WO2020043167A1 - 一种可快速植入型缓释微针贴片及其制备方法 - Google Patents

一种可快速植入型缓释微针贴片及其制备方法 Download PDF

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WO2020043167A1
WO2020043167A1 PCT/CN2019/103331 CN2019103331W WO2020043167A1 WO 2020043167 A1 WO2020043167 A1 WO 2020043167A1 CN 2019103331 W CN2019103331 W CN 2019103331W WO 2020043167 A1 WO2020043167 A1 WO 2020043167A1
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microneedle
needle
needle tip
release
mold
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PCT/CN2019/103331
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English (en)
French (fr)
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高云华
杨国忠
张锁慧
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中科微针（北京）科技有限公司
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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
    • 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
    • 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
    • A61K47/06—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
    • 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
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0204—Specific forms not provided for by any of groups A61K8/0208 - A61K8/14
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/85—Polyesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/88—Polyamides
    • 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
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • 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
    • 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

Definitions

  • the invention relates to the field of medical technology. More specifically, it relates to a fast-implantable sustained-release microneedle patch and a preparation method thereof.
  • Transdermal preparations are a form of drug delivery through the skin, which can avoid the interference of the gastrointestinal environment on the efficacy and the "first pass effect" of the liver, maintain a constant optimal blood concentration or physiological effect, and prolong the effective time.
  • patients can self-administer and have better compliance.
  • the cuticle of the outer layer of the skin will hinder the absorption of the drug, and the drug will not easily penetrate into the body, resulting in very limited choice of drugs.
  • microneedle technology has received widespread attention. It is one of the physical penetration-promoting methods for transdermal administration, which can achieve painless and accurate administration.
  • microneedles made of metal, glass, and silicon materials will inevitably break into the skin during use due to the properties of the materials, causing damage to the human body.
  • polymer microneedles have emerged.
  • the materials used include water-soluble polymers, biocompatible polymers, and biodegradable polymers that can be absorbed by the skin, which greatly reduces the risk of use. Low cost, simple production process, mass production, and environmental friendliness.
  • Microneedle production can achieve controlled release of drugs by selecting water-soluble polymer materials or biodegradable polymer materials with different physical and chemical properties.
  • many researchers have devoted themselves to making polymer microneedles with good biocompatibility, natural degradation and easy preparation from polylactic acid-based degradable polymer materials.
  • Chinese patent discloses a polymer solid microneedle and a batch preparation method thereof.
  • the material described in the present invention is a biodegradable water-insoluble polymer material.
  • the preparation method used is to place the polymer material particles on a microneedle mold, heat them in a closed heating device until the particles melt, and use the preparation device to dissolve the particles. The melt is hot-molded.
  • the microneedles prepared in this patent cannot carry drugs, and the microneedles only serve to pretreat the skin and destroy the skin's stratum corneum barrier when in use.
  • SSPP system solid drug solution perforator
  • the SSPP system includes an active pharmaceutical ingredient in the form of a particle or a drug adsorbed on the particle surface of a matrix material that dissolves upon contact with the patient's body.
  • the inert particles are lactic acid-glycolic acid copolymer (PLGA) or aluminum hydroxide and aluminum phosphate.
  • PLGA lactic acid-glycolic acid copolymer
  • the microneedles produced by this method can be loaded with protein and vaccine drugs, but since the drug is adsorbed on the PLGA inert particles, its sustained release effect is basically not.
  • Literature 1 (Pharmaceutical Research. 2006 May; 23 (5): 1008-19.) Proposes a method for preparing microneedles by using a polylactic acid-glycolic acid copolymer (PLGA) as a microneedle scaffold material. Or the microspheres loaded with polylactic acid or sodium carboxymethylcellulose are loaded into the microneedles to achieve the controlled release of the drug.
  • PLGA polylactic acid-glycolic acid copolymer
  • the drug users need to apply it for a long time. Until the scaffold material PLGA is completely degraded.
  • microneedle production can be divided into two categories. First, polylactic acid-based degradable polymer materials and drugs are first made into microspheres, and then added to the microneedle mold. After heating, melting and cooling, microneedles with a certain mechanical strength are formed. Such microneedles can be loaded with drugs, but they need to be made into microspheres and then formed into microneedles, which is cumbersome and costly; the other is to add polylactic acid powder directly to the micro The needle mold is heated and melted (higher than 200 ° C) and then cooled to form microneedles, and this manufacturing method is difficult to load drugs.
  • the first object of the present invention is to provide a fast-implantable sustained-release microneedle.
  • the microneedle can implant a biodegradable needle tip into the skin to achieve convenient, safe, biodegradable, slow-release and efficient administration. Medicine purpose.
  • a second object of the present invention is to provide a method for preparing the above-mentioned rapid-implantable sustained-release microneedle, which is simple in process and low in cost.
  • a third object of the present invention is to provide a microneedle patch including the above-mentioned rapid-implantable sustained-release microneedle.
  • the present invention adopts the following technical solutions:
  • the invention provides a fast-implantable sustained-release microneedle, which includes a needle tip, an intermediate layer, a needle body, and a base; the needle tip is formed of a matrix containing a biodegradable insoluble polymer material; and the intermediate layer is composed of A matrix of a hydrophilic material is formed; the needle body and the substrate are formed of a matrix containing a biocompatible polymer material.
  • the needle tip further includes at least one active ingredient; preferably, the mass ratio of the biodegradable water-insoluble polymer material to the active ingredient is 0.5: 1 to 1000: 1 to ensure the mechanical strength of the microneedle And skin puncture.
  • the needle tip further comprises a porogen, which helps the intradermal water molecules to enter the interior of the needle tip matrix and regulates the drug release rate.
  • the porogen includes, but is not limited to, sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, trehalose, maltose, polyethylene glycol, cyclodextrin and its derivatives, polymethylpyrrolidone (PVP), One or more of low molecular weight hyaluronic acid and its sodium salt (molecular weight: 5-100 kDa) and low molecular weight cellulose derivatives (molecular weight: 5-100 kDa).
  • the porogen comprises 0.1% to 10% of the total mass of the needle tip.
  • the needle tip further includes a protective agent.
  • the protective agent includes, but is not limited to, polyhydroxy compounds (mannitol, sorbitol, xylitol, polyethylene glycol, etc.), sugar compounds (trehalose , Dextrin, lactose, sucrose, maltose, etc.), one or more of serum albumin, polyvinylpyrrolidone, chondroitin sulfate, amino acids (proline, tryptophan, glutamic acid, glycine, etc.).
  • the protective agent accounts for 0.1% to 10% of the total mass of the needle tip.
  • the hydrophilic material includes, but is not limited to, a monomer polymer or copolymer of polyvinylpyrrolidone and its derivatives, poly ⁇ -glutamic acid, pullulan, hyaluronic acid and its sodium salt, and trehalose. Or sucrose, sorbitol, mannitol, xylitol, sodium alginate, or pectin.
  • the biocompatible polymer materials in the needle body and the substrate include, but are not limited to, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, and polyvinyl alcohol derivatives
  • polyvinylpyrrolidone derivative sodium hyaluronate, chondroitin sulfate, dextran, silk protein, gelatin; preferably, the molecular weight of the biocompatible polymer material is 10-2000kDa.
  • the needle body and the substrate further include small molecular weight sugars and polyhydric alcohol compounds, specifically one or more of trehalose, sucrose, sorbitol, mannitol, xylitol, etc., to accelerate water solubility Dissolution rate of polymer materials.
  • small molecular weight sugars and polyhydric alcohol compounds specifically one or more of trehalose, sucrose, sorbitol, mannitol, xylitol, etc., to accelerate water solubility Dissolution rate of polymer materials.
  • the tip is conical or polygonal, preferably, the tip is conical; the density of the microneedle tip is: 250-1000 per square centimeter of the base; the tip, the middle layer, and the needle
  • the total height of the body is 0.3-2mm, the angle of the needle tip is 10-60 °, and the thickness of the base is 10-300 ⁇ m; the height of the needle tip is not greater than two thirds of the total height of the needle tip, the middle layer, and the needle body.
  • the invention also provides a method for preparing the above-mentioned rapid-implantable sustained-release microneedle, which includes the following steps:
  • the organic solvent includes, but is not limited to, acetone, ethyl acetate, chloroform, dichloromethane, dimethyl sulfoxide, or N-methylpyrrolidone; preferably, the organic solvent is N-methylpyrrolidone.
  • the mass concentration of the biodegradable water-insoluble polymer material in the base material of the needle-point injection molding liquid is 5-30%; the mass concentration of the hydrophilic material in the intermediate layer injection molding liquid is 0.5-10%.
  • the mass concentration of the biocompatible polymer material in the needle body and the base injection molding liquid is 10-40%; the mass ratio of the biodegradable water-insoluble polymer material and the active ingredient is 0.5 to 1000: 1 .
  • each injection liquid is added to the microneedle mold by using a pressure method or a vacuum method, thereby avoiding the generation of air bubbles in the microneedle during production.
  • the pressurization method is used, the applied pressure is 0.2-0.6 MPa, and the applied time is 1-20 min.
  • the vacuum method is adopted, the vacuum degree is 0.05-0.1MPa, and the vacuum time is 3-20min.
  • the injection temperature of the needle tip injection liquid into the microneedle mold is heated at a temperature of 30-80 ° C., and the heating time is 1-24 hours to volatilize the organic solvent, and ensure that the microneedle has sufficient mechanical strength and skin puncture ability after cooling.
  • the drying conditions after the intermediate layer or the needle body and the base injection liquid are injected into the microneedle mold are dried at 20-50 ° C and 10% -45% humidity for 0.5-6h.
  • the invention further provides a rapid-implantable sustained-release microneedle patch, which includes the microneedle array and a lining composed of the above-mentioned rapid-implantable sustained-release microneedle; preferably, the lining is a pressure-sensitive adhesive Lined or silicone lined or hydrocolloid.
  • the preparation method of the quick-implantable sustained-release microneedle patch is to prepare a microneedle array on the basis of preparing a quick-implantable sustained-release microneedle patch, and further affix a lining on the back surface of the microneedle array substrate Demolding is just fine.
  • microneedle patch of the invention can be applied in the fields of disease treatment, prevention, health care and beauty.
  • active ingredient refers to a substance for diagnostic, therapeutic, preventive, cosmetic, or health care purposes that is delivered transdermally through the microneedles or microneedles patches of the present invention and has an effect on animals or human bodies.
  • the active ingredients include, but are not limited to, pharmaceutical active ingredients, vaccine active ingredients, cosmetic active ingredients, health care product active ingredients, and the like, and are specifically selected according to actual needs.
  • a microneedle tip is made of a biodegradable water-insoluble polymer material
  • a microneedle intermediate layer is made of a hydrophilic material
  • a needle body and a base are made of a biocompatible polymer material.
  • Multi-layered microneedles whose needle tips are hardly soluble in water are formed. After they act on the skin, they absorb the moisture in the skin and quickly separate the needle tips from the needle body and the base within 1 hour. After the patch base is removed, the microneedle tips will be Remaining in the skin, the user does not need to apply a microneedle patch for a long time to ensure long-term release of the drug in the body.
  • microneedle patches are not limited by the production area. By increasing the area, the drug loading can be greatly increased, which is suitable for long-term intradermal release of various drugs.
  • the microneedle preparation process of the present invention avoids the tedious process of encapsulating drugs in microsphere liposomes, but uses a low-toxicity organic solvent such as N-methylpyrrolidone to dissolve biodegradable insoluble polymer materials, and the process cost It is reduced, and the process is similar to the ordinary method of making dissolved microneedles. The operation is simple and fast, does not require high temperature melting, and the applicable drug range is wide.
  • FIG. 1 shows a schematic diagram of a microneedle patch structure.
  • Fig. 2 shows a photograph of a microneedle patch stereo microscope.
  • Figure 3 shows a side view under a microneedle patch microscope.
  • Figure 4 shows the skin puncture capability of the microneedle patch.
  • Fig. 5 shows a fluorescence micrograph of a microneedle patch with a portion of polylactic acid implanted into pig skin.
  • microneedle is released after drying.
  • microneedles are shown in FIG. 1, the microneedles are 300 needles / 0.5 cm 2, and the needle length is 0.5 mm.
  • the separation time of the needle tip from the needle body and the substrate was 0.5 h, and the in vitro release experiment showed that the sustained release time of etonogestrel was 30 days.
  • etonogestrel can be replaced with other active ingredients of heat-resistant small-molecule compounds, including, but not limited to, for example, ethinyl estradiol, levonorgestrel, norgestrel, gestodenone, and desogrol.
  • the obtained microneedle patches have similar sustained-release effects on the active ingredients such as norosterone, desogestrel, artemisinin derivatives, and paclitaxel derivatives.
  • the polyvinylpyrrolidone of the intermediate layer injection liquid of this embodiment can be polyvinylpyrrolidone derivative, poly ⁇ -glutamic acid, pullulan, hyaluronic acid and its sodium salt, trehalose, sucrose, sorbitol, mannose Substituting alcohol, xylitol, sodium alginate, pectin, gelatin, etc., the obtained microneedle patch has a similar sustained-release effect.
  • the polyvinyl alcohol in the needle body and the base injection molding liquid of this embodiment can be carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, polyvinyl alcohol, polyethylene Substituting one or more of pyrrolidone, sodium hyaluronate, and chondroitin sulfate, the obtained microneedle patch has a similar sustained-release effect.
  • Pore-forming agents such as 0.1-5% sodium chloride, 0.1-5% sodium carbonate, 0.1-3% sodium bicarbonate, 0.1-3% ammonium bicarbonate, and 1-10% can be added to the needle-point injection molding liquid of this embodiment.
  • the microneedle patch is capable of sustained release for 5-20 days.
  • microneedle is released after drying.
  • the prepared microneedles are shown in FIG. 1, and the stereo microscope images are shown in FIGS. 2 and 3.
  • the microneedles are 400 needles / cm 2 and the needle length is 0.7 mm.
  • the separation time of the needle tip from the needle body and the base is 1h.
  • the fluorescent red may be replaced with other active ingredients of heat-resistant small-molecular-weight compounds, and the obtained microneedle patch has a similar sustained-release effect.
  • microneedle is released after drying.
  • the separation time of the needle tip from the needle body and the base is 0.75 h.
  • the results of in vitro release experiments showed that the interferon a-2b sustained release time was about 30 days.
  • interferon a-2b can be replaced with other types of active ingredients, especially proteins or polypeptides with poor heat resistance.
  • active ingredients especially proteins or polypeptides with poor heat resistance.
  • microneedle patches obtained from insulin, growth hormone, nerve growth factor, etc. have similar effects. ⁇ ⁇ Release effect.
  • the trehalose in the intermediate layer injection liquid of this embodiment can be made of polyvinylpyrrolidone derivative, poly ⁇ -glutamic acid, pullulan, hyaluronic acid and its sodium salt, trehalose, sucrose, sorbitol, mannitol , Xylitol, sodium alginate, pectin, gelatin, etc., the resulting microneedle patch has a similar sustained release effect.
  • the polyvinyl alcohol in the needle body and the base injection molding liquid of this embodiment can be carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, polyvinyl alcohol, polyethylene One or more of pyrrolidone, sodium hyaluronate, chondroitin sulfate, and dextran are substituted, and the obtained microneedle patch has a similar sustained-release effect.
  • Porosity agents such as 0.1-5% sodium chloride, 0.1-5% sodium carbonate, 0.1-3% sodium bicarbonate, 0.1-3% ammonium bicarbonate, 1-10 can be added to the needle-point injection molding liquid in this embodiment.
  • the sustained release time of the obtained microneedle patch can be controlled within 5-20 days.
  • Protective agents such as 1 to 10% polyhydroxy compounds (such as 1% glycerol, 3% butanediol, 1 to 5% xylitol, 1 to 10% mannitol) can be added to the needle-point injection molding liquid of this embodiment, One or more of 1 to 10% sugar compounds (1 to 10% trehalose, 1 to 5% sucrose), 0.1 to 5% serum albumin, 1 to 10% polyvinyl pyrrolidone, and 1 to 10% amino acids
  • the sustained release time of the obtained microneedle patch can be controlled within 5 days to 20 days.
  • microneedles are shown in FIG. 1, the microneedles are 1000 needles / cm 2, and the needle length is 0.3 mm.
  • the separation time between the needle tip and the needle body and the substrate is 0.5 h.
  • In vitro release results show that the sustained release time of granisetron hydrochloride is about 15 days.
  • granisetron hydrochloride can also be replaced with other active ingredients, such as leuprorelin acetate, octreotide acetate, amlodipine besylate / ketoprofen, cyclosporine, diclofenac sodium controlled release, everolimo Substituted for pharmacokinetics, methylphenidate, clarithromycin, mycophenolic acid, griseofulvin, mabilone, tacrolimus, etc., and the resulting microneedle patch has similar sustained release .
  • active ingredients such as leuprorelin acetate, octreotide acetate, amlodipine besylate / ketoprofen, cyclosporine, diclofenac sodium controlled release, everolimo Substituted for pharmacokinetics, methylphenidate, clarithromycin, mycophenolic acid, griseofulvin, mabilone, tacrolimus, etc.
  • microneedle is released after drying.
  • microneedles are shown in FIG. 1, the microneedles are 600 needles / cm2, and the needle length is 0.4 mm.
  • the separation time of the needle tip from the needle body and the base was 1.5h.
  • the polylactic acid PLGA of this embodiment can be replaced with other biodegradable, water-insoluble polymer materials, and the obtained microneedle patch has a sustained release effect.
  • microneedle is released after drying.
  • microneedles are shown in FIG. 1, the microneedles are 200 needles / cm 2, and the needle length is 0.8 mm.
  • the separation time between the needle tip and the substrate was 1.0 h; in vitro release showed that the sustained release time of estradiol was 14 days.
  • microneedle patch has a sustained release effect.
  • microneedle is released after drying.
  • microneedles are shown in FIG. 1, the microneedles are 500 needles / cm 2, and the needle length is 1.0 mm.
  • the separation time between the needle tip and the substrate was 1.5 h; in vitro release showed that the sustained release time of vinpocetine was 10 days.
  • the vinpocetine of this embodiment can be replaced with other small molecule active ingredients, and the obtained microneedle patch has a sustained release effect.
  • Example 5 According to the preparation method of Example 5, respectively, rapid implantable sustained-release microneedles containing a porogen were prepared, and the specific formula is shown in Table 1.
  • Example 2 The preparation method of Examples 20-30 is as in Example 1, wherein the specific parameters of each component in Examples 20-30 are shown in Table 2.
  • Example 3 The preparation methods of Examples 31-37 are as in Example 3, and the specific parameters of each component in Examples 31-37 are shown in Table 3.
  • Examples 31-37 are also applicable to the preparation of other biomacromolecules or vaccine microneedle patches.
  • the prepared microneedle patch is shown in FIG. 1, the microneedle patch is 49 pins / cm 2, and the height of the needle tip and the needle body is 1.5 mm.
  • the microneedle patch is applied to pig skin, and the substrate can be completely peeled off after 50 minutes, and the sustained release time can reach 15 days.
  • Example 39-44 The preparation methods of Examples 39-44 are as in Example 38, and the specific parameters of each component are shown in Table 4.
  • Example 45 Skin-piercing experiment of a rapid-implantable sustained-release microneedle
  • Example 19 Apply the microneedle patch prepared in Example 1-44 (except Example 19) to fresh pig skin, press with your finger for 1 min, stain with 1% trypan blue for 20 min, and use a cotton swab to wipe off the excess Trypan blue, and then observe whether there are pinholes on the skin.
  • Figure 4 taking Example 1 as an example
  • micropinholes can be clearly seen.
  • the effects of other embodiments are the same as those of the first embodiment.
  • Example 46 Intradermal implantation of a rapid implantable sustained-release microneedle

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Abstract

一种可快速植入型缓释微针，包括针尖、中间层、针体和基底；所述针尖由包含生物可降解不溶于水的高分子材料基质形成；所述中间层由包含亲水性材料基质形成；所述针体和基底由包含生物兼容性高分子材料基质形成。上述微针的制备方法。一种可快速植入型缓释微针贴片，包括上述微针构成的微针阵列和背衬。

Description

一种可快速植入型缓释微针贴片及其制备方法 技术领域
本发明涉及医药技术领域。更具体地，涉及一种可快速植入型缓释微针贴片及其制备方法。
背景技术
经皮给药制剂是药物通过皮肤给药的一种剂型，可以避免肠胃环境对药效的干扰和肝脏“首过效应”，维持恒定的最佳血药浓度或生理效应，延长有效作用时间，减少用药次数，患者可自主给药，依从性较好。但皮肤外层的角质层会对药物的吸收造成阻碍，药物也不易深入体内，导致对药物的选择非常局限。近年来，微针技术得到了广泛的关注，它是经皮给药的物理促渗方法之一，可实现无痛精确给药。
传统的金属、玻璃以及硅材料制作的微针因其材料本身的性能，在使用时不可避免的会断落在皮肤内，对人体造成损伤。近年来新兴的聚合物微针，所用的材料包括可被皮肤吸收的水溶性高分子、生物相容性高分子和生物可降解高分子材料，大大降低了使用风险，同时聚合物微针具有生产成本低，制作工艺简单，可大批量生产，以及环境友好等优势，微针制作通过选择不同理化性质的水溶性高分子材料或生物可降解高分子材料能实现药物的可控释放。近年来，众多科研工作者致力于用聚乳酸类可降解高分子材料制作生物相容性好、可自然降解且易制备的聚合物微针。
中国专利(CN104888343 A)中公开了一种高分子实心微针及其批量制备方法。本发明中所述的材料为生物可降解水中难溶高分子材料，所用的制备方法是将高分子材料颗粒放在微针模具上，在密闭加热装置中加热至颗粒融化，并通过制备装置将熔体趁热压模成型。但该专利中制备的微针无法负载药物，在使用时微针仅起到预处理皮肤、破坏皮肤角质层屏障的作用。
国际专利(WO2007/030477)中公开了一种含有药物颗粒和/或吸附有或加有药物的颗粒和相关药物贮器的固体药物溶液穿孔器(SSPP系统)。为了进行药物递送，所述SSPP系统包括颗粒形式的活性药物成分或吸附于基质材料的颗粒表面，一与患者身体接触就溶解的药物。所述的惰性颗粒是乳酸-羟基乙酸共聚物(PLGA)或氢氧化铝和磷酸铝。该方法制作的微针可负载蛋白、疫苗类药物，但该方法中因药物是吸附在PLGA惰性颗粒上，其缓释作用基本没有。
文献1(Pharmaceutical Research.2006 May；23(5):1008-19.)提出了一种用 聚乳酸-羟基乙酸共聚物(PLGA)做微针支架材料制备微针的方法，该方法通过将药物或者负载药物的聚乳酸或羧甲基纤维素钠的微球载入微针中，以实现药物的可控释放，但该方法中因微针的主体基质材料为PLGA，用药者需长期贴敷直至支架材料PLGA完全降解。
文献2(Biomed Microdevices.2007 Apr；9(2):223-34)提出了一种用PLA、PGA或PLGA微球制备多孔、多层生物可降解微针的方法。该方法是通过将生物可降解高分子材料制作的微球注入到模具中，并通过挤压以及超声焊接或热焊接技术制备多孔或多层微针，该微针制作需先经过喷雾干燥技术或乳化法制备微球，工艺复杂。所述的多孔、多层微针相比于单一微针而言较弱、易折断，难以有效地从模具中脱模。
综上，就目前来看，以聚乳酸微针为例，微针制作可以分成两类，一是先把聚乳酸类可降解高分子材料及药物制作成微球，然后加入微针模具上，然后加热熔融冷却后形成具有一定机械强度的微针，这种微针可以负载药物，但是需先制作成微球再形成微针，操作繁琐，成本高；另外一种是将聚乳酸粉末直接加入微针模具上，加热熔融(高于200℃)后冷却形成微针，而这种制作方法很难负载药物。
因此，需要提供一种工艺简单，安全性高，无需长期贴敷的可快速植入型缓释微针。
发明内容
本发明的第一个目的在于提供一种可快速植入型缓释微针，该微针可将生物可降解针尖植入皮内，实现方便、安全、可生物降解、缓释和高效的给药目的。
本发明的第二个目的在于提供一种上述可快速植入型缓释微针的制备方法，该方法工艺简单、成本低。
本发明的第三个目的在于提供包含上述可快速植入型缓释微针的微针贴片。
为达到上述目的，本发明采用下述技术方案：
本发明提供一种可快速植入型缓释微针，包括针尖、中间层、针体和基底；所述针尖由包含生物可降解不溶于水的高分子材料基质形成；所述中间层由包含亲水性材料基质形成；所述针体和基底由包含生物兼容性高分子材料基质形成。
进一步，所述针尖还包括包含至少一种活性成分；优选的，所述生物可降 解不溶于水的高分子材料与活性成分的质量比为0.5:1～1000:1，以保证微针机械强度及皮肤穿刺性。
在本发明优选的实施方式中，所述针尖还包括致孔剂，所述致孔剂有助于皮内水分子进入针尖基质内部，调控药物释放速率。所述致孔剂包括但不限于氯化钠、碳酸钠、碳酸氢钠、碳酸氢铵、海藻糖、麦芽糖、聚乙二醇、环糊精及其衍生物、聚甲基吡咯烷酮(PVP)、低分子量透明质酸及其钠盐(分子量为5–100kDa)、低分子量纤维素类衍生物(分子量为5–100kDa)中的一种或几种。
优选地，所述致孔剂占针尖总质量的0.1％-10％。
在本发明优选的实施方式中，所述针尖还包括保护剂，保护剂包括但不限于多羟基化合物(甘露醇、山梨醇、木糖醇、聚乙二醇等)、糖类化合物(海藻糖、糊精、乳糖、蔗糖、麦芽糖等)、血清白蛋白、聚乙烯基吡咯烷酮、硫酸软骨素、氨基酸(脯氨酸、色氨酸、谷氨酸、甘氨酸等)中的一种或几种。
优选地，所述保护剂占针尖总质量的0.1％-10％。
进一步，所述亲水性材料包括但不限于聚乙烯吡咯烷酮及其衍生物的单体聚合物或共聚物、聚γ-谷氨酸、普鲁兰多糖、透明质酸及其钠盐、海藻糖、蔗糖、山梨醇、甘露醇、木糖醇、海藻酸钠、果胶中的一种或几种。
所述针体和基底中的生物兼容性高分子材料包括但不限于羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧甲基壳聚糖、聚乙烯醇衍生物、聚乙烯吡咯烷酮衍生物、透明质酸钠、硫酸软骨素，葡聚糖、蚕丝蛋白、明胶的一种或几种；优选的，所述生物兼容性高分子材料分子量为10-2000kDa。
优选地，所述针体和基底还包括小分子量糖类和多元醇类化合物，具体的可以为海藻糖、蔗糖、山梨醇、甘露醇、木糖醇等一种或者几种，以加速水溶性高分子材料的溶解速度。
进一步，所述针尖为圆锥状或多角锥状，优选地，针尖为圆锥状；所述微针针尖的密度为：每平方厘米的基底上具有250-1000个；所述针尖、中间层和针体的总高度为0.3-2mm，针尖角度为10-60°，基底厚度为10-300μm；所述针尖的高度不大于针尖、中间层和针体总高度的三分之二。
本发明还提供了上述可快速植入型缓释微针的制备方法，包括以下步骤：
1)将生物可降解不溶于水的高分子材料与一部分有机溶剂混合，加入或不加入致孔剂，加入或不加入保护剂，制备针尖基质材料溶液；将活性成分与剩余有机溶剂混合制备药物溶液；将药物溶液与针尖基质材料溶液混合， 得到针尖注模液；
或者，
将生物可降解不溶于水的高分子材料与有机溶剂混合，加入或不加入致孔剂，加入或不加入保护剂，加入活性成分，混合均匀得到针尖注模液；
2)将亲水性材料与水混合，得到中间层注模液；将生物兼容性高分子材料与水混合，得到针体和基底注模液；
3)将所述针尖注模液注入微针模具中，加热，去除有机溶剂并冷却；将所述中间层注模液注入上述微针模具中，干燥；将所述针体和基底注模液注入微针模具中制备针体和基底，干燥，脱模，即可。
进一步，所述有机溶剂包括但不限于丙酮、乙酸乙酯、氯仿、二氯甲烷、二甲亚砜或N-甲基吡咯烷酮；优选地，所述有机溶剂为N-甲基吡咯烷酮。
进一步，所述针尖注模液基质材料中生物可降解不溶于水的高分子材料的质量浓度为5-30％；所述中间层注模液中亲水性材料的质量浓度为0.5-10％；所述针体和基底注模液中生物兼容性高分子材料的质量浓度为10-40％；所述生物可降解不溶于水的高分子材料与活性成分的质量比为0.5～1000:1。
进一步，所述步骤3)中用加压法或抽真空法使各注模液加入到微针模具中，从而避免制作中微针内气泡的产生。若采用加压法，施加的压力为0.2-0.6MPa，施压的时间为1-20min。若采用抽真空法，真空度为0.05-0.1MPa，抽真空的时间为3-20min。
优选地，针尖注模液注入微针模具中后加热的温度为30-80℃，加热时间为1-24h，使有机溶剂挥发，并保证冷却后微针有足够的机械强度及皮肤穿刺能力。
优选地，中间层或针体和基底注模液注入微针模具中后的干燥条件为在20-50℃、10％-45％的湿度条件下干燥0.5-6h。
本发明进一步提供了一种可快速植入型缓释微针贴片，包括上述可快速植入型缓释微针构成的微针阵列和被衬；优选的，所述被衬为压敏胶被衬或者硅胶被衬或者水胶体。
上述可快速植入型缓释微针贴片的制备方法，是在制备可快速植入型缓释微针的基础上，制备微针阵列，进一步在微针阵列的基底背面贴上被衬后脱模，即可。
本发明所述微针贴片可应用于疾病治疗、预防、保健、美容领域。
术语“活性成分”指通过本发明的微针或微针贴片以透皮方式传递、且具有对动物或人体起作用的效能的用于诊断、治疗、预防、化妆或保健目的的物质。依据本发明，所述活性成分包括但不限于医药活性成分、疫苗活性成分、化妆品活性成分、保健品活性成分等，具体根据实际需要进行选择。
本发明的有益效果如下：
本发明微针或微针贴片用含有生物可降解不溶于水的高分子材料制作微针针尖，用亲水性材料制作微针中间层，用生物兼容性高分子材料制作针体和基底，形成针尖难溶于水的多层微针，其作用于皮肤后，吸收皮肤内的水分，使针尖与针体和基底在1h内快速分离，贴片基底被揭下后，微针针尖会被留在皮内，用药者不需长时间贴敷微针贴片，就能保证药物在体内长效释放。此类微针贴片不受制作面积的限制，通过扩大面积可以极大地提高载药量，适用于各类药物的皮内长效释放。另外，本发明微针制备工艺避免了将药物包裹在微球脂质体中等繁琐工艺，而是使用低毒性有机溶剂如N-甲基吡咯烷酮溶解生物可降解不溶于水的高分子材料，工艺成本降低，且工艺与普通的溶解微针制作方法相似，操作简单、快速，不需要高温熔融，适用的药物范围广泛。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出微针贴片结构示意图。
图2示出微针贴片体视显微镜下的照片。
图3示出微针贴片显微镜下的侧视图。
图4示出微针贴片的皮肤穿刺能力。
图5示出微针贴片针尖聚乳酸部分植入猪皮内的荧光显微镜下照片。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例和附图对本发明做进一步的说明。附图中相似的部件以相同的附图标记进行表示。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1 可快速植入型缓释微针的制备
1、称取分子量20kDa的PLGA(80/20)0.3g，加入0.7ml N-甲基吡咯烷酮，配制成质量分数为30％的PLGA溶液；称取依托孕烯100mg，加入1ml的N-甲基吡咯烷酮，配制成100mg/ml的依托孕烯溶液；将上述依托孕烯溶 液0.5ml与上述PLGA溶液0.5ml混合均匀，配制成含依托孕烯(50mg/ml)的15％PLGA溶液，作为针尖注模液。
2、称取分子量为10kDa的聚乙烯吡咯酮0.25g，加入4.75ml水，配制质量分数5％的聚乙烯吡咯烷酮的水溶液，作为中间层注模液；称取分子量50kDa的聚乙烯醇3.5g。加入6.5ml水，置于80℃下加热2h，配制质量分数为35％的聚乙烯醇水溶液，作为针体和基底注模液。
3、将上述针尖注模液加入到上述微针模具中，通过抽真空的方式，使针尖注模液进入到微针模具针孔中，移除模具上多余的溶液，并于70℃下加热3小时；将30μl上述中间层注模液加入到模具中，通过抽真空的方式，使中间层注模液进入上述冷却后的微针模具针孔中，移除模具上多余的溶液，并置于25℃、20％的湿度条件下干燥10分钟；将上述针体和基底注模液150μl加入到上述微针模具上，并抽真空，避免气泡的产生；将上述微针模具置于25℃、10％的湿度条件下干燥6小时。
4、干燥后的微针脱模。
所制得的微针如图1所示，微针300针/0.5平方厘米，针长度0.5mm。
微针贴片使用后针尖与针体和基底的分离时间0.5h，体外释放实验显示依托孕烯的缓释时间为30天。
本实施例中依托孕烯可以用其他耐热80度的小分子化合物的活性成分取代，包括但不限于例如炔雌醇、左炔诺孕酮、诺孕酮、孕二烯酮、地索高诺酮、去氧孕烯、青蒿素衍生物、紫杉醇衍生物等活性成分，得到的微针贴片具有类似的缓释效果。
本实施例的中间层注模液的聚乙烯吡咯烷酮可以被聚乙烯吡咯烷酮衍生物、聚γ-谷氨酸、普鲁兰多糖、透明质酸及其钠盐、海藻糖、蔗糖、山梨醇、甘露醇、木糖醇、海藻酸钠、果胶、明胶等取代，得到的微针贴片具有类似的缓释效果。
本实施例的针体和基底注模液中聚乙烯醇可以被羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧甲基壳聚糖、聚乙烯醇、聚乙烯吡咯烷酮、透明质酸钠、硫酸软骨素中的一种或几种取代，得到的微针贴片具有类似的缓释效果。
在本实施例针尖注模液中可以添加致孔剂如0.1-5％氯化钠、0.1-5％碳酸钠、0.1-3％碳酸氢钠、0.1-3％碳酸氢铵、1～10％海藻糖、1～10％麦芽糖、1～10％环糊精及其衍生物、1～10％聚甲基吡咯烷酮、1～10％透明质酸钠、1～10％羧甲 基纤维素，得到的微针贴片能够缓释5天-20天。
实施例2 可快速植入型缓释微针的制备
1、称取分子量10kDa的聚乳酸(PLA)0.4g，加入0.6ml N-甲基吡咯烷酮，配制成质量分数为40％的PLA溶液；称取红色荧光染料10mg，加入1ml的N-甲基吡咯烷酮，配制成质量分数为10mg/ml的脂溶性模拟药物红色荧光染料溶液；将红色荧光染料溶液0.5ml与PLA溶液0.5ml混合均匀，配制成含红色荧光染料5mg/ml的20％的PLA溶液，作为针尖注模液。
2、称取普鲁兰0.05g，加入9.95ml水，配制成质量分数为0.5％的普鲁兰水溶液，作为中间层注模液；称取分子量200kDa的羧甲基纤维素钠2.5g，加入7.5ml水，配制成质量分数为25％的羧甲基纤维素钠的水溶液，作为针体和基底注模液。
3、将上述针尖注模液加入到上述微针模具中，通过抽真空的方式，使针尖注模液进入到微针模具针孔中，移除模具上多余的溶液，并于80℃下加热2小时；将50μl中间层注模液加入到上述冷却后的微针模具中，通过施加压力的方式，使中间层注模液进入微针模具针孔中，置于25℃、30％的湿度条件下干燥10分钟；将上述针体和基底注模液150μl加入到上述微针模具上，并抽真空，避免气泡的产生；将上述微针模具置于25℃、35％的湿度条件下干燥0.5小时。
4、干燥后的微针脱模。
所制得的微针如图1所示，体视显微镜图如图2和图3所示，微针400针/平方厘米，针长度0.7mm。
微针贴片使用后针尖与针体和基底的分离时间为1h。
本实施例中荧光大红可以用其他耐热80度的小分子化合物的活性成分取代，得到的微针贴片具有类似的缓释效果。
实施例3 可快速植入型缓释微针的制备
1、称取分子量10kDa的PLGA(75/25)0.3g，加入0.7ml N-甲基吡咯烷酮，配制成质量分数为30％的PLGA溶液；称取15mg干扰素a-2b溶于无菌注射用水中，加入经过微粉化和灭菌处理后的35mg氢氧化锌，涡旋混合10min，形成1g锌盐干扰素a-2b溶液；将1g锌盐干扰素a-2b溶液加入到上述30％的PLGA溶液中，搅拌，形成含载药溶胶体系，作为针尖注模液。
2、称取海藻糖0.25g，加入水4.75ml，配成质量分数为5％的海藻糖的水溶液，作为中间层注模液；称取分子量70kDa的聚乙烯醇3g，加入7ml水， 置于85℃下加热2h，配制质量分数为30％的聚乙烯醇水溶液，作为针体和基底注模液。
3、将上述针尖注模液加入到微针模具中，通过抽真空的方式，使针尖注模液进入到微针模具针孔中，移除模具上多余的溶液，并于30℃下加热12小时；将20μl上述中间层注模液加入到冷却后的上述模具中，通过施加压力的方式，使中间层注模液进入微针模具针孔中，移除模具上多余的溶液，并置于25℃、30％的湿度条件下干燥20分钟；将上述针体和基底注模液200μl加入到上述微针模具上，并抽真空，避免气泡的产生，将上述微针模具置于25℃、10％的湿度条件下干燥6小时。
4、干燥后的微针脱模。
所制得的微针如图1所示。
微针贴片使用后针尖与针体和基底的分离时间为0.75h。体外释放实验结果显示，干扰素a-2b缓释时间为30天左右。
本实施例中干扰素a-2b可以用其他类型活性成分取代，特别是耐热性比较差的蛋白或者多肽取代，例如胰岛素、生长激素、神经生长因子等得到的微针贴片具有类似的缓释效果。
本实施例的中间层注模液的海藻糖可以被聚乙烯吡咯烷酮衍生物、聚γ-谷氨酸、普鲁兰多糖、透明质酸及其钠盐、海藻糖、蔗糖、山梨醇、甘露醇、木糖醇、海藻酸钠、果胶、明胶等取代，得到的微针贴片具有类似的缓释效果。
本实施例的针体和基底注模液中聚乙烯醇可以被羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧甲基壳聚糖、聚乙烯醇、聚乙烯吡咯烷酮、透明质酸钠、硫酸软骨素，葡聚糖中的一种或几种取代，得到的微针贴片具有类似的缓释效果。
在本实施例针尖注模液中可以添加致孔剂，如0.1-5％氯化钠、0.1-5％碳酸钠、0.1-3％碳酸氢钠、0.1-3％碳酸氢铵、1～10％海藻糖、1～10％麦芽糖、1～10％环糊精及其衍生物、1～10％聚甲基吡咯烷酮、1～10％透明质酸钠、1～10％羧甲基纤维素，得到的微针贴片缓释时间可以控制在5天-20天。
在本实施例针尖注模液中可以添加保护剂，如1～10％多羟基化合物(如1％甘油、3％丁二醇、1～5％木糖醇、1～10％甘露醇)、1～10％糖类化合物(1～10％海藻糖、1～5％蔗糖)、0.1-5％血清白蛋白、1～10％聚乙烯基吡咯烷酮、1～10％氨基酸中的一种或几种，，得到的微针贴片缓释时间可以控制在5天-20天。
实施例4 可快速植入型缓释微针的制备
1、称取分子量15kDa的PLGA(50/50)0.3g，加入0.7ml N-甲基吡咯烷酮，配制成质量分数为30％的PLGA溶液；称取盐酸格拉司琼40mg，加入1ml的N-甲基吡咯烷酮，配制成质量分数为40mg/ml的盐酸格拉司琼溶液；将盐酸格拉司琼溶液0.5ml与PLGA溶液0.5ml混合均匀，配制成含盐酸格拉司琼20mg/ml的15％PLGA溶液，作为针尖注模液。
2、称取明胶1g，加入水9ml，配成质量分数10％的明胶水溶液，作为中间层注模液；称取分子量40kDa的硫酸软骨素4g，加入水6ml，配成质量分数为40％的硫酸软骨素水溶液，作为针体基底注模液。
3、将上述针尖注模液加入到上述微针模具中，通过抽真空的方式，使针尖注模液进入到上述微针模具针孔中，移除模具上多余的溶液，并于60℃下加热2小时；将20μl上述中间层注模液加入到上述冷却后的模具中，通过施加压力的方式，使中间层注模液进入微针模具针孔中，并置于25℃、30％的湿度条件下干燥15分钟；将上述针体和基底注模液150μl加入到微针模具上，并抽真空，避免气泡的产生；将上述微针模具置于25℃、35％的湿度条件下干燥4小时。
4、干燥后的微针脱模
所制得的微针如图1所示，微针1000针/平方厘米，针长度0.3mm。
微针贴片使用后针尖与针体与基底的分离时间为0.5h。体外释放结果显示，盐酸格拉司琼的缓释时间为15天左右。
本实施例中盐酸格拉司琼也可以用其他活性成分取代，例如用醋酸亮丙瑞林、醋酸奥曲肽、苯磺酸氨氯地平/酮洛芬、环孢素、双氯芬酸钠控释、依维莫司、哌甲酯、克拉霉素、麦考酚酸、灰黄霉素、大麻隆(mabilone)、他克莫司(tacrolimus)等药物代取代，得到的微针贴片具有类似的缓释效果。
实施例5 可快速植入型缓释微针的制备
1、称取分子量15kDa的PLGA(80/20)0.2g，加入0.8ml N-甲基吡咯烷酮，配制成质量分数为20％的PLGA溶液，作为针尖注模液。
2、称取分子量70kDa的葡聚糖0.05g，加入4.95ml水，配制质量分数为1％的葡聚糖水溶液，作为中间层注模液。称取分子量50kDa的海藻酸钠3.5g。加入6.5ml水，配制质量分数为35％的海藻酸钠水溶液，作为针体和基底注模液。
3、将上述针尖注模液加入到微针模具中，通过抽真空的方式，使针尖注模液进入到上述微针模具针孔中，移除模具上多余的溶液，并于60℃下加热 1小时；将10μl中间层注模液加入到上述冷却后的模具中，通过抽真空的方式，使中间层注模液进入微针模具针孔中，移除模具上多余的溶液，并置于25℃、20％的湿度条件下干燥10分钟；将上述针体和基底注模液150μl加入到上述微针模具上，并抽真空，避免气泡的产生；将上述微针模具置于25℃、10％的湿度条件下干燥6小时；
4、干燥后的微针脱模。
所制得的微针如图1所示，微针600针/平方厘米，针长度0.4mm。
微针贴片使用后针尖与针体和基底的分离时间为1.5h。
本实施例的聚乳酸PLGA可以用其他生物可降解不溶于水的高分子材料取代，得到的微针贴片缓释效果。
实施例6 可快速植入型缓释微针的制备
1、称取聚原酸酯(t-CDM：1,6-HD 35:65)0.20，加入0.80ml N-甲基吡咯烷酮，配制成质量分数20％的聚原酸酯的溶液，称取左炔诺孕酮20mg，加入1ml的N-甲基吡咯烷酮，配制成20mg/ml的雌二醇溶液；将1ml的左炔诺孕酮溶液与1ml的聚原酸酯溶液混合，配制成含雌二醇的针尖注模液。
2、称取分子量100kDa的透明质酸钠0.5g，加入4.5ml水，配制质量分数为10％的透明质酸钠水溶液，作为中间层注模液；称取分子量200kDa的羟丙基甲基纤维素2.0g，加入8.0ml水，配制成质量分数为20％的羟丙基甲基纤维素水溶液，作为针体和基底注模液。
3、将针尖注模液加入到微针模具中，通过抽真空的方式，使针尖注模液进入到微针模具针孔中，移除模具上多余的溶液，并于70℃下加热3小时；将20μl上述中间层注模液加入到模具中，通过抽真空的方式，使中间层注模液进入微针模具针孔中，并置于25℃、30％的湿度条件下干燥10分钟；将上述针体和基底注模液200μl加入到上述冷却后的微针模具上，并抽真空，避免气泡的产生；将上述微针模具置于25℃、30％的湿度条件下干燥6小时；
4、干燥后的微针脱模。
所制得的微针如图1所示，微针200针/平方厘米，针长度0.8mm。
微针贴片使用后针尖与基底的分离时间为1.0h；体外释放显示，雌二醇的缓释时间为14天。
本实施例可以用其他小分子活性成分取代，得到的微针贴片缓释效果。
实施例7 针尖中添加致孔剂的可快速植入型缓释微针的制备
1、称取分子量20kDa的PLGA(80/20)3g，加入7ml N-甲基吡咯烷酮， 再加入0.15g的PVP K30作为致孔剂，配制成含PVP K30的PLGA溶液；称取长春西汀50mg，加入1ml的N-甲基吡咯烷酮，配制成50mg/ml的长春西汀溶液；将1ml的长春西汀溶液与1ml的含PVP K30的PLGA溶液混合，配制成含长春西汀的针尖注模液。
2、称取聚γ-谷氨酸0.05g，加入4.95ml水，配制质量分数为1％的聚γ-谷氨酸水溶液，作为中间层注模液；称取分子量50kDa的聚乙烯醇3.5g，加入6.5ml水，置于85℃下加热2h，配制质量分数为35％的聚乙烯醇水溶液，作为针体和基底注模液。
3、将针尖注模液加入到微针模具中，通过抽真空的方式，使针尖注模液进入到微针模具针孔中，移除模具上多余的溶液，并于70℃下加热3小时；将10μl上述中间层注模液加入到模具中，通过抽真空的方式，使中间层注模液进入微针模具针孔中，并置于25℃、20％的湿度条件下干燥10分钟；将上述针体和基底注模液150μl加入到上述冷却后的微针模具上，并抽真空，避免气泡的产生；将上述微针模具置于25℃、10％的湿度条件下干燥6小时；
4、干燥后的微针脱模。
所制得的微针如图1所示，微针500针/平方厘米，针长度1.0mm。
微针贴片使用后针尖与基底的分离时间为1.5h；体外释放显示，长春西汀的缓释时间为10天。
本实施例的长春西汀可以用其他小分子活性成分取代，得到的微针贴片缓释效果。
实施例8-19
按照实施例5的制备方法，分别制备了含致孔剂的可快速植入型缓释微针，具体配方见表1。
表1 含致孔剂的聚乳酸类缓释微针贴片的制备
Figure PCTCN2019103331-appb-000001
Figure PCTCN2019103331-appb-000002
实施例20-30 小分子药物植入型聚乳酸缓释微针贴片的制备
实施例20-30的制备方法如实施例1，其中实施例20-30中各组分的具体参数见如表2。
表2 小分子药物微针贴片的制备
Figure PCTCN2019103331-appb-000003
Figure PCTCN2019103331-appb-000004
实施例31-37 大分子药物的植入型聚乳酸类缓释微针贴片的制备
实施例31-37的制备方法如实施例3，其中实施例31-37中各组分的具体参数见如表3。
表3 大分子药物的微针贴片的制备
Figure PCTCN2019103331-appb-000005
Figure PCTCN2019103331-appb-000006
实施例31-37也适用于其他生物大分子药物或者疫苗微针贴片的制备。
实施例38 积雪草苷的植入型聚乳酸类缓释微针贴片的制备
1、称取分子量50kDa的透明质酸钠0.05g，加入4.95ml水，置于85℃加热1h，配制质量分数为1％的透明质酸钠水溶液，作为中间层注模液。称取分子量50kDa的聚乙烯醇3.5g和0.35g海藻糖，加入6.5ml水，置于85℃下加热2h，配制质量分数为35％的聚乙烯醇-海藻糖水溶液，作为针体和基底注模液。
2、称取分子量20kDa的PLGA(75/25)0.3g，加入0.7ml N-甲基吡咯烷酮，配制成30％的PLGA溶液；将20mg积雪草苷分散于上述30％的PLGA溶液，作为针尖注模液；
3、将针尖注模液加入到微针模具中，通过抽真空的方式，使针尖注模液进入到微针模具针孔中，移除模具上多余的溶液，并于60℃下加热6小时；将10μl上述中间层注模液加入到模具中，通过抽真空的方式，使中间层注模液进入微针模具针孔中，并置于25℃、20％的湿度条件下干燥10分钟；将上述针体和基底注模液150μl加入到上述冷却后的微针模具上，并抽真空，避免气泡的产生；将上述微针模具置于25℃、10％的湿度条件下干燥6小时；
4、在干燥后的微针基底背面贴上压敏胶被衬；脱模。
所制得的微针贴片如图1所示，微针贴片49针/平方厘米，针尖和针体高度为1.5mm。
将微针贴片作用于猪皮，50分钟后基底能够完整剥离，缓释时间可达15天。
实施例39-44 含化妆品成分的植入型聚乳酸类缓释微针贴片的制备
实施例39-44的制备方法如实施例38，各组分的具体参数见如表4。
表4 化妆品微针贴片的制备
Figure PCTCN2019103331-appb-000007
Figure PCTCN2019103331-appb-000008
实施例45 可快速植入型缓释微针的皮肤穿刺性实验
将实施例1-44(除实施例19)中制作好的微针贴片，作用于新鲜猪皮上，用手指按压1min，使用1％浓度的台盼蓝染色20min，使用棉签拭去多余的台盼蓝，然后观察皮肤上是否有针孔，如图4所示(以实施例1为例)为台盼蓝染色猪皮的照片，可以明显的看到微针针孔。其他实施例的效果同实施例1。
实施例46 可快速植入型缓释微针的皮内植入
将实施例1-44(除实施例19)中制作好的微针，作用于新鲜猪皮上，用手指按压1min，并保持微针贴片停留在皮上1小时，然后在荧光显微镜下观察针尖的皮内植入情况。如图5所示(以实施例2为例)为荧光显微镜下，负载有荧光染料的聚乳酸微针针尖后植入皮内的照片，可以明显看到荧光染料的阵列式植入。其他实施例的效果同实施例1。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。

Claims (10)

  1. 一种可快速植入型缓释微针，其特征在于，包括针尖、中间层、针体和基底；所述针尖由包含生物可降解不溶于水的高分子材料基质形成；所述中间层由包含亲水性材料基质形成；所述针体和基底由包含生物兼容性高分子材料基质形成。
  2. 根据权利要求1所述的可快速植入型缓释微针，其特征在于，所述针尖包含至少一种活性成分；优选的，所述生物可降解不溶于水的高分子材料与活性成分的质量比为0.5:1～1000:1。
  3. 根据权利要求1所述的可快速植入型缓释微针，其特征在于，所述生物可降解不溶于水的高分子材料为聚酸酐、聚原酸酯、聚磷酸酯、脂肪族聚酯、聚三亚甲基碳酸酯、聚对二氧环已酮及其衍生物中的一种或几种。
  4. 根据权利要求1所述的可快速植入型缓释微针，其特征在于，所述针尖还包括致孔剂；其中，所述致孔剂为氯化钠、碳酸钠、碳酸氢钠、碳酸氢铵、海藻糖、麦芽糖、环糊精及其衍生物、聚甲基吡咯烷酮、透明质酸及其钠盐、纤维素类衍生物中的一种或几种；优选的，所述致孔剂占针尖总质量的0.1％-10％；更优选的，所述针尖还包括保护剂；其中，所述保护剂为多羟基化合物、糖类化合物、血清白蛋白、聚乙烯基吡咯烷酮、硫酸软骨素、氨基酸中的一种或几种；更优选的，所述保护剂占针尖总质量的0.1％-10％。
  5. 根据权利要求1所述的可快速植入型缓释微针，其特征在于，所述亲水性材料包括聚乙烯吡咯烷酮及其衍生物的单体聚合物或共聚物、聚γ-谷氨酸、普鲁兰多糖、透明质酸及其钠盐、海藻糖、蔗糖、山梨醇、甘露醇、木糖醇、海藻酸钠、果胶中的一种或几种。
  6. 根据权利要求1所述的可快速植入型缓释微针，其特征在于，所述生物兼容性高分子材料包括羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧甲基壳聚糖、聚乙烯醇衍生物、聚乙烯吡咯烷酮衍生物、透明质酸钠、硫酸软骨素，葡聚糖、蚕丝蛋白、明胶的一种或几种；优选的，所述生物兼容性高分子材料分子量为10-2000kDa。
  7. 根据权利要求1所述的可快速植入型缓释微针，其特征在于，所述针尖的高度小于等于针尖、中间层和针体总高度的三分之二。
  8. 一种如权利要求1-7任一所述的可快速植入型缓释微针的制备方法，其特征在于，包括以下步骤：
    将生物可降解不溶于水的高分子材料与一部分有机溶剂混合，加入或不 加入致孔剂，加入或不加入保护剂，制备针尖基质材料溶液；将活性成分与剩余有机溶剂混合制备药物溶液；将药物溶液与针尖基质材料溶液混合，得到针尖注模液；
    或者，
    将生物可降解不溶于水的高分子材料与有机溶剂混合，加入或不加入致孔剂，加入或不加入保护剂，加入活性成分，混合均匀得到针尖注模液；
    将亲水性材料与水混合，得到中间层注模液；将生物兼容性高分子材料与水混合，得到针体和基底注模液；
    将所述针尖注模液注入微针模具中，加热，去除有机溶剂并冷却；将所述中间层注模液注入上述微针模具中，干燥；将所述针体和基底注模液注入微针模具中制备针体和基底，干燥，脱模，即可。
  9. 一种可快速植入型缓释微针贴片，其特征在于，包括如权利要求1-7任一所述的可快速植入型缓释微针构成的微针阵列和被衬。
  10. 根据权利要求9所述的可快速植入型缓释微针贴片，其特征在于，该微针贴片应用于疾病治疗、预防、保健、美容领域。
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