Microneedle preparation and method for manufacturing microneedle patch

Abstract

To overcome the problem of insufficient mechanical strength of existing soluble microneedles, which affects the quality of drug delivery, the present invention provides a microneedle formulation. The microneedle formulation is characterized by comprising the following component A: polyvinyl alcohol, polyvinylpyrrolidone, and hydroxyethyl cellulose. The polyvinyl alcohol comprises a first polyvinyl alcohol and a second polyvinyl alcohol, the viscosity of the first polyvinyl alcohol being 2.4-12.3 mPa·s, and the viscosity of the second polyvinyl alcohol being 17.2-42.6 mPa·s. The polyvinylpyrrolidone comprises a first polyvinylpyrrolidone and a second polyvinylpyrrolidone, the molecular weight of the first polyvinylpyrrolidone being 3500-150,000, and the molecular weight of the second polyvinylpyrrolidone being 210,000-1,500,000. The present invention also provides a method for manufacturing a microneedle patch. The microneedle formulation provided by the present invention can effectively improve the structural strength of the microneedles obtained by the manufacture.

Description

[Technical Field]

[0001] The present invention relates to the technical field of drug formulations, and more particularly to a method for producing a microneedle formulation and a microneedle patch. [Background technology]

[0002] Soluble microneedles have attracted widespread attention in the microneedle market due to their low production costs, excellent biological stability, ease of use, and ability to effectively control the drug release curve. Unlike solid or hollow needles, soluble microneedles remain in the skin after a single puncture, allowing for controlled drug release rates. This rate primarily depends on the microneedle structure, so the drug release rate can be easily controlled by modifying the microneedle formulation.

[0003] However, soluble microneedles still have drawbacks. For example, soluble microneedles use water-soluble molecules as excipients, which fundamentally differ from other types of microneedles in terms of mechanical strength during use and physical stability during storage. Existing soluble microneedle formulations suffer from insufficient mechanical strength, resulting in insufficient penetration depth when applied to the skin and prone to breakage before reaching the target depth, affecting the dosage and making them unsuitable for maintaining dosage stability. Furthermore, the production efficiency of current soluble microneedles, particularly the dehydration efficiency, is low. The temperature and time during the dehydration process are too high, leading to the API contained in the soluble microneedles easily losing its physical, chemical, and biological activity. Therefore, the mechanical strength of soluble microneedles is significantly affected by the thoroughness of dehydration, and whether the dehydration conditions are harsh or mild significantly affects the quality of the soluble microneedle product.

[0004] Therefore, finding an appropriate formulation of dissolving microneedles and a gentle and efficient dehydration method for dissolving microneedles is extremely important for the production efficiency and quality control of dissolving microneedles. Summary of the Invention

[0005] In response to the problems of insufficient mechanical strength of existing soluble microneedles, low production efficiency, and impact on the quality of drug administration, the present invention provides a method for manufacturing a microneedle preparation and a microneedle patch.

[0006] The technical solutions adopted by the present invention to solve the above technical problems are as follows: In one aspect, the present invention provides a microneedle formulation, the microneedle formulation comprising the following component A: Polyvinyl alcohol, polyvinylpyrrolidone and hydroxyethyl cellulose, wherein the molecular weight of the hydroxyethyl cellulose is 80,000 to 780,000, the polyvinyl alcohol includes a first polyvinyl alcohol and a second polyvinyl alcohol, the viscosity of the first polyvinyl alcohol is 2.4 to 12.3 mPa s, and the viscosity of the second polyvinyl alcohol is 17.2 to 42.6 mPa s; The polyvinylpyrrolidone includes a first polyvinylpyrrolidone and a second polyvinylpyrrolidone, the first polyvinylpyrrolidone having a molecular weight of 3,500 to 150,000, and the second polyvinylpyrrolidone having a molecular weight of 210,000 to 1,500,000.

[0007] Optionally, the viscosity of the first polyvinylpyrrolidone is 0.8 to 10.6 mPa·s, and the viscosity of the second polyvinylpyrrolidone is 16.5 to 88.4 mPa·s.

[0008] Optionally, the A component includes the following weight amounts of components: Polyvinyl alcohol 2 to 6 parts, polyvinylpyrrolidone 9.5 to 15 parts, hydroxyethyl cellulose 5 to 7 parts, Here, 0.5 to 2.5 parts of the first polyvinyl alcohol, 1.5 to 3.5 parts of the second polyvinyl alcohol, 2.5 to 5 parts of first polyvinylpyrrolidone, 7 to 10 parts of second polyvinylpyrrolidone.

[0009] Optionally, the A component further comprises 35 to 49 parts by weight of a first solvent.

[0010] Optionally, the soluble microneedles further comprise the following B component: Sugars, buffers and salts.

[0011] Optionally, the B component comprises the following components by weight: 11-16 parts sugar, 0.3-0.8 parts buffer, 0.5-2 parts salt.

[0012] Optionally, the sugars include 1 to 3 parts by weight of sucrose and 10 to 13 parts by weight of trehalose, and the B component further includes 0.002 to 0.01 parts by weight of sodium hydroxide and 14 to 17 parts by weight of a second solvent.

[0013] Optionally, the weight ratio of the A component to the B component is (16.5-77):(11.8-35.81).

[0014] Optionally, the microneedle formulation further comprises a pharmaceutically active ingredient, and the weight ratio of the A component to the pharmaceutically active ingredient is (16.5-77):(0.6-22.46).

[0015] In another aspect, the present invention provides a method for manufacturing a microneedle patch, the method comprising: A step of obtaining a pharmaceutically active ingredient and the microneedle preparation according to any one of claims 1 to 8, and preparing a molding liquid for molding microneedles; Applying the molding liquid to a microneedle mold, dehydrating it until the water content is less than 15%, and demolding it to obtain a microneedle patch; and placing the microneedle patch in a protective member and then in a sealed bag containing a dehydrating agent to reduce the moisture content of the microneedle patch to less than 3%. Preferably, the moisture content of the microneedle patch is as low as 1% or less.

[0016] Optionally, the sealed bag has a water vapor transmission rate of 0.8 g / m 2 Less than 24 hours.

[0017] Optionally, the sealed bag is a blend of one or more of the following films: biaxially oriented polypropylene film, polyethylene terephthalate, chlorinated polypropylene resin, and aluminum foil.

[0018] Optionally, the material of the blister and / or adhesive plate has a water vapor transmission rate of 1 to 20 g / m 2 -24-hour barrier material.

[0019] Optionally, the blister material is polyvinyl chloride or polyethylene glycol terephthalate.

[0020] Optionally, the adhesive plate material is spunbond olefin or aluminum plastic film.

[0021] According to the microneedle preparation provided by the present invention, the inventors have found through numerous experiments that by combining hydroxyethyl cellulose of a specific molecular weight, first and second polyvinyl alcohols of a specific viscosity, and first and second polyvinyl pyrrolidones of a specific molecular weight as the backbone material that plays the main role of supporting the strength of the microneedle preparation, the structural strength of the microneedle prepared by the microneedle preparation can be effectively improved, so that it will not break under the action of a relatively large pressure, can penetrate deep into the skin, and the quality of drug administration can be improved.It is believed that the combination of the first polyvinyl alcohol and second polyvinyl alcohol within the above viscosity range and the first polyvinyl pyrrolidone and second polyvinyl pyrrolidone within the above molecular weight range allows the polyvinyl alcohol and polyvinyl pyrrolidone to intertwine with each other, and the difference in the length of their molecular chains plays a complementary role, so that the first polyvinyl alcohol, second polyvinyl alcohol, first polyvinyl pyrrolidone, and second polyvinyl pyrrolidone intertwine with each other to form a more stable supporting backbone, thereby improving the overall strength of the microneedle. [Brief explanation of the drawings]

[0022] [Figure 1] 1 shows the results of a parafilm puncture experiment conducted on the microneedle patch provided in Example 1 of the present invention. [Figure 2] 1 shows the results of a parafilm puncture experiment carried out on the microneedle patches provided in Comparative Examples 1 to 4 of the present invention. [Figure 3] 1 shows the results of a leaf puncture experiment conducted on the microneedle patch provided in Example 1 of the present invention. [Figure 4] 1 shows the results of a leaf puncture experiment carried out on the microneedle patches provided in Comparative Examples 1 to 4 of the present invention. [Figure 5] FIG. 1 is a diagram showing the configuration of the microneedle patch provided in Example 1 of the present invention before puncture. [Figure 6] FIG. 1 is a diagram showing the morphology of the microneedle patch provided in Example 1 of the present invention after puncture. [Figure 7] FIG. 2 is a diagram showing the morphology of the microneedle patches provided in Comparative Examples 1 to 4 of the present invention before puncture. [Figure 8] FIG. 2 is a diagram showing the morphology of the microneedle patches provided in Comparative Examples 1 to 4 of the present invention after puncture. [Figure 9] FIG. 1 is a structural schematic diagram of an integrated microneedle. [Figure 10] FIG. 1 is a structural schematic diagram of a split-layer microneedle. DETAILED DESCRIPTION OF THE INVENTION

[0023] In order to further clarify the technical problems, technical solutions and beneficial effects that the present invention aims to solve, the present invention will be described in more detail below in combination with drawings and examples. It should be understood that the specific examples described herein are used for the interpretation of the present invention and are not intended to limit the present invention.

[0024] In the description of this invention, the term "molecular weight" means the weight average molecular weight.

[0025] The term "barrier material" refers to the barrier properties of a material at a constant pressure (1 mPa), a constant temperature (23°C), a constant humidity, a unit time (24 hours), and a unit area (1 m 2 ) refers to the volume or weight of small molecules that can permeate a plastic product of a certain thickness.

[0026] One embodiment of the present invention provides a microneedle formulation, which comprises the following component A: Polyvinyl alcohol and polyvinylpyrrolidone. Here, the polyvinyl alcohol includes a first polyvinyl alcohol and a second polyvinyl alcohol, the viscosity of the first polyvinyl alcohol being 2.4 to 12.3 mPa·s, and the viscosity of the second polyvinyl alcohol being 17.2 to 42.6 mPa·s. The polyvinylpyrrolidone includes a first polyvinylpyrrolidone and a second polyvinylpyrrolidone, the first polyvinylpyrrolidone having a molecular weight of 3,500 to 150,000, and the second polyvinylpyrrolidone having a molecular weight of 210,000 to 1,500,000.

[0027] Through numerous experiments, the inventors have found that by combining hydroxyethyl cellulose with a specific molecular weight, first and second polyvinyl alcohols with specific viscosities, and first and second polyvinyl pyrrolidones with specific molecular weights as the backbone material that plays a key role in supporting the strength of the microneedle preparation, the structural strength of the microneedle prepared by the microneedle preparation can be effectively improved, so that the microneedles will not break under the action of relatively large pressure, can penetrate deep into the skin, and the quality of drug administration can be improved.It is believed that the combination of the first polyvinyl alcohol and second polyvinyl alcohol within the above viscosity range and the first polyvinyl pyrrolidone and second polyvinyl pyrrolidone within the above molecular weight range allows the polyvinyl alcohol and polyvinyl pyrrolidone to intertwine with each other, and the difference in the length of their molecular chains plays a complementary role, so that the first polyvinyl alcohol, second polyvinyl alcohol, first polyvinyl pyrrolidone, and second polyvinyl pyrrolidone intertwine with each other to form a more stable supporting backbone, thereby improving the overall strength of the microneedle.

[0028] In a preferred embodiment, the viscosity of the first polyvinylpyrrolidone is 0.8 to 10.6 mPa·s, and the viscosity of the second polyvinylpyrrolidone is 16.5 to 88.4 mPa·s.

[0029] In some embodiments, the A component includes the following components by weight: Polyvinyl alcohol 2 to 6 parts, polyvinylpyrrolidone 9.5 to 15 parts, hydroxyethyl cellulose 5 to 7 parts, Here, 0.5 to 2.5 parts of the first polyvinyl alcohol, 1.5 to 3.5 parts of the second polyvinyl alcohol, 2.5 to 5 parts of first polyvinylpyrrolidone, 7 to 10 parts of second polyvinylpyrrolidone.

[0030] Limiting the amounts of the first polyvinyl alcohol and second polyvinyl alcohol with different viscosities and the first polyvinylpyrrolidone and second polyvinylpyrrolidone with different molecular weights is advantageous in maintaining the overall strength of the microneedles obtained from the microneedle formulation. If the amounts of the first polyvinyl alcohol, second polyvinyl alcohol, first polyvinylpyrrolidone, and second polyvinylpyrrolidone added are outside the above ranges, the structural strength of the obtained microneedles may be reduced.

[0031] In some embodiments, the A component further comprises 35 to 49 parts by weight of a first solvent.

[0032] The first solvent is used to disperse the first polyvinyl alcohol, the second polyvinyl alcohol, the first polyvinyl pyrrolidone, the second polyvinyl pyrrolidone, and the like in the component A.

[0033] Since the first polyvinyl alcohol, the second polyvinyl alcohol, the first polyvinylpyrrolidone, and the second polyvinylpyrrolidone are all water-soluble molecules, in a preferred embodiment, water is selected as the first solvent, and more preferably, water for injection is selected as the first solvent.

[0034] Since component A contains a large amount of high molecular weight substances, it is necessary to dissolve and disperse component A under heated conditions, preferably at 65°C to 95°C. To avoid denaturation of some temperature-sensitive substances due to heating of component A, in some embodiments, the soluble microneedles further contain component B. The temperature-sensitive substance may be added to component B and mixed after component A has cooled.

[0035] In other embodiments, when the microneedle preparation does not contain a temperature-sensitive substance or when the component A is not heat-treated, the components are not particularly distinguished, and the component A and the component B mentioned in the present invention may be mixed as the same component.

[0036] In some embodiments, the B component comprises sugars, buffers and salts.

[0037] In some embodiments, the B component includes the following components by weight: 11-16 parts sugar, 0.3-0.8 parts buffer, 0.5-2 parts salt.

[0038] The sugars may be sucrose and / or trehalose, which are primarily used as stabilizers in microneedle patches. They are carbohydrates with good biocompatibility, high stability, low cost, and good safety. The resulting microneedles have good mechanical strength and can rapidly release active ingredients into the skin upon administration. When sucrose is absorbed by the skin, it is biodegraded in the body and gradually eliminated by the kidneys.

[0039] As the salt, sodium chloride is selected.

[0040] In some embodiments, sodium citrate is selected as the buffering agent, which is mainly combined with sodium chloride in the microneedle patch to form a buffer solution, preventing large fluctuations in pH value during the preparation process of the formulation.

[0041] In some embodiments, the sugars include 1 to 3 parts by weight of sucrose and 10 to 13 parts by weight of trehalose, and the component B further includes 0.002 to 0.01 parts by weight of sodium hydroxide and 14 to 17 parts by weight of a second solvent.

[0042] The sucrose can also be replaced with other monosaccharides or disaccharides such as maltose, lactose, fructose, etc.

[0043] The sodium hydroxide is used to adjust the pH value of the microneedle formulation.

[0044] In the microneedle molding process, the solvent must be removed by dehydration. At this time, most of the first and second solvents are removed. At the same time, a small amount of solvent remaining after dehydration is acceptable, but excessive solvent residue will affect the strength of the microneedles.

[0045] In some embodiments, the weight ratio of the A component to the B component is (16.5-77):(11.8-35.81).

[0046] In some embodiments, the microneedle formulation further comprises a pharmaceutically active ingredient, and the weight ratio of the component A to the pharmaceutically active ingredient is (16.5-77):(0.6-22.46).

[0047] In some embodiments, the active pharmaceutical ingredient is a small molecule drug or a biological drug, including nucleic acid drugs such as DNA and RNA, proteins, peptides, etc.

[0048] The active pharmaceutical ingredient may be selected from suitable naturally occurring, synthetic, or recombinantly produced proteins, peptides, and fragments thereof. Representative examples of the types of APIs used for delivery include antibiotics, antivirals, analgesics, anesthetics, antihistamines, anti-inflammatory drugs, anticoagulants, allergens, vitamins, and antitumor drugs. Bioactive ingredients include various types of hormones, vaccines used for infectious diseases, and therapeutic vaccines used for cancer, neurological disorders, allergies, smoking cessation, or other addictions. Examples of antigens include influenza antigens (influenza vaccines), HBs antigen (hepatitis B virus surface antigen), HBe antigen (hepatitis B e antigen), BCG (Bacille de Calmette et Guerin) antigen, measles antigen, rubella antigen, chickenpox antigen, yellow fever antigen, shingles antigen, rotavirus antigen, Hib (Haemophilus influenzae type b) antigen, rabies antigen, cholera antigen, diphtheria antigen, pertussis antigen, tetanus antigen, inactivated poliomyelitis antigen, Japanese encephalitis antigen, human papillomavirus antigen, and mixed antigens of the above viruses.

[0049] In some embodiments, the microneedle formulation is used to fabricate monolithic or layered microneedles.

[0050] As shown in FIG. 9, when the microneedles to be produced are integrated microneedles, the component A, the component B and the pharmaceutically active ingredient are directly mixed to obtain a microneedle preparation for producing microneedles.

[0051] As shown in Figure 10, when the microneedle to be manufactured is a layered microneedle, first, component A and component B are mixed to obtain a base film liquid, and then a pharmaceutically active ingredient is added to a portion of the base film liquid to obtain a needle tip liquid. The needle tip liquid is used to form the needle tip portion of the microneedle, and the base film liquid is used to form the needle body portion and base film portion of the microneedle.

[0052] Another embodiment of the present invention provides a method for producing the above-described microneedle formulation, the method comprising: The method includes the steps of adding hydroxyethyl cellulose, a first polyvinyl alcohol, a second polyvinyl alcohol, a first polyvinyl pyrrolidone, and a second polyvinyl pyrrolidone to a first solvent, and dispersing the mixture by heating to obtain component A.

[0053] In some embodiments, the heating and dispersing temperature is between 65°C and 95°C.

[0054] In some embodiments, dissolving the sugar, buffer, sodium hydroxide and salt in a second solvent to obtain component B; The method further includes the step of mixing component A and component B to obtain a microneedle preparation.

[0055] In some embodiments, the microneedle formulation further comprises an active pharmaceutical ingredient.

[0056] In the dehydration stage of the manufacturing process of soluble microneedles, in order to prevent the microneedles from melting due to heat or the active pharmaceutical ingredients and other substances from being deactivated due to heat, they are often dehydrated by air drying at room temperature or below. At the same time, in order to prevent the microneedles from being deformed by wind, excessively fast wind speeds cannot be used. However, if such dehydration conditions are used, the dehydration speed will be too slow, especially when the water content of the microneedles is relatively low, the removal rate of water molecules will be reduced, and the dehydration speed will be slower than in the initial stage, which cannot meet the needs of large-scale production. At the same time, if the water content of the manufactured microneedles is too low, it will not be helpful in improving the structural strength.

[0057] To solve the above problems, another embodiment of the present invention provides a method for manufacturing a microneedle patch, the method comprising: An operation step of obtaining a pharmaceutically active ingredient and the microneedle formulation and preparing a molding liquid for microneedle molding; an operation step of applying the molding liquid to a microneedle mold, dehydrating it until the water content is 3 to 15%, and demolding it to obtain a microneedle patch; The method includes an operation step of placing the microneedle patch in a protective member and then placing it in a sealed bag containing a dehydrating agent to reduce the moisture content of the microneedle patch to less than 3%.

[0058] The sealed bag has a water vapor permeability of 0.8 g / m 2 The film may be a biaxially oriented polypropylene film, polyethylene terephthalate, chlorinated polypropylene resin, or aluminum foil, or a mixed film of two or more of these.

[0059] Pre-dehydrating the microneedle patch at temperatures between -40 and 35°C until the moisture content reaches 3-15% effectively shortens the time required for pre-dehydration, speeding up production and reducing production costs. Further dehydration slightly increases the required time, so a humidity level of 3-15% is used as the critical point for pre-dehydration. More importantly, under these moisture content conditions, the resulting microneedle patch does not completely solidify and retains a certain degree of toughness, facilitating the demolding process. This prevents the microneedle patch from breaking in the microneedle mold due to its high rigidity, and improves the morphological integrity of the microneedles.

[0060] After preliminary dehydration, the microneedle patch is placed in a protective member and then placed in a sealed bag containing a dehydrating agent. The dehydrating agent absorbs moisture from the microneedle patch through the protective member, reducing the moisture content of the microneedle patch to less than 3%. The dehydrating agent is a water-absorbing material such as molecular sieves or silica gel. The protective member can be used as a packaging material for the microneedle patch. By continuing dehydration in the protective member for 3 to 5 days, the moisture content of the microneedle patch can be reduced to less than 3%. The microneedle patch maintains optimal structural strength at this moisture content without incurring additional time or cost.

[0061] In some embodiments, the dehydration is performed by cold air dehydration, specifically by air drying for 3 to 4 hours at a temperature of −40 to 35° C. At the same time, by controlling the air speed within the range of 0.5 to 5 m / s, the molding liquid is not blown away from the microneedle mold, and the solidification rate is not reduced due to an air speed that is too low, which affects production efficiency.

[0062] In some embodiments, the protective member comprises a blister and an adhesive plate, the blister being disposed on the adhesive plate, and the microneedle patch being disposed within the blister.

[0063] The blister and the adhesive plate are attached together to form an excellent protective structure, which can prevent the microneedle patch from being damaged by external forces, while also exerting an excellent barrier effect, isolating external sources of contamination such as bacteria and viruses, and meeting the sterility requirements of GMP regulations.

[0064] The material of the blister and / or adhesive plate must have a water vapor permeability of 1 to 20 g / m 2 A 24-hour barrier material. This range of water vapor transmission rate ensures a relatively fast dehydration rate for the microneedle patch while simultaneously preventing external bacteria from easily passing through the protective material and causing contamination. In some embodiments, the blister material is polyvinyl chloride or polyethylene glycol terephthalate. In some embodiments, the blister material may be polyester aluminum vapor deposition film, polyethylene, biaxially oriented polypropylene, aluminum foil, polyvinylidene chloride-coated polypropylene, or aluminum vapor deposition unoriented polypropylene film.

[0065] In some embodiments, the adhesive plate is made of a spunbond olefin or aluminum plastic film. In some embodiments, the adhesive plate may be made of a nonwoven high-density polyethylene film, polyester aluminum vapor-deposited film, polyethylene, biaxially oriented polypropylene, aluminum foil, polyvinylidene chloride-coated polypropylene, or aluminum vapor-deposited unoriented polypropylene film.

[0066] In some embodiments, the microneedle patch produced is a layered microneedle. The process for producing the microneedle patch comprises: The forming liquid includes a base film liquid and a needle tip liquid, and the above-mentioned microneedle formulation is obtained. A step of taking a part of the microneedle formulation as a base film liquid and another part of the microneedle formulation as a needle tip liquid and adding a pharmaceutically active ingredient thereto; a step of applying a needle tip liquid to the inside of a microneedle cavity of a microneedle forming mold, dehydrating and shrinking the liquid to obtain a needle tip portion of the microneedle, subsequently applying a base film liquid onto the microneedle forming mold, dehydrating the liquid to obtain a needle body portion connected to the needle tip portion and a base film connected to the needle body portion, dehydrating the liquid until the water content is 3 to 15%, and demolding the liquid to obtain a microneedle patch; The method includes the step of placing the microneedle patch in a protective member and placing it in a sealed bag containing a dehydrating agent to reduce the moisture content of the microneedle patch to less than 3%.

[0067] In some embodiments, the microneedle patch produced is an integral microneedle. The process for producing the microneedle patch comprises: Obtaining the above microneedle formulation and adding a pharmaceutically active ingredient to the microneedle formulation as a forming liquid; applying the molding liquid to a microneedle mold, dehydrating the mold to obtain microneedles and a base film connected to the microneedles, dehydrating the mold to a moisture content of 3 to 15%, and demolding the mold to obtain a microneedle patch; The method includes the step of placing the microneedle patch in a protective member and placing it in a sealed bag containing a dehydrating agent to reduce the moisture content of the microneedle patch to less than 3%.

[0068] In some embodiments, the microneedles on the microneedle patch have a conical structure, such as a circular pointed cone, an elliptical pointed cone, a regular polygonal pointed cone, or an irregular polygonal pointed cone. The height of the microneedles is 0.001 μm to 1000 μm, and the maximum diameter is 0.005 to 3000 μm. At the same time, the distance between the microneedles is 4 μm to 1000 μm to ensure a uniform density of the microneedle array.

[0069] In some embodiments, the microneedle mold comprises a support plate and a plurality of microneedle forming areas, the shape of the microneedle forming areas conforming to the shape of the base film of the microneedle patch to be manufactured, the plurality of microneedle forming areas being embedded in the support plate at intervals, the support plate being made of a rigid material, and the microneedle forming areas being made of a flexible, breathable material.

[0070] In some embodiments, the rigid material is selected from single crystal silicon, stainless steel, aluminum plate, titanium plate, silicate glass, quartz glass, ceramic, polytetrafluoroethylene, polyetheretherketone (PEEK), propanesulfonic acid pyridinium salt, etc., and the flexible material is selected from siloxane.

[0071] In this embodiment, a microneedle mold is manufactured by combining a flexible material and a rigid material. A flexible microneedle molding area is fixed onto a rigid support plate, which supports and fixes the microneedle molding area and maintains the stability of the microneedle molding area's shape. The microneedle cavities in the microneedle molding area are used for solidification and molding of the microneedles. The use of a flexible material is advantageous for reducing the stress experienced by the microneedles during the demolding process and improving the integrity of the microneedles after demolding. At the same time, fixing the shape of the microneedle molding area with a rigid support plate prevents the microneedle molding area from deforming during the solidification and shrinkage process of the molding liquid, thereby effectively improving the molding effect and demolding integrity of the microneedles.

[0072] In some embodiments, the microneedle mold is vacuum treated when the molding solution is applied to the microneedle mold, thereby facilitating the filling rate of the microneedle mold and simultaneously avoiding the formation of air bubbles in the molded microneedles.

[0073] In different embodiments, when applying the molding liquid, the molding liquid may be introduced into the microneedle mold by pressurized injection, atomized injection, roller coating, brush coating, injection, screen printing, or knife coating.

[0074] In a preferred embodiment, the molding liquid is applied to the microneedle mold by knife coating.

[0075] The present invention will now be further illustrated by the following examples. JPEG2025533152000002.jpg118170Table 2 JPEG2025533152000003.jpg62170 (Example 1)

[0076] This example is intended to illustrate the microneedle patch and its manufacturing method disclosed in the present invention, and includes the following steps: 0.5 parts by weight of the first polyvinyl alcohol (viscosity 2.4 mPa·s), 1.5 parts by weight of the second polyvinyl alcohol (viscosity 17.2 mPa·s), 5 parts by weight of hydroxyethyl cellulose, 2.5 parts by weight of the first polyvinylpyrrolidone (molecular weight 3500), and 7 parts by weight of the second polyvinylpyrrolidone (molecular weight 210000) were weighed out, added to 15 parts by weight of water, heated and dispersed at 90°C, and then cooled to obtain component A. Component B was obtained by weighing out 1 part by weight of sucrose, 10 parts by weight of trehalose, 0.3 parts by weight of sodium citrate, 0.5 parts by weight of sodium chloride, and 0.002 parts by weight of sodium hydroxide and dissolving them in 12 parts by weight of water. The component A and the component B were mixed to obtain a microneedle preparation.

[0077] The above microneedle preparation was obtained. A part of the microneedle preparation was taken as a base film liquid, and another part of the microneedle preparation was taken as a needle tip liquid, and a pharmaceutically active ingredient was added to it. The needle tip liquid was applied to the inside of the microneedle cavity of the microneedle mold with a knife, and the microneedle cavity was dehydrated and shrunk to obtain the needle tip portion of the microneedle. Subsequently, the base film liquid was applied to the microneedle mold with a knife and dehydrated to obtain the needle body portion connected to the needle tip portion and the base film connected to the needle body portion. The base film was then pre-dehydrated until the moisture content was 3%, and the microneedle patch was obtained by demolding. The microneedle patch was placed in a protective material, then placed in an aluminum plastic film containing a dehydrating agent to continue dehydration.After leaving it undisturbed for three days, the moisture content of the microneedle patch was measured and found to have decreased to 1%. Examples 2 to 7

[0078] Examples 2 to 7 are intended to illustrate the microneedle patch and its manufacture disclosed in the present invention, and include most of the operations of Example 1, with the following differences: The constituent components with the substance contents shown in Examples 2 to 7 in Table 1 were used, and the water contents of the initial dehydration and the water contents after continued dehydration for Examples 2 to 7 are as shown in Table 2. Comparative Examples 1 to 4

[0079] Comparative Examples 1 to 4 are intended to illustrate the microneedle patch and its manufacture disclosed in the present invention, and include most of the operations of Example 1, with the following differences: The constituent components with the substance contents shown in Comparative Examples 1 to 4 in Table 1 were used, and the water contents of the initial dehydration and the water contents after continued dehydration for Comparative Examples 1 to 4 are as shown in Table 2. Comparative Example 5

[0080] Comparative Example 5 is intended to illustrate the microneedle patch and its preparation disclosed in the present invention, and includes most of the operations of Example 1, with the following differences: In Comparative Example 5, only preliminary dehydration was performed, and the moisture content was directly reduced to 1% using a water-permeable protective material and dehydrating agent without subsequent drying, but the time required was not the same. Performance Test

[0081] 1. The needle strength was tested by vertical pressure using a universal material testing machine: The microneedle patches manufactured in Examples 2 to 7 and Comparative Examples 1 to 4 above were placed on the compression plate of the universal material testing machine, the machine was started, and the pressure sensor was moved downward. When the pressure sensor detected the breakage of the microneedles, the pressure at the breakage point was recorded. The pressure sensor's pressure head had a diameter of 8 mm, and a total of approximately 194 needles were pressed, and the following experimental results were obtained. JPEG2025533152000004.jpg57170

[0082] The microneedle patch manufactured by the method provided by the present invention clearly has higher structural strength of the microneedles, while Comparative Examples 1 to 4, which lack any one of the first polyvinyl alcohol, the second polyvinyl alcohol, the first polyvinylpyrrolidone, and the second polyvinylpyrrolidone, show reduced strength of the microneedles. This indicates that the first polyvinyl alcohol, the second polyvinyl alcohol, the first polyvinylpyrrolidone, and the second polyvinylpyrrolidone exert an excellent synergistic effect in improving the strength of the microneedles.

[0083] 2. Parafilm sealing film puncture experiment: Microneedle patches from Example 1 and Comparative Examples 1 to 4 were selected, and multiple layers of parafilm were stacked on top of each other. The microneedle patches were placed under a universal testing machine with the needle tips facing the parafilm film. The microneedles were pressed with a force of 147 N (approximately the pressure of an adult's finger) to penetrate the parafilm. After the experiment, the parafilm was removed, and red ink was used to penetrate the parafilm. The number of layers of parafilm penetrated by the microneedles was determined by examining whether the red ink could penetrate the parafilm.

[0084] The results obtained in Example 1 are shown in FIG. 1, and the results obtained in Comparative Examples 1 to 4 are shown in FIG.

[0085] As can be seen from Figures 1 and 2, after the microneedle patch of Example 1 was punctured into the parafilm sealing film, the red ink was able to penetrate up to the fourth layer, i.e., it can be determined that the microneedles punctured up to the fourth layer of parafilm under 147 N.

[0086] In all of Comparative Examples 1 to 4, the liquid only penetrated up to the third layer, and did not penetrate up to the fourth layer.

[0087] 3. Leaf puncture: The microneedle patches of Example 1 and Comparative Examples 1 to 4 were selected and punctured into a leaf (Zamioculcas) and attached. After completion, the microneedle patch was removed and placed under a microscope to observe the state of microneedle puncture on the surface of the leaf.

[0088] The results of leaf puncture for the microneedle patch of Example 1 are shown in Figure 3. The results of leaf puncture for the microneedle patches of Comparative Examples 1 to 4 are shown in Figure 4. It can be seen that the microneedle patch provided in Example 1 completely punctured the leaf and the penetration depth was relatively deep, whereas the penetration depths of Comparative Examples 1 and 2 were shallower, and 3 and 4 were even shallower.

[0089] The shape of the microneedle patch of Example 1 before puncturing is shown in Figure 5, and the shape after puncturing is shown in Figure 6. The shape of the microneedle patches of Comparative Examples 1 to 4 before puncturing is shown in Figure 7, and the shape after puncturing is shown in Figure 8.

[0090] It can be seen that the microneedle patch of Example 1 retains a complete needle shape even after puncturing, whereas the microneedle patches of Comparative Examples 1 to 4 do not generally retain a complete needle shape even after puncturing.

[0091] The above is only a preferred embodiment of the present invention, and the present invention is not limited thereto. As long as it falls within the spirit and principle of the present invention, all modifications, equivalent replacements, improvements, etc., made should be included within the protection scope of the present invention.

Claims

1. A microneedle formulation comprising the following A component: Polyvinyl alcohol, polyvinylpyrrolidone and hydroxyethyl cellulose, wherein the polyvinyl alcohol includes a first polyvinyl alcohol and a second polyvinyl alcohol, the viscosity of the first polyvinyl alcohol is 2.4 to 12.3 mPa·s, and the viscosity of the second polyvinyl alcohol is 17.2 to 42.6 mPa·s; The polyvinylpyrrolidone includes a first polyvinylpyrrolidone and a second polyvinylpyrrolidone, the first polyvinylpyrrolidone having a molecular weight of 3,500 to 150,000, and the second polyvinylpyrrolidone having a molecular weight of 210,000 to 1,500,000.

2. The microneedle preparation according to claim 1, characterized in that the viscosity of the first polyvinylpyrrolidone is 0.8 to 10.6 mPa·s, and the viscosity of the second polyvinylpyrrolidone is 16.5 to 88.4 mPa·s.

3. The microneedle formulation according to claim 1, characterized in that the component A contains the following components by weight: 2 to 6 parts of polyvinyl alcohol, 9.5 to 15 parts of polyvinylpyrrolidone, 5 to 7 parts of hydroxyethyl cellulose, Here, 0.5 to 2.5 parts of the first polyvinyl alcohol, 1.5 to 3.5 parts of the second polyvinyl alcohol, 2.5 to 5 parts of first polyvinylpyrrolidone, 7 to 10 parts of second polyvinylpyrrolidone.

4. The microneedle preparation according to claim 1, wherein the component A further comprises 35 to 49 parts by weight of a first solvent.

5. 2. The microneedle formulation of claim 1, wherein the soluble microneedles further comprise the following B component: Sugars, buffers and salts.

6. The microneedle formulation according to claim 5, characterized in that the B component contains the following components by weight: 11-16 parts sugar, 0.3-0.8 parts buffer, 0.5-2 parts salt.

7. The microneedle preparation according to claim 6, characterized in that the saccharides include 1 to 3 parts by weight of sucrose and 10 to 13 parts by weight of trehalose, and the B component further includes 0.002 to 0.01 parts by weight of sodium hydroxide and 14 to 17 parts by weight of a second solvent.

8. The microneedle preparation according to claim 5, characterized in that the weight ratio of the component A to the component B is (16.5 to 77):(11.8 to 35.81).

9. The microneedle preparation according to claim 1, characterized in that the microneedle preparation further comprises a pharmaceutically active ingredient, and the weight ratio of the A component to the pharmaceutically active ingredient is (16.5 to 77):(0.6 to 22.46).

10. A step of obtaining a pharmaceutically active ingredient and the microneedle formulation according to any one of claims 1 to 8, and preparing a molding liquid for molding microneedles; Applying the molding liquid to a microneedle mold, dehydrating it at a temperature of -40 to 35°C until the water content is 3 to 15%, and then demolding it to obtain a microneedle patch; placing the microneedle patch in a protective material and then in a sealed bag containing a dehydrating agent to reduce the moisture content of the microneedle patch to less than 3%; A method for producing a microneedle patch comprising:

11. The manufacturing method according to claim 10, wherein the protective member includes a blister and an adhesive plate, the blister is placed on the adhesive plate, and the microneedle patch is placed in the blister.

12. The water vapor permeability of the sealed bag is 0.8 g / m 2 The method according to claim 10, characterized in that the time is less than 24 hours.

13. 13. The method according to claim 12, wherein the sealed bag is made of one or a mixture of two or more of biaxially oriented polypropylene film, polyethylene terephthalate, chlorinated polypropylene resin, and aluminum foil.

14. The material of the blister and / or adhesive plate has a water vapor permeability of 1 to 20 g / m 2 The method according to claim 11, characterized in that it is a 24h barrier material.

15. The manufacturing method according to claim 14, wherein the material of the blister is polyvinyl chloride or polyethylene glycol terephthalate.

16. 13. The manufacturing method according to claim 12, wherein the adhesive plate is made of a spunbond olefin or aluminum plastic film.

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