CN116212215B - Microneedle patch with multilayer structure and manufacturing method thereof - Google Patents
Microneedle patch with multilayer structure and manufacturing method thereofInfo
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- CN116212215B CN116212215B CN202111461251.6A CN202111461251A CN116212215B CN 116212215 B CN116212215 B CN 116212215B CN 202111461251 A CN202111461251 A CN 202111461251A CN 116212215 B CN116212215 B CN 116212215B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明的微针贴片包含基底部和由基底部凸设成型的多个针体部，基底部由阻隔层及针底层所形成，各针体部由针尖层、阻隔层及针底层所形成，各针体部的阻隔层形成在相应针体部的针尖层和针底层间，基底部的阻隔层与针体部的阻隔层、基底部的针底层与针体部的针底层皆为一体成型结构；针尖层包含HA、PVP及第一糖类，阻隔层包含第二糖类、PVA及HP‑β‑CD，针底层包含第三糖类、PVA及HP‑β‑CD。所述微针贴片的阻隔层具有阻隔效果，避免针尖层的活性成分扩散至针底层，将其限制于针尖并控制携带量。
The microneedle patch of the present invention comprises a base portion and a plurality of needle bodies formed by protrusions from the base portion. The base portion is formed by a barrier layer and a needle base layer. Each needle body portion is formed by a needle tip layer, a barrier layer, and a needle base layer. The barrier layer of each needle body portion is formed between the needle tip layer and the needle base layer of the corresponding needle body portion. The barrier layer of the base portion and the barrier layer of the needle body portion, and the needle base layer of the base portion and the needle base layer of the needle body portion are all integrally formed structures. The needle tip layer contains HA, PVP, and a first saccharide, the barrier layer contains a second saccharide, PVA, and HP-β-CD, and the needle base layer contains a third saccharide, PVA, and HP-β-CD. The barrier layer of the microneedle patch has a barrier effect, preventing the active ingredients of the needle tip layer from diffusing to the needle base layer, confining them to the needle tip and controlling the amount carried.
Description
Technical Field
The invention relates to a microneedle patch structure and a manufacturing method thereof, in particular to a medical, medical or vaccine microneedle patch and a manufacturing method thereof.
Background
Transdermal drug delivery (TRANSDERMAL DRUG DELIVERY) has recently been attracting attention as a mode of administration that allows an active substance (e.g., a drug or vaccine) to be absorbed through the skin by a non-invasive mode of administration to exert its drug effect. Transdermal delivery can avoid the destruction of the digestive system and the primary metabolism of the liver by oral administration, and simultaneously can avoid fear and pain caused by subcutaneous injection, but is not suitable for delivering water-soluble drugs or water-soluble vaccines through the traditional transdermal delivery system because the stratum corneum of the skin has both hydrophobic and negatively charged properties.
In view of the above problems, the prior art has developed a microneedle patch having a substrate covered with a plurality of micrometer-sized needles that pierce the stratum corneum of the skin and deliver a drug or vaccine to the epidermis for delivery. The microneedle patch is used for drug administration, so that various problems existing in the prior oral administration or subcutaneous injection can be solved, the types of drugs or vaccines to be delivered can be expanded into the categories of fat solubility and water solubility, and the drugs and vaccines of different types can be directly delivered to an epidermis layer or a dermis layer through a needle body on the microneedle patch to release drug effects without pain.
Based on the advantages of microneedle patches, the industry has actively put into the development of microneedle patches. For example, taiwan patent No. 201400140a discloses a method for manufacturing an inlaid transdermal drug delivery patch, which comprises the steps of firstly irrigating a biodegradable polymer colloid containing a drug to obtain a plurality of biodegradable carriers, secondly manufacturing a support substrate with a plurality of protruding support shafts, coating an adhesive on the support substrate in advance, and then aligning the protruding support shafts on the surface of the support substrate with the biodegradable carriers and adhering the protruding support shafts and the biodegradable carriers to each other to obtain the inlaid transdermal drug delivery patch.
However, the above-mentioned manufacturing method must additionally consider the spacing and alignment problems between the plurality of protruding support shafts and the plurality of carriers on the support substrate, increasing the difficulty of the manufacturing process, and the support substrate and the carriers must be bonded by a step of coating the adhesive in advance during the manufacturing process, without increasing the complexity and production cost of the manufacturing process.
Furthermore, when microneedle patches are particularly used for delivering pharmaceutical or vaccine active ingredients, it becomes important how to control the carrying amount of the pharmaceutical or vaccine active ingredient. Generally, the microneedle patch has a needle length of between 100 micrometers (μm) and 1000 μm, and the skin is not uniform in thickness depending on the human body part, and the epidermis layer may have a thickness of only about 30 μm to 300 μm. If the desired effect of the amount of active substance carried by the microneedle patch is to be achieved, the carried active substance needs to be localized near the tip of the needle to accurately release the active substance to the epidermis to be affected. If the carried active substance is spread over the entire needle, the desired effect cannot be achieved, in which case the carried active substance content needs to be additionally increased if the desired effect is to be achieved, but this causes waste of the active substance. The above-described process does not teach or suggest how to effectively control the carrying amount of pharmaceutical or vaccine active ingredients in a microneedle patch, and thus the need for improvement of the existing process is still felt.
Disclosure of Invention
In view of the above technical problems, the present invention aims to effectively limit active ingredients on the tip layer of a microneedle and precisely control the carrying amount, so that the active ingredients can be used for manufacturing medical microneedle patches or vaccine microneedle patches.
The present invention provides a microneedle patch, comprising a base portion and a plurality of needle portions protruding from the base portion, wherein the base portion is formed by a barrier layer and a needle bottom layer, each needle portion is formed by a needle tip layer, a barrier layer and a needle bottom layer, the barrier layer of each needle portion is formed between the needle tip layer of the corresponding needle portion and the needle bottom layer of the needle portion, wherein the barrier layer of the base portion and the barrier layers of the plurality of needle portions are integrally formed, and the needle bottom layer of the base portion and the needle bottom layer of the plurality of needle portions are integrally formed; wherein each needle portion has a thickness of 300 μm to 1000 μm, the base portion has a thickness of 200 μm to 400 μm, a needle bottom layer of the base portion is measured as a thickness amount toward a tip end of the needle portion, a ratio of the thickness of the needle bottom layer of the needle portion and a barrier layer of the needle portion to the thickness of the needle portion is 0.54 to 0.81, wherein a material of the needle tip layer comprises hyaluronic acid, polyvinylpyrrolidone and a first saccharide, wherein the hyaluronic acid has a molecular weight of 2 kilodaltons to 50 kilodaltons, the hyaluronic acid has a weight ratio of 1:0.8 to 1:2 to the polyvinylpyrrolidone, the material of the barrier layer comprises a second saccharide, polyvinyl alcohol and 2-hydroxypropyl-beta-cyclodextrin, wherein the weight ratio of the second saccharide to the polyvinyl alcohol is 1:1.8 to 1:3, the weight ratio of the second saccharide to the 2-hydroxypropyl-beta-cyclodextrin is 1:1.8 to 1:3, the material of the needle bottom layer comprises a third saccharide, and 2-hydroxypropyl-beta-cyclodextrin, wherein the weight ratio of the third saccharide to the polyvinyl alcohol is 1:1.8 to 1:3, and the weight ratio of the third saccharide to the 2-hydroxypropyl-beta-cyclodextrin is 1:1.8 to 1:3.
By simultaneously controlling the components of the three layers of the needle point layer, the blocking layer, the needle bottom layer and the like of the microneedle patch, the thickness of the needle body part, the thickness of the base part, the thicknesses of the needle bottom layer and the blocking layer of the needle body part and the proportion relative to the thickness of the needle body part, the blocking layer can exert the blocking effect, the active component is limited to the needle point layer, and the active component of the needle point layer is prevented from diffusing to the needle bottom layer, so that the control of the carrying amount of the active component in the microneedle patch is facilitated, and the expected effect is achieved.
According to the invention, the shortest distance from the projection point of the tip of the needle body projected to the base to the tip of the needle body extends is used as the thickness measuring line. More specifically, the base portion has a bottom surface opposite to the needle portion, and the shortest distance between the projection point of the tip of the needle portion projected onto the bottom surface and the tip of the needle portion extends to the tip of the needle portion is the thickness measuring line, which should be understood that the thickness of the bottom layer of the base portion, the thickness of the bottom layer of the needle portion, the thickness of the barrier layer of the needle portion, and the thickness of the needle layer are all measured along the thickness measuring line in the present specification.
According to the present invention, the tip layer further comprises glycerin and polysorbate twenty.
According to the present invention, the first saccharide of the needle tip layer is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, dextrin, maltodextrin, beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, dextran and combinations thereof.
According to the present invention, the second saccharide of the barrier layer is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan and combinations thereof.
According to the present invention, the third saccharide of the needle bottom layer is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan and combinations thereof.
According to the present invention, the tip layer further comprises an active ingredient. The active ingredient may be a pharmaceutical active ingredient or a vaccine active ingredient. Specifically, the pharmaceutically active ingredient may be a small molecule compound, a biological agent, a biosimilar drug, a protein drug, a botanical drug, or the like. Specifically, the vaccine active ingredient may be attenuated vaccine (attenuated vaccine), inactivated vaccine (INACTIVATED VACCINE), viroid particle (virus-LIKE PARTICLE, VLP), purified subunit antigen (purified subunit antigen), antigen expressed by gene recombination (recombinant antigen), synthetic peptide (SYNTHETIC PEPTIDE), gene recombinant vector (recombinant vector), gene vaccine (DNA VACCINE), nucleic acid vaccine (nucleic ACID VACCINE), mucosal immunity (mucosal immunization), combined vaccine (combined vaccine), and the like.
According to the present invention, the mechanical strength of the needle body of the microneedle patch is greater than 0.058 newton/needle (N/needle), so that the microneedle patch of the present invention can pierce the stratum corneum without breaking. Preferably, the mechanical strength of the needle body of the microneedle patch is greater than 0.14N/needle. More preferably, the mechanical strength of the needle body of the microneedle patch is greater than 0.20N/needle.
According to the invention, the weight ratio of hyaluronic acid relative to the first saccharide is between 1:5 and 1:8.
In one embodiment, the thickness of the needle body (i.e., the needle length of the needle body) is 400 μm to 1000 μm. In another embodiment, the thickness of the needle body is 600 μm to 900 μm.
In one embodiment, the thickness of the needle tip layer is 170 μm to 190 μm. In another embodiment, the tip layer thickness is 210 μm to 240 μm. In another embodiment, the tip layer thickness is 170 μm to 265 μm. In another aspect, the needle tip layer thickness is 200 μm to 265 μm.
In one embodiment, the thickness of the barrier layer of the base portion is 110 μm to 210 μm. It should be understood that the barrier layer of the base portion as described herein refers to a portion of the base portion other than the region where the molded needle body is protruding.
In one embodiment, the thickness of the base portion is 200 μm to 360 μm. In another embodiment, the thickness of the base portion is 210 μm to 360 μm.
In one embodiment, the sum of the thicknesses of the needle bottom layer of the base portion, the needle bottom layer of the needle body portion and the barrier layer of the needle body portion is 550 μm to 1100 μm. In another embodiment, the sum of the thicknesses of the needle bottom layer of the base portion, the needle bottom layer of the needle body portion and the barrier layer of the needle body portion is 570 μm to 1100 μm.
According to the invention, the manufacturing method of the microneedle patch comprises the following steps:
Providing a female die, wherein the female die is provided with a reference surface and a plurality of holes, and the holes are concavely arranged downwards from the reference surface for forming;
Filling a needle tip mixed solution into the holes of the female mold, wherein the solid content of the needle tip mixed solution is more than 5 weight percent (wt%) and less than 40wt%, the needle tip mixed solution comprises hyaluronic acid, polyvinylpyrrolidone and a first saccharide, the molecular weight of the hyaluronic acid is between 2 kilodaltons and 50 kilodaltons, and the weight ratio of the hyaluronic acid to the polyvinylpyrrolidone is 1:0.8-1:2;
step (c), drying the pinpoint mixed liquid into a pinpoint layer, wherein the surface of the pinpoint layer is lower than the reference surface of the master model;
Filling a barrier mixed solution into the holes of the master mold, covering the needle tip layer and the reference surface of the master mold so that the vertical distance between the liquid level of the barrier mixed solution and the reference surface of the master mold is 600-1500 μm, wherein the solid content of the barrier mixed solution is more than 30wt% and less than or equal to 45wt%, the barrier mixed solution comprises a second saccharide, polyvinyl alcohol and 2-hydroxypropyl-beta-cyclodextrin, the weight ratio of the second saccharide to the polyvinyl alcohol is 1:1.8-1:3, and the weight ratio of the second saccharide to the 2-hydroxypropyl-beta-cyclodextrin is 1:1.8-1:3;
drying the barrier mixed solution into a barrier layer, wherein the barrier layer is formed on the needle tip layer and the reference surface of the master model;
Filling a needle bottom mixed solution into the holes of the master mold, covering the blocking layers in the holes and the blocking layers on the reference surface of the master mold so that the vertical distance between the liquid level of the needle bottom mixed solution and the reference surface of the master mold is 450-850 μm, wherein the solid content of the needle bottom mixed solution is more than or equal to 30-45wt%, the needle bottom mixed solution comprises a third saccharide, polyvinyl alcohol and 2-hydroxypropyl-beta-cyclodextrin, the weight ratio of the third saccharide to the polyvinyl alcohol is 1:1.8-1:3, the weight ratio of the third saccharide to the 2-hydroxypropyl-beta-cyclodextrin is 1:1.8-1:3, and the solid content of the needle bottom mixed solution is less than the solid content of the blocking mixed solution;
Step (g) of drying the needle bottom mixture to form a needle bottom layer, adhering the barrier layer between the needle tip layer and the needle bottom layer, and
And (h) detaching the needle tip layer, the barrier layer and the needle bottom layer which are mutually adhered from the female die to obtain the microneedle patch.
According to the manufacturing method of the microneedle patch, the active ingredients can be limited to the needle point layer, and the active ingredients on the needle point layer are prevented from diffusing to the needle bottom layer, so that the method is beneficial to accurately controlling the carrying amount of the active ingredients in the microneedle patch and avoiding the waste of the active ingredients.
According to the present invention, the master mold may be a hard master mold, and the hard master mold may be made of glass, quartz, silicon wafer, metal oxide, or metal alloy, but is not limited thereto. In another embodiment, the master mold may be a soft master mold, and the soft master mold may be made of a polymer, a metal foil (metal foil), or flexible glass, wherein the polymer is polydimethylsiloxane (poly (dimethylsiloxane), PDMS), polymethyl methacrylate (poly (methyl methacrylate), PMMA), polycarbonate (polycarbonate, PC), polyethersulfone (PES), or the like, but is not limited thereto.
According to the present invention, the shape of the hole in the master mold may be conical, square conical or pointed tower, but is not limited thereto. In the female die, the female die is provided with a reference surface and a plurality of holes, and each hole is concavely formed by the reference surface. The depth of each hole is 75 μm to 1500 μm, preferably 150 μm to 1200 μm, more preferably 175 μm to 1000 μm, still more preferably 200 μm to 1000 μm. The maximum width of each aperture is 38 μm to 800. Mu.m, preferably 75 μm to 650. Mu.m, more preferably 85 μm to 550. Mu.m.
In the microneedle patch, the needle shape of each needle body may be conical, square conical or pointed, but is not limited thereto.
In the microneedle patch, the needle body may have a density of 1needle per square centimeter (needle/cm 2) to 1000needles/cm 2, preferably 1needle/cm 2 to 500needles/cm 2.
According to the invention, the needle tip mixture further comprises glycerin and polysorbate twenty.
According to the present invention, the content of glycerin is 0.005 to 0.2wt% and the content of polysorbate twenty is 0.001 to 0.1wt% based on the total weight of the needle tip mixture.
In accordance with the present invention, the tip mixture has a viscosity of 8 centipoise (cP) to 25000cP, preferably 8cP to 20000cP, measured at 25 ℃ and a shear rate (SHEAR RATE) of 1s -1.
According to the invention, the viscosity of the barrier mixture is 5000 to 220000cP, preferably 10000 to 200000cP, more preferably 30000 to 200000cP, measured at 25 ℃ and a shear rate of 1s -1.
According to the invention, the viscosity of the needle bottom mixture measured at 25 ℃ and shearing rate of 1s -1 is 3000cP to 100000cP, preferably 5000cP to 100000cP, more preferably 7000cP to 90000cP.
According to the invention, the needle tip mixed solution, the blocking mixed solution and the needle bottom mixed solution can be polymer water solutions, and the needle tip mixed solution is polymer water solution containing active ingredients. Preferably, the solid content of the needle tip mixture is 10wt% to 35wt%.
According to the present invention, the polymer material contained in the needle tip mixed solution, the barrier mixed solution and the needle bottom mixed solution may be a material having solubility (dissolvable) or bulking (swellable). More specifically, the polymer material may be a biocompatible (biocompatible) material or a biodegradable (biodegradable) material. For example, the polymer material may be pullulan (amylopectin), starch (starch), sodium hyaluronate (sodium hyaluronate), methyl vinyl ether-maleic anhydride copolymer (poly (METHYL VINYL ETHER-alt-MALEIC ANHYDRIDE), PMVE/MA), sodium carboxymethyl cellulose (sodium carboxymethylcellulose, CMC), methylcellulose (methylcellulose, MC), hydroxypropyl methylcellulose (hydroxypropylmethylcellulose, HPMC), hydroxypropyl cellulose (hydroxypropyl cellulose, HPC), gelatin (gelatin), polyvinyl alcohol (poly (vinyl alcohol), PVA), polyvinylpyrrolidone (polyvinylpyrrolidone, PVP), polyethylene glycol (polyethylene glycol, PEG), polylactic acid (PLA), polyglycolic acid (poly (glycolic acid), PGA), polylactic acid-glycolic acid copolymer (poly (lactic-co-glycolic acid), PLGA), chitosan (chitosan), or a combination thereof, but is not limited thereto. In this case, when the polymer material contains glucose, galactose, lactose, sucrose, trehalose, maltose, dextrin, maltodextrin, β -cyclodextrin, 2-hydroxypropyl- β -cyclodextrin, dextran, or the like, it is advantageous to improve the mechanical strength of the microneedle patch. In addition, in the preparation of vaccine microneedle patches, the above glucose, galactose, lactose, sucrose, trehalose, maltose, dextrin and the like may also be used as antigen protectants.
Preferably, the step (b) may comprise:
step (b 1) forming a needle tip mixed solution on the master model, and flowing the needle tip mixed solution into the holes so that the needle tip mixed solution covers the reference surface and the holes of the master model, and
And (b 2) removing the needlepoint mixed liquid on the reference surface, so that the liquid level of the needlepoint mixed liquid is flush with the reference surface of the master model.
According to the present invention, in the step (b), the method of filling the tip mixture into the plurality of holes of the master mold includes a vacuum pumping method and a centrifugation method. In one embodiment, the invention can place the pinpoint mixed solution and the female die in an oven for air extraction, thereby enabling the pinpoint mixed solution to cover the reference surface and the plurality of holes of the female die, and in another embodiment, the invention can centrifuge the pinpoint mixed solution and the female die together, thereby enabling the pinpoint mixed solution to cover the reference surface and the plurality of holes of the female die. Here, the pressure in the oven may be controlled at-700 mm Hg (mmHg) to-800 mmHg, preferably-710 mmHg to-760 mmHg. The rotational speed of the centrifugation step can be controlled to 20 times the gravity (xg) to 20000xg, preferably 20xg to 12000xg.
Preferably, the step (d) may comprise:
Step (d 1) forming a blocking mixture on the master model, flowing the blocking mixture into the plurality of holes to cover the reference surface and the plurality of holes of the master model, and
And (d 2) removing a part of the barrier mixed solution on the reference surface so that the vertical distance between the liquid surface of the barrier mixed solution and the reference surface of the master model is 600-1500 mu m.
According to the present invention, in the step (d), the method of filling the barrier mixture into the plurality of holes of the master mold includes a vacuum pumping method and a centrifugation method. In one embodiment, the present invention may be used to pump air from the mold to cover the base surface and holes of the mold, and in another embodiment, the present invention may be used to centrifuge the mold to cover the base surface and holes of the mold. Here, the pressure in the oven may be controlled to be from-700 mmHg to-800 mmHg, preferably from-710 mmHg to-760 mmHg. The rotational speed of the centrifugation step may be controlled to 20Xg to 20000Xg, preferably 20Xg to 12000Xg.
Preferably, the step (f) may comprise:
Step (f 1) forming a needle bottom mixture on the master model, flowing the needle bottom mixture into the plurality of holes, thereby covering the barrier layer on the reference surface of the master model and the barrier layers in the plurality of holes with the needle bottom mixture, and
And (f 2) removing a part of the needle bottom mixture on the reference surface so that the vertical distance between the liquid surface of the needle bottom mixture and the reference surface of the master mold is 450-850 μm.
According to the present invention, in the step (f), the method of filling the needle bottom mixture into the plurality of holes of the master mold includes a vacuum pumping method and a centrifugation method. In one embodiment, the invention can place the needle bottom mixed solution and the female die in the oven for air extraction, thereby enabling the needle bottom mixed solution to cover the barrier layer on the reference surface of the female die and the barrier layers in the holes, and in another embodiment, the invention can centrifuge the needle bottom mixed solution and the female die together, thereby enabling the needle bottom mixed solution to cover the barrier layer on the reference surface of the female die and the barrier layers in the holes. Here, the pressure in the oven may be controlled to be from-700 mmHg to-800 mmHg, preferably from-710 mmHg to-760 mmHg. The rotational speed of the centrifugation step may be controlled to 20Xg to 20000Xg, preferably 20Xg to 12000Xg.
Preferably, the steps (b), (d) and (f) may each independently use a slit coating method (slit or slot die coating), a blade coating method (blade coating), a dip coating method (dip coating), a jet printing method (nozzle printing), a dispensing method (dispensing) or a combination thereof to form the tip mixture, the barrier mixture and the needle bottom mixture on the master mold, but are not limited to the above. The method of forming the needle tip mixture on the master model in the step (b) can be the same as or different from the method of forming the barrier mixture on the master model in the step (d) and the method of forming the needle base mixture on the master model in the step (f). Preferably, the manufacturing method of the microneedle patch of the invention can adopt a slit coating method to sequentially coat the needle tip mixed solution, the barrier mixed solution and the needle bottom mixed solution on the master model. More preferably, the manufacturing method of the microneedle patch adopts a dispensing method, and the needle point mixed liquid, the blocking mixed liquid and the needle bottom mixed liquid are sequentially formed on the female die.
In one embodiment, when the slit coating method is used to coat the needle tip mixture in the step (b), the coating gap can be controlled to be 1 μm to 5000 μm, the coating speed can be controlled to be 1 meter/min to 100m/min, and the process parameters can be adjusted according to the characteristics of the selected needle tip mixture and the specifications of the microneedle patch. When the slit coating method is used to coat the barrier mixed solution in the step (d), the coating gap can be controlled to be 1 μm to 3000 μm, and the coating speed can be controlled to be 1m/min to 100m/min. In addition, when the slit coating method is used to coat the needle bottom mixture in the step (f), the coating gap can be controlled to be 1-3000 μm, the coating speed can be controlled to be 1-100 m/min, and the process parameters can be adjusted according to the characteristics of the selected barrier mixture and the needle bottom mixture and the specifications of the micro-needle patch.
Preferably, in the step (b), the coating gap is controlled to be 100 μm to 5000 μm and the coating speed is controlled to be 1m/min to 100m/min, in the step (d), the coating gap is controlled to be 100 μm to 3000 μm and the coating speed is controlled to be 1m/min to 100m/min, and in the step (f), the coating gap is controlled to be 100 μm to 3000 μm and the coating speed is controlled to be 1m/min to 100m/min.
In the present specification, the "wet film thickness" refers to the vertical distance between the height of the liquid surface after the liquid is placed in the cavity of the master mold and the reference surface of the master mold. For example, a "wet film thickness of the barrier mixture is 600 μm to 1500 μm" means that the vertical distance between the liquid level of the barrier mixture and the reference surface of the master mold is 600 μm to 1500 μm after the barrier mixture is filled into the hole of the master mold and the needle tip layer is covered. Preferably, in the step (d), the vertical distance between the liquid level of the barrier mixture and the reference surface of the master model is 600 μm to 850 μm.
According to the present invention, the above steps (c), (e) and (g) may be performed by freeze-drying or normal temperature drying. Preferably, the drying temperature in the steps (C), (e) and (g) can be controlled to be-80 ℃ to 100 ℃. More specifically, when the medical microneedle patch is to be manufactured, the drying temperature in the steps (C), (e) and (g) can be controlled between-80 ℃ and 100 ℃ so as to avoid the problem that the drying temperature above 100 ℃ damages the molecular structure of the medical active ingredient and the derivative active ingredient fails. On the other hand, when a vaccine microneedle patch is to be manufactured, the drying temperature in the steps (C), (e) and (g) can be controlled to be-80 ℃ to 40 ℃ so as to avoid the inactivation of the vaccine caused by the drying temperature above 40 ℃.
In the present specification, the "wet film thickness of the needle bottom mixture is 450 μm to 850 μm" means that the vertical distance between the liquid surface height of the needle bottom mixture and the reference surface of the master mold is 450 μm to 850 μm after the needle bottom mixture is filled into the hole of the master mold and the barrier layer is covered. Preferably, in the step (f), the vertical distance between the liquid surface height of the needle bottom mixture and the reference surface of the master model is 450 μm to 750 μm.
In application, by controlling the needle length of the microneedle patch, the microneedle patch can avoid touching the nervous system below the dermis layer when in use, so that the fear of a user can be reduced and the pain can be avoided.
In the present specification, a range expressed by "small value to large value" means that the range is larger than or equal to the small value and smaller than or equal to the large value unless otherwise specified. For example, a thickness of 300 μm to 1000 μm, i.e., a thickness in the range of "greater than or equal to 300 μm and less than or equal to 1000 μm" is indicated.
Drawings
Fig. 1 is a schematic diagram illustrating the expected barrier effect of the barrier layer in the microneedle patch of the embodiment.
Fig. 2 is a schematic diagram illustrating that the barrier layer does not have the expected barrier effect in the microneedle patch of the comparative example.
Fig. 3A to 3C are schematic diagrams illustrating the meaning represented in the present specification of the wet film thickness.
Detailed Description
The technical means adopted by the invention to achieve the preset aim are further described below by matching the specification, the drawings and the preferred embodiments of the invention.
The following description illustrates embodiments of the invention by way of example only, and those skilled in the art will readily appreciate that many modifications and variations are possible in the practice or application of the present invention without materially departing from the novel teachings of the invention.
Description of reagents
1. Hyaluronic Acid (HA), agent, jingming chemical Co., ltd, molecular weight 10 kilodaltons.
2. Polyvinylpyrrolidone (polyvinylpyrrolidone, PVP), agent, huimin pharmaceutical Co., ltd.
3. Sucrose (sucrose), agency, jingming chemical Co., ltd.
4. Trehalose (trehalose), agent, jingming chemical Co., ltd.
5. Polyvinyl alcohol (polyvinyl alcohol, PVA), agent, yuan Sheng applied materials Co., ltd.
2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CD), available from Shang Kesheng medical industries, inc., under the trade designation Cavitron W HP7 Pharm.
7. Glycerol (glycerol), agency, jingming chemical Co., ltd.
8. Polysorbate twenty (polysorbate 20, tween 20), commercially available from yuba corporation under the trade designation MASEMUL PS.
Preparation example Polymer Material
Three polymer materials with different compositions are prepared firstly to prepare the needle point mixed liquid of the needle point layer of the micro-needle patch, the blocking mixed liquid of the blocking layer and the needle bottom mixed liquid of the needle bottom layer. The formulation components and weight ratios of the polymer materials numbered A, B and C are shown in Table 1 below.
TABLE 1 formulation components of Polymer materials and weight ratio thereof
| Numbering device | Formula components and weight proportion of high polymer material |
| A | Hyaluronic acid of molecular weight 10 ten thousand daltons, polyvinylpyrrolidone, sucrose=2:2:11 |
| B | Hyaluronic acid of molecular weight 10 ten thousand daltons, polyvinylpyrrolidone, trehalose=2:2:11 |
| C | Trehalose: polyvinyl alcohol: 2-hydroxypropyl-beta-cyclodextrin = 1:2:2 |
Test example 1 viscosity test
In this test example, a proper amount of polymer materials A, B and C were weighed and dissolved in different solvents, respectively, to prepare a needle tip mixed solution, a barrier mixed solution and a needle bottom mixed solution with different solid contents, and glycerin and polysorbate twenty (Tween 20) were optionally added according to the following table 2, to obtain each sample to be tested. Wherein, polymer material A is dissolved in phosphate buffered saline (phosphate buffered saline, PBS), and polymer materials B and C are dissolved in deionized water (deionized water, DI water). Taking the example of the needlepoint mixture of example 1, which contains 10wt% of the polymer material A, 0.0067wt% of glycerin and 0.011wt% of polysorbate twenty, and the balance PBS, taking the example of the barrier mixture of example 1, which contains 40wt% of the polymer material C and 60wt% of DI water, and taking the example of the needle bottom mixture of example 1, which contains 35wt% of the polymer material C and 65wt% of DI water.
The viscosity of each sample to be tested was measured by a viscometer (instrument model MCR302, available from Anton Paar) at 25 ℃ with a shear rate of 1s -1. The viscosity of each sample to be tested is shown in table 2 below.
Examples 1 to 9 microneedle patches
As shown in Table 2, the microneedle patches of examples 1 to 9 were each prepared by the following method using the above-mentioned needlepoint mixture, barrier mixture, and needle bottom mixture.
Firstly, a female die with a reference surface and a plurality of holes is taken, each hole is concavely arranged from the reference surface to be molded, and the holes are concavely arranged on the female die in a matrix arrangement. The female mold is made of Polydimethylsiloxane (PDMS), the density of holes on the female mold is 266 holes/square centimeter (holes/cm 2), the array range of the holes is 1.5 centimeters (cm) diameter circular arrangement, and the shape of each hole is square cone. Examples 1 to 8 selected the cavity depth of the master mold (i.e., the perpendicular distance of the tip of the cavity from the master mold reference surface) to be about 580 μm to 620 μm, the cavity maximum width (i.e., the maximum inner diameter of the horizontal plane of the cavity flush with the master mold reference surface) to be about 290 μm to 310 μm, while example 9 selected the cavity depth of the master mold (i.e., the perpendicular distance of the tip of the cavity from the master mold reference surface) to be about 880 μm to 920 μm, and the cavity maximum width (i.e., the maximum inner diameter of the horizontal plane of the cavity flush with the master mold reference surface) to be about 440 μm to 460 μm.
Then, a pinpoint mixture with the volume of 0.1 milliliter (ml) is dripped on the master model by a dispensing method, the pinpoint mixture covers a plurality of holes on the master model, then the master model with the pinpoint mixture is placed in a vacuum oven for pumping, the pressure is reduced to-730 mmHg to-760 mmHg, the pinpoint mixture downwards flows into the holes of the master model from the master model reference surface and covers the master model reference surface and all the holes, the step can also be finished by adopting a centrifugal mode, for example, the master model with the pinpoint mixture is placed in a centrifugal machine, and the pinpoint mixture downwards flows into the holes of the master model from the master model reference surface and covers the master model reference surface and all the holes by continuous centrifugation at the rotating speed of 2300xg for 6 minutes. Then, the pinpoint mixed solution on the reference surface of the master model is completely scraped by a scraper, and then the master model with the pinpoint mixed solution is placed in an environment with the temperature of 30 ℃ and the relative humidity of 20-65% for continuous drying for 1 hour, so that the pinpoint mixed solution is dried into a pinpoint layer, and the surface of the pinpoint layer is lower than the reference surface of the master model, thereby obtaining the master model with the pinpoint layer. Here, the thickness (dry film thickness) of the tip layer of the microneedle patch of examples 1 to 9 is the vertical distance from the tip of the hole to the surface of the tip layer, wherein if the surface of the tip layer is not a flat surface but an inward concave plane, the thickness (dry film thickness) of the tip layer is the vertical distance from the tip of the hole to the lowest point of the surface of the tip layer. The ratio of the thickness of the tip layer to the depth of the cavity of the master mold (i.e., the ratio of the thickness of the tip layer to the thickness of the needle body) for the microneedle patches of examples 1-9 is set forth in table 3 below.
Then, a blocking mixture having a volume of 0.8ml was dropped onto the master mold with the tip layer by dispensing method, and the blocking mixture was allowed to cover the plurality of holes. And then, placing the master model with the blocking mixed liquid in a centrifugal machine, and continuously centrifuging for 6 minutes at a rotation speed of 2300xg, so that the blocking mixed liquid flows downwards from the reference surface to a plurality of holes of the master model, and covers the reference surface of the master model and the needle point layers in all the holes. Then, a part of the blocking mixture on the reference surface of the master model is scraped off by a scraper, so that the thickness of the wet film of the blocking mixture is shown in table 2, for example, if the thickness of the wet film of the blocking mixture is 700 μm, the vertical distance from the liquid surface of the blocking mixture to the reference surface of the master model is 700 μm. And then, placing the mother die filled with the blocking mixed solution in an environment with the temperature of 30 ℃ and the relative humidity of 20-65% for continuous drying for 24-48 hours, thereby drying the blocking mixed solution into a blocking layer and bonding the blocking layer on the pinpoint layer and the reference surface of the mother die, and obtaining the mother die with the pinpoint layer and the blocking layer.
Then, a needle bottom mixture having a volume of 0.8ml was dropped onto the master mold having the needle tip layer and the barrier layer by dispensing as well, and the needle bottom mixture was allowed to cover the plurality of holes thereon. And then, placing the master model with the needle bottom mixed liquid in a centrifugal machine, and continuously centrifuging for 40 minutes at a rotation speed of 2300xg, so that the needle bottom mixed liquid flows downwards from the reference surface to a plurality of holes of the master model, and covers the barrier layer on the reference surface of the master model and the barrier layers in all the holes. Next, a part of the needle bottom mixture on the master model reference surface was scraped off with a spatula so that the wet film thickness of the needle bottom mixture in each example was as shown in table 2. And then, placing the mother die filled with the needle bottom mixed solution in an environment with the temperature of 30 ℃ and the relative humidity of 20-65% for continuous drying for 24-48 hours, thereby drying the needle bottom mixed solution into a needle bottom layer and bonding the needle bottom layer on the barrier layer, and bonding the barrier layer of the needle body part between the needle point layer and the needle bottom layer of the needle body part, so as to obtain the mother die with a finished product. Here, the ratio of the thicknesses of the needle bottom layer and the barrier layer of the needle body portion (i.e., the perpendicular distance from the master reference surface to the needle tip layer surface) of the microneedle patches of examples 1 to 9 to the thickness of the needle body portion (i.e., the depth of the master hole) measured along the thickness measurement line, with the shortest distance extending from the projection point of the tip of the hole onto the surface of the needle bottom layer to the tip, as the thickness measurement line, is shown in table 3 below, and the thicknesses of the base portions of the microneedle patches of examples 1 to 9 (i.e., the perpendicular distance from the surface of the needle bottom layer to the master reference surface) are also shown in table 3 below.
Finally, the finished product was removed from the master mold having the finished product to obtain the microneedle patches of examples 1 to 9. In the method for manufacturing the microneedle patch, the mixed solution of the needle tip may contain a pharmaceutically active ingredient or a vaccine active ingredient.
As shown in fig. 1, the microneedle patch 1 of the present invention includes a base 12 and a plurality of needle portions 11 protruding from the base 12, wherein the base 12 is formed of a barrier layer 122 of the base and a needle bottom layer 123 of the base, each needle portion 11 is formed of a needle tip layer 111, a barrier layer 112 of the needle portion and a needle bottom layer 113 of the needle portion, and the barrier layer 112 of the needle portion is formed between the needle tip layer 111 of the needle portion and the needle bottom layer 113 of the needle portion, wherein the barrier layer 122 of the base and the barrier layer 112 of the needle portion are integrally formed, and the needle bottom layer 123 of the base and the needle bottom layer 113 of the needle portion are integrally formed. The thickness measurement line L is used as a reference line for measuring the thickness H 123 of the needle bottom layer 123 of the base portion, the thickness H 113 of the needle bottom layer 113 of the needle body portion, the thickness H 112 of the barrier layer 112 of the needle body portion, and the thickness H 111 of the needle tip layer 111 by the shortest distance that the projection point of the tip of the needle body portion onto the base portion extends toward the tip with respect to the bottom surface of the needle body portion. as shown in fig. 1, the thickness H 123 of the needle bottom layer 123 of the base portion measured along the thickness measuring line L is equal to the sum of the thicknesses of the barrier layer 122 of the base portion and the needle bottom layer 123 of the base portion, simply referred to as the thickness of the base portion 12, and the sum of the thickness H 113 of the needle bottom layer 113 of the needle portion, the thickness H 112 of the barrier layer 112 of the needle portion, and the thickness H 111 of the needle tip layer 111 measured along the thickness measuring line L is the thickness of the needle portion 11. The ratio of the sum of the thickness H 113 of the needle bottom layer 113 of the needle body and the thickness H 112 of the barrier layer 112 of the needle body relative to the master cavity depth (i.e., the thickness of the needle body) of the microneedle patches of examples 1 to 9 is also set forth in table 3 below. In addition, the sum of the thickness H 123 of the needle bottom layer 123 of the base portion, the thickness H 113 of the needle bottom layer 113 of the needle body portion, and the thickness H 112 of the barrier layer 112 of the needle body portion measured along the thickness measuring line L is 550 μm to 1100 μm.
In order to further specifically explain the meaning represented by the wet film thickness, the following description will be given by taking the preparation process of the barrier layer and the needle bottom layer in the microneedle patch as an example and referring to fig. 3A to 3C.
As shown in fig. 3A, a master mold 30 having a spike layer has a reference surface 301, a plurality of holes 302 formed by recessing the reference surface 301, and a spike layer 311 formed in the holes 302.
Next, as shown in fig. 3B, a barrier mixed solution 32A is injected into the hole 302 and covers the surface of the needle tip layer 311 and the reference surface 301 of the master mold, and at this time, the vertical distance H1 between the liquid surface 32B of the barrier mixed solution 32A and the reference surface 301 of the master mold is the wet film thickness of the barrier mixed solution 32A.
Next, as shown in fig. 3C, the above-mentioned barrier mixed solution forms a barrier layer 312 of the needle portion on the surface of the needle tip layer 311 and a barrier layer 322 of the base portion on the reference surface 301 of the master mold, and then a bottom mixed solution 33A is injected into the hole 302 and covers the surface of the barrier layer 312 of the needle portion and the surface of the barrier layer 322 of the base portion, and at this time, the vertical distance H2 between the liquid surface 33B of the bottom mixed solution 33A and the reference surface 301 of the master mold is the wet film thickness of the bottom mixed solution 33A.
Comparative example 1 and 2 microneedle patch
The microneedle patches of comparative examples 1 and 2 were substantially the same as the above-described method for producing the microneedle patch of example 8, except that the wet film thickness of the needle base mixture of the microneedle patches of comparative examples 1 and 2 was different from the wet film thickness of the needle base mixture of the microneedle patch of example 8.
Table 2 composition and viscosity of the tip mixed solution, composition and viscosity of the barrier mixed solution and wet film thickness, and composition and viscosity of the needle bottom mixed solution and wet film thickness used for manufacturing the microneedle patches of examples 1 to 9.
Table 3 microneedle patches examples 1 to 9 were tested for the ratio of the thickness of the needle tip layer to the thickness of the needle body, the thickness of the base portion, the ratio of the thickness of the needle base layer and the barrier layer of the needle body measured along the thickness measuring line to the thickness of the needle body, the mechanical strength, and the diffusion prevention test results.
Test example 2 mechanical Strength test of microneedle patch
After placing the microneedle patches of examples 1 to 9 and comparative examples 1 and 2 in a moisture proof box for 2 days, the mechanical strength of each microneedle patch was further tested with a universal material tester (instrument model 3343, available from INSTRON). In this test example, the displacement was set to 10 millimeters (mm), and the compression test was performed at a speed of 66mm/min while taking 500 compression stress values per second. The mechanical strength of the microneedle patches of examples 1 to 9 and comparative examples 1 and 2 is shown in table 3 above.
As can be seen from the results of Table 3 above, the microneedle patches of examples 1 to 9 all had mechanical strengths higher than that required for piercing the stratum corneum without breaking (0.058N/needle), whereas the microneedle patches of examples 2 to 9 all had mechanical strengths higher than 0.20N/needle, whereas the microneedle patch of example 9 had the best mechanical strength (0.3N/needle), whereas the microneedle patch of comparative example 2 had mechanical strengths of only 0.05N/needle, which is clearly difficult to pierce the stratum corneum and is easily broken, which is disadvantageous for the application of the microneedle patch.
Test example 3 anti-diffusion Effect test of microneedle patch
In the test example, a bicolor fluorescence observation method is adopted to test whether the blocking layer effectively prevents the active ingredients of the needle point layer from diffusing to the needle bottom layer so as to control the carrying amount of the active ingredients of the needle point layer in the microneedle patch. In the microneedle patches of production examples 1 to 9 and comparative examples 1 and 2, 29.6 μg/ml of green fluorescence was added to the needle tip mixed solution, and 29.6 μg/ml of red fluorescence was added to the needle base mixed solution. After the microneedle patches of examples 1 to 9 and comparative examples 1 and 2 were prepared, each microneedle patch was placed under an inverted fluorescence microscope (instrument model NIB410-FL, commercially available from NEXCOPE) to observe whether diffusion occurred between layers. If the needle bottom layer still exhibits red fluorescence under observation by an inverted fluorescence microscope, it indicates that the green fluorescence of the needle tip layer is not diffused, as shown in the needle body 11 of the microneedle patch 1 of fig. 1, wherein the barrier layer 112 of the needle body has a barrier effect and can limit the active ingredient to the needle tip layer 111, it is indicated as "o" in table 3 above, and if the needle bottom layer exhibits orange fluorescence, it indicates that the green fluorescence of the needle tip layer has diffused to the needle bottom layer and mixed with the red fluorescence of the needle bottom layer, as shown in the needle body 21 of the microneedle patch 2 of fig. 2, wherein the barrier layer 212 of the needle body does not have a barrier effect, so that the active ingredient is diffused from the needle tip layer 211 to the needle bottom layer 223 of the base portion, so that it is indicated as "q" in table 3 above.
From the results of table 3 above, it is apparent that the microneedle patches of examples 1 to 9 are each capable of effectively preventing the active ingredient from diffusing from the needle tip layer to the needle bottom layer, and that the microneedle patches of comparative examples 1 and 2 are each incapable of preventing the active ingredient from diffusing from the needle tip layer to the needle bottom layer, and in particular, even though the microneedle patch of comparative example 2 has a mechanical strength capable of penetrating the stratum corneum, they are still incapable of preventing the active ingredient from diffusing from the needle tip layer to the needle bottom layer, thereby affecting the therapeutic effect of applying the microneedle patch containing the active ingredient.
In summary, by controlling the composition components of the needle tip layer, the barrier layer and the needle bottom layer and the thickness of the layer body, the obtained microneedle patch has good mechanical strength, is beneficial to the application of the microneedle patch, and can effectively prevent the active ingredient from diffusing from the needle tip layer to the needle bottom layer, so that the carried active ingredient can be limited at the position close to the needle tip, the active ingredient can be accurately released to the position to be acted, and the preset curative effect can be ensured.
The present invention is not limited to the above-described preferred embodiments, but is intended to be limited to the following description, and any modifications, equivalent changes and variations in the above-described embodiments according to the technical principles of the present invention will fall within the scope of the present invention, as long as they do not depart from the scope of the present invention.
Claims (18)
1. A microneedle patch is characterized by comprising a base part and a plurality of needle parts formed by protruding from the base part, wherein the base part is formed by a barrier layer and a needle bottom layer, each needle part is formed by a needle point layer, a barrier layer and a needle bottom layer, the barrier layer of each needle part is formed between the needle point layer of the corresponding needle part and the needle bottom layer of the needle part, the barrier layer of the base part and the barrier layers of the needle parts are in an integrally formed structure, the needle bottom layer of the base part and the needle bottom layer of the needle parts are in an integrally formed structure, the thickness of each needle part is 300-1000 microns, the thickness of the base part is 200-400 microns, and the ratio of the thickness of the needle bottom layer of the needle part to the thickness of the barrier layer of the needle part to the thickness of the needle part is 0.54-0.81 by taking the tip of the needle bottom layer of the base part towards the needle part as a thickness measuring line;
Wherein the material of the needle tip layer comprises hyaluronic acid, polyvinylpyrrolidone and a first saccharide, wherein the molecular weight of the hyaluronic acid is between 2 kilodaltons and 50 kilodaltons, the weight ratio of the hyaluronic acid to the polyvinylpyrrolidone is 1:0.8 to 1:2, the material of the barrier layer comprises a second saccharide, polyvinyl alcohol and 2-hydroxypropyl-beta-cyclodextrin, the weight ratio of the second saccharide to the polyvinyl alcohol in the material of the barrier layer is 1:1.8 to 1:3, the weight ratio of the second saccharide to the 2-hydroxypropyl-beta-cyclodextrin in the material of the barrier layer is 1:1.8 to 1:3, the material of the needle bottom layer comprises a third saccharide, polyvinyl alcohol and 2-hydroxypropyl-beta-cyclodextrin, the weight ratio of the third saccharide to the polyvinyl alcohol in the material of the needle bottom layer is 1:1.8 to 1:3, and the weight ratio of the third saccharide to the 2-hydroxypropyl-beta-cyclodextrin in the material of the needle bottom layer is 1:1.8 to 1:3.
2. The microneedle patch of claim 1, wherein the needle tip layer further comprises glycerin and polysorbate twenty.
3. The microneedle patch of claim 1 or 2, wherein the first saccharide is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, dextrin, 2-hydroxypropyl-beta-cyclodextrin, dextran, and combinations thereof, the second saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof, and the third saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, and combinations thereof.
4. The microneedle patch of claim 1 or 2, wherein the first saccharide is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, maltodextrin, beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, dextran, and combinations thereof, the second saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof, and the third saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof.
5. The microneedle patch of claim 3, wherein the needle tip layer comprises an active ingredient comprising an attenuated vaccine, a inactivated vaccine, viroid particles, purified subunit antigens, antigens expressed by genetic recombination, synthetic peptides, genetic recombinant vectors, genetic vaccines, nucleic acid vaccines, mucosal immunity, or combination vaccines.
6. The microneedle patch of claim 1, wherein the weight ratio of hyaluronic acid to the first saccharide is from 1:5 to 1:8.
7. A method of manufacturing the microneedle patch according to any one of claims 1 to 6, comprising the steps of:
Providing a female die, wherein the female die is provided with a reference surface and a plurality of holes, and the holes are concavely arranged downwards from the reference surface for forming;
Filling a needle point mixed solution into the holes of the female die, wherein the solid content of the needle point mixed solution is more than 5 weight percent and less than 40 weight percent, the needle point mixed solution comprises hyaluronic acid, polyvinylpyrrolidone and a first saccharide, the molecular weight of the hyaluronic acid is between 2 kilodaltons and 50 kilodaltons, and the weight ratio of the hyaluronic acid to the polyvinylpyrrolidone is 1:0.8-1:2;
step (c), drying the pinpoint mixed liquid into a pinpoint layer, wherein the surface of the pinpoint layer is lower than the reference surface of the master model;
Filling a barrier mixed solution into the holes of the master mold, covering the needle tip layer and the reference surface of the master mold so that the vertical distance between the liquid level of the barrier mixed solution and the reference surface of the master mold is 600-1500 micrometers, wherein the solid content of the barrier mixed solution is more than 30 weight percent and less than or equal to 45 weight percent, the barrier mixed solution comprises a second saccharide, polyvinyl alcohol and 2-hydroxypropyl-beta-cyclodextrin, the weight ratio of the second saccharide to the polyvinyl alcohol in the barrier mixed solution is 1:1.8-1:3, and the weight ratio of the second saccharide to the 2-hydroxypropyl-beta-cyclodextrin in the barrier mixed solution is 1:1.8-1:3;
drying the barrier mixed solution into a barrier layer, wherein the barrier layer is formed on the needle tip layer and the reference surface of the master model;
Filling a needle bottom mixture into the holes of the master mold, covering a barrier layer in the holes and the barrier layer on the reference surface of the master mold so that the vertical distance between the liquid level of the needle bottom mixture and the reference surface of the master mold is 450-850 micrometers, wherein the solid content of the needle bottom mixture is greater than or equal to 30-45 weight percent, the needle bottom mixture comprises a third saccharide, polyvinyl alcohol and 2-hydroxypropyl-beta-cyclodextrin, the weight ratio of the third saccharide to the polyvinyl alcohol in the needle bottom mixture is 1:1.8-1:3, the weight ratio of the third saccharide to the 2-hydroxypropyl-beta-cyclodextrin in the needle bottom mixture is 1:1.8-1:3, and the solid content of the needle bottom mixture is less than the solid content of the barrier mixture;
Step (g) of drying the needle bottom mixture to form a needle bottom layer, adhering the barrier layer between the needle tip layer and the needle bottom layer, and
And (h) detaching the needle tip layer, the barrier layer and the needle bottom layer which are mutually adhered from the female die to obtain the microneedle patch.
8. The method of manufacturing a microneedle patch of claim 7, wherein the tip mixture further comprises glycerin and polysorbate twenty.
9. The method of manufacturing a microneedle patch according to claim 8, wherein the glycerol is contained in an amount of 0.005 to 0.2 wt% and the polysorbate twenty is contained in an amount of 0.001 to 0.1 wt% based on the total weight of the needlepoint mixture.
10. The method of claim 8, wherein the viscosity of the tip mixture is 8 centipoise to 25000 centipoise.
11. The method of claim 8, wherein the viscosity of the barrier mixture is from 5000 centipoise to 220000 centipoise.
12. The method of claim 8, wherein the viscosity of the mixture is 3000 cps to 100000 cps.
13. The method of manufacturing a microneedle patch according to claim 7, wherein in the step (b), the weight ratio of the hyaluronic acid to the first saccharide is 1:5 to 1:8.
14. The method of manufacturing a microneedle patch according to claim 7, wherein in the step (d), a vertical distance between a liquid level of the barrier mixture and the reference surface of the master mold is 600 μm to 850 μm.
15. The method of manufacturing a microneedle patch according to any one of claims 7 to 14, wherein the first saccharide is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, dextrin, 2-hydroxypropyl-beta-cyclodextrin, dextran, and combinations thereof, and the second saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof, and the third saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, and combinations thereof.
16. The method of manufacturing a microneedle patch according to any one of claims 7 to 14, wherein the first saccharide is selected from the group consisting of glucose, galactose, sucrose, trehalose, maltose, lactose, maltodextrin, beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, dextran, and combinations thereof, and the second saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof, and the third saccharide is selected from the group consisting of trehalose, amylose, amylopectin, chitin, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelatin, chitosan, and combinations thereof.
17. The method of claim 7, wherein in the step (b), the method of filling the tip mixture into the plurality of holes of the master mold comprises a vacuum pumping method and a centrifugation method, wherein in the step (d), the method of filling the barrier mixture into the plurality of holes of the master mold comprises a vacuum pumping method and a centrifugation method, and wherein in the step (f), the method of filling the needle bottom mixture into the plurality of holes of the master mold comprises a vacuum pumping method and a centrifugation method.
18. The method of claim 7, wherein the mixed solution of tips comprises an active ingredient comprising an attenuated vaccine, a inactivated vaccine, a viroid, a purified subunit antigen, a gene recombinant expressed antigen, a synthetic peptide, a gene recombinant vector, a gene vaccine, a nucleic acid vaccine, a mucosal immunity or a combination vaccine.
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