d1) of Fig. 4, the barrier solution 22' was applied to the master mold having the tip layer by the doctor blade coating method at a coating gap of 500 μm and a coating speed of 3 m/min using a doctor blade S1A. 10B. The barrier solution 22' is a 30 wt% aqueous solution of polyvinyl alcohol, that is, the barrier solution 22' contains 70% by weight of water and 30% by weight of an aqueous solution of polyvinyl alcohol, and the blocking solution 22' is measured at 25 ° C, ¹ S ^-1 The resulting viscosity was 270,000 cP, the pH was 6-7, and the molecular weight of the polyvinyl alcohol was 90,000 Da. Next, as shown in step (d2) of FIG. 4, the barrier solution 22' and the master mold 10B having the tip layer are placed together in a vacuum oven at a pressure of 35 torr, thereby allowing the barrier solution 22' to be self-referenced. 11 flows through the plurality of holes 12 of the master mold 10 through the pumping, and covers the needle tip layer 21, the reference surface 11, and all the holes 12. Then, as shown in step (d3) of FIG. 2, the barrier solution 22' on the reference surface 11 is scraped off using the squeegee S2 until the liquid level of the blocking solution 22' is flush with the reference surface 11, and a barrier is obtained. The master mold 10C of the solution is in the state of the step (d4) shown in FIG. In another embodiment, the step (d2) can also be performed by centrifugation; for example, placing a master mold containing a barrier solution in a centrifuge and continuously centrifuging at 1600 rpm for 15 minutes to make the blocking solution It can flow from the reference face down and be fixed in the holes of the master mold and cover the tip layer, the reference surface and all the holes.

Thereafter, in the step (f) shown in FIG. 1, a needle bottom liquid mixture 23' is formed on the barrier layer 22 and the plurality of holes 12, whereby the needle bottom liquid mixture 22' covers the barrier layer 22, the reference The face 11 and the plurality of holes 12 obtain a master 10E equipped with a mixture of needle bottoms. Specifically, as shown in the step (f1) shown in FIG. 4, the step (f1) of the present embodiment is also performed by a doctor blade coating method at a coating gap of 1600 μm and a coating speed of 3 m/min using a doctor blade S1A. The needle bottom liquid mixture 23' is applied to the master mold 10D having the barrier layer. Next, as shown in step (f2) of FIG. 4, the needle bottom liquid mixture 23' and the master mold 10D having the barrier layer are simultaneously pumped in a vacuum oven having a pressure of 30 torr, thereby making the needle bottom liquid mixture 23' The master mold 10E equipped with the needle bottom mixed liquid can be obtained by pumping air from the reference surface 11 into the plurality of holes 12. Here, the needle bottom liquid mixture 23' is a 50% by weight aqueous solution of polyvinyl alcohol/β-cyclodextrin/trehalose, and the viscosity of the needle bottom liquid mixture 23' measured at 25 ° C and ¹ S ^-1 is 230,000 cP. The surface tension is 37 dyne/cm. Based on the total weight of the needle bottom liquid mixture 23', the needle bottom liquid mixture 23' contains 50% by weight of water and 50% by weight of a mixture of polyvinyl alcohol, β-cyclodextrin and trehalose; Based on the total weight of β-cyclodextrin and trehalose, the content of polyvinyl alcohol is 40% by weight, and the content of β-cyclodextrin is not more than 50% by weight.

Next, as shown in step (g) of FIG. 1 and FIG. 4, the master mold 10E containing the needle bottom liquid mixture is continuously dried at a temperature of 30 ° C for 12 to 16 hours, thereby making the needle bottom liquid mixture 23' is dried as the needle bottom layer 23A, and the barrier layer 22 is adhered between the needle tip layer 21 and the needle bottom layer 23A, thereby obtaining a master mold 10F having a finished product; finally, the (h1) as described in Embodiment 1 is sequentially performed. And (h2) the step of completing the process of the medical microneedle patch 20A of the present embodiment. Here, in the present embodiment, the step of scraping the needle bottom mixed liquid is omitted, so that the needle bottom layer 23A is simultaneously bonded to the barrier layer 22 and covers the reference surface 11 to constitute a structure as shown in FIG.

Referring to FIG. 5, the medical microneedle patch 20A is sequentially bonded from bottom to top to form a back layer 23, a needle bottom layer 23A, a barrier layer 22 and a tip layer 21, and each of the needle bottom layer 23A and the barrier layer 22 adhered to each other. Together with the tip layer 21, a conical structure is formed, and the needle bottom layers 23A are connected to each other to form the back layer 24, and the conical structures are arranged in a spaced and matrix manner.

It should be noted that the preparation method of Example 2 is not limited to the production of a medical microneedle patch, and those having ordinary knowledge in the art can replace the pharmaceutically active ingredient in the needle tip mixture with the vaccine active ingredient, as described above. Other methods of making microneedle patches (eg, vaccine microneedle patches).

Example 3: Vaccine microneedle patch

In this embodiment, a vaccine microneedle patch is prepared by the method described in the foregoing Embodiment 1, and the difference mainly lies in that the present embodiment is applied by a doctor blade coating method to apply a needle tip mixture and a needle bottom mixture. The needle bottom mixed solution is fixed in a plurality of holes by centrifugation, and the step of scraping the needle bottom mixed liquid is omitted.

Specifically, after the step (a), the step (b1) is carried out by a doctor blade coating method, and a tip mixture is applied onto the master mold at a coating gap of 1000 μm and a coating speed of 3 m/min; Further, through the steps (b2) to (b4) and (c) as described in Example 1, a master having a tip layer is obtained. The tip mixture is a 20% by weight enterovirus 71 vaccine and an aqueous solution of methyl vinyl ether-maleic anhydride copolymer/maltose, and the viscosity of the tip mixture is 50 cP measured at 25 ° C and ¹ S ^-1 . The surface tension was 30 dyne/cm and the pH was adjusted to 7. Based on the total weight of the whole tip mixture, the tip mixture contained 80% by weight of water and 20% by weight of a mixture of the Enterovirus 71 vaccine and methyl vinyl ether-maleic anhydride copolymer and maltose.

Next, the master mold containing the tip mixture is continuously dried at a temperature of 30 ° C for 1 hour, thereby drying the tip mixture to a tip layer and lowering the surface of the tip layer below the reference surface. A master mold with a tip layer.

Thereafter, the step (d1) is further carried out by a doctor blade coating method, and a barrier solution is applied to the master mold at a coating gap of 800 μm and a coating speed of 3 m/min; and then, a master mold containing the barrier solution is applied. Placed in a centrifuge and continuously centrifuged at 3600 rpm for 15 minutes, so that the barrier solution can flow downward from the reference surface and be fixed in the holes of the master mold, and cover the needle tip layer, the reference surface and all the holes; Through the step (e) as described in Example 1, a master having a tip layer and a barrier layer is obtained. The barrier solution is a 15% by weight aqueous solution of polyvinylpyrrolidone, and the viscosity of the barrier solution measured at 25 ° C and ¹ S ^-1 is 70,000 cP. The barrier solution contained 85 wt% of water and 15 wt% of an aqueous solution of polyvinylpyrrolidone based on the total weight of the overall barrier solution.

Next, the step (f1) is carried out by a doctor blade coating method, and the needle bottom liquid is applied to the master mold at a coating gap of 1600 μm and a coating speed of 3 m/min; The master mold is placed in a centrifuge and continuously centrifuged at 3600 rpm for 15 minutes to allow the needle bottom liquid to flow downward from the reference surface and be fixed in the holes of the master mold, covering the barrier layer, the reference surface and all In the hole, a master mold having a finished product is obtained through the step (g) as described in Example 1. Herein, the needle bottom liquid is 15% by weight of an aqueous solution containing polyvinyl alcohol and polyvinylpyrrolidone, the weight ratio of the polyvinyl alcohol to the polyvinylpyrrolidone is 4:1, and the needle bottom liquid mixture is at 25 ° C, The viscosity measured at 1S ^-1 was 11,000 cP and the surface tension was 37 dyne/cm.

In this embodiment, the barrier layer can be bonded to the tip layer and the bottom layer of the needle by the polymer force of the material itself; therefore, after the step (g), it can be directly removed from the master mold having the finished product. The needle tip layer, the barrier layer and the needle bottom layer adhered to each other, and the step (h) is completed to obtain the vaccine microneedle patch of the present embodiment. Herein, the thickness of the needle tip layer, the barrier layer and the needle bottom layer of the vaccine microneedle patch are 450±50 μm, 150±50 μm, 150±50 μm.

Comparative Example 1: Medical microneedle patch

In this comparative example, a medical microneedle patch is produced substantially as in the method described in Example 1, except that the comparative example does not perform step (d) and step (e), that is, after step (c) Steps (f) to (h) described in Example 1 were directly carried out.

In the method for producing the medical microneedle patch of the comparative example, the needle bottom liquid is formed on the needle tip layer and in the plurality of holes, thereby covering the needle tip layer, the reference surface and the plurality of holes in the needle bottom mixed solution. , obtaining a master mold with a mixture of needle bottoms. Then, the microneedle patch of the comparative example was obtained by sequentially passing the dry needle bottom liquid mixture, removing the finished product from the master mold having the finished product, and the like.

In this comparative example, the microneedle patch has a tip layer and a needle bottom layer, but there is no barrier layer between the needle tip layer and the needle bottom layer.

Test example 1

In order to confirm that the finished product prepared by the method for producing the microneedle patch can release the active ingredient carried by the sample as scheduled, the pig skin of the hair removal is selected as the puncture object in the test case, and the external puncture test is performed to observe the micro needle sticker. The penetration depth of the piece.

In the test example, the medical microneedle patch of the above-mentioned Example 1 was selected as a representative example, and the medical microneedle patch was attached to the self-made jig and pressed against the depilated pig skin for about 5 minutes. The puncture point of the medical microneedle patch did appear on the surface of the pig skin by the naked eye.

In addition, in this test, the puncture pig skin was soaked in the formalin, the tissue was fixed, sliced and stained, and the depth of the puncture point in the puncture pig skin was observed by an optical microscope, and the puncture depth of the medical microneedle patch was observed. From about 90 μm to 150 μm; it can be seen that the medical microneedle patch prepared by the above preparation method can puncture the stratum corneum layer with the isolation barrier and reach above the epidermis layer and the dermis layer, so that the medicine in the medical microneedle patch The active ingredient exerts the desired effect in the body.

Test example 2

In order to confirm that the finished product prepared by the method for producing the microneedle patch can release the active ingredient carried by the patient as scheduled, this experiment uses a mouse of 6 weeks of age (the strain is Balb/C) as a puncture target, and performs living body. Puncture test to observe the puncture of the microneedle patch.

In the test example, the medical microneedle patch of the above-mentioned Example 1 was selected as a representative example, and the medical microneedle patch was attached to the self-made jig.

Two days before the in vivo puncture test, the area on the mouse to be subjected to the puncture test was depilated using a depilatory cream to be used as an observation target for the medical microneedle patch. In the biopsy test, the mice were anesthetized, and the medical microneedle patch of Example 1 was pressed against the depilated area of the mouse for about 1 minute, and the medical microneedle patch was continuously attached to the mouse skin for about 1 hour. The puncture point of the medical microneedle patch was indeed observed as expected by visually observing the surface of the mouse skin.

In addition, in this test example, the height change of the microneedle structure on the medical microneedle patch before and after the puncture was observed using an optical microscope. Referring to FIG. 6A, the needle height of the medical microneedle patch is 750 μm before the puncture; as shown in FIG. 6B, after the puncture, the needle height of the medical microneedle patch is 345 μm.

It can be seen from the results of FIG. 6A and FIG. 6B that since the medical microneedle patch of Example 1 has been dissolved in the mouse after the puncture, and the needle tip layer contains the medicinal active ingredient, the medicine of the medical microneedle patch can be seen. The active ingredient has been delivered to the body as expected and is dissolved therein to exert the desired medical effect.

Test Example 3

In order to confirm whether the barrier layer is provided to help control the carrying amount of the active ingredient of the microneedle patch, the test examples mainly use the microneedle patches as in the first embodiment and the comparative example 1 as the experimental group and the control group for analysis, but It is convenient to use the fluorescence microscope to observe the distribution of the active ingredients in the microneedle patch. The test example is replaced by fluorescein isothiocyanate-labeled bovine serum albumin (BSA-FITC). The needles of Example 1 and Comparative Example 1 The insulin used in the sharp layer was observed with a fluorescence microscope (excitation wavelength set to 495 nm) to observe a microneedle patch containing BSA-FITC as an active ingredient (as in the experimental group of the microneedle patch of Example 1 and as in Comparative Example 1) The result of the microneedle patch control group is shown in Fig. 7A and Fig. 7B.

Referring to FIG. 7A, the microneedle patch of the experimental group (like the microneedle patch of Example 1) was observed under a fluorescence microscope, and it was found that the fluorescence reaction mainly concentrated on the position of the tip layer, and the back layer had almost no fluorescence. Reaction; in contrast, in Figure 7B, the microneedle patch of the control group was observed under a fluorescence microscope (like the microneedle patch of Comparative Example 1), and it was found that the fluorescence reaction was simultaneously distributed at the position of the tip layer and the bottom layer of the needle, and the back layer thereof Obvious fluorescence reactions were also observed.

Comparing the results of the experimental group and the control group under the fluorescence microscope, it can be seen that by providing a barrier layer between the tip layer and the underlayer of the needle, the effect of diffusing the active ingredient in the needle tip layer to the bottom layer of the needle can be specifically improved. The active ingredient can stay in the tip layer as scheduled, thereby controlling the carrying amount of the active ingredient in the microneedle patch, so that the microneedle patch of the present invention can be applied in the fields of medicine or vaccine.

Claims (25)

A method for manufacturing a microneedle patch comprises the following steps: (a) providing a master mold having a reference surface and a plurality of holes, the plurality of holes being recessed from the reference surface; (b) A tip mixture is formed in a plurality of holes of the master mold, so that the tip mixture fills a plurality of holes of the master mold to obtain a master mold with a tip mixture, and the liquid mixture of the tip mixture The reference surface of the master mold is flush, and the needle tip mixture contains the active ingredient; (c) drying the tip mixture to the tip layer to obtain a master mold having a needle tip layer whose surface is lower than the base surface of the master mold (d) forming a barrier solution on the tip layer and the plurality of holes, thereby allowing the barrier solution to cover the tip layer and the reference surface of the master mold and the plurality of holes to obtain a master mold containing the barrier solution. (e) drying the barrier solution as a barrier layer to obtain a master having a tip layer and a barrier layer, the surface of the barrier layer being lower than the reference plane of the master mold; (f) forming a needle bottom liquid in the barrier layer Above and above the plurality of holes, thereby making the needle bottom mixed solution Forming a master mold with a needle bottom liquid mixture in the barrier layer and the reference surface of the master mold and the plurality of holes; (g) drying the needle bottom liquid mixture to the needle bottom layer, thereby bonding the barrier layer to the needle tip layer Between the bottom layer of the needle; and (h) removing the mutually adhered tip layer, barrier layer and needle bottom layer from the master mold to obtain the microneedle patch. The production method according to claim 1, wherein the barrier solution comprises a barrier material comprising trehalose, dextrin, maltodextrin, b-cyclodextrin, 2-hydroxypropyl-b-cyclodextrin. , dextran, amylopectin, methyl vinyl ether-maleic anhydride copolymer, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, poly a vinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan or a combination thereof, and the viscosity of the barrier solution is greater than the viscosity of the tip mixture and greater than The viscosity of the needle bottom mixture. The method of claim 2, wherein the barrier material has a molecular weight greater than 1000 Da. The method according to claim 1, wherein the viscosity of the tip mixture is lower than the viscosity of the bottom liquid mixture. The method of claim 4, wherein the tip mixture has a viscosity of from 3 centipoise to 500,000 centipoise. The method of claim 2, wherein the needle bottom liquid has a viscosity of from 100 centipoise to 600,000 centipoise. The production method according to claim 1, wherein the concentration of the tip mixture is 5 wt% to 50 wt%. The production method according to claim 1, wherein the concentration of the needle bottom liquid is from 10 wt% to 95 wt%. The method according to claim 1, wherein the tip tension mixture has a surface tension of less than or equal to 70 dyne/cm. The production method according to claim 1, wherein the surface tension of the needle bottom liquid is less than or equal to 50 dyne/cm. The method according to claim 1, wherein the pH of the tip mixture is between 4 and 8. The production method according to claim 1, wherein the pH of the tip mixture is between 5 and 9. The production method according to claim 1, wherein the steps (c), (e) and (g) are carried out by freeze drying or room temperature drying. The production method according to claim 1, wherein the drying temperature of the steps (c), (e) and (g) is from -60 ° C to 100 ° C. The production method according to claim 1, wherein the drying temperature of the steps (c), (e) and (g) is from -60 ° C to 40 ° C. The method according to claim 1, wherein the step (g) comprises: drying the needle bottom liquid at -60 ° C to 0 ° C to form a bottom layer of the needle, to obtain a first dry needle bottom layer, a barrier layer and a needle tip. Layer; the first dry needle bottom layer, the barrier layer and the needle tip layer are placed at 2 ° C to 10 ° C to obtain a second dry needle bottom layer, a barrier layer and a needle tip layer; and the second dry needle bottom layer The barrier layer and the tip layer are dried at room temperature, thereby bonding the barrier layer between the tip layer and the bottom layer of the needle. The manufacturing method according to claim 1, wherein after the step (g), the step (h) comprises: forming a back layer on the master mold and the bottom layer of the needle, thereby making the needle tip layer and the barrier layer And a pin bottom layer is interposed between the master mold and the back layer; and simultaneously removing the needle tip layer, the needle bottom layer and the back layer from the master mold having the needle tip layer, the barrier layer and the needle bottom layer, obtaining the micro Needle patch. The manufacturing method according to claim 1, wherein the step (b) comprises: forming a tip mixture on the master mold, and flowing the tip mixture into the plurality of holes, thereby covering the needle mixture with the mother The reference surface of the mold and the plurality of holes; and the tip mixture on the reference surface is removed, so that the liquid level of the tip mixture is flush with the reference surface of the master. The method of claim 18, wherein the method of flowing the tip mixture into the plurality of holes comprises vacuum evacuation and centrifugation. The method according to claim 1, wherein the step (f) comprises: forming a needle bottom liquid on the barrier layer and the master mold, and flowing the needle bottom liquid into the plurality of holes, thereby making the needle bottom The mixed solution covers the barrier layer and the reference surface of the master mold and a plurality of holes to obtain the master mold containing the needle bottom mixed liquid. The production method according to claim 19, wherein the method of flowing the needle bottom mixed liquid into the plurality of holes comprises vacuum evacuation and centrifugation. The production method according to any one of claims 1 to 21, wherein the method of forming the tip mixture in the plurality of holes of the master mold in the step (b) includes a slit coating method and a doctor blade method. a coating method, a slanting plate coating method, a dip coating method, an inkjet printing method or a nozzle printing method; the method of forming the barrier solution on the needle tip layer and the plurality of holes in the step (d) includes slit coating a cloth method, a doctor blade coating method, a slanting plate coating method, a dip coating method, an inkjet printing method or a nozzle printing method; and the above (f) step forms a needle bottom mixed liquid on the barrier layer and the plurality of holes The method includes a slit coating method, a knife coating method, a swash plate coating method, a dip coating method, an inkjet printing method, or a nozzle printing method. The production method according to any one of claims 1 to 21, wherein the active ingredient comprises a small molecule compound, a protein drug or a botanical drug or the like. The production method according to any one of claims 1 to 21, wherein the active ingredient comprises an attenuated vaccine, a deactivated vaccine, a viroid-like particle, a purified subunit antigen, an antigen expressed by a recombinant gene, a synthetic peptide, Gene recombinant vector, genetic vaccine, nucleic acid vaccine, mucosal immune or combination vaccine. The method according to any one of claims 1 to 21, 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 carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polylactic acid , polyglycolic acid, polylactic acid-glycolic acid copolymer, chitosan and combinations thereof.