A microneedle patch and a preparation method thereof

Abstract

The application provides a microneedle patch and a preparation method thereof, the microneedle patch comprising a base, microneedles and a coating layer on the surface of the microneedles, the coating layer being prepared from a coating liquid, the coating liquid being prepared from a coating material, the coating material comprising one or more of a coating base material, a humectant, a protein protective agent and an antibiotic, the coating base material comprising at least one of high-molecular-weight hyaluronic acid with a molecular weight of 250KDa-1000KDa and a concentration of 5-30% (w / v) and polyvinylpyrrolidone (PVP-K30) with a concentration of 25-45% (w / v), and the active ingredient comprising at least one of a small-molecule compound, a vaccine, a protein drug, a peptide drug and a nucleic acid drug.

Description

Technical Field

[0001] This invention relates to the field of transdermal drug delivery microneedle patch formulations, and particularly to drug-coated microneedle patches and their preparation methods. Background Technology

[0002] Microneedles are designed using microfabrication techniques to create needles at the micrometer level from needle-like materials. When inserted into the skin and mucous membranes, these needles do not touch nerve tissue, thus achieving painless drug delivery. Microneedle drug delivery offers numerous advantages, such as painless administration, significantly increasing user compliance; minimal technical skill required, allowing patients to administer medication themselves; the inherently low-humidity environment of microneedles improves drug stability; and the solid form of the drug facilitates transportation and storage.

[0003] Microneedles include soluble microneedles and insoluble microneedles (water-insoluble microneedles). The current limitation in the development of soluble microneedles is the difficulty in mass production, while water-insoluble microneedles are developing most rapidly because they can be quickly mass-produced using various microfabrication technologies, such as injection molding and 3D printing. However, due to limitations in mass production processes and materials, the active ingredient cannot be directly loaded into the needle body during the microneedle preparation process. Therefore, water-insoluble microneedles are used in two ways for drug delivery: First, after treating the skin with blank microneedles, the drug is applied to the treated skin, and the drug diffuses freely into the skin through the pores created by the microneedles. Second, after blank microneedles are produced, the active ingredient is coated onto the surface of the needle body—that is, coated microneedles—before skin drug delivery. The first method suffers from inaccurate drug delivery and is therefore rarely used in the pharmaceutical field. The second method, due to its accurate drug dosage, is widely used, but coating has drawbacks such as low drug loading capacity.

[0004] Microneedles are small in size and surface area, and drug delivery cannot be carried within the coated microneedle body. Coated microneedles are limited by low drug delivery capacity. Ordinary coating formulations, processes, and methods have many drawbacks. For example, increasing the number of coatings and the amount of coating to improve drug delivery capacity will thicken the needle tip, making the needle less sharp and resulting in poor puncture effect, leading to inaccurate dosage or even drug delivery failure. Ordinary coating processes can also lead to drug delivery failure, where the solution soaks into the needle base, resulting in inaccurate dosage. Spray coating or micromanipulation drug delivery will greatly increase manufacturing time and mass production costs, which is extremely detrimental to industrial production. Therefore, developing low-cost coating formulations and methods suitable for water-insoluble microneedles and meeting the requirements for high-dose drug delivery is an urgent problem to be solved. Summary of the Invention

[0005] One of the objectives of this invention is to provide a microneedle patch, which includes a base, microneedles, and a coating layer on the surface of the microneedles.

[0006] The microneedle patch of the present invention has a spacing of 1-5 mm between the microneedles. The coating layer is prepared by a coating solution, which is prepared by dissolving coating materials and active ingredients in water or a buffer solution. The coating material includes a coating matrix material, a moisturizer, a protein protectant, and an antibiotic. The coating matrix material includes at least one of hyaluronic acid and polyvinylpyrrolidone. The molecular weight of the hyaluronic acid is 250 kDa-1000 kDa. The polyvinylpyrrolidone is PVP-K30. The moisturizer includes glycerin. The protein protectant includes at least one of trehalose, human serum albumin, sucrose, and arginine.

[0007] Compared to ordinary coated microneedle patches, the microneedle patch of the present invention has a higher loading capacity of active ingredients and can load a variety of different active ingredients to meet different clinical needs.

[0008] The microneedle patch of the present invention has a microneedle body that is conical or pyramidal, with a height of 60-900 μm, preferably 100-700 μm, more preferably 200-500 μm; a tip width or diameter of 5-40 μm, preferably 10-30 μm; and a tip width or diameter of 50-300 μm, preferably 100-250 μm.

[0009] In some embodiments, the microneedles and the base are made of water-insoluble materials, including polymers, metals, and ceramics. The polymers include polyvinyl chloride, polycarbonate, polystyrene, polypropylene, polycaprolactone, LCP, and photosensitive resins. The metals include stainless steel, titanium, and nickel.

[0010] In some embodiments, the coating matrix material is hyaluronic acid with a molecular weight of 250-1000 kDa, preferably 510-950 kDa, and a concentration of 5-30% (w / v), preferably 11-19% (w / v).

[0011] In some embodiments, the coating matrix material is polyvinylpyrrolidone (PVP-K30), and the concentration of PVP-K30 is 25-45% (w / v).

[0012] In some embodiments, the coating material further includes a humectant and a protein protectant. The humectant includes glycerin and has a concentration of 0.5-2.5%, preferably 1-2%. The protein protectant is at least one of trehalose, sucrose, arginine, and human serum albumin and has a concentration of 1-5%, preferably 2-4%.

[0013] In some embodiments, the viscosity of the coating liquid is 370,000-1,200,000 centipoise, preferably 750,000-1,050,000 centipoise.

[0014] In some embodiments, the buffer includes HEPES buffer, phosphate buffer, carbonate buffer, and Tris buffer.

[0015] In some embodiments, the coating solution is obtained by dissolving the coating material and the active ingredient in water or an aqueous buffer solution.

[0016] In some embodiments, the active ingredient includes at least one of small molecule compounds, vaccines, protein drugs, peptide drugs, and nucleic acid drugs.

[0017] In some embodiments, the small molecule compounds include lidocaine, bupivacaine, ropivacaine, propranolol, zolmitriptan, levonorgestrel, minoxidil, finasteride, orlistat, and the concentration of the small molecule compounds in the coating solution is 10-40%.

[0018] In some embodiments, the protein drug includes insulin, the peptide drug includes semaglutide, and the concentration of the protein drug and peptide drug in the coating solution is 4-10%.

[0019] In some embodiments, the vaccine includes cancer treatment vaccines, anthrax vaccines, influenza vaccines, Lyme disease vaccines, rabies vaccines, measles vaccines, mumps vaccines, varicella vaccines, smallpox vaccines, hepatitis vaccines, hepatitis A vaccines, hepatitis B vaccines, hepatitis C vaccines, pertussis vaccines, rubella vaccines, diphtheria vaccines, encephalitis vaccines, Japanese encephalitis vaccines, respiratory syncytial virus vaccines, yellow fever vaccines, polio vaccines, herpes vaccines, human papillomavirus vaccines, rotavirus vaccines, pneumococcal vaccines, meningitis vaccines, pertussis vaccines, tetanus vaccines, typhoid fever vaccines, cholera vaccines, tuberculosis vaccines, severe acute respiratory syndrome (SARS) vaccines, HSV-1 vaccines, HSV-2 vaccines, and HIV vaccines, wherein the concentration of the vaccine in the coating solution is 4-10%.

[0020] In some embodiments, the vaccine also includes one or more adjuvants.

[0021] In some embodiments, the quantitative determination of the vaccine and protein drug is performed using the Coomassie Brilliant Blue assay, the quantitative determination of the small molecule compound and peptide drug is performed using high performance liquid chromatography, and the quantitative determination of the nucleic acid drug is performed using absorbance.

[0022] In some embodiments, the activity detection method for the vaccine and protein drug is ELISA, the activity detection method for the peptide is WB, and the activity detection method for the plasmid is qPCR sequencing.

[0023] In some embodiments, the evaluation of the puncture effect is based on the results of the Evans blue staining method. Specifically, the microneedle patch is pressed onto the detached skin of a young Panamanian miniature pig, removed after 20 seconds, and then coated with a 4% Evans blue solution for 1 minute. Excess dye is rinsed off with sterile water. If the microneedle puncture is successful, a corresponding blue hole will appear on the skin. When the number of successful punctures reaches 95% of the needle body, the puncture is considered excellent; if the number of successful punctures does not exceed 60% of the needle body, the puncture effect is considered poor.

[0024] The present invention further provides a method for preparing microneedle patches, the preparation method including a coating process in which the microneedle body is vertically inserted into a coating liquid, and after the needle body adsorbs a layer of coating liquid, it is pulled out, the needle body is placed vertically downward, and then a vertically upward airflow is given below the needle body to make the coating liquid uniformly maintained on the surface of the needle body and dry quickly, so that the active ingredient is loaded on the surface of the needle body.

[0025] In some embodiments, the coating solution needs to be degassed first. Degassed methods include depressurization, pressurization, centrifugation, and settling. Then, the coating solution is filled into the solution tank completely. After the liquid surface is completely level, the microneedle is inserted into the coating solution. The edge height of the solution tank can be 1 / 3, 1 / 2, or 3 / 4 of the height of the microneedle, that is, the liquid level height of the coating solution can be 1 / 3, 1 / 2, or 3 / 4 of the height of the needle, but there is no specific range. The insertion and immersion time is 5-30 seconds.

[0026] In some embodiments, after the coating liquid is filled into the solution tank, it must be placed in a constant humidity environment with a humidity of 60-90% in subsequent operations.

[0027] In some embodiments, the microneedle is vertically inserted into the coating liquid, then pulled out and placed vertically downward. Then, an upward airflow is applied below the needle, with an airflow speed of 0.5m-10m / s, preferably 0.7-4.5m / s, an airflow humidity of 1-60%, and an airflow holding time of 1-30min, preferably 5-30min. Preferably, the product is obtained after drying.

[0028] In some embodiments, the airflow also has a drying function, and the holding time is the drying time of the coating solution on the microneedle surface.

[0029] In some embodiments, the microneedle patch can be coated once more after drying.

[0030] In some embodiments, the coating thickness of the microneedle patch after drying is 2-10 μm, which does not affect the puncture performance of the microneedle itself and has a good puncture effect. The coating thickness is detected by scanning electron microscopy.

[0031] Compared with existing technical solutions, the present invention has the following beneficial effects:

[0032] 1. Compared with conventional methods for preparing coated microneedles, the preparation method of the present invention has a shorter preparation time, higher drug loading capacity, smaller batch-to-batch variation, simpler operation, and lower cost, making it highly suitable for industrial production.

[0033] 2. Compared with ordinary coated microneedles, the microneedle patch of the present invention can keep the coating liquid uniformly on the surface of the needle body without displacement under the action of the ventilation system, and the drying speed is fast. The thickness of the drug-loaded part of the resulting microneedle body is thin, only 2-10μm thick, with intact needle shape, sharpness, excellent puncture performance, and accurate drug delivery.

[0034] 3. The coating solution formulation and preparation method described in this invention are applicable to various types of active ingredients and microneedles of different materials, and have good versatility. Detailed Implementation

[0035] The following embodiments are further illustrations of the present invention, but are by no means limitations on the scope of the invention. The present invention is further described in detail below with reference to the embodiments; however, those skilled in the art should understand that the present invention is not limited to these embodiments and the preparation methods used. Furthermore, those skilled in the art can make equivalent substitutions, combinations, improvements, or modifications to the present invention based on the description thereof, but all such substitutions and modifications will be included within the scope of the present invention.

[0036] Example 1

[0037] This embodiment provides a microneedle patch;

[0038] Among them, the microneedles are made of polycarbonate, the spacing between the microneedles is 1 mm, the microneedles are conical with a height of 500 μm, a tip width of 10 μm, and a needle end diameter of 250 μm;

[0039] The coating solution includes hyaluronic acid with a molecular weight of 300 kDa, human serum albumin, glycerol, hepatitis B vaccine, and water, and the viscosity of the coating solution is 750,000 centipoise.

[0040] The concentrations of human serum albumin, hyaluronic acid, glycerol, and hepatitis B vaccine in the coating solution were 5%, 30%, 2.5%, and 4%, respectively.

[0041] The preparation method of microneedle patches includes the following steps:

[0042] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 30 seconds, then apply airflow for 30 minutes to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0043] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0044] The humidity of the airflow is 60%, and the airflow velocity is 0.7 m / s;

[0045] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0046] Example 2

[0047] This embodiment provides a microneedle patch;

[0048] The microneedles are made of polypropylene, with a spacing of 1 mm between them. Each microneedle is a cone with a height of 500 μm, a tip width of 10 μm, and a tip diameter of 250 μm.

[0049] The coating solution includes hyaluronic acid with a molecular weight of 300 kDa, arginine, glycerol, hepatitis B vaccine, and water, and has a viscosity of 600,000 centipoise.

[0050] The concentrations of arginine, hyaluronic acid, glycerol, and hepatitis B vaccine in the coating solution were 4%, 19%, 2%, and 10%, respectively.

[0051] The preparation method of microneedle patches includes the following steps:

[0052] The needle is slowly and vertically inserted into the coating solution to remove air bubbles, soaked for 15 seconds, and then airflow is applied for 20 minutes to keep the coating solution uniform and dry, thus obtaining a microneedle patch.

[0053] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0054] The humidity of the airflow is 30%, and the airflow velocity is 2 m / s;

[0055] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0056] Example 3

[0057] This embodiment provides a microneedle patch;

[0058] Among them, the microneedles are prepared from polycaprolactone, the spacing between the microneedles is 1 mm, the microneedles are conical with a height of 500 μm, a tip width of 10 μm, and a needle end diameter of 250 μm;

[0059] The coating solution includes hyaluronic acid with a molecular weight of 300 kDa, sucrose, glycerin, hepatitis B vaccine, and water, and has a viscosity of 510,000 centipoise.

[0060] The concentration of sucrose in the coating solution is 3%, the concentration of hyaluronic acid in the coating solution is 11%, the concentration of glycerol in the coating solution is 1%, and the concentration of hepatitis B vaccine in the coating solution is 4%.

[0061] The preparation method of microneedle patches includes the following steps:

[0062] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 10 seconds, then apply airflow for 5 minutes to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0063] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0064] The humidity of the airflow is 10%, and the airflow speed is 4 m / s;

[0065] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0066] Example 4

[0067] This embodiment provides a microneedle patch;

[0068] Among them, the microneedles are made of titanium metal, the spacing between the microneedles is 1 mm, the microneedles are conical, the height is 500 μm, the tip width is 10 μm, and the diameter of the end of the needle body is 250 μm;

[0069] The coating solution includes hyaluronic acid with a molecular weight of 300 kDa, trehalose, glycerin, hepatitis B vaccine, and water, and has a viscosity of 520,000 centipoise.

[0070] The concentration of trehalose in the coating solution is 2%, the concentration of hyaluronic acid in the coating solution is 11%, the concentration of glycerol in the coating solution is 1%, and the concentration of hepatitis B vaccine in the coating solution is 10%.

[0071] The preparation method of microneedle patches includes the following steps:

[0072] The needle is slowly and vertically inserted into the coating solution to remove air bubbles, soaked for 10 seconds, and then airflow is applied for 5 minutes to keep the coating solution uniform and dry, thus obtaining a microneedle patch.

[0073] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0074] The humidity of the airflow is 5%, and the airflow velocity is 4.5 m / s;

[0075] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0076] Example 5

[0077] This embodiment provides a microneedle patch;

[0078] Among them, the microneedles are made of polystyrene, the spacing between the microneedles is 1 mm, the microneedles are conical, the height is 500 μm, the tip width is 10 μm, and the end diameter of the needle body is 250 μm;

[0079] The coating solution includes hyaluronic acid with a molecular weight of 300 kDa, human serum albumin, glycerol, hepatitis B vaccine, and water, and the viscosity of the coating solution is 370,000 centipoise.

[0080] The concentrations of human serum albumin, hyaluronic acid, glycerol, and hepatitis B vaccine in the coating solution were 1%, 5%, 0.5%, and 4%, respectively.

[0081] The preparation method of microneedle patches includes the following steps:

[0082] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 5 seconds, then apply airflow for 1 minute to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0083] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0084] The airflow humidity is 1%, and the airflow velocity is 10 m / s;

[0085] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0086] Example 6

[0087] This embodiment provides a microneedle patch;

[0088] Among them, the microneedles are made of polycarbonate, the spacing between the microneedles is 1 mm, the microneedles are conical with a height of 500 μm, a tip width of 10 μm, and a needle end diameter of 250 μm;

[0089] The coating solution includes hyaluronic acid with a molecular weight of 510 kDa, human serum albumin, glycerol, hepatitis B vaccine, and water, and has a viscosity of 920,000 centipoise.

[0090] The concentrations of human serum albumin, hyaluronic acid, glycerol, and hepatitis B vaccine in the coating solution were 5%, 30%, 2.5%, and 4%, respectively.

[0091] The preparation method of microneedle patches includes the following steps:

[0092] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 30 seconds, then apply airflow for 30 minutes to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0093] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0094] The humidity of the airflow is 60%, and the airflow velocity is 0.7 m / s;

[0095] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0096] Example 7

[0097] This embodiment provides a microneedle patch;

[0098] The microneedles are made of polypropylene, with a spacing of 1 mm between them. Each microneedle is a cone with a height of 500 μm, a tip width of 10 μm, and a tip diameter of 250 μm.

[0099] The coating solution includes hyaluronic acid with a molecular weight of 510 kDa, arginine, glycerol, hepatitis B vaccine, and water, and has a viscosity of 850,000 centipoise.

[0100] The concentrations of arginine, hyaluronic acid, glycerol, and hepatitis B vaccine in the coating solution were 4%, 19%, 2%, and 10%, respectively.

[0101] The preparation method of microneedle patches includes the following steps:

[0102] The needle is slowly and vertically inserted into the coating solution to remove air bubbles, soaked for 15 seconds, and then airflow is applied for 20 minutes to keep the coating solution uniform and dry, thus obtaining a microneedle patch.

[0103] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0104] The humidity of the airflow is 30%, and the airflow velocity is 2 m / s;

[0105] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0106] Example 8

[0107] This embodiment provides a microneedle patch;

[0108] Among them, the microneedles are prepared from polycaprolactone, the spacing between the microneedles is 1 mm, the microneedles are conical with a height of 500 μm, a tip width of 10 μm, and a needle end diameter of 250 μm;

[0109] The coating solution includes hyaluronic acid with a molecular weight of 510 kDa, sucrose, glycerin, hepatitis B vaccine, and water, and has a viscosity of 780,000 centipoise.

[0110] The concentration of sucrose in the coating solution is 2%, the concentration of hyaluronic acid in the coating solution is 11%, the concentration of glycerol in the coating solution is 1%, and the concentration of hepatitis B vaccine in the coating solution is 4%.

[0111] The preparation method of microneedle patches includes the following steps:

[0112] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 10 seconds, then apply airflow for 5 minutes to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0113] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0114] The humidity of the airflow is 10%, and the airflow speed is 4 m / s;

[0115] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0116] Example 9

[0117] This embodiment provides a microneedle patch;

[0118] Among them, the microneedles are made of titanium metal, the spacing between the microneedles is 1 mm, the microneedles are conical, the height is 500 μm, the tip width is 10 μm, and the diameter of the end of the needle body is 250 μm;

[0119] The coating solution includes hyaluronic acid with a molecular weight of 510 kDa, trehalose, glycerin, hepatitis B vaccine, and water, and has a viscosity of 770,000 centipoise.

[0120] The concentration of trehalose in the coating solution is 2%, the concentration of hyaluronic acid in the coating solution is 11%, the concentration of glycerol in the coating solution is 1%, and the concentration of hepatitis B vaccine in the coating solution is 10%.

[0121] The preparation method of microneedle patches includes the following steps:

[0122] The needle is slowly and vertically inserted into the coating solution to remove air bubbles, soaked for 10 seconds, and then airflow is applied for 5 minutes to keep the coating solution uniform and dry, thus obtaining a microneedle patch.

[0123] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0124] The humidity of the airflow is 5%, and the airflow velocity is 4.5 m / s;

[0125] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0126] Example 10

[0127] This embodiment provides a microneedle patch;

[0128] Among them, the microneedles are made of polystyrene, the spacing between the microneedles is 1 mm, the microneedles are conical, the height is 500 μm, the tip width is 10 μm, and the end diameter of the needle body is 250 μm;

[0129] The coating solution includes hyaluronic acid with a molecular weight of 510 kDa, human serum albumin, glycerol, hepatitis B vaccine, and water, and has a viscosity of 520,000 centipoise.

[0130] The concentrations of human serum albumin, hyaluronic acid, glycerol, and hepatitis B vaccine in the coating solution were 1%, 5%, 0.5%, and 4%, respectively.

[0131] The preparation method of microneedle patches includes the following steps:

[0132] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 5 seconds, then apply airflow for 1 minute to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0133] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0134] The airflow humidity is 1%, and the airflow velocity is 10 m / s;

[0135] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0136] Example 11

[0137] This embodiment provides a microneedle patch;

[0138] Among them, the microneedles are made of polycarbonate, the spacing between the microneedles is 1 mm, the microneedles are conical with a height of 500 μm, a tip width of 10 μm, and a needle end diameter of 250 μm;

[0139] The coating solution includes hyaluronic acid with a molecular weight of 950 kDa, human serum albumin, glycerol, hepatitis B vaccine, and water, and has a viscosity of 1,200,000 centipoise.

[0140] The concentrations of human serum albumin, hyaluronic acid, glycerol, and hepatitis B vaccine in the coating solution were 5%, 30%, 2.5%, and 4%, respectively.

[0141] The preparation method of microneedle patches includes the following steps:

[0142] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 30 seconds, then apply airflow for 30 minutes to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0143] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0144] The humidity of the airflow is 60%, and the airflow velocity is 0.7 m / s;

[0145] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0146] Example 12

[0147] This embodiment provides a microneedle patch;

[0148] The microneedles are made of polypropylene, with a spacing of 1 mm between them. Each microneedle is a cone with a height of 500 μm, a tip width of 10 μm, and a tip diameter of 250 μm.

[0149] The coating solution includes hyaluronic acid with a molecular weight of 950 kDa, arginine, glycerol, hepatitis B vaccine, and water, and has a viscosity of 1,050,000 centipoise.

[0150] The concentrations of arginine, hyaluronic acid, glycerol, and hepatitis B vaccine in the coating solution were 4%, 19%, 2%, and 10%, respectively.

[0151] The preparation method of microneedle patches includes the following steps:

[0152] The needle is slowly and vertically inserted into the coating solution to remove air bubbles, soaked for 15 seconds, and then airflow is applied for 20 minutes to keep the coating solution uniform and dry, thus obtaining a microneedle patch.

[0153] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0154] The humidity of the airflow is 30%, and the airflow velocity is 2 m / s;

[0155] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0156] Example 13

[0157] This embodiment provides a microneedle patch;

[0158] Among them, the microneedles are prepared from polycaprolactone, the spacing between the microneedles is 1 mm, the microneedles are conical with a height of 500 μm, a tip width of 10 μm, and a needle end diameter of 250 μm;

[0159] The coating solution includes hyaluronic acid with a molecular weight of 950 kDa, sucrose, glycerin, hepatitis B vaccine, and water, and has a viscosity of 880,000 centipoise.

[0160] The concentration of sucrose in the coating solution is 3%, the concentration of hyaluronic acid in the coating solution is 11%, the concentration of glycerol in the coating solution is 1%, and the concentration of hepatitis B vaccine in the coating solution is 4%.

[0161] The preparation method of microneedle patches includes the following steps:

[0162] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 10 seconds, then apply airflow for 5 minutes to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0163] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0164] The humidity of the airflow is 10%, and the airflow speed is 4 m / s;

[0165] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0166] Example 14

[0167] This embodiment provides a microneedle patch;

[0168] Among them, the microneedles are made of titanium metal, the spacing between the microneedles is 1 mm, the microneedles are conical, the height is 500 μm, the tip width is 10 μm, and the diameter of the end of the needle body is 250 μm;

[0169] The coating solution includes hyaluronic acid with a molecular weight of 950 kDa, trehalose, glycerin, hepatitis B vaccine, and water, and has a viscosity of 860,000 centipoise.

[0170] The concentration of trehalose in the coating solution is 2%, the concentration of hyaluronic acid in the coating solution is 11%, the concentration of glycerol in the coating solution is 1%, and the concentration of hepatitis B vaccine in the coating solution is 10%.

[0171] The preparation method of microneedle patches includes the following steps:

[0172] The needle is slowly and vertically inserted into the coating solution to remove air bubbles, soaked for 10 seconds, and then airflow is applied for 5 minutes to keep the coating solution uniform and dry, thus obtaining a microneedle patch.

[0173] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0174] The humidity of the airflow is 5%, and the airflow velocity is 4.5 m / s;

[0175] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0176] Example 15

[0177] This embodiment provides a microneedle patch;

[0178] Among them, the microneedles are made of polystyrene, the spacing between the microneedles is 1 mm, the microneedles are conical, the height is 500 μm, the tip width is 10 μm, and the end diameter of the needle body is 250 μm;

[0179] The coating solution includes hyaluronic acid with a molecular weight of 950 kDa, human serum albumin, glycerol, hepatitis B vaccine, and water, and the viscosity of the coating solution is 750,000 centipoise.

[0180] The concentrations of human serum albumin, hyaluronic acid, glycerol, and hepatitis B vaccine in the coating solution were 1%, 5%, 0.5%, and 4%, respectively.

[0181] The preparation method of microneedle patches includes the following steps:

[0182] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 5 seconds, then apply airflow for 1 minute to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0183] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0184] The airflow humidity is 1%, and the airflow velocity is 10 m / s;

[0185] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0186] Example 16

[0187] This embodiment provides a microneedle patch;

[0188] Among them, the microneedles are made of polycarbonate, the spacing between the microneedles is 1 mm, the microneedles are conical with a height of 500 μm, a tip width of 10 μm, and a needle end diameter of 250 μm;

[0189] The coating solution includes PVP-K30, human serum albumin, glycerol, hepatitis B vaccine, and water, and the viscosity of the coating solution is 870,000 centipoise.

[0190] The concentrations of human serum albumin in the coating solution were 4%, PVP-K30 in the coating solution were 45%, glycerol in the coating solution were 2%, and hepatitis B vaccine in the coating solution were 10%.

[0191] The preparation method of microneedle patches includes the following steps:

[0192] The needle is slowly and vertically inserted into the coating solution to remove air bubbles, soaked for 20 seconds, and then airflow is applied for 15 minutes to keep the coating solution uniform and dry, thus obtaining a microneedle patch.

[0193] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0194] The humidity of the airflow is 30%, and the airflow velocity is 2 m / s;

[0195] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0196] Example 17

[0197] This embodiment provides a microneedle patch;

[0198] Among them, the microneedles are made of titanium metal, the spacing between the microneedles is 1 mm, the microneedles are conical, the height is 500 μm, the tip width is 10 μm, and the diameter of the end of the needle body is 250 μm;

[0199] The coating solution includes PVP-K30, trehalose, glycerol, hepatitis B vaccine, and water, with a viscosity of 770,000 centipoise. The concentration of trehalose in the coating solution is 2%, the concentration of PVP-K30 is 25%, the concentration of glycerol is 1%, and the concentration of hepatitis B vaccine is 4%.

[0200] The preparation method of microneedle patches includes the following steps:

[0201] Slowly and vertically insert the needle into the coating solution after removing air bubbles, soak for 20 seconds, then apply airflow for 10 minutes to keep the coating solution uniform and dry. Repeat this step once to obtain a microneedle patch.

[0202] Specifically, the liquid level of the coating solution is 3 / 4 of the needle height;

[0203] The humidity of the airflow is 10%, and the airflow velocity is 3 m / s;

[0204] Place the microneedle vertically downwards, with the airflow system located below the needle body. Use a blowing method to make the airflow direction opposite to the needle tip direction.

[0205] Example 18

[0206] The difference between this embodiment and Embodiment 8 is that the hepatitis B vaccine is replaced with an influenza vaccine (COVID-19 vaccine-RBD protein) with a mass concentration of 4%; the other components and preparation methods are the same as in Embodiment 8.

[0207] Example 19

[0208] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with a 10% concentration influenza vaccine (COVID-19 vaccine-RBD protein); the other components and preparation methods are the same as in Embodiment 12.

[0209] Example 20

[0210] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with an influenza vaccine (COVID-19 vaccine-RBD protein) with a mass concentration of 4%; the other components and preparation methods are the same as in Embodiment 16.

[0211] Example 21

[0212] The difference between this embodiment and embodiment 8 is that the hepatitis B vaccine is replaced with a tetanus vaccine with a mass concentration of 4%; the other components and preparation methods are the same as in embodiment 8.

[0213] Example 22

[0214] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with a tetanus vaccine with a mass concentration of 10%; the other components and preparation methods are the same as in Embodiment 12.

[0215] Example 23

[0216] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with a tetanus vaccine with a mass concentration of 4%; the other components and preparation methods are the same as in Embodiment 16.

[0217] Example 24

[0218] The difference between this embodiment and embodiment 8 is that the hepatitis B vaccine is replaced with insulin at a mass concentration of 4%; the other components and preparation methods are the same as in embodiment 8.

[0219] Example 25

[0220] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with insulin at a mass concentration of 10%; the other components and preparation methods are the same as in Embodiment 12.

[0221] Example 26

[0222] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with insulin at a mass concentration of 4%; the other components and preparation methods are the same as in Embodiment 16.

[0223] Example 27

[0224] The difference between this embodiment and Example 8 is that the hepatitis B vaccine is replaced with 4% semaglutide; the other components and preparation methods are the same as in Example 8.

[0225] Example 28

[0226] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with 10% semaglutide; the other components and preparation methods are the same as in Embodiment 12.

[0227] Example 29

[0228] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with 4% semaglutide; the other components and preparation methods are the same as in Embodiment 16.

[0229] Example 30

[0230] The difference between this embodiment and Example 8 is that the hepatitis B vaccine is replaced with a plasmid (expressing COVID-19 RBD protein) at a mass concentration of 4%; the other components and preparation methods are the same as in Example 8.

[0231] Example 31

[0232] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with a plasmid (expressing COVID-19 RBD protein) at a mass concentration of 10%; the other components and preparation methods are the same as in Embodiment 12.

[0233] Example 32

[0234] The difference between this embodiment and Example 16 is that the hepatitis B vaccine is replaced with a plasmid (expressing COVID-19 RBD protein) at a mass concentration of 4%; the other components and preparation methods are the same as in Example 16.

[0235] Example 33

[0236] The difference between this embodiment and embodiment 8 is that the hepatitis B vaccine is replaced with lidocaine at a mass concentration of 10%; the other components and preparation methods are the same as in embodiment 8.

[0237] Example 34

[0238] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with lidocaine at a mass concentration of 40%; the other components and preparation methods are the same as in Embodiment 12.

[0239] Example 35

[0240] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with lidocaine at a mass concentration of 10%; the other components and preparation methods are the same as in Embodiment 16.

[0241] Example 36

[0242] The difference between this embodiment and embodiment 8 is that the hepatitis B vaccine is replaced with 10% ropivacaine; the other components and preparation methods are the same as in embodiment 8.

[0243] Example 37

[0244] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with 40% ropivacaine; the other components and preparation methods are the same as in Embodiment 12.

[0245] Example 38

[0246] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with 10% ropivacaine; the other components and preparation methods are the same as in Embodiment 16.

[0247] Example 39

[0248] The difference between this embodiment and Example 8 is that the hepatitis B vaccine is replaced with zolmitriptan at a mass concentration of 10%; the other components and preparation methods are the same as in Example 8.

[0249] Example 40

[0250] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with zolmitriptan at a mass concentration of 40%; the other components and preparation methods are the same as in Embodiment 12.

[0251] Example 41

[0252] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with zolmitriptan at a mass concentration of 10%; the other components and preparation methods are the same as in Embodiment 16.

[0253] Example 42

[0254] The difference between this embodiment and Example 8 is that the hepatitis B vaccine is replaced with levonorgestrel at a mass concentration of 10%; the other components and preparation methods are the same as in Example 8.

[0255] Example 43

[0256] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with levonorgestrel at a mass concentration of 40%; the other components and preparation methods are the same as in Embodiment 12.

[0257] Example 44

[0258] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with levonorgestrel at a mass concentration of 10%; the other components and preparation methods are the same as in Embodiment 16.

[0259] Example 45

[0260] The difference between this embodiment and embodiment 8 is that the hepatitis B vaccine is replaced with minoxidil at a mass concentration of 10%; the other components and preparation methods are the same as in embodiment 8.

[0261] Example 46

[0262] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with minoxidil at a mass concentration of 40%; the other components and preparation methods are the same as in Embodiment 12.

[0263] Example 47

[0264] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with minoxidil at a mass concentration of 10%; the other components and preparation methods are the same as in Embodiment 16.

[0265] Example 48

[0266] The difference between this embodiment and embodiment 8 is that the hepatitis B vaccine is replaced with orlistat at a mass concentration of 10%; the other components and preparation methods are the same as in embodiment 8.

[0267] Example 49

[0268] The difference between this embodiment and Embodiment 12 is that the hepatitis B vaccine is replaced with orlistat at a mass concentration of 40%; the other components and preparation methods are the same as in Embodiment 12.

[0269] Example 50

[0270] The difference between this embodiment and Embodiment 16 is that the hepatitis B vaccine is replaced with orlistat at a mass concentration of 10%; the other components and preparation methods are the same as in Embodiment 16.

[0271] Comparative Example 1

[0272] The difference between this comparative example and Example 8 is that the concentration of hyaluronic acid is increased to 70%, and the viscosity of the coating solution is 1,300,000 centipoise; the other components and preparation methods are the same as in Example 8.

[0273] Comparative Example 2

[0274] The difference between this comparative example and Example 8 is that the concentration of hyaluronic acid is reduced to 1%, and the viscosity of the coating solution is 80,000 centipoise; the other components and preparation methods are the same as in Example 8.

[0275] Comparative Example 3

[0276] The difference between this comparative example and Example 8 is that the molecular weight of hyaluronic acid is increased to 2000 kDa, the concentration is 10%, the viscosity of the coating solution is 830,000 centipoise, and the maximum solubility of the hepatitis B vaccine is only 0.5%. Other components and preparation methods are the same as in Example 8.

[0277] Comparative Example 4

[0278] The difference between this comparative example and Example 8 is that the molecular weight of hyaluronic acid is reduced to 100 kDa, the concentration is 70%, the viscosity of the coating solution is 360,000 centipoise, and the other components and preparation methods are the same as in Example 8.

[0279] Comparative Example 5

[0280] The difference between this comparative example and Example 8 is that the molecular weight of hyaluronic acid is reduced to 100 kDa, the concentration is 10%, the viscosity of the coating solution is 30,000 centipoise, and the other components and preparation methods are the same as in Example 8.

[0281] Comparative Example 6

[0282] The difference between this comparative example and Example 8 is that no airflow was introduced, but the other components and preparation methods are the same as in Example 8.

[0283] Comparative Example 7

[0284] The difference between this comparative example and Example 8 is that the airflow direction is the same as the needle tip direction, that is, the needle tip is vertically upward, the airflow system is above the needle tip and draws air, and the other components and preparation methods are the same as in Example 8.

[0285] Comparative Example 8

[0286] The difference between this comparative example and Example 8 is that no sucrose was added, while the other ingredients and preparation methods are the same as in Example 8.

[0287] Comparative Example 9

[0288] The difference between this comparative example and Example 1 is that human serum albumin was not added, while the other components and preparation methods are the same as in Example 1.

[0289] Comparative Example 10

[0290] The difference between this comparative example and Example 16 is that PVP-K30 is replaced with PVP-K90, the concentration is 30%, the viscosity of the coating solution is 1,400,000 centipoise, and the maximum solubility of the hepatitis B vaccine is only 1%. Other components and preparation methods are the same as in Example 16.

[0291] Comparative Example 11

[0292] The difference between this comparative example and Example 16 is that the concentration of PVP-K30 is increased to 70%, the viscosity of the coating solution is 1,250,000 centipoise, and the other components and preparation methods are the same as in Example 16.

[0293] Comparative Example 12

[0294] The difference between this comparative example and Example 16 is that PVP-K30 is replaced with PVP-K10, the concentration is 70%, the viscosity of the coating solution is 340,000 centipoise, and the other components and preparation methods are the same as in Example 16.

[0295] Specific testing indicators and results are shown in Table 1:

[0296] Table 1

[0297]

[0298]

[0299]

[0300]

[0301]

[0302] Among them, the microneedles of Comparative Examples 1, 4, 11, and 12 had too thick a coating after drying, making it impossible for the needles to effectively puncture the skin.

[0303] In Comparative Examples 2 and 5, when the microneedles are immersed in the coating solution, the coating solution is adsorbed onto the base, and the solution coated on the needle tip is further migrated to the base due to surface tension.

[0304] In the coating solutions of Comparative Examples 3 and 10, the solubility of the drug was significantly reduced.

[0305] In Comparative Example 6, after the microneedles were soaked in the coating solution, no airflow was introduced. Due to gravity and the inability to dry quickly, the coating solution would accumulate at the needle tip. After drying, the needle tip would appear as a water droplet. The rear section of the needle body with the coating layer was extremely thin, and the coating layer was displaced 60 micrometers towards the needle tip, resulting in poor puncture effect.

[0306] In Comparative Example 7, after coating and drying, the coating layer remained uniformly applied to the needle body. However, compared to the results in Example 8, the coating layer migrated 60 μm along the needle body towards the base, resulting in a coating height of 430 μm on the microneedle body. In contrast, the coating layer in Example 8 did not migrate, and its coating height on the microneedle body was 370 μm. This indicator was detected using SEM. After administration of the microneedles obtained in Comparative Example 7 to the skin on the back of mice, due to skin elasticity, the latter half of the needle body was not completely drug-eluting, leaving 10% of the drug load on the needle body. In contrast, the microneedles in Example 8 were completely drug-eluting. This result was detected by reconstituted the drug-eluting microneedles and quantitatively measuring the drug using the Bradford method.

[0307] In Comparative Examples 8 and 9, the amount of active pharmaceutical ingredients loaded onto the microneedles decreased significantly after drying.

[0308] The results from Comparative Examples 1, 2, 4, 8, 10, 11, 12, and 16 show that when the coating matrix material is hyaluronic acid and polyvinylpyrrolidone K30 with a molecular weight of 250-1000 kDa, if the concentration of the coating matrix material is higher than 45%, the needle coating layer is thick, resulting in poor puncture effect and failing to meet clinical needs. If the concentration of the coating matrix material is lower than 5%, the coating solution will be adsorbed onto the needle base, leading to coating failure. When the coating matrix material is hyaluronic acid with a molecular weight lower than 250 kDa and PVP with a molecular weight lower than K30, a high concentration of matrix material is required for suitable coating; otherwise, it will be directly adsorbed onto the base. Under this condition, the microneedle coating layer is thick, resulting in poor puncture effect and still failing to meet the requirements. When the coating matrix material is polyvinylpyrrolidone with a molecular weight higher than 1000 kDa and higher than K30, the excessively high molecular weight causes a sharp decline in drug solubility in the system, resulting in an excessively low drug loading capacity of the microneedle and failing to meet the requirements.

[0309] In summary, the microneedle patch prepared by this invention has a more intact needle morphology and better puncture performance compared to ordinary coated microneedles. Its needle surface can carry more active ingredients, and the coating layer is evenly distributed on the coated area of ​​the needle and does not migrate. It can meet the loading requirements of various active ingredients and has good versatility. The preparation method of the microneedle patch of this invention is simple, fast, and has good repeatability. It meets the coating and drug loading requirements of different types of water-insoluble microneedles and is extremely suitable for industrial production.

[0310] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the technical solution of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention shall still fall within the scope of the technical solution of the present invention.

Claims

1. A microneedle patch, characterized in that: The microneedle patch includes a base, microneedles, and a coating layer on the surface of the microneedles. The coating layer is prepared from a coating solution, which is prepared by dissolving coating materials and active ingredients in water or a buffer solution. The coating material includes one or more of a coating matrix material, a moisturizer, a protein protectant, and an antibiotic. The coating matrix material includes at least one of high molecular weight hyaluronic acid and polyvinylpyrrolidone. The hyaluronic acid has a molecular weight of 250 kDa-1000 kDa and a concentration of 5-30% (w / v). The polyvinylpyrrolidone is PVP-K30 and has a concentration of 25-45% (w / v). The viscosity of the coating solution is 370,000-1,200,000 centipoise. The preparation method of the microneedle patch includes a coating process, which involves inserting the microneedles into the coating solution for 5-30 seconds, removing them, placing them vertically downwards, and then providing an upward airflow at a velocity of 0.5 ppm. m-10 m / s, humidity 1-60%, airflow duration 1-30 min.

2. The microneedle patch according to claim 1, wherein the moisturizer comprises glycerin, and the protein protectant comprises at least one selected from trehalose, human serum albumin, sucrose, and arginine.

3. The microneedle patch according to claim 1, characterized in that, The microneedle is a cone or a multi-faceted pyramid, the height of the microneedle is 60-900 μm, the width or diameter of the tip of the microneedle is 5-40 μm, the width or diameter of the end of the microneedle body is 50-300 μm, and the spacing between the microneedles is 1-5 mm.

4. The microneedle patch according to claim 1, characterized in that, The concentration of the humectant is 0.5-2.5% (w / v).

5. The microneedle patch according to claim 1, characterized in that, The concentration of the protein protectant is 1-5% (w / v).

6. The microneedle patch according to claim 1, characterized in that, The active ingredient includes at least one of small molecule compounds, protein drugs, peptide drugs, and nucleic acid drugs.

7. Use of the microneedle patch as described in any one of claims 1-6 in encapsulating a drug, wherein the drug comprises at least one of small molecule compounds, protein drugs, peptide drugs, and nucleic acid drugs.

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