WO2013131215A1 - 聚合物微针阵列芯片及其制备方法和应用 - Google Patents

聚合物微针阵列芯片及其制备方法和应用 Download PDF

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WO2013131215A1
WO2013131215A1 PCT/CN2012/000726 CN2012000726W WO2013131215A1 WO 2013131215 A1 WO2013131215 A1 WO 2013131215A1 CN 2012000726 W CN2012000726 W CN 2012000726W WO 2013131215 A1 WO2013131215 A1 WO 2013131215A1
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microneedle array
polymer
array chip
substrate
mixture
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PCT/CN2012/000726
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English (en)
French (fr)
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吴飞鹏
苗元华
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中国科学院理化技术研究所
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Priority to EP12870619.9A priority Critical patent/EP2823850A4/en
Priority to US14/383,490 priority patent/US20150030642A1/en
Publication of WO2013131215A1 publication Critical patent/WO2013131215A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • A61K39/145Orthomyxoviridae, e.g. influenza virus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/28Insulins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38Albumins
    • A61K38/385Serum albumin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29CSHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C39/00Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
    • B29C39/02Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles
    • B29C39/026Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles characterised by the shape of the surface
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F120/00Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F120/02Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F120/52Amides or imides
    • C08F120/54Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F120/56Acrylamide; Methacrylamide
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023Drug applicators using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046Solid microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES 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
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053Methods for producing microneedles
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29KINDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2033/00Use of polymers of unsaturated acids or derivatives thereof as moulding material
    • B29K2033/26Polymers of acrylamide or methacrylamide
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B29WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29KINDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2901/00Use of unspecified macromolecular compounds as mould material
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L33/00Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • C08L33/24Homopolymers or copolymers of amides or imides
    • C08L33/26Homopolymers or copolymers of acrylamide or methacrylamide
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011Details
    • C12N2760/16011Orthomyxoviridae
    • C12N2760/16034Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the invention relates to a polymer microneedle array chip, a preparation method and application thereof, and belongs to the field of biomedical materials and micromachining.
  • Transdermal administration refers to a method in which a drug is permeated through the skin at a certain rate and absorbed into the systemic blood circulation system through capillary blood vessels to produce a drug effect. Due to the barrier function of the stratum corneum of the outermost layer of human skin, which is about 30-50 microns thick, the traditional transdermal delivery method is only suitable for drugs with a molecular weight of less than 500 Daltons and high lipolysis. In order to improve the transdermal permeability of macromolecular drugs such as peptides, proteins and vaccines, researchers in the 1970s proposed the concept of "microneedle patch" drug delivery, ie microneedle or microneedle arrays made using micromachining technology.
  • the stratum corneum that pierces the skin produces microscopic physical channels that allow macromolecular drugs to penetrate deeper layers of the skin.
  • Transdermal administration of microneedles can avoid the "first pass effect” of the liver and the “inactivation effect” of the stomach.
  • the trauma to the skin is very small, and there is almost no pain, so it has broad application prospects.
  • microneedle transdermal patch Due to the limitations of scientific and technological conditions, the experimental study of microneedle transdermal patch was first reported in 1998 by Professor Prausnitz's research group (Journal of Pharmaceutical Sciences, 1998, 87, 922-925). The experimental results show that the microneedle Dermal administration increases the transdermal permeation rate of the model drug calcein by four orders of magnitude over conventional transdermal administration. The microneedle transdermal administration has attracted more and more researchers to carry out related research, and various types of microneedle transdermal patch have been developed.
  • the core component of the microneedle transdermal patch is a microneedle array chip, which is generally composed of a regularly arranged microneedle array and a substrate supporting the microneedle array, and has the characteristics of good biocompatibility and high safety.
  • the early preparation of microneedle array chips is mainly made of semiconductor materials such as single crystal silicon or silicon dioxide, and is processed by photolithography combined with electrochemical etching (US 5879326, US6503231) o
  • the semiconductor microneedles have good biocompatibility, 'hardness High, easy to pierce the skin, but more brittle, can not degrade if left in the body after breaking.
  • the single crystal silicon microneedle array chip itself cannot store the drug, and the preparation of the corresponding microneedle transdermal patch requires design and preparation of a complicated drug storage and sustained release system (CN 102039000A, CN102018655 A), so the processing technology is complicated. The cost is relatively low, which limits its clinical application.
  • the metal microneedle array chip appears later than the semiconductor microneedle array chip, and is generally made of stainless steel such as titanium or nickel alloy, and is prepared by a precision micromachining technique such as laser or electric spark or photolithography combined with electrochemical etching technology.
  • Metal microneedles are biosafety, and the tip of the needle is easy to pierce the skin without breaking.
  • the metal microneedle array chip itself cannot store drugs.
  • the preparation of the corresponding microneedle patch also requires a drug storage and sustained release system, so it is currently not widely available in clinical practice. Polymer microneedles appeared around 2004, but because of their good biocompatibility, they can be degraded in the body and have high safety, so they develop very rapidly.
  • polymer microneedles are mainly prepared by using a template method such as polymethyl methacrylate, polylactic acid, polyglycolic acid, polyglycolic acid, vinylpyrrolidone and polydioxanone and copolymers thereof.
  • a template method such as polymethyl methacrylate, polylactic acid, polyglycolic acid, polyglycolic acid, vinylpyrrolidone and polydioxanone and copolymers thereof.
  • the shortcomings of polymer microneedles are that the mechanical strength is generally insufficient to pierce the skin.
  • most of the polymer materials for preparing microneedles cannot be dissolved in water, and casting, compression molding, etc. are required in a molten state.
  • High temperature treatment makes it easy to inactivate drugs that are sensitive to high temperatures, such as proteins and peptides.
  • Polyacrylamide polymers have a long history as medical materials and have high safety characteristics. Currently, they are mainly used as body filling or repairing materials for beauty or treatment of human body function damage (GB 4746551, GB 2164343A, DE 1594389, CN 94195147, CN 1450118A) o
  • An aqueous solution of a polyacrylamide-based polymer having a suitable molecular weight or a suitable molecular weight ratio still has fluidity at a mass fraction of 050%) without forming a gel, so that a template method can be utilized To prepare a polymer microneedle array chip.
  • the present inventors creatively used a polyacrylamide-based polymer that conforms to medical standards, and obtained a polymer microneedle array chip in which a needle body can coat a biologically active substance or a drug by using a template method, and based on the above, A polymer microneedle administration patch which is simple in operation, convenient to use, safe and reliable is prepared. Summary of the invention
  • a first technical problem to be solved by the present invention is to provide a polymer microneedle array chip.
  • the polymer enamel array chip has high mechanical strength, sharp needle tip, and can easily pierce the stratum corneum of the skin; no high-temperature processing steps are required, which are beneficial for biomacromolecules such as polypeptides and proteins to maintain activity; easily dissolve or swell in an aqueous environment , which facilitates the sustained release of the drug in the skin.
  • a second technical problem to be solved by the present invention is to provide a method for preparing a polymer microneedle array chip.
  • a third technical problem to be solved by the present invention is to provide a polymer microneedle array chip for use in a transdermal patch.
  • the technical solution provided by the present invention is a polymer microneedle array chip comprising a microneedle array and a substrate on which the microneedle stands and is arranged;
  • the matrix material used in the microneedle array of the microneedle array chip is a polyacrylamide polymer.
  • polyacrylamide-based polymer is polymerized from an acrylamide monomer.
  • reaction equation is as follows:
  • the polyacrylamide-based polymer has a molecular weight of 1.0 X 10 4 to 2.0 X 10 5 .
  • the polyacrylamide-based polymer has good water solubility and can be mixed with water to obtain an aqueous solution having a polymer mass percentage of 1 to 80%.
  • the polyacrylamide-based polymer has a Vickers hardness of 150 to 600 (HV). Under the aforementioned hardness conditions, the microneedle array chip has high mechanical strength and sharp needle tip, and can easily pierce the stratum corneum of the skin.
  • the polyacrylamide-based polymer has an impact strength of 5 to 30 J/M.
  • the polymer is less likely to break under the aforementioned impact strength.
  • a square thin plate having a thickness of 2 mm and a side length of 1 cm is prepared by using the polyacrylamide-based polymer material, and the square thin plate is immersed in a physiological saline solution at rest, and at least 50% is dissolved in 6 hours. .
  • the polyacrylamide-based polymer is mixed with a biologically active substance or a drug, and the mass percentage of the biologically active substance or drug in the mixture is 0.1 to 50%; preferably, the mass percentage is 10 to 20%.
  • the mass percentage of the bioactive substance or drug in the mixture can be adjusted depending on the desired dose and the spatial characteristics of the prepared microneedle array chip.
  • the biologically active substance or drug is selected from one or more of the following: a vaccine, a polypeptide, a protein, a polysaccharide, a nucleic acid, a hormone, an anticancer drug, a genetic engineering drug, a natural product drug, a Chinese medicine ingredient or a nutrition. ingredient.
  • the polyacrylamide-based polymer has a residual acrylamide monomer content of 0.5 ppm, which is in compliance with medical standards prescribed by the World Health Organization.
  • the microneedle array of the polymer microneedle array chip comprises at least two microneedles; the microneedle comprises a needle bar and a needle; the needle bar is a main part of the microneedle, and one end is fixed On the substrate of the microneedle array chip; the needle is the top of the microneedle, and one end is connected to the needle bar, and the shape of the needle is any tip-like structure.
  • the maximum cross-section circle or circumscribed circle of the microneedle has a diameter of 50-1000 microns; and the micro-needle has a length of 100-5000 microns.
  • the substrate has a thickness of 50 to 5000 ⁇ m.
  • the substrate includes a substrate thin layer and a substrate body layer, and the substrate thin layer refers to the microneedle array portion
  • the substrate thin layer refers to the microneedle array portion
  • a thin film structure having a thickness of less than 50 micrometers is connected, and the substrate body layer is connected to the substrate thin layer to form the entire substrate; preferably, the substrate is made of a polyacrylamide-based polymer.
  • the substrate is made of a mixture of a polyacrylamide-based polymer and a biologically active substance or a drug, and the mass percentage of the biologically active substance or drug in the mixture is 0.1 to 50%; preferably, the mass The percentage is 10-20%.
  • the microneedle array and the substrate layer are made of a polyacrylamide-based polymer
  • the substrate body layer is made of polylactic acid, polyethylene, polypropylene, polybutylene succinate.
  • the microneedle array and the substrate layer are made of a mixture of a polyacrylamide polymer and a biologically active substance or a drug; the mass percentage of the biologically active substance or drug in the mixture is 0.1 to 50. Preferably, the mass percentage is 10-20%; the substrate body layer is made of polylactic acid, polyethylene, polypropylene, polybutylene succinate, rubber, latex, glass, metal thermoplastic composite A layered combination of one or more materials in a material.
  • the present invention provides a synthesis method for preparing the polyacrylamide-based polymer, and the synthesis reaction system mainly comprises an organic solvent mainly composed of an alcohol, water, an acrylamide monomer and an initiator;
  • the reaction system is intermittently protected with pure nitrogen gas, kept agitated, and then kept warm after the temperature is raised to the target temperature; after the reaction is finished, the reaction product is first treated to remove the acrylamide monomer, and then dried to obtain a poly Acrylamide polymer.
  • the synthesis method is mild, simple and easy to produce, and the yield is high, and the obtained polymer meets the medical standards stipulated by the World Health Organization.
  • the synthetic polyacrylamide-based polymer mainly comprises the following steps:
  • the organic solvent is mainly alcohol, and the ketone is supplemented.
  • the alcohol is selected from at least one or a mixture of two or more of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like.
  • the volume percentage of the alcohol solvent in the reaction system is 60% ;
  • the ketone is selected from one or a mixture of two or more of acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone.
  • the volume percentage of the ketone solvent in the reaction system is 25%; the present invention can control the molecular weight of the polymer by changing the volume percentage of the organic solvent in the reaction system;
  • the volume percentage of the water in the reaction system is 25%; the molecular weight of the obtained polymer can be adjusted by adjusting the volume percentage of water in the reaction system;
  • the initial concentration of the acrylamide monomer in the reaction system is from 0.1 to 3 mol/L.
  • the invention can be changed by changing C
  • the initial concentration of the olefinamide monomer in the reaction system adjusts the molecular weight of the obtained polymer;
  • high-purity nitrogen gas is passed through a reactor containing a reaction system composed of the above solvent, water and acrylamide monomers to remove oxygen, and the reaction system is heated and heated to a target temperature.
  • the target temperature is 30-85 ° C; preferably, the target temperature is 40-70. C ;
  • the present invention can adjust the molecular weight of the obtained polymer by changing the target temperature at the time of synthesis;
  • the initiator may be an azo initiator such as azobisisobutyronitrile, azobisisoheptanenitrile, azobisisobutylphosphonium hydrochloride, diisobutyl azobisbutyrate, azo At least one or a mixture of two or more of dimethyl diisobutyrate; the initiator may also be an inorganic or organic peroxide such as ammonium persulfate, sodium persulfate, potassium persulfate, t-butyl At least one or a mixture of two or more of hydrogen peroxide, dicumyl peroxide, benzoyl peroxide, and a reducing agent such as sodium hydrogen sulfite or sodium metabisulfite may be added to make the polymerization reaction faster. More thorough reaction;
  • the initiator is generally used in an amount of 0.01 to 1% by weight based on the weight of the above acrylamide monomer; the synthesis method can control the molecular weight of the obtained polymer by changing the amount of the initiator;
  • reaction system of the present invention is kept at a constant temperature for 8 to 30 hours; preferably, the constant temperature is maintained.
  • the time is 12-20 hours;
  • the dried reaction product is dissolved in an appropriate amount of water, and after being completely dissolved, an organic solvent which can only dissolve the acrylamide monomer and cannot dissolve the polymerization product is reprecipitated to remove the unreacted acrylamide monomer.
  • the organic solvent is at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone or a mixture of two or more;
  • the reaction product after removing the acrylamide monomer is dried in a vacuum oven at a temperature of 30-70 ° C for 20-50 hours to obtain a polyacrylamide-based polymer; the dried polypropylene
  • the amide polymer is stored in a dry, closed container.
  • the obtained polyacrylamide-based polymer may be mixed with water to obtain an aqueous solution, which is then poured into a mold, and a bulk material is obtained by drying.
  • the Vickers hardness of the polyacrylamide polymer was about 150-600 HV according to the GB/T 4340.2 standard; the impact strength was measured to be about 5-30 J/m according to the D-256 standard of the American ATSM.
  • the residual acrylamide monomer content in the polyacrylamide polymer was measured by Shimadzu liquid chromatography (LC-20A/SPD-20AV). The measured content of acrylamide monomer content in the total amount of polyacrylamide was 0.5 ppm .
  • the method for preparing a polymer microneedle array chip comprises the following steps:
  • drying treatment is carried out to cure the polyacrylamide-based polymer in the aqueous solution poured into the negative mold to obtain a polymer microneedle array chip.
  • the metal material in the step 1) is selected from one or more of the following materials: titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy.
  • the polymer material in the step 2) is selected from one or more of the following: polyethylene, polypropylene, polylactic acid, polybutylene succinate, polydimethylsiloxane.
  • the polyacrylamide-based polymer is mixed with water at a temperature of 10 to 90 ° C to form an aqueous solution; the mass percentage of the polyacrylamide polymer in the aqueous solution is 1 to 80% ; Preferably, the mass percentage is 10-50%; preferably, the above aqueous solution is sonicated to remove bubbles therein.
  • step 5 before the aqueous solution prepared in the step 4) is poured into the negative mold, the female mold is washed with water, and then the female mold is placed on the horizontal operating platform; preferably, the mold and the horizontal operation are performed.
  • the platform is placed in a closed system; preferably, a viscous liquid seal is used between the horizontal operating platform and the mold.
  • steps 5) and 6) include the following specific steps:
  • the aqueous solution injected into the negative mold can be directly dried to the polyacrylamide-based polymer therein. Curing and molding to obtain a polymer microneedle array chip;
  • the partial moisture in the aqueous solution poured in the negative mold can be removed by drying treatment. Then, the casting is performed twice or more times until the polyacrylamide polymer in the negative mold can meet the needs of preparing the microneedle array chip, and finally the polyacrylamide polymer is cured by drying to obtain a polymer micro. Needle array chip.
  • the method for preparing a polymer microneedle array chip provided by the invention comprises the following steps:
  • step 5) mixing the mixture prepared in step 4) with water to obtain a mixed solution
  • step 6) pouring the mixture prepared in step 5) into a negative mold
  • the metal material in the step 1) is selected from one or more of the following materials: titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy.
  • the polymer material in the step 2) is selected from one or more of the following materials: polyethylene, polypropylene, polylactic acid, polybutylene succinate, polydimethylsiloxane.
  • step 4 in the mixture of the polyacrylamide-based polymer and the biologically active substance or drug; the mass percentage of the biologically active substance or drug is 3 ⁇ 4 0.1 ⁇ 50%; preferably, the mass percentage is 10 ⁇ 20%.
  • step 5 the mixture obtained in the step 4) is mixed with water at a temperature of 10 to 90 ° C to form a mixed solution; the mass percentage of the mixture in the mixed solution is 1 to 80% ; The mass percentage is 10 to 50%; preferably, the above mixture is ultrasonicated to remove bubbles therein.
  • step 6 before the pouring liquid prepared in the step 5) is poured into the negative mold, the female mold is washed with water, and then the female mold is placed on the horizontal operating platform; preferably, the mold and the level are The operating platform is placed in the seal In a closed system; preferably, a viscous liquid seal is used between the horizontal operating platform and the mold.
  • step 7 the drying temperature is 20 to 90 °C.
  • steps 6) and 7) include the following specific steps:
  • a mixture of a polyacrylamide-based polymer and a biologically active substance or a drug in a mixed solution poured into a negative mold can satisfy the requirements for preparing a polymer microneedle array chip, the mixed solution can be injected into the negative mold.
  • a mixture of a polyacrylamide-based polymer directly dried therein and a bioactive substance or a drug is solidified to obtain a polymer microneedle array chip;
  • the method for preparing a polymer microneedle array chip comprises the following steps:
  • step 5) mixing the mixture prepared in step 4) with water to obtain a mixed solution
  • step 6) pouring the mixture prepared in step 5) into a negative mold
  • the metal material in the step 1) is selected from one or more of the following materials: titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy.
  • the polymer material in the step 2) is selected from one or more of the following materials: polyethylene, polypropylene, polylactic acid, polybutylene succinate, polydimethylsiloxane.
  • the mass percentage of the biologically active substance or drug is 0.1 to 50%; preferably, the mass percentage is 10 to 20%.
  • the mixture obtained in the step 4) is mixed with water at a temperature of 10 to 90 ° C to form a mixed solution; the mass percentage of the mixture in the mixed solution is 1 to 80%; The mass percentage is 10 to 50%; preferably, the above mixture is ultrasonicated to remove bubbles therein.
  • step 6 before the pouring liquid prepared in the step 5) is poured into the negative mold, the female mold is washed with water, and then the female mold is placed on the horizontal operating platform; preferably, the mold and the level are The operating platform is placed in a closed system; preferably, a viscous liquid seal is used between the horizontal operating platform and the mold.
  • step 7 the drying temperature is 20 to 90 °C.
  • steps 6) and 7) include the following specific steps:
  • a mixture of a polyacrylamide-based polymer and a biologically active substance or a drug in an aqueous solution or a mixture poured into a negative mold at one time can satisfy the need for preparing a microneedle array portion and a substrate thin layer of the microneedle array chip
  • the aqueous solution or mixture injected into the negative mold is directly dried to a mixture of the polyacrylamide-based polymer and the biologically active substance or the drug, the microneedle array portion and the lining of the polymer microneedle array chip are obtained.
  • the polyacrylamide polymer is mixed with water at a temperature of 10 to 90 ° C to form an aqueous solution; the mass percentage of the polyacrylamide polymer in the aqueous solution is 20 to 80% ; Preferably, the mass percentage is 40-60%; preferably, the above aqueous solution is sonicated to remove air bubbles therein.
  • step 9) the concentration of the polyacrylamide-based polymer in the aqueous solution is higher than that in the step 5) The concentration of the polyacrylamide-based polymer in the mixture; to reduce the diffusion of the bioactive substance or drug contained in the microneedle array portion prepared by the steps 1) to 7) into the substrate portion.
  • the drying temperature is 20 to 9 (TC.
  • the preparation method of the polymer microneedle array chip provided by the invention comprises the following steps:
  • microneedle array portion of the microneedle array chip prepared in the step 6) and the substrate thin layer are joined together with other single layer or multilayer film materials to obtain a polymer microneedle array chip.
  • the metal material in the step 1) is selected from one or more of the following materials: titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy.
  • the polymer material in the step 2) is selected from one or more of the following materials: polyethylene, polypropylene, polylactic acid, polybutylene succinate, polydimethylsiloxane.
  • a mixed liquid is formed at a temperature of 10 to 90 ° C; the mass percentage of the polyacrylamide-based polymer in the aqueous solution is 1 to 80%; preferably, the mass percentage is 10 to 50 %; preferably, the aqueous solution is sonicated to remove air bubbles therein.
  • step 5 before the aqueous solution prepared in the step 4) is poured into the negative mold, the negative mold is washed with water, and then the female mold is placed on the horizontal operating platform; preferably, the mold and the level are The operating platform is placed in a closed system; preferably, a viscous liquid seal is used between the horizontal operating platform and the mold.
  • step 6 the drying temperature is 20 to 90'C.
  • step 6 includes the following specific steps:
  • the aqueous solution injected into the negative mold is directly dried.
  • Polypropylene The enamide polymer is solidified and molded, and the microneedle array portion and the substrate thin layer portion of the polymer microneedle array chip satisfying the design requirements are obtained;
  • the casting is first removed by the drying process. Part of the moisture in the aqueous solution is then subjected to two or more castings until the polyacrylamide-based polymer in the negative mold satisfies the need to prepare the microneedle array portion of the microneedle array chip and the thin layer portion of the substrate. Finally, the polyacrylamide polymer is solidified by drying treatment to obtain a microneedle array portion and a substrate thin layer portion of the polymer microneedle array chip according to the design requirements.
  • the other single layer or multilayer film is selected from the group consisting of polyethylene, polypropylene, polybutylene succinate, polydimethylsiloxane, rubber, polylactic acid, latex, Prepared by one of glass or metal thermoplastic composite material or a combination of materials; preferably, the other single layer or multilayer film is bonded, fused, bonded and thinned to the substrate Tightly combined.
  • the invention provides a method for preparing a polymer microneedle array chip, comprising the following steps -
  • step 5) mixing the mixture prepared in step 4) with water to obtain a mixed solution
  • step 6) pouring the mixture prepared in step 5) into a negative mold
  • microneedle array portion of the microneedle array chip prepared in the step 7) and the substrate thin layer having a thickness of less than 50 ⁇ m are joined together with other single layer or multilayer film materials to obtain a polymer microneedle array chip.
  • the metal material in the step 1) is selected from one or more of the following materials: titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy.
  • the polymer material in the step 2) is selected from one or more of the following materials: polyethylene, polypropylene, Polylactic acid, polybutylene succinate, polydimethylsiloxane.
  • the mass percentage of the biologically active substance or drug is 0.1 to 50%; preferably, the mass percentage is 10 to 20%.
  • the mixture forms a mixed liquid with water at a temperature of 10 to 90 ° C; the mass percentage of the mixture in the mixed solution is 1 to 80%; preferably, the mass percentage is 10 to 10 50%; Preferably, the above mixture is sonicated to remove air bubbles therein.
  • step 6 before the pouring liquid prepared in the step 5) is poured into the negative mold, the female mold is washed with water, and then the female mold is placed on the horizontal operating platform; preferably, the mold and the level are The operating platform is placed in a closed system; preferably, a viscous liquid seal is used between the horizontal operating platform and the mold.
  • step 7 the drying temperature is 20 to 90 °C.
  • steps 6) and 7) include the following specific steps:
  • a mixture of a polyacrylamide-based polymer and a biologically active substance or a drug in a mixture poured into a negative mold at one time can satisfy the needs of preparing the microneedle array portion and the thin layer portion of the substrate of the microneedle array chip a mixture of a polyacrylamide-based polymer directly injected into a negative mold into a mixture of a polyacrylamide-based polymer and a biologically active substance or a drug to form a microneedle of a polymer microneedle array chip that meets design requirements Array portion and substrate thin layer portion;
  • the other single layer or multilayer film is selected from the group consisting of polyethylene, polypropylene, polybutylene succinate, polydimethylsiloxane, rubber, polylactic acid, latex, Prepared by one of glass or metal thermoplastic composite material or a combination of materials; preferably, the other single layer or multilayer film is bonded, fused, bonded and thinned to the substrate Tightly combined.
  • the technical solution provided by the present invention is:
  • a transdermal patch using a polymer microneedle array chip comprising a polymer microneedle array chip, a substrate, a barrier gasket, a release layer, an adhesive tape, and an anti-seepage layer; and may also include microneedle array protection Device; '
  • the microneedle array chip comprises a microneedle array and a substrate on which the microneedle array is placed, and is a core component of the microneedle transdermal patch;
  • the microneedle array protection device is a device for protecting the microneedle array from being damaged by the external environment before use; preferably, a mold for preparing a polymer microneedle array chip is used as a device for protecting the microneedle array;
  • the substrate refers to a layer or a plurality of films adhered to the back surface of the polymer microneedle array chip substrate, and the microneedle array can conveniently pierce the skin when applied;
  • the anti-seepage gasket refers to a layer of a gasket that protects the edge of the microneedle array chip substrate and the microneedle patch substrate.
  • the release layer covering refers to a protective film covering the outer region of the microneedle chip, and the release layer can be easily peeled off during application;
  • the adhesive tape is a double-sided adhesive tape having adhesive on both inner and outer sides, the inner side of which covers the substrate of the microneedle patch or the substrate of the microneedle array chip, the anti-seepage gasket and the release layer, and the outer side is bonded to the anti-seepage layer. Together, the adhesive tape is mainly used for fixing when applied;
  • the anti-seepage layer is a protective film coated on the outer side of the adhesive tape, mainly for preventing the microneedle array chip inside the patch from being affected by the external environment.
  • the method for preparing a transdermal patch using the polymer microneedle array chip according to the present invention mainly comprises the following steps:
  • the release layer is disposed on the outer side of the microneedle substrate or the microneedle array chip substrate;
  • the microneedle in the polymer microneedle array chip of the present invention has high mechanical strength, sharp needle tip, and can easily pierce the stratum corneum of the skin;
  • the microneedle array portion of the polymer microneedle array chip of the present invention uses a water-soluble polyacrylamide polymer as a matrix material, and can utilize an aqueous solution thereof and an aqueous solution thereof with a biologically active substance or a drug and water. Or the mixed liquid prepares the polymer microneedle array chip by molding, avoiding the high temperature processing and processing steps, and is beneficial to maintaining the activity of the biological macromolecular drugs such as polypeptides and proteins;
  • the polyacrylamide polymer of the present invention is easily dissolved or swelled in an aqueous environment, which is beneficial to the sustained release of the drug in the skin;
  • the preparation method of the transdermal patch based on the polymer microneedle array chip of the invention is simple, and can be mass-produced by using the currently mature processing technology.
  • Figure 1 Schematic diagram of a microneedle array chip
  • FIG. 2-1 Schematic diagram of the needle structure of the microneedle
  • Figure 2-2 Schematic diagram of the needle structure of the microneedle
  • FIG. 2-3 Schematic diagram of the needle structure of the microneedle
  • Figure 2-4 Schematic diagram of the needle structure of the microneedle
  • FIG. 5 Schematic diagram of the needle structure of the microneedle
  • Figure 3 A cross-sectional view of the structure when the center axis of the microneedle is perpendicular or inclined to the plane in which the substrate is located;
  • Figure 4 Schematic diagram of a hollow microneedle
  • Figure 5 Schematic diagram of a microneedle array chip with a rectangular, elliptical, triangular, and irregular pattern.
  • Figure 6 Schematic diagram of a technical route for preparing a polymer microneedle array chip;
  • Figure 7 Schematic diagram of a plurality of Class A microneedle prototypes arranged on the same smooth flat bottom surface 6;
  • Figure 8 Schematic diagram of a prototype of a Class B microneedle array
  • Figure 9 Schematic diagram of a prototype of a C-type microneedle array
  • Figure 10 Schematic diagram of the three-dimensional structure when preparing a negative mold using a prototype of a type A microneedle array chip
  • FIG. 11 Schematic diagram of a single negative mold for preparing a microneedle array chip
  • Figure 12 Schematic diagram of a template containing a plurality of negative molds for preparing a microneedle array chip
  • FIG. 13 Schematic diagram of microneedle transdermal administration
  • Figure 14 A schematic cross-sectional view of a prototype of a Class A microneedle array chip
  • Figure 15 A schematic cross-sectional view of a prototype of a Class B microneedle array chip
  • Figure 16 Schematic cross-sectional view of a prototype of a C-type microneedle array chip
  • Figure 17 is a diagram showing the overall topography of a solid polymer microneedle array chip prepared in an embodiment of the present invention.
  • the microneedle array chip of the present invention comprises a microneedle array 1 and two parts of a substrate 2 on which the microneedle array 1 is placed.
  • the matrix material of the microneedle array 1 is polyacrylamide.
  • the polyacrylamide polymer of the present invention refers to a kind of medical polymer, which is obtained by polymerizing an acrylamide monomer, and the reaction equation is
  • the polymer structure of the present invention may be a linear homopolymer, a copolymer or a crosslinked polymer.
  • the polymer is a linear homopolymer, and the main features are: molecular weight of 1.0 ⁇ 10 4 to 2.0 ⁇ 10 5 ; Vickers hardness of 150 to 600 (HV); impact strength of 5 to 30 J/ M ; residual acrylamide monomer content measured 0.5ppm, in line with medical standards prescribed by the World Health Organization.
  • the polyacrylamide-based polymer of the present invention has good water solubility and can be mixed with water to obtain an aqueous solution having a mass percentage of 1 to 80%.
  • an aqueous solution having a mass percentage of 1 to 80%.
  • the microneedle array 1 of the polymer microneedle array chip of the present invention may be prepared from a polyacrylamide-based polymer; or may be prepared from a mixture of a polyacrylamide-based polymer and a biologically active substance or a drug.
  • the substrate 2 of the polymer microneedle array chip of the present invention may be prepared from a pure polyacrylamide-based polymer; or may be prepared from a mixture of a polyacrylamide-based polymer and a biologically active substance or a drug; It may also be prepared by one of materials such as polylactic acid, polyethylene, polypropylene, polybutylene succinate, rubber, latex, glass or metal thermoplastic composite materials or a combination of several materials.
  • the biologically active substance or drug of the present invention is one or more of a vaccine, a polypeptide, a protein, a polysaccharide, a nucleic acid, a hormone, an anticancer drug, a genetic engineering drug, a natural product drug, a Chinese medicine component or a nutrient component of any molecular weight. a combination of components; the bioactive substance or drug of the present invention has a mass percentage of 0.1 to 50% in a mixture thereof with a polyacrylamide-based polymer ; preferably, the mass percentage is 10 to 20%; The ratio can be adjusted according to the required dose of the biologically active substance or drug and the spatial characteristics of the prepared microneedle array chip.
  • the mixture may be mixed with water to obtain a fluid aqueous solution or mixture, and the mass percentage of the above mixture in the aqueous solution or mixture is from 1 to 80% ; preferably, the above mass percentage is from 10 to 50%.
  • the invention provides a synthesis method for preparing the above polyacrylamide-based polymer, which mainly comprises the following steps:
  • the organic solvent described in the present invention is mainly an alcohol, and a ketone is supplemented.
  • the alcohol is selected from at least one or a mixture of two or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, etc.; preferably, the volume percentage of the alcohol solvent in the reaction system is 60%;
  • the ketone is selected from one or a mixture of two or more of acetone, butanone, methyl isobutyl ketone and cyclohexanone.
  • the volume percentage of the ketone solvent in the reaction system is 25%; the present invention can control the molecular weight of the polymer by changing the volume percentage of the organic solvent in the reaction system;
  • the volume percentage of water in the reaction system of the present invention accounts for 25%; the present invention can adjust the molecular weight of the obtained polymer by adjusting the volume percentage of the water in the reaction system;
  • the initial concentration of the acrylamide monomer in the reaction system of the present invention is 0.1-3 mol/L ; the molecular weight of the obtained polymer can be adjusted by changing the initial concentration of the acrylamide monomer in the reaction system;
  • the target temperature is 30- 85 ° C;
  • the initiator of the present invention may be an azo initiator such as azobisisobutyronitrile, azobisisoheptanenitrile, azobisisobutylphosphonium hydrochloride, diisobutyl azobisbutyrate, At least one or a mixture of two or more of dimethyl azobisisobutyrate;
  • the initiator of the present invention may also be an inorganic or organic peroxide such as ammonium persulfate, sodium persulfate, potassium persulfate, toluene butyl hydroperoxide, dicumyl peroxide, benzoyl peroxide. At least one or a mixture of two or more, and a reducing agent such as sodium hydrogen sulfite or sodium metabisulfite may be added to make the polymerization reaction faster and the reaction more thorough; the amount of the initiator used in the present invention is generally the above The weight of the acrylamide monomer is 0.01 to 1%.
  • the present invention can control the molecular weight of the obtained polymer by changing the amount of the initiator;
  • the temperature is kept constant at the target temperature for a certain period of time, and stirring and nitrogen gas permeation are maintained; the reaction system of the present invention is kept at a constant temperature for 8 to 30 hours.
  • the time for maintaining the constant temperature is 12 ⁇ 20 hours;
  • the dried reaction product is dissolved in an appropriate amount of water, and after being completely dissolved, an organic solvent which can only dissolve the acrylamide monomer and cannot dissolve the polymerization product is reprecipitated to remove the unreacted acrylamide monomer.
  • the organic solvent is at least one of a mixture of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, butanone, methyl isobutyl ketone, and cyclohexanone or a mixture of two or more thereof.
  • reaction product after removing the acrylamide monomer is dried in a vacuum oven at a temperature of 30-70 ° C for 20-50 hours.
  • the dried sample is stored in a dry closed container;
  • the molecular weight is measured according to the method of GB 17514-2008 combined with static light scattering method (Wyatt DAWN HELEOS- ⁇ ); the molecular weight of the polymer under different synthesis conditions is measured at 1.0 X 10 4 ⁇ 2.0 X 10 5 Distribution
  • the obtained polymer is mixed with water to obtain an aqueous solution, and then cast into a mold, and a bulk material is obtained by drying, and the Vickers hardness of the bulk material is measured according to the GB/T4340.2 standard. 150-600HV; The impact strength measured according to the American ATSM D-256 standard is about 5-30J/m.
  • the microneedle array 1 of the polymer microneedle array chip of the present invention comprises more than two microneedles; the microneedle is composed of a needle bar 3 and a needle 4; the needle bar 3 is a main part of the microneedle, and the rear part thereof is micro The substrate 2 of the needle array chip is connected; the microneedle 4 is the top of the microneedle, that is, the tip portion.
  • the needle structure of the microneedle according to the present invention may be any one of various types shown in FIGS. 2-1 to 2-5 - the needle rod 31 and the needle 41 of the present invention are integrated into a conical structure.
  • the diameter of the cross section of the needle bar 31 and the substrate 2 is 20-3000 ⁇ m, and the sum of the heights of the needle bar 31 and the needle 41 is 50-5000 ⁇ m; preferably, the diameter of the cross-section circle is 50-1000
  • the height of the needle bar 31 and the needle 41 is 200-2000 ⁇ m; the radius of curvature of the circumscribed circle at the tip end of the needle 41 is 50 nm - 300 ⁇ m; preferably, the above radius of curvature is less than 10 ⁇ m.
  • the needle bar 32 of the present invention is a cylinder, the needle 42 is a cone; the diameter of the cross section of the needle bar 32 is 20-3000 microns, and the height of the needle bar 32 is 50-3000 microns; preferably, the diameter of the cross-section circle 50-1000 microns, the height of the needle bar 32 is 200-2000 microns; the diameter of the bottom surface of the needle 42 is the same as the diameter of the cross-section circle of the needle bar 32, and the height is 50-2000 microns; preferably, the height is 50-1000 microns;
  • the radius of curvature of the circumcircle at the tip of the needle 4-2 is 50 nanometers Meter - 300 microns; Preferably, the above radius of curvature is less than 10 microns.
  • the needle bar 33 and the needle 43 of the present invention are an integrated triangular pyramid structure; the needle bar 35 and the needle 45 are an integrated quadrangular pyramid structure; the needle bar 37 and the needle 47 are pentagonal pyramid structures; the pyramid is connected with the substrate 2
  • the diameter of the circumscribed circle of the cross section is 20-3000 ⁇ m, and the sum of the heights of the needle bar 3 and the needle 4 is 50-3000 ⁇ m; preferably, the diameter of the circumscribed circle is 50-1000 ⁇ m, the needle bar 3 and the needle
  • the sum of the heights of 4 is 200-2000 ⁇ m; the circumscribed circle at the tip end of the pyramidal needle 4 has a radius of curvature of 50 nm to 300 ⁇ m; preferably, the above radius of curvature is less than 10 ⁇ m.
  • the needle bar 34 of the present invention is a triangular prism, the needle 44 is a triangular pyramid; the needle bar 36 is a quadrangular prism, the needle 46 is a quadrangular pyramid; the needle bar 38 is a pentagonal prism, the needle 48 is a pentagonal pyramid; and the prismatic needle is
  • the diameter of the cross-section of the rod 3 is 20-3000 microns, and the height of the needle bar 3 is 50-4000 microns; preferably, the diameter of the cross-section circle is 50-1000 microns, and the diameter of the needle bar 3 is 200-2000 microns;
  • the diameter of the circumscribed circle of the bottom surface of the pyramid needle 4 is the same as the diameter of the circumscribed circle of the connected pyramid, and the height of the pyramid needle 4 is 50-2000 ⁇ m; preferably, the height of the above-mentioned pyramid 4 is 50-1000 ⁇ m
  • the circumscribed circle at the tip end of the pyramid needle 4 has a radius of curvature of 50 nm
  • the needle bar 39 of the present invention is a cylinder, and the needle 49 is an elliptical plane whose upper surface is at an acute angle with the plane of the substrate 2; the needle bar 310 is a cylinder, and the needle 410 is two and the substrate
  • the plane is an elliptical plane with an acute angle; similarly, when the needle bar 3 is a cylinder, the needle 4 can be a plurality of pointed structures formed by an elliptical or fan-shaped plane set at an acute angle to the plane of the substrate 2.
  • the diameter of the cross-section circle of the needle bars 39 and 310 is 20-3000 ⁇ m, and the heights of the needle bars 39 and 310 are 50-3000 ⁇ m, respectively; preferably, the diameter of the above-mentioned cross-section circle is 50-1000 ⁇ m, and the heights of the needle bars 39 and 310
  • the diameters of the bottom surfaces of the needles 49 and 410 are respectively equal to the diameters of the cross-section circles of the needle bars 39 and 310, and the height is 50-2000 ⁇ m; preferably, the above-mentioned height is 50-1000 ⁇ m; the above-mentioned needle 4
  • the thickness of the blade at the tip end is 50 nm to 300 ⁇ m; preferably, the thickness of the blade portion of the above-mentioned needle 4 is less than 10 ⁇ m.
  • the needle bar 3 and the needle 4 of the present invention may be composed of a combination of prisms and pyramids having more sides; the microneedle body may be any other structure having a pointed shape.
  • the center axis of the needle bar 3 and the needle 4 of the present invention may be perpendicular or inclined at an angle to the plane in which the substrate 2 is located; preferably, the center axis of the needle bar 3 and the needle 4 and the substrate The plane where 2 is located is kept vertical.
  • the polymer microneedles constituting the microneedle array 1 of the present invention may be solid microneedles or hollow microneedles.
  • the hollow microneedle is composed of a needle bar 3, a needle 4 and an inner hole 5; similarly, each of the figures shown in Figs. 2-1 to 2-5
  • Various types of solid microneedles can be processed into hollow microneedles containing internal pores; preferably, the polymeric microneedles are solid microneedles.
  • the spatial arrangement of the microneedle array 1 of the present invention may be linear; it may be a rectangle, a square, a parallelogram as shown in FIG. 5, a circle, an ellipse, a triangle or the like.
  • the microneedle array 1 of the present invention may be a solid microneedle array 1 or a hollow microneedle array 1, or a hybrid array of the two; preferably, the microneedle array 1 is a solid microneedle array 1.
  • the substrate 2 in the microneedle array chip of the present invention has a thickness of 50 to 5000 ⁇ m; preferably, the substrate has a thickness of 100 to 2000 ⁇ m.
  • the spatial parameters of the microneedle array chip according to the present invention including the shape, length, pitch, number of the microneedles, the arrangement of the microneedle array 1, and the thickness of the substrate 2 can be adjusted as needed.
  • the method for preparing a polymer microneedle array chip according to the present invention is as shown in FIG. 6, and mainly includes the following steps - F-01, preparing a prototype having the same spatial characteristics as the polymer target microneedle array chip
  • the prototype of the microneedle array chip of the present invention may be processed by numerically controlled laser processing by any one of titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy or other metal or alloy. Prepared by micro-electromechanical processing technology such as electric discharge machining;
  • the prototype of the microneedle array chip of the present invention can be divided into three types: A, B and C;
  • the prototype of the class A microneedle array chip of the present invention and the microneedle array chip shown in Fig. 1 have the same spatial characteristics, including the microneedle array 1 and the substrate 2;
  • the shortest distance between the outermost microneedle at the interface of the outermost microneedle and the substrate in the prototype of the type A microneedle array chip of the present invention is the shortest distance from the outer surface of the upper surface of the substrate 2 is 100-5000 micrometers; preferably, the shortest distance is 500-2000 micrometers; the plurality of class A microneedle array chip prototypes of the present invention can be arranged on the same smooth and flat bottom surface 6 according to any topological structure, as shown in FIG. 7;
  • the bottom surface 6 of the present invention may be prepared by any one of titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy or other metal or alloy, or may be made of glass, Preparation of materials such as silicon and silicon dioxide;
  • the spatial parameters of the prototype of the class A microneedle array of the present invention include the number, height, spacing of the microneedles, and the angle formed by the plane of the substrate 2; the arrangement of the microneedle array 1; the thickness of the substrate 2. Etc., can be adjusted according to the needs of the target polymer microneedle array chip;
  • the prototype of the B-type microneedle array chip of the present invention is shown in FIG. 8.
  • the microneedle array 1, the substrate 2 and the concave ring 7 surrounding the substrate 2 are directly processed on the bottom surface 6;
  • the shortest distance between the outermost microneedle and the substrate at the boundary of the substrate is 100-5000 micrometers; preferably, the shortest distance is 500-2000 ⁇ m;
  • the concave ring 7 in the prototype of the B-type microneedle array of the present invention may have a rectangular, square or semi-circular shape, or an irregular shape;
  • the maximum depth of the concave ring 7 is 100- 5000 microns, the maximum width is 100-5000 microns;
  • the concave ring 7 has a maximum depth of 100-2000 microns in section and a maximum width of 100-2000 microns;
  • the prototype of the B-type microneedle array chip of the present invention can separately process one microneedle array 1, the substrate 2 and the corresponding concave ring 7 on the bottom surface 6, or can process multiple micros on the same bottom surface 6 at a time. Needle array 1, substrate 2 and corresponding concave ring 7; a plurality of microneedle array 1, substrate 2 and corresponding concave ring 7 can be arranged on the bottom surface 6 according to any topology; Class B microneedles according to the present invention
  • the spatial parameters of the array chip prototype including the number, height, spacing of the microneedles, the angle with the plane in which the substrate is located; the thickness of the substrate; the microneedle array 1, the substrate 1 and the corresponding concave ring 7 on the bottom surface 6
  • the arrangement of the above, etc., can be adjusted according to the needs of the target polymer microneedle array chip;
  • the prototype of the C-type microneedle array chip of the present invention is shown in FIG. 9.
  • the microneedle array 1, the substrate 2, the concave ring 7 surrounding the substrate 2, the side 8 perpendicular to the substrate 2 and surrounding the concave ring 7 Directly processed on the bottom surface 6;
  • the shortest distance between the outermost microneedle and the substrate 2 in the prototype of the C-type microneedle array chip of the present invention is the shortest distance from the outer surface of the upper surface of the substrate 2 of 100-5000 micrometers; preferably, the shortest distance described above
  • the cross-section of the concave ring 7 in the prototype of the C-type microneedle array chip of the present invention may be a regular or irregular shape such as a rectangle, a square or a semicircle, and the maximum depth of the cross section of the concave ring 7 is 100. - 5000 microns, a maximum width of 100-5000 microns; preferably, the maximum depth is 100-2000 microns, and the maximum width is 100-2000 microns;
  • the vertical distance of any position outside the concave ring 7 from the side surface 8 is 0-5000 micrometers; preferably, the distance is 0 micrometers, that is, the outer side of the concave ring 7 coincides with the inner side of the side surface 8 ;
  • the vertical surface of the side surface 8 of the present invention is perpendicular to the upper surface of the substrate 2 from the vertical height of the surface of the microneedle needle 4 from the surface of the substrate 2 by 50-5000 microns; preferably, the difference of the above vertical height is 200. - 2000 microns;
  • the prototype of the C-type microneedle array chip of the present invention can be processed separately on the bottom surface 6 at a time, or a plurality of microneedle arrays 1, a substrate 2, a corresponding concave ring 7 and one time can be processed on the same bottom surface 6.
  • Side 8; a plurality of microneedle array 1, substrate 2, and corresponding concave ring 7 and side 8 can be arranged on the bottom surface 6 according to any topology;
  • the spatial parameters of the prototype of the C-type microneedle array chip according to the present invention include the number, height, spacing of the microneedles, and the angle formed by the plane where the substrate is located; the thickness of the substrate; the microneedle array 1, the substrate 1 And the corresponding concave ring 7 and side 8 are
  • the arrangement on the bottom surface 6 and the like can be adjusted according to the needs of the target polymer microneedle array chip; F-02, using the above microneedle array chip prototype to prepare a negative mold'
  • a single or a plurality of microneedle array chip prototypes prepared by F-01 are first placed on the bottom surface 6; then in each microneedle array A closed side 8 is formed around the prototype of the chip perpendicular to the bottom surface 6, surrounding the prototype of the microneedle array; finally forming a bottom surface 6 and a side surface 8 closed, the upper three-dimensional structure;
  • the material for preparing the side surface 8 may be titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy or other metal. Or any of the alloys, which may be any of materials such as glass, silicon, and silica;
  • the shortest distance between the inner side of the boundary between the side surface 8 and the bottom surface 6 and the outermost side at the boundary between the substrate 2 and the bottom surface 6 is 100-5000 micrometers.
  • the shortest distance described above is 500-2000 microns;
  • the vertical height of the upper surface of the side surface 8 from the upper surface of the bottom surface 6 is greater than the sum of the vertical heights of the substrate 2 and the microneedle of the microneedle array chip prototype. -5000 microns; preferably, the above vertical height difference is 100-2000 microns;
  • the liquid or molten state polymer may be poured from the upper opening to the three-dimensional structure to be filled;
  • the polymer It is at least one of polypropylene, polyethylene, polylactic acid, polybutylene succinate, polydimethylsiloxane or other polymers; preferably, the liquid or molten state for casting
  • the polymer needs to be relatively easily subjected to mold release treatment; further preferably, the polymer has a suitable hardness after curing and molding to facilitate preparation of the microneedle array chip; using the type B microneedle array chip prototype
  • a closed side surface 8 perpendicular to the bottom surface 6 and surrounding the concave ring 7 is formed on the bottom surface 6, and finally a three-dimensional structure with a bottom surface 6 and a side surface 8 closed as shown in FIG.
  • the material of the side 8 may be titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy or other metal or Any one of the alloys may be any one of materials such as glass, silicon, and silicon dioxide;
  • the shortest distance between the arbitrary inner side of the boundary between the side surface 8 and the bottom surface 6 and the outer side of the concave ring 7 is 0-5000 micrometers; preferably, the shortest distance is 0 micrometers, that is, the inner side of the concave ring 7 and the side surface 8 overlap;
  • the vertical height of the upper surface of the side surface 8 from the upper surface of the substrate 2 is greater than the vertical height of the top end of the microneedle needle 4 from the upper surface of the substrate 2 50-5000.
  • Micron preferably, the above vertical height difference is 100-2000 microns;
  • the liquid or molten polymer can be poured from the upper opening to the three-dimensional structure to be filled.
  • the polymer is at least one of polypropylene, polyethylene, polylactic acid, polybutylene succinate, polydimethylsiloxane or other polymers; preferably, the casting is used.
  • the polymer in a liquid or molten state needs to be relatively easily subjected to a release treatment; further preferably, the polymer has a suitable hardness after solidification molding to facilitate preparation of a microneedle array chip; using the C-type microneedle
  • the array chip prototype is used to prepare a negative mold, a liquid or molten polymer can be poured from the upper opening of each solid structure until the solid structure is filled.
  • the polymer is at least one of polypropylene, polyethylene, polylactic acid, polybutylene succinate, polydimethylsiloxane or other polymers; preferably, the casting is used
  • the polymer in a liquid or molten state needs to be relatively easily subjected to a release treatment; more preferably, the polymer has a suitable hardness after curing and molding to facilitate preparation of the microneedle array chip;
  • the microneedle array chip prototype is demoulded to obtain a negative mold
  • Figure 11 shows a single female mold on the polymer template 9, including a microneedle cavity 10 and a substrate cavity 11.
  • Figure 12 shows a plurality of negative molds on the polymer template 9, each of which is composed of a microneedle cavity 10 and a substrate cavity 11;
  • the polyacrylamide-based polymer or a mixture thereof with a biologically active substance or drug is used in the present invention.
  • the method for preparing the microneedle array chip can be divided into three types: Fl, F2 and F3.
  • the F1 type method of the present invention refers to the use of the same type of material for the microneedle array 1 and the substrate 2 when preparing the polymer microneedle array chip;
  • the same type of material as used in the present invention refers to a polyacrylamide-based polymer or a mixture thereof with a biologically active substance or a drug.
  • the biologically active substance or drug of the present invention is one or more of a vaccine, a polypeptide, a protein, a polysaccharide, a nucleic acid, a hormone, an anticancer drug, a genetic engineering drug, a natural product drug, a Chinese medicine component or a nutrient component of any molecular weight. a combination of components;
  • the specific preparation steps are as follows: 1. If the preparation material is a mixture of a polyacrylamide polymer and a biologically active substance or a drug, it is first necessary to mix the polyacrylamide polymer with a solid or liquid biologically active substance or drug in a certain ratio; The mass percentage of the biologically active substance or drug in the mixture thereof with the polyacrylamide polymer is
  • the mass percentage is 10-20%, to ensure that the mechanical strength of the prepared microneedle can easily puncture the skin;
  • the specific mixing ratio of the polyacrylamide polymer to the biologically active substance or the drug can be Adjusted according to the dose required to treat the disease and the spatial characteristics of the prepared polymer microneedle array chip;
  • step F-03 The mold obtained in step F-03 is cleaned with water and then placed on a horizontal operating platform; preferably, the mold and the horizontal operating platform are placed in a closed system to ensure the preparation of the polymer microneedle array chip process It is not affected by the external environment; preferably, a viscous liquid seal is used between the horizontal operating platform and the mold to ensure that the mold is tightly fixed on the horizontal operating platform, and the mold can be conveniently removed from the operating platform after the end of the experiment;
  • the aqueous solution or mixture prepared in step 2 is cast in F-03, as shown in Figure 11 or 12; the volume of the aqueous solution or mixture to be poured by the microneedle array cavity 10 The volume, the volume of the substrate cavity 11, and the mass fraction of the polyacrylamide polymer or a mixture thereof with the biologically active substance or drug in an aqueous solution or mixture;
  • the step 4 is poured into the aqueous solution or mixture in the negative mold for drying, and the drying temperature is 20 to 90 ° C ; preferably, the drying temperature is 20-50 ° C; if it is poured into the negative mold once
  • the polyacrylamide-based polymer in the aqueous solution or mixture or the mixture thereof with the biologically active substance or the drug can satisfy the requirement of preparing the microneedle array chip, and the aqueous solution or mixture injected into the negative mold can be directly dried to the same.
  • the polyacrylamide polymer or a mixture thereof with a bioactive substance or a drug is solidified to obtain a polymer microneedle array chip which meets the design requirements; if the polyacrylamide is poured into an aqueous solution or a mixture in a negative mold at a time The polymer or the mixture thereof with the biologically active substance or the drug cannot satisfy the requirement of preparing the microneedle array chip, and the partial moisture in the aqueous solution or the mixed solution poured in the negative mold can be removed by drying treatment, and then subjected to secondary or Casting multiple times until the polyacrylamide polymer in the negative mold or its mixture with bioactive substances or drugs can satisfy the preparation When the needle array chip is needed, the mixture of the polyacrylamide polymer and the bioactive substance or the drug is solidified by drying treatment to obtain a polymer microneedle array chip meeting the design requirements; F2 type polymer microneedle array chip:
  • the F2 type method of the present invention refers to the use of different types of materials in the microneedle array 1 portion and the substrate 2 portion when preparing the polymer microneedle array chip;
  • the microneedle body 1 is prepared by mixing a thin layer of a substrate having a thickness of less than 50 micrometers with a mixture of a polyacrylamide polymer and a biologically active substance or a drug;
  • the acrylamide polymer is prepared.
  • the biologically active substance or drug of the present invention is one or more of a vaccine, a polypeptide, a protein, a polysaccharide, a nucleic acid, a hormone, an anticancer drug, a genetic engineering drug, a natural product drug, a Chinese medicine component or a nutrient component of any molecular weight. a combination of components;
  • the female mold obtained in the step F-03 is cleaned with water and then placed on a horizontal operating platform; preferably, the mold and the horizontal operating platform are placed in a closed system to ensure preparation of the polymer microneedle array chip
  • the process is not affected by the external environment; preferably, a viscous liquid seal is used between the horizontal operating platform and the mold to ensure that the mold is tightly fixed on the horizontal operating platform, and the mold can be easily removed from the operating platform after the experiment is completed. ;
  • the aqueous solution or mixture prepared in step 2 is cast in F-03, as shown in Figure 11 or 12; the volume of the aqueous solution or mixture to be poured by the microneedle array cavity 10 The volume, and the mass fraction of the mixture of the polyacrylamide polymer and the biologically active substance or drug in the aqueous solution or mixture;
  • the step 4 is poured into the aqueous solution or mixture in the negative mold for drying, and the drying temperature is 20 to 90 ° C ; preferably, the drying temperature is 20-50. C ; if a mixture of a polyacrylamide-based polymer and a biologically active substance or a drug in an aqueous solution or a mixture poured into a negative mold at one time can satisfy the portion of the microneedle array 1 for preparing the microneedle array chip and the thickness of the connection is less than When a 50 micron substrate 2 thin layer is needed, the aqueous solution or mixture injected into the negative mold can be directly baked.
  • the mixture of the polyacrylamide polymer and the biologically active substance or drug dried therein is solidified to obtain a microneedle array 1 portion of the polymer microneedle array chip conforming to the design requirements and a substrate having a thickness of less than 50 ⁇ m connected thereto.
  • a thin layer if a mixture of a polyacrylamide-based polymer and a biologically active substance or a drug in an aqueous solution or a mixture which is poured into a negative mold at one time cannot satisfy the thickness of the microneedle array 1 for preparing the microneedle array chip and the thickness to which it is attached
  • a thin layer of the substrate 2 of less than 50 ⁇ m part of the moisture in the aqueous solution or the mixed solution poured in the negative mold may be removed by drying treatment, and then subjected to secondary or multiple casting until the polypropylene in the negative mold
  • the mixture of the amide polymer and the biologically active substance or drug can satisfy the requirement of preparing the microneedle array 1 portion of the microneedle array chip and the thin layer of the substrate 2 having a thickness of less than 50 micrometers, and finally drying.
  • the mixture of the polyacrylamide polymer and the biologically active substance or the drug is solidified to obtain a polymer meeting the design requirements.
  • the microneedle array 1 portion of the composition needle array chip and the thin layer of the substrate to which the thickness is less than 50 microns is connected.
  • the polyacrylamide polymer is blended with water at a temperature of 10 to 90 ° C to obtain an aqueous solution.
  • the mass fraction of the polyacrylamide-based polymer in the aqueous solution is 20 to 80% ; preferably, the above mass fraction is 40 to 60%; preferably, the polyacrylamide-based polymer which can be poured into the aqueous solution in the negative mold at one time can Satisfying the need to prepare a substrate body layer of the microneedle array chip; preferably, ultrasonically treating the above aqueous solution or mixture to remove bubbles contained therein;
  • the aqueous solution of the pure polyacrylamide-based polymer prepared in the step 6 is cast into the negative mold used in the steps 3 to 5; the volume of the aqueous polymer solution poured is from the partial volume of the substrate chamber 11, and The mass fraction of the polyacrylamide polymer in the aqueous solution is determined;
  • the step 7 is poured into the aqueous solution in the negative mold for drying; the drying temperature is 20 to 90 ° C ; preferably, the drying temperature is 20 to 50 ° C ; by drying, the casting is carried out in the negative mold.
  • the polyacrylamide-based polymer is completely cured and molded to obtain a substrate main layer in the polymer microneedle array chip, and a complete polymer microneedle array chip is obtained;
  • the F3 type method of the present invention refers to the use of different types of materials for the microneedle array 1 and the substrate 2 when preparing the polymer microneedle array chip;
  • the microneedle body 1 and the connected thin layer of the substrate having a thickness of less than 50 micrometers are prepared from a mixture of a acrylamide-based polymer or a bioactive substance or a drug thereof;
  • a material such as a medical polymer such as ethylene, polypropylene, polybutylene succinate, polydimethylsiloxane, rubber, polylactic acid or latex, glass or metal thermoplastic composite material
  • the materials are prepared by layered combination;
  • the preparation material is a mixture of a polyacrylamide polymer and a biologically active substance or a drug
  • the mass percentage of the bioactive substance or drug in the mixture thereof with the polyacrylamide polymer is
  • the mass percentage is 10 ⁇ 20%, to ensure that the mechanical strength of the prepared microneedle can easily rupture the skin; preferably, the polyacrylamide polymer and the biological active substance or the drug specific
  • the mixing ratio can be adjusted according to the dosage required for treating the disease and the spatial characteristics of the prepared polymer microneedle array chip;
  • step F-03 The mold obtained in step F-03 is cleaned with water and then placed on a horizontal operating platform; preferably, the mold and the horizontal operating platform are placed in a closed system to ensure the preparation of the polymer microneedle array chip process It is not affected by the external environment; preferably, a viscous liquid seal is used between the horizontal operating platform and the mold to ensure that the mold is tightly fixed on the horizontal operating platform, and the mold can be conveniently removed from the operating platform after the end of the experiment;
  • the aqueous solution or mixture prepared in step 2 is cast in F-03, as shown in Figure 11 or 12; the volume of the aqueous solution or mixture to be poured by the microneedle array cavity 10 The volume, and the mass fraction of the polyacrylamide polymer or a mixture thereof with the biologically active substance or drug in an aqueous solution or mixture;
  • the step 4 is poured into the aqueous solution or mixture in the negative mold for drying, and the drying temperature is 20 to 90 ° C ; preferably, the drying temperature is 20-50 ° C; if it is poured into the negative mold once
  • the polyacrylamide-based polymer in the aqueous solution or mixture or a mixture thereof with the biologically active substance or drug can satisfy the microneedle array 1 for preparing the microneedle array chip and the thin layer of the substrate to which the thickness is less than 50 ⁇ m is required.
  • the aqueous solution or mixture injected into the negative mold is directly dried to a polyacrylamide-based polymer or a mixture thereof with a biologically active substance or a drug, the polymer microneedle array chip meeting the design requirements can be obtained.
  • part of the water in the aqueous solution or the mixed solution poured in the negative mold can be removed by drying, and then carried out two or more times.
  • the polyacrylamide-based polymer in the negative mold or a mixture thereof with the biologically active substance or drug can satisfy the microneedle array 1 for preparing the microneedle array chip and the thin layer of the substrate to which the thickness is less than 50 ⁇ m is connected
  • the polyacrylamide-based polymer or a mixture thereof with the bioactive substance or the drug is solidified by a drying treatment to obtain a microneedle array 1 of the polymer microneedle array chip conforming to the design requirements and the connected a thin layer of substrate having a thickness of less than 50 microns; 6.
  • the single or multilayer film is made of polyethylene, polypropylene, polybutylene succinate
  • a medical polymer such as an ester, a polydimethylsiloxane, a rubber, a polylactic acid, or a latex, or a glass or a metal thermoplastic composite.
  • the prepared polymer microneedle array chip can be taken out from the female mold, stored in a suitable device, or can be further stored in the negative mold; preferably, the prepared polymer microneedle array chip is continuously stored in the negative mold In order to carry out the preparation of the next microneedle transdermal patch.
  • the microneedle array chip composed of the substrate 2 further includes: a substrate 12, an anti-seepage gasket 13, a release layer 14, an adhesive tape 15 and a barrier layer 16; the substrate 12 is pasted on the back surface of the substrate 2, the The permeation gasket 13 surrounds the edge of the substrate 2 and the substrate 12; the release layer 14 covers the outside of the barrier gasket; the adhesive tape 15 is a double-sided tape having adhesive on both inner and outer sides, and the inner side covers the substrate 12 , the anti-seepage gasket 13 and the release layer 14 , the outer side is bonded to the anti-seepage layer 16; the outer side of the adhesive tape 15 is covered with the anti-seepage layer 16; the substrate 12 of the present invention refers to the micro-needle array One or more layers of film
  • the back surface of the substrate 2 of the microneedle array chip is adhered to the substrate 12, and the substrate 2 of the microneedle array sheet is prepared by using other materials, especially when the water-insoluble material is prepared, and the back surface is not sticky. Attached to the substrate 12;
  • the anti-seepage gasket 13 of the present invention surrounds the microneedle percutaneously applied patch substrate 12, and mainly protects the microneedle array chip from the external environment, especially the intrusion of an aqueous solution; can be made of latex, rubber, medical plastic
  • One or more of the polymers are prepared; the shape of the barrier gasket 13 is determined by the shape of the microneedle percutaneously applied patch substrate 12, that is, the shape of the inner side of the barrier gasket 13 and the substrate.
  • the outer shape of 12 is uniform; the cross section of the seepage washer 13
  • the surface can be rectangular, round or the like.
  • the cross-section of the barrier gasket 4 is rectangular; the cross-section of the barrier gasket 13 is slightly greater than or equal to the height of the substrate 12 of the microneedle transdermal patch; preferably, the height of the barrier gasket 13 and the substrate 12
  • the height of the section of the barrier gasket 13 is 20-5000 micrometers; preferably, the width of the cross-section of the barrier gasket 13 is 200-2000 micrometers; the microneedle transdermal patch of the present invention may include
  • the barrier gasket 13 may also not include the barrier gasket 13; preferably, if the microneedle transdermal patch comprises the substrate 12, the permeation gasket 13 is surrounded around the substrate 12, if the microneedle is percutaneously applied The agent does not include the substrate 12, and the barrier gasket 13 may not be included.
  • the release layer 14 of the present invention is a film covering the outside of the anti-seepage gasket of the microneedle transdermal preparation, and is prepared from a material which does not adhere to the adhesive tape 15;
  • the layer 14 can be easily peeled off, and the adhesive tape 15 is conveniently used to fix the transdermal patch; the area and shape of the release layer 14 is determined by the adhesive tape 15 on the outside; as shown in Fig. 13, the adhesive tape 15
  • the size and area are the sum of the areas of the substrate 12, the barrier gasket 13 and the release layer 14; if the microneedle transdermal patch does not include the substrate 12 and the barrier gasket 13, the area of the adhesive tape 15 is lining The sum of the areas of the bottom 2 and the release layer 5;
  • the inner side of the adhesive tape 15 of the present invention is coated with a microneedle for transdermal administration of a substrate 12, an anti-seepage gasket 13 and an anti-adhesive layer 14, and the outer side is bonded to the barrier layer 16.
  • the release layer 14 is peeled off during application, and the adhesive tape 15 can fix the microneedle percutaneous patch to the skin surface; the adhesive tape can be any shape; preferably, the adhesive tape is rectangular.
  • the adhesive tape has a length of 1-150 mm and a width of 1-100 mm. Preferably, the length is 10-50 mm, and the width is 5-30.
  • the anti-seepage layer 16 of the present invention is a protective film coated on the outer side of the adhesive tape 15, and the size and shape of the adhesive tape 15 are similar or slightly
  • the anti-seepage layer 16 is mainly used to prevent the intrusion of the aqueous solution into the polymer microneedle array chip, and can be prepared from one or a mixture of various types of fibers, latex, rubber, etc. which have been subjected to hydrophobic treatment;
  • the microneedle array chip of the present invention generally needs to be placed in the protection device before use to prevent the microneedle from being broken due to external force; preferably, the microneedle array chip is continuously stored after being prepared as shown in FIG. 11 or 12.
  • the mold for preparing the microneedle array chip comprises a template 9, a microneedle cavity 10 and a substrate cavity 11 in three parts. Further preferably, when the microneedle transdermal patch is prepared and preserved, the microneedle array array chip is always stored in the mold until it is required to be removed from the mold by using the microneedle transdermal preparation for treatment;
  • the method for preparing a microneedle transdermal patch according to the present invention comprises the following steps:
  • Adhering the substrate 12 to the substrate 2 of the microneedle array chip specifically, when the adhesion substrate 12 is adhered on the back surface of the microneedle array chip substrate 2, if the substrate 12 is a single layer film, the adhesive can be utilized.
  • the layers may be bonded to each other first, and then the substrate 12 composed of the multilayer film is adhered to the substrate 2 of the microneedle array chip; the multilayer film may also be Gradually adhered to the back surface of the substrate 2 of the microneedle array chip in a certain order; preferably, the substrate 12 containing the multilayer film structure is first prepared, and then adhered to the substrate 2 of the microneedle array chip; 2 does not need to adhere the substrate 12 behind, the preparation method does not include this step;
  • the anti-seepage gasket 13 is fixed around the substrate 12 of the microneedle transdermal patch; specifically, the impermeable gasket 13 having the same inner diameter as the substrate 12 is first processed, and then the barrier gasket 13 is fixed by physical means.
  • the preparation method does not include this step;
  • the release layer 14 is placed on the outside of the microneedle substrate 12 or the microneedle array chip substrate 2; specifically, firstly, according to the shape and area of the adhesive tape 15, and the shape and area of the barrier gasket 13, pre-processing The release layer 14, and then the processed release layer 14 is placed on the outside of the barrier gasket 13; if the microneedle transdermal patch does not include the substrate 12 and the barrier gasket 13, according to the adhesive tape 15 and the liner The shape and area of the bottom 2, the release layer 14 is pre-processed, and then the processed release layer 14 is placed on the outside of the substrate 2;
  • the adhesive tape 15 to the barrier layer 16 is pre-processed according to the shape and area of the adhesive tape 15, and then the two are bonded together.
  • the adhesive tape 15 and the barrier layer 16 may be bonded together, and then cut according to the shape and area requirements;
  • the inside of the adhesive tape 15 to the substrate 12 of the microneedle transdermal patch, the barrier gasket 13 and the release layer 14; specifically, the bond which has been bonded to the barrier layer 16
  • the tape 15 is overlaid on the substrate 12 of the microneedle transdermal patch, the barrier gasket 13 and the release layer 14, and bonded together. If the microneedle transdermal patch does not include the substrate 12 and the barrier gasket 13, the inner side of the adhesive tape 15 is bonded to the substrate 2 and the release layer 14;
  • the steps F-04 and F-05 of the invention can be adjusted according to the actual situation.
  • Examples 1-14 are used to illustrate a method for synthesizing a medically water-soluble polyacrylamide polymer using an acrylamide monomer, and the synthesized polyacrylamide polymer can be used for preparing a medical polymer microneedle array. chip.
  • Examples 1-3 are used to illustrate the effect of the ratio of water and various organic solvents on the acrylamide polyfeed reaction.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with the static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 9.1 ⁇ 10 4 .
  • the corresponding bulk material has a Vickers hardness of about 430 HV measured according to the GB/T 4340.2 standard.
  • the impact strength measured according to the American ATSM D-256 standard was about 20 J/m.
  • Example 2 In the same manner as in Example 1, the ratio of the water, ethanol, acetone and isopropanol in the solvent was changed to 5:5:10:80.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with a static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 1.35 X 1 0 5 .
  • the corresponding bulk material has a Vickers hardness of about 300 HV measured according to the GB/T4340.2 standard.
  • the impact strength measured according to the American ATSM D-256 standard is about 25 J/m.
  • Example 2 In the same manner as in Example 1, the ratio of the water, ethanol, acetone and isopropanol in the solvent was changed to 10:5:10:80.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with a static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 2.0 ⁇ 10 5 .
  • the corresponding bulk material has a Vickers hardness of about 150 HV measured according to the GB/T 4340.2 standard.
  • the impact strength measured according to the American ATSM D-256 standard was about 30 J/m.
  • Examples 1, 4-6 are used to illustrate the effect of the initial concentration of the acrylamide monomer in the reaction system on the polymerization of acrylamide. ..
  • Example 2 In the same manner as in Example 1, the mass of the acrylamide monomer was changed to 3.56 g.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with the static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 6.3 ⁇ 10 4 .
  • Corresponding block material is measured according to GB/T4340.2 standard Vickers hardness is about 550HV.
  • the impact strength was measured to be about 9 J/m according to the D-256 standard of the American ATSM.
  • Example 2 In the same manner as in Example 1, the mass of the acrylamide monomer was changed to 7.11 g.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with a static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 7.6 ⁇ 10 4 .
  • the corresponding bulk material has a Vickers hardness of about 510 HV measured according to the GB/T 4340.2 standard.
  • the impact strength was measured to be about 14 J/m according to the D-256 standard of the American ATSM.
  • Example 2 In the same manner as in Example 1, the mass of the acrylamide monomer was changed to 14.22 g.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with a static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 1.2 ⁇ 10 5 .
  • the corresponding bulk material has a Vickers hardness of about 330 HV measured according to the GB/T 4340.2 standard.
  • the impact strength measured according to the American ATSM D-256 standard was about 24 J/m.
  • Examples 1, 7-9 are used to illustrate the effect of reaction temperature on the polymerization of acrylamide.
  • Example 1 the temperature of the target of the set thermostat phase was changed to 55 °C.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with a static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 9.5 ⁇ 10 4 .
  • the corresponding bulk material has a Vickers hardness of about 410 HV measured according to the GB/T 4340.2 standard.
  • the impact strength measured according to the American ATSM D-256 standard was about 21 J/m.
  • the temperature of the target of the set thermostat phase was changed to 65 °C.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight of the polymer obtained was measured according to the method of GB 17514-2008 in combination with a static light scattering method (Wyatt DAWN HELEOS-II).
  • the molecular weight of the obtained polymer was about 8.7 X 1 0 4 .
  • the corresponding bulk material has a Vickers hardness of about 450 HV measured according to the GB/T 4340.2 standard.
  • the impact strength measured according to the American ATSM D-256 standard was about 19 J/m.
  • the temperature of the target of the set thermostat phase was changed to 70. C.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • LC-20A/SPD-20AV Shimadzu liquid chromatograph
  • the molecular weight of the 17514-2008 method was measured in combination with a static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 7.8 ⁇ 10 4 .
  • the corresponding bulk material has a Vickers hardness of approximately 490 HV as measured by the GB/T 4340.2 standard.
  • the impact strength measured according to the American ATSM D-256 standard was about 16 J/m.
  • Examples 1, 10-13 are used to illustrate the effect of the amount of initiator on the polymerization of acrylamide.
  • Example 2 In the same manner as in Example 1, the amount of the initiator azobisisobutyronitrile dissolved in 10 ml of isopropanol was changed to 53.5 mg.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV) with a measured value of 0.5 ppm.
  • LC-20A/SPD-20AV Shimadzu liquid chromatograph
  • Wyatt DAWN HELEOS-II static light scattering
  • the corresponding bulk material has a Vickers hardness of about 250 HV measured according to the GB/T 4340.2 standard.
  • the impact strength measured according to the American ATSM D-256 standard was about 28 J/m.
  • Example 2 In the same manner as in Example 1, the amount of the initiator azobisisobutyronitrile dissolved in 10 ml of isopropyl alcohol was changed to 214 mg.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV) with a measured value of 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with a static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 4.3 ⁇ 10 4 .
  • the corresponding bulk material has a Vickers hardness of about 600 HV measured according to the GB/T 4340.2 standard.
  • the impact strength was measured to be about 10 J/m according to the D-256 standard of the American ATSM.
  • Example 2 In the same manner as in Example 1, the amount of the initiator azobisisobutyronitrile was weighed to 53.5 mg, which was directly added to the reactor while adding 1 ml of isopropyl alcohol to maintain the gas reaction conditions in the same manner as in Example 1.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with a static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 1.0 ⁇ 10 4 .
  • the corresponding bulk material has a Vickers hardness of about 500 HV measured according to the GB/T 4340.2 standard.
  • the impact strength was measured to be about 5 J/m according to the American D-256 standard of ATSM.
  • Example 1, 1.3-14 illustrates the effect of the type of initiator on the polymerization of acrylamide.
  • Example 2 In the same manner as in Example 1, the initiator was changed to 107 mg of ammonium persulfate, and the solvent isopropanol in which the initiator was dissolved was changed to 10 ml of water.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with the static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 7.7 ⁇ 10 4 .
  • Corresponding block material The GB/T4340.2 standard measures a Vickers hardness of approximately 500 HV.
  • the impact strength was measured to be about 15 J/m according to the American D-256 standard of ATSM.
  • Example 2 In the same manner as in Example 1, the initiator was changed to 107 mg of dodecyl peroxide, and the solvent isopropanol in which the initiator was dissolved was changed to 10 ml of water.
  • the residual acrylamide monomer content in the polymer was measured using a Shimadzu liquid chromatograph (LC-20A/SPD-20AV), and the measured value was 0.5 ppm.
  • the molecular weight was measured according to the method of GB 17514-2008 in combination with the static light scattering method (Wyatt DAWN HELEOS-II), and the molecular weight of the obtained polymer was about 8.2 ⁇ 10 4 Daltons.
  • the corresponding bulk material has a Vickers hardness of approximately 470 HV as measured by the GB/T 4340.2 standard.
  • the impact strength measured according to the American ATSM D-256 standard is about 18 J/m.
  • This embodiment is for explaining the preparation method of the prototype of the class A microneedle array chip of the present invention.
  • Nickel-chromium stainless steel alloy is selected as the material for preparing the prototype of the microneedle array; firstly, the wire is cut by the electric spark precision machining technology, and then polished by electrochemical etching to obtain the 8 ⁇ 8 microneedle array chip as shown in FIG.
  • needle bar 3 and needle 4 are pentagonal pyramids with integrated structure, the diameter of the circumcircle at the junction of the bottom of the needle bar 3 and the substrate 2 is 250 micrometers, and two circumscribed circles at the junction of the needle bar 3 and the substrate 2
  • the shortest distance is 500 microns
  • the height of the microneedles is 1000 microns
  • the radius of curvature of the microneedle tip is less than 10 microns
  • the thickness of the substrate 2 of the microneedle array chip prototype is 500 microns; any position outside the microneedle substrate 2
  • the shortest distance from the microneedle array 1 is 1000 microns;
  • the spatial parameters of the above-mentioned prototype of the A-type microneedle array chip include the number, height, spacing, thickness of the substrate, and the shortest distance between the outermost side of the substrate and the microneedle array. And adjust as needed;
  • the above type A microneedle array chip prototype can be prepared by laser numerical control micromachining combined with electrochemical etching; the above type A microneedle array chip prototype can be made of titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, Any one of aluminum alloy, copper alloy or other metal or alloy, prepared by micro-electromechanical processing technology such as numerical control laser processing or electric discharge machining;
  • This embodiment is for explaining the preparation method of the prototype of the class B microneedle array chip of the present invention.
  • Nickel-chromium stainless steel alloy is selected as the material for preparing the microneedle array prototype; firstly, the wire is cut by the electric spark precision machining technology, and then polished by electrochemical etching to obtain the 8 ⁇ 8 microneedle array chip as shown in FIG. Prototype; needle bar 3 and needle 4 are triangular pyramids with integrated structure, the diameter of the circumcircle at the junction of the bottom of the needle bar 3 and the substrate 2 is 300 micrometers, and the needle bar 3 and the substrate 2 are bordered by two adjacent circumscribed circles.
  • the shortest distance is 750 microns, microneedle
  • the height is 1200 ⁇ m, the radius of curvature of the microneedle tip is less than 10 ⁇ m, the thickness of the microneedle array chip prototype bio-substrate 2 is 800 ⁇ m;
  • the cross section of the concave ring 7 surrounding the microneedle array is rectangular, and the height of the cross section of the concave ring 7 500 microns, width 600 microns, the shortest distance from the microneedle matrix anywhere on the inner surface of the concave ring 7 is 1000 microns;
  • the spatial parameters of the prototype of the above-mentioned class B microneedle array chip include the number, height, spacing of the microneedles, the thickness of the substrate 2, the height and width of the concave ring 7, the outermost position of the upper surface of the concave ring 7, and the microneedle.
  • the shortest distance of the array 1 and the like can be adjusted according to the needs of the target microneedle array chip;
  • the above-mentioned prototype of the B-type microneedle array chip can be prepared by laser numerical control micro-machining combined with electrochemical etching; the above-mentioned B-type microneedle array chip prototype can adopt titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, Any one of aluminum alloy, copper alloy or other metal or alloy is prepared by micro-electromechanical processing technology such as numerical control laser processing or electric discharge machining.
  • This embodiment is for explaining the preparation method of the prototype of the C-type microneedle array chip of the present invention.
  • Nickel-chromium stainless steel alloy is selected as the material for preparing the microneedle array prototype; firstly, the wire is cut by the electric spark precision machining technology, and then polished by electrochemical etching to obtain the 8 ⁇ 8 microneedle array chip as shown in FIG. Prototype; the microneedle is a quadrangular pyramid with the needle bar 3 and the needle 4 as an integrated structure, the diameter of the circumcircle at the junction of the bottom of the needle bar 3 and the substrate 2 is 200 micrometers, and the needle bar 3 and the substrate 2 are bordered by two nearest neighbors.
  • the shortest distance of the circumscribed circle is 600 ⁇ m
  • the height of the microneedle is 900 ⁇ m
  • the radius of curvature of the tip of the microneedle is less than 10 ⁇ m
  • the thickness of the prototype substrate of the microneedle array chip is 1000 ⁇ m.
  • the concave ring 7 surrounding the array of microneedles has a rectangular cross section.
  • the height of the cross section of the concave ring 7 is 600 ⁇ m and the width is 500 ⁇ m.
  • the shortest distance from the microneedle array 1 at any position on the inner side of the upper surface of the concave ring 7 is 1000 ⁇ m
  • the outer side of the concave ring 7 and the side 8 and the substrate 2 are at the boundary.
  • the inside is coincident.
  • the vertical height of the upper surface of the side surface 8 from the upper surface of the substrate 2 is greater than the vertical height of the top end of the microneedle needle 4 from the upper surface of the substrate 2 of 500
  • the spatial parameters of the above-mentioned prototype of the C-type microneedle array chip include the number, height, spacing of the microneedles, the thickness of the substrate 2, the height and width of the concave ring 7, the outermost position of the upper surface of the concave ring 7, and the microneedle.
  • the above-mentioned C-type microneedle array chip prototype can be prepared by laser numerical control micromachining combined with electrochemical etching; the above-mentioned C-type microneedle array chip prototype can be made of titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, Any one of aluminum alloy, copper alloy or other metal or alloy is prepared by micro-electromechanical processing technology such as numerical control laser processing or electric discharge machining.
  • Example 18 This embodiment is for explaining a method for preparing a female mold by using the prototype of the type A microneedle array chip prepared in Example 1; the specific steps are as follows:
  • the prototype of the type A microneedle array chip prepared in the first embodiment is first fixed on the bottom surface 6 of the glass, and a closed surface perpendicular to the bottom surface 6 is formed on the bottom surface 6 of the glass to surround the prototype of the microneedle array.
  • the side surface 8 of the glass finally forms a three-dimensional structure in which the bottom surface 6 and the side surface 8 are closed and the upper surface is open. Any position on the inner side of the boundary between the side 8 and the bottom surface 6 is kept equal to the shortest distance outside the substrate 2 of the prototype of the microneedle array chip, both of which are 3000 micrometers, and the height of the side surface 8 is 1500 micrometers;
  • the ultrasonically treated polydimethyl siloxane AB glue is poured from the upper opening of the three-dimensional structure until the vertical structure is substantially filled;
  • the polydimethylsiloxane AB glue which is solidified and formed by drying is taken out from the constructed three-dimensional structure to obtain a single or a plurality of prepared polymer microneedle array chips as shown in FIG. 11 or 12.
  • the negative model is taken out from the constructed three-dimensional structure to obtain a single or a plurality of prepared polymer microneedle array chips as shown in FIG. 11 or 12. The negative model.
  • the above glass plate for preparing the bottom surface 6 and the side surface 8 may be replaced by any one of titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy or other metal or alloy;
  • the polydimethyl siloxane AB glue cast in the three-dimensional structure may have a drying temperature of 20-150. Between C, the drying time decreases as the drying temperature increases;
  • the above polydimethylsiloxane AB gum cast in a three-dimensional structure may be replaced by one of liquid or molten polypropylene, polyethylene, polylactic acid, polybutylene succinate or other polymers.
  • This embodiment is for explaining a method for preparing a female mold by using the prototype of the B-type microneedle array chip prepared in Example 2: The specific steps are as follows:
  • a closed side 8 which is perpendicular to the substrate 2 and surrounds the outside of the concave ring 7 is constructed on the substrate by using stainless steel, and finally a substrate 2 and a side surface 8 are closed, and the upper three-dimensional structure is opened (as shown in FIG. 9).
  • the inner side of the boundary between the side surface 8 and the substrate 2 coincides with the outer side of the concave ring 7, and the height of the side surface is 1500 micrometers;
  • the molten polyethylene is poured from the upper opening of the three-dimensional structure until the three-dimensional structure is substantially filled; after the injected polyethylene is cooled to room temperature, it can be taken out from the three-dimensional structure, and the obtained structure can be obtained as shown in FIG. 11 or A single or a plurality of negative molds for preparing a polymer microneedle array chip as shown at 12.
  • the above-mentioned prepared stainless steel may be replaced by any one of titanium, copper, aluminum, nickel, tungsten, titanium alloy, nickel alloy, aluminum alloy, copper alloy or other metals or alloys, and may also be made of glass, silicon, silicon dioxide, etc. Any one of the semiconductor materials;
  • polyethylene cast in a three-dimensional structure may be replaced by one of liquid or molten polypropylene, polydimethylsiloxane, polylactic acid, polybutylene succinate or other polymers.
  • This embodiment is for explaining a method for preparing a female mold using the prototype of the C-type microneedle array chip prepared in Example 3: The specific steps are as follows:
  • the high-temperature molten polylactic acid is poured from the upper opening of the three-dimensional structure until the three-dimensional structure is substantially filled; after the injected polylactic acid is cooled to room temperature, it can be taken out from the three-dimensional structure, and the obtained structure can be obtained as shown in FIG. 11 or 12. a single or a plurality of female molds for preparing a polymer microneedle array chip as shown;
  • the above polylactic acid cast in a three-dimensional structure may be replaced by one of liquid or molten polypropylene, polyethylene, polydimethylsiloxane, polybutylene succinate or other polymers.
  • This example is intended to illustrate a method for preparing a polymer microneedle array chip using the negative molds prepared in Examples 18-20; the materials used in the preparation of the microneedle array 1 and the substrate 2 in this embodiment are all about a molecular weight.
  • the polyacrylamide polymer and water are mixed at a mass ratio of 35:65. After the polymer is completely dissolved, the aqueous solution of the polymer is treated with ultrasonic waves for 5 minutes to eliminate bubbles therein;
  • the cured polyacrylamide polymer is taken out from the negative mold to obtain a polymer microneedle array chip as shown in Fig. 17.
  • Molecular weight of the polyacrylamide-based polymer may be a 5.0X 10 4 ⁇ value between 2.0X 10 5; may also be a molecular weight of 5.0 X 10 4 ⁇ polyacrylamide different molecular weights between 2.0 X 10 5 in accordance with a mixture of a certain proportion; the mass fraction of the above polyacrylamide polymer in an aqueous solution may vary between 1 and 80%; the above drying temperature may vary between 30 and 90 ° C;
  • the above drying time can be adjusted according to changes in temperature and other conditions.
  • the material used for the change is changed to a mixture of the polyacrylamide-based polymer and the target drug;
  • the target drug in this embodiment is bovine serum albumin, and the polyacrylamide-based polymer is 20:80 by mass. Used after blending;
  • the mass fraction of the above bovine serum albumin in a mixture with the polyacrylamide polymer may vary between 0.5 and 50%;
  • the bovine serum albumin may be replaced by one or a combination of components of any molecular weight vaccine, polypeptide, protein, polysaccharide, nucleic acid, hormone, anticancer drug, genetic engineering drug, natural product drug, Chinese medicine ingredient or nutrient.
  • a microneedle array 1 is prepared using a mixture of a polyacrylamide-based polymer and a target drug.
  • the polyacrylamide-based polymer in this embodiment has a molecular weight of about 8.0 X 10 4 ;
  • the target drug in this embodiment is insulin, which is blended with a polyacrylamide-based polymer at a mass ratio of 15:85;
  • the material used for preparing the substrate 2 of the microneedle array chip is a pure polyacrylamide polymer;
  • a mixture of the above polyacrylamide-based polymer and insulin is mixed with water at a mass percentage of 20:80, and mixed uniformly using an oscillating meter, and then the mixture is treated with ultrasonic waves for 5 minutes to eliminate bubbles therein. ;
  • the mixed solution prepared in step 1 is placed in the glove box in the female mold and the horizontal operating platform prepared in the examples 4-6; the lubricating oil is evenly applied on the surface of the horizontal operating platform, and the female mold is fixed at Horizontally operating the surface of the platform; 3.
  • the mixture prepared in the step 1 was cast into a negative mold as shown in Fig. 11 or 12.
  • the volume of the mixture required to prepare the polymer microneedle array 1 and the thin layer of the substrate 2 is determined by the volume of the microneedle array cavity 10, the partial volume of the substrate cavity 11, and the polyacrylamide polymer and its
  • the mass percentage of the mixture of insulin is determined in the mixture. Drying the aqueous solution of the polymer to be poured, the drying temperature is 40 ° C; drying until the aqueous solution of the mixture of the polymer and the target drug loses fluidity and then stops;
  • the aqueous solution of the polymer prepared in the above step 4 is cast into the negative mold used in the step 3; the volume of the aqueous solution of the polymer to be poured by the microneedle array chip is prepared by the substrate cavity 11. Partial volume, and the mass fraction of the polyacrylamide polymer in the aqueous solution; drying the aqueous solution of the polymer to be poured, the drying temperature is 40 ° C; if the polymer aqueous solution is poured into the negative mold once When the need to prepare the substrate 2 of the microneedle array chip is not satisfied, the partial moisture in the aqueous solution of the polymer partially poured into the mold may be evaporated for two or more times, and then the drying process is continued, and finally The polymer and the target drug in the aqueous solution cast into the mold are solidified and molded to obtain a polymer microneedle array chip satisfying the design requirements;
  • Molecular weight of the polyacrylamide-based polymer can be 5.0 X 10 4 ⁇ a value between 2.0 X 10 5; may also be a molecular weight of 5.0 X 10 4 ⁇ polyacrylamide different molecular weights between 2.0 X 10 5 in accordance with Mixing the mixture in a certain proportion; the mass fraction of the above insulin in the mixture with the polyacrylamide polymer may vary between 0.1 and 50%;
  • the mass fraction of the mixture of the above polyacrylamide polymer and insulin in the mixed solution may vary from 1 to 80%;
  • the mass fraction of the above-described pure polyacrylamide polymer in its aqueous solution can vary between 30 to 80%; and the drying temperature may be 30-90. Change between C;
  • the time of the above drying treatment can be adjusted according to changes in temperature and other conditions
  • the above insulin may be replaced by one or a combination of components of any molecular weight vaccine, polypeptide, protein, polysaccharide, nucleic acid, hormone, anticancer drug, genetic engineering drug, natural product drug, Chinese medicine ingredient or nutrient.
  • a microneedle needle is prepared using a mixture of a polyacrylamide-based polymer and a target drug; the target drug in this embodiment is insulin, which is blended with a polyacrylamide polymer at a mass ratio of 10:90.
  • the material used for preparing the substrate 2 of the microneedle array chip in this embodiment is a polylactic acid film;
  • a mixture of the above polyacrylamide-based polymer and insulin is mixed with water at a mass percentage of 15:85, and mixed uniformly using an oscillating meter, and then the mixture is treated with ultrasonic waves for 5 minutes to eliminate bubbles therein. ;
  • step 2 The mixed solution prepared in step 1 is placed in the glove box in the female mold and the horizontal operating platform prepared in the examples 4-6; the lubricating oil is evenly applied on the surface of the horizontal operating platform, and then the female mold is fixed. On the surface of the horizontal operating platform;
  • the mixed solution prepared in the step 1 is cast in a negative mold as shown in FIG. 11 or 12; the volume of the mixed solution required for preparing the polymer microneedle array 1 and the connected substrate thin layer is made up of microneedles The volume of the array cavity 10, the partial volume of the substrate cavity 11, and the mass percentage of the mixture of the polyacrylamide polymer and the insulin in the mixed solution are determined; the poured mixture is dried, dried The temperature is 40 ° C; drying to the polyacrylamide polymer in the poured mixture and the insulin is completely cured and stops;
  • microneedle array chip bonded with the polylactic acid film is taken out from the negative mold to obtain a polymer microneedle array chip as shown in FIG.
  • the mass fraction of the above insulin in its mixture with the polyacrylamide polymer may vary between 0.1 and 50%;
  • Molecular weight of the polyacrylamide-based polymer can be 5.0 X 10 4 ⁇ a value between 2.0 X 10 5; may also be a molecular weight of 5.0 X 10 4 ⁇ polyacrylamide different molecular weights between 2.0 X 10 5 in accordance with a mixture of a certain proportion of the mixture; the mass fraction of the mixture of the above polyacrylamide polymer and insulin in the mixture may vary between 1 and 80%;
  • the above drying temperature can be in the range of 30-90. Change between C;
  • the time of the above drying treatment can be adjusted according to changes in temperature and other conditions
  • the above insulin may be replaced by one or a combination of components of any molecular weight vaccine, polypeptide, protein, polysaccharide, nucleic acid, hormone, anticancer drug, genetic engineering drug, natural product drug, Chinese medicine ingredient or nutrient.
  • Example 25 This embodiment is for explaining a method for preparing a microneedle transdermal patch using the polymer microneedle array chip prepared in Example 21;
  • the medical plastic is processed into the same shape as the substrate 2, that is, a square having a side length of 7.5 mm, a substrate 3 having a thickness of 200 ⁇ m, and then the substrate 3 is bonded to the back surface of the substrate 2;
  • the anti-seepage washer 4 is made of natural rubber; the shape of the inner side of the anti-seepage washer 4 is the same as the shape of the enclosed substrate 3, that is, the side length is 7.5 mm; the cross-section of the anti-seepage washer 4 is rectangular, height and surrounded.
  • the height of the substrate 3 is uniform, that is, 200 micrometers, and the width is 500 micrometers;
  • the anti-seepage layer ⁇ is a cotton fiber which has been subjected to hydrophobic treatment;
  • the inner side of the adhesive tape which has been bonded to the barrier layer 7 is overlaid on the substrate 3, the barrier gasket 4 and the release layer 5, and bonded together.
  • microneedle array of the prepared polymer microneedle transdermal patch 1 is further stored in a mold for preparing a polymer microneedle array chip;
  • the spatial parameters of the microneedle array chip include the number, height, spacing of the microneedles, the thickness of the substrate 2, the shortest distance between the outermost position of the substrate 2 and the microneedle array 1, etc., which can be adjusted as needed;
  • the substrate 12 may be prepared from at least one of a medical polymer, a synthetic resin, a latex, a rubber, a glass, a ceramic, a metal or a composite material; the substrate 12 may be a multilayer film prepared from the above materials, between each layer Bonded, fused, bonded or physically bonded together;
  • the above-mentioned barrier gasket 4 may be prepared from at least one of latex, rubber, medical plastic, and polymer; the above-mentioned barrier layer 7 may be prepared from any one of hydrophobic fibers, latex, rubber, and the like. .
  • This example is intended to illustrate a method of preparing a microneedle transdermal patch using the polymer microneedle array chip prepared in Example 22;
  • the material for preparing the microneedle array chip is a mixture of a polyacrylamide polymer and a target drug;
  • the target drug in the embodiment is bovine serum albumin, and the mass fraction is 20%;
  • the mass fraction of the above bovine serum albumin in a mixture with the polyacrylamide-based polymer may be Change between 0.5 ⁇ 50%;
  • the bovine serum albumin may be replaced by one or a combination of components of any molecular weight vaccine, polypeptide, protein, polysaccharide, nucleic acid, hormone, anticancer drug, genetic engineering drug, natural product drug, Chinese medicine ingredient or nutrient.
  • This example is intended to illustrate a method of preparing a microneedle transdermal patch using the polymer microneedle array chip prepared in Example 23;
  • the material of the microneedle array 1 in the preparation of the microneedle array chip is a mixture of a polyacrylamide polymer and a target drug; the target drug in the embodiment is insulin, and the mass fraction is 15%;
  • the mass fraction of the above insulin in its mixture with the polyacrylamide polymer may vary between 0.5 and 50%;
  • the above insulin may be replaced by one or a combination of components of any molecular weight vaccine, polypeptide, protein, polysaccharide, nucleic acid, hormone, anticancer drug, genetic engineering drug, natural product drug, Chinese medicine ingredient or nutrient.
  • This example is intended to illustrate a method of preparing a microneedle transdermal patch using the polymer microneedle array chip prepared in Example 24;
  • the material for preparing the microneedle array 1 in the microneedle array chip is a mixture of a polyacrylamide polymer and a target drug; the material for preparing the substrate 2 is polylactic acid; the target drug in the embodiment is insulin, mass fraction 10%; when preparing the patch, the substrate 2 does not need to be bonded to the substrate 12, and the surrounding liner 13 is no longer surrounded;
  • the shape and area of the intermediate portion of the release layer 14 are the same as the shape and area of the substrate 2, and then the cut release layer 14 is placed around the substrate 2.
  • the inner side of the adhesive tape 6 which is bonded to the barrier layer 16 is directly overlaid on the substrate 2 and the release layer 14, and bonded together.
  • the mass fraction of the above insulin in its mixture with the polyacrylamide polymer may vary between 0.5 and 50%;
  • the above insulin may be replaced by one or a combination of components of any molecular weight vaccine, polypeptide, protein, polysaccharide, nucleic acid, hormone, anticancer drug, genetic engineering drug, natural product drug, Chinese medicine ingredient or nutrient.
  • Examples 29-31 are used to illustrate the use of the polymeric microneedle transdermal patch prepared in the above Examples 25-28. Law.
  • the frozen pig skin used to simulate human skin is thawed; after the thawing, the application site is cleaned and disinfected; the microneedle percutaneous patch prepared in Example 25 is taken out from the mold and placed under a magnifying glass for observation. Found that the number of broken needles is less than / equal to 2;
  • the release layer 14 was peeled off, and the microneedle array was pierced into the thawed pig skin by a light press, and removed one minute later; the influenza vaccine mixed with the fluorescent marker dye FITC was coated on the microneedle array. The surface of the broken pig skin is then placed in an environment where the temperature is not higher than 36 ° C and the relative humidity is not lower than 40%, and is allowed to stand for half an hour;
  • the pig skin coated with the influenza vaccine was observed under a fluorescence microscope, and it was found that the surface had obvious micropores, and the dye could penetrate into the interior of the pig skin;
  • the frozen pig skin used to simulate human skin is thawed; after the thawing, the application site is cleaned and disinfected; the microneedle percutaneous patch prepared in Example 26 is taken out from the mold and placed under a magnifying glass for observation. Found that the number of broken needles is less than / equal to 2;
  • the release layer 14 is torn off, the microneedle array 1 is pierced into the thawed pig skin by a light press, and the microneedle is applied to the skin surface by the adhesive tape 6;
  • the skin and microneedle patches are placed in an environment where the temperature is not higher than 36 ° C and the relative humidity is not less than 40%. After 1 hour, the microneedle transdermal patch was removed from the pigskin;
  • the pig skin with the microneedle transdermal patch was placed under a magnifying glass to observe that the surface had obvious micropores, and the bovine serum albumin could penetrate into the interior of the pig skin;
  • the microneedle transdermal patch prepared in the embodiment 27 or 28 is modified.
  • the above application method is suitable for a drug which is relatively expensive and has strict requirements on the dosage. Medication.
  • the present invention has been described in detail in the above detailed embodiments and examples. The above detailed description is to enable those skilled in the art to understand the invention. Those skilled in the art can make appropriate changes or modifications to the technical solutions on the basis of the present invention, and therefore all equivalent technical solutions are also within the scope of the present invention. Patent of the invention The scope of protection is limited by the claims

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Abstract

提供一种聚合物微针阵列芯片,其包括微针阵列和微针阵列立于其上的衬底;所述微针阵列的材料采用聚丙烯酰胺类聚合物,该聚丙烯酰胺类聚合物的分子量为1.0x104-2.0x105,维氏硬度在150-600HV之间,冲击强度在5-30J/m之间。该聚合物微针阵列芯片机械强度高,针尖锋利,遇含水环境易溶解或溶胀,有利于药物在皮肤内缓解。

Description

聚合物微针阵列芯片及其制备方法和应用 技术领域
本发明涉及一种聚合物微针阵列芯片及制备方法和应用, 属于生物医用材料及微加工 领域。
背景技术
经皮给药, 是指药物以一定的速率透过皮肤, 经毛细血管吸收进入全身血液循环系统 而产生药效的给药方法。 由于人体皮肤最外层厚约 30-50微米的角质层的屏障作用,所以传 统的透皮给药方式仅适合分子量小于 500道尔顿、 高溶脂性的药物。 为了提高多肽、 蛋白 质和疫苗等大分子药物的经皮渗透性, 20世纪 70年代科研人员提出了 "微针贴片"给药的概 念, 即利用微加工技术制成的微针或者微针阵列刺破皮肤的角质层产生微米量级的物理通 道,使大分子药物能够透入皮肤的深层组织。微针经皮给药可以避免肝脏的"首过效应"和肠 胃的"灭活效应",对皮肤产生的创伤非常小,几乎不产生疼痛感,因此具有广泛的应用前景。
由于科技条件的限制, 微针经皮给药贴剂的实验研究 1998年才由美国 Prausnitz教授 课题组首先报道, (Journal of Pharmaceutical Sciences, 1998, 87, 922-925 ) , 实验结果表明 微针经皮给药可将模型药物钙黄绿素的经皮渗透速率比传统经皮给药方法提高四个数量 级。 微针经皮给药方式从此吸引了越来越多的科研人员开展了相关研究, 各种类型的微针 经皮给药贴剂相继被研发出来。
微针经皮给药贴剂的核心元件是微针阵列芯片, 一般由规则排列的微针阵列和支撑微 针阵列的衬底组成, 具有生物相容性好, 安全性高的特点。 早期制备微针阵列芯片主要采 用单晶硅或二氧化硅等半导体材料,利用光刻结合电化学腐蚀的方法加工而成 (US 5879326, US6503231)o 半导体微针的生物相容性好,'硬度高, 容易刺穿皮肤, 但比较脆, 若折断后 滞留在体内时无法降解。 单晶硅微针阵列芯片本身无法存储药物, 制备相应的微针经皮给 药贴剂时需要设计和制备复杂的储药和缓释.系统 (CN 102039000A, CN102018655 A) , 因 此加工工艺复杂, 成本较髙, 限制了其在临床上的应用。 金属微针阵列芯片比半导体微针 阵列芯片稍晚出现, 一般采用钛、 镍合金等不锈钢材料, 利用激光和电火花等精密微加工 技术或光刻结合电化学腐蚀技术等方法制备而成 (CN 100402107C, CN 1415385A, CN 1562402A, CN 101254326A, CN101507857A, CN 101829396A, CN 101912663A)o金属微针 的生物安全性好, 针尖易于刺穿皮肤而不断裂。 但金属微针阵列芯片本身也无法存储药物, 制备相应的微针贴剂同样需要附设储药和缓释系统, 因此目前也无法在临床上获得广泛应 用。聚合物微针于 2004年左右出现, 但因为生物相容性好, 在体内可以被降解, 安全性高, 所以发展非常迅速。 目前聚合物微针主要釆用聚甲基丙烯酸甲酯、 聚乳酸、 聚乙醇酸, 聚 羟基乙酸, 乙烯基吡咯烷酮和聚对二氧环己酮及其共聚物等材料,利用模板法制备而成(US 6312612, US 6451240, US 20020082543 , WO 2009048607, CN 100513145, CN 102000020A, CN 1415385A, CN 101072668A, CN 101254326A, CN 10202691 OA )0聚合物微针的针体本 身可以包覆药物, 无需设计复杂的储药系统, 制备工艺相对简单, 可以较经济地批量生产。 目前聚合物微针的不足之处一方面在于其机械强度普遍不足以刺破皮肤, 另外一方面制备 微针的聚合物材料大多数无法在水中溶解, 需要在熔融状态下进行浇注、 压模等高温处理, 容易使对高温敏感的药物, 如蛋白质和多肽类药物, 失去活性。
聚丙烯酰胺类聚合物作为医用材料已有比较长的历史, 具有安全性高的特点, 目前主 要是作为人体填充或者修复材料用于美容或治疗人体功能损伤(GB 4746551, GB 2164343A, DE 1594389, CN 94195147, CN 1450118A) o 具有合适分子量或者一组合适分子量配比的 聚丙烯酰胺类聚合物的水溶液在质量分数较高 050%) 时仍然具有流动性而不形成凝胶, 因此可利用模板法来制备聚合物微针阵列芯片。
基于以上科学和技术问题, 本发明人创造性的采用符合医用标准的聚丙烯酰胺类聚合 物, 利用模板法制得了针体可包覆生物活性物质或药物的聚合物微针阵列芯片, 并在此基 础上制备了操作简单、 使用方便、 安全可靠的聚合物微针给药贴剂。 发明内容
本发明要解决的第一个技术问题是提供一种聚合物微针阵列芯片。 该聚合物徼针阵列 芯片机械强度高, 针尖锋利, 可以容易地刺穿皮肤的角质层; 无需高温加工处理步骤, 有 利于多肽、 蛋白质等生物大分子药物保持活性; 遇含水环境易溶解或溶胀, 有利于药物在 皮肤内缓释。
本发明要解决的第二个技术问题是提供一种聚合物微针阵列芯片的制备方法。
本发明要解决的第三个技术问题是提供一种聚合物微针阵列芯片在经皮给药贴剂中的 应用。
为解决上述第一个技术问题, 本发明所提供的技术方案是- 一种聚合物微针阵列芯片, 其包括微针阵列和微针立于并排列于其上的衬底; 所述聚 合物微针阵列芯片的微针阵列采用的基体材料为聚丙烯酰胺类聚合物。
进一步地, 所述聚丙烯酰胺类聚合物由丙烯酰胺单体聚合而成。 反应方程式如下:
Figure imgf000004_0001
进一步地,所述聚丙烯酰胺类聚合物分子量为 1.0 X 104~2.0 X 105。所述聚丙烯酰胺类聚 合物具有良好的水溶性, 可与水混合得到聚合物质量百分数为 1~80%的水溶液。
进一步地, 所述聚丙烯酰胺类聚合物维氏硬度为 150〜600 (HV)。 该聚合物在前述硬度 条件下, 微针阵列芯片的机械强度高, 针尖锋利, 可以容易地刺穿皮肤的角质层。
进一步地,所述聚丙烯酰胺类聚合物冲击强度为 5~30J/M。该聚合物在前述冲击强度下, 不易发生折断。
进一步地, 利用所述聚丙烯酰胺类聚合物材料制备出厚度为 2毫米, 边长为 1厘米的 正方形薄板, 将该正方形薄板浸泡在静止浸泡在生理盐水中时, 经 6小时至少溶解 50%。
进一步地, 所述聚丙烯酰胺类聚合物中混合有生物活性物质或药物, 所述生物活性物 质或药物在混合物中的质量百分数为 0.1〜50%; 优选地, 质量百分数为 10~20%。 所述生物 活性物质或药物在混合物中的质量百分数可以根据所需要的剂量以及所制备的微针阵列芯 片的空间特征进行调整。
进一步地, 所述生物活性物质或药物选自下列物质中的一种或多种: 疫苗、 多肽、 蛋 白质、 多糖、 核酸、 激素、 抗癌药物、 基因工程药物、 天然产物药物、 中药成分或者营养 成分。
进一步地, 所述聚丙烯酰胺类聚合物中残余丙烯酰胺单体含量 0.5ppm, 符合世界卫 生组织规定的医用标准。
进一步地, 所述聚合物微针阵列芯片的微针阵列包括至少 2个以上的微针; 所述微针 包括针杆和针头两部分; 所述针杆为微针的主体部分, 其一端固定在微针阵列芯片的衬底 上; 所述针头为微针的顶部, 一端与针杆相连接, 针头的形状为任意尖端状结构。
优选地, 所述微针的最大截面圆或外接圆的直径为 50-1000微米; 所述微针的长度为 100-5000微米。
进一步地, 所述衬底的厚度为 50~5000微米。
进一步地, 所述衬底包括衬底薄层和衬底主体层, 所述衬底薄层是指与微针阵列部分 相连的厚度小于 50微米的薄膜结构, 衬底主体层与衬底薄层相连构成整个衬底; 优选地, 所述衬底采用的材料为聚丙烯酰胺类聚合物。
优选地, 所述衬底采用的材料为聚丙烯酰胺类聚合物与生物活性物质或药物构成的混 合物, 所述生物活性物质或药物在混合物中的质量百分数为 0.1〜50%; 优选地, 质量百分数 为 10~20%。
优选地, 所述微针阵列和衬底薄层采用的材料是聚丙烯酰胺类聚合物, 所述衬底主体 层采用的材料是聚乳酸、 聚乙烯、 聚丙烯、 聚丁二酸丁二醇酯、 橡胶、 乳胶、 玻璃、 金属 热塑性复合材料中的一种或两种以上材料的分层组合。
优选地, 所述微针阵列和衬底薄层采用的材料是聚丙烯酰胺类聚合物与生物活性物质 或药物构成的混合物;所述生物活性物质或药物在混合物中的质量百分数为 0.1〜50%;优选 地, 质量百分数为 10~20%; 所述衬底主体层采用的材料是聚乳酸、 聚乙烯、 聚丙烯、 聚丁 二酸丁二醇酯、 橡胶、 乳胶、 玻璃、 金属热塑性复合材料中的一种或两种以上材料的分层 组合。
进一步地, 本发明提供了制备所述聚丙烯酰胺类聚合物的合成方法, 合成反应体系主 要包括以醇类为主的有机溶剂、 水、 丙烯酰胺单体和引发剂四部分; 反应过程中不间断地 对反应体系通髙纯氮气进行保护、 保持搅拌、 在温度升高至目标温度后进行保温; 反应结 束后, 先对反应产物进行去除丙烯酰胺单体的处理, 然后进行烘千以得到聚丙烯酰胺类聚 合物。 所述合成方法条件温和, 简单易行, 产率较高, 所制得的聚合物符合世界卫生组织 规定的医用标准。
具体地, 合成聚丙烯酰胺类聚合物主要包括如下步骤:
S-l, 在配有搅拌装置的反应器内, 按照设定值加入有机溶剂、 水、 丙烯酰胺单体。 所述的有机溶剂以醇类为主, 酮类为辅。 醇类选自甲醇、 乙醇、 正丙醇、 异丙醇、 正 丁醇等组分中的至少一种或者两种以上混合物。 优选地, 醇类溶剂在反应体系中的体积百 分数 60%; 所述酮类选自丙酮、丁酮、 甲基异丁基酮和环己酮中等组分中的一种或者两种 以上的混合物。优选地, 酮类溶剂在反应体系中的体积百分数 25%; 本发明可以通过改变 所述有机溶剂在反应体系中所占的体积百分比对聚合物的分子量进行控制;
所述水在反应体系中的体积百分数占应 25%; 可以通过调整水在反应体系中的体积 百分比对所得到的聚合物的分子量进行调整;
所述的丙烯酰胺单体在反应体系中的初始浓度为 0.1-3mol/L。 本发明可以通过改变丙 烯酰胺单体在反应体系中的初始浓度对所得到的聚合物的分子量进行调整;
S-2, 向包含上述溶剂、水和丙烯酰胺单体组成的反应体系的反应器内通高纯氮气以除 氧, 搅拌, 同时将反应体系加热升温至目标温度。 所述的目标温度为 30-85 °C; 优选地,所 述目标温度为 40-70。C; 本发明可以通过改变合成时的目标温度对所得到的聚合物的分子量 进行调整;
S-3 , 反应体系温度达到目标温度后, 将引发剂加入上述反应体系中, 保持搅拌和氮气 通入;
所述的引发剂可以为偶氮类引发剂, 如偶氮二异丁腈、 偶氮二异庚腈, 偶氮二异丁脒 盐酸盐, 偶氮二丁酸二异丁酯, 偶氮二异丁酸二甲酯中的至少一种或者两种以上的混合物; 所述的引发剂也可以为无机或有机过氧化物, 如过硫酸铵、 过硫酸钠、 过硫酸钾、 叔 丁基过氧化氢、 过氧化二异丙苯、 过氧化苯甲酰中的至少一种或者两种以上的混合物, 同 时可加入还原剂, 如亚硫酸氢钠或偏亚硫酸钠, 使聚合反应速度更快, 反应更彻底;
所述的引发剂的的用量一般为上述丙烯酰胺单体重量的 0.01~1%; 本合成方法可以通 过改变引发剂的用量对所得到的聚合物的分子量进行控制;
S-4, 加入引发剂后, 在目标温度下继续恒温一定时间, 并保持搅拌和氮气通入; 本发明所述的反应体系保持恒温的时间为 8~30小时;优选地,所述保持恒温的时间为 12-20小时;
S-5 , 反应结束后, 首先将反应器内的固液混合物进行真空过滤, 然后将得到的固体产 物放在真空烘箱内进行干燥, 温度为 30~70。C之间;
S-6, 将干燥后的反应产物用适量水溶解, 待完全溶解后, 加入只能溶解丙烯酰胺单体 而不能溶解聚合产物的有机溶剂进行重沉淀, 以去除未反应的丙烯酰胺单体, 所述有机溶 剂为甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇、 丙酮、 丁酮、 甲基异丁基酮和环己酮中的至 少一种或者两种以上的混合物;
重复以上 S-5— S-6两个步骤 2~4次; ,
S-7, 将除掉丙烯酰胺单体后的反应产物在真空烘箱中进行干燥, 温度为 30-70 °C, 时 间为 20-50小时, 得到聚丙烯酰胺类聚合物; 干燥后的聚丙烯酰胺类聚合物在干燥密闭容器 内进行保存。
可以将得到的聚丙烯酰胺类聚合物与水混合得到水溶液, 然后浇注于模具中, 通过烘 干处理制得块体材料。 按照 GB/T4340.2标准测聚丙烯酰胺类聚合物的维氏硬度约为 150-600HV; 按照美国 ATSM 的 D-256标准测得冲击强度约为 5-30J/m。
利用岛津液相色谱仪 (LC-20A/SPD-20AV) 测量聚丙烯酰胺类聚合物中的残余丙烯酰 胺单体含量, 丙烯酰胺单体含量占聚丙烯酰胺总量的测量值均 0.5ppm;
按照 GB 17514-2008方法并结合静态光散射方法 (Wyatt DAWN HELEOS-II ) 测量步 骤 S-7所制备的聚合物分子量; 不同合成条件下的聚合物的分子量的测量值在 1.0 X 104~2.0X 105之间分布; 为解决上述第二个技术问题, 本发明提供的一种聚合物微针阵列芯片的制备方法, 包 括如下步骤:
1 )利用金属材料制得与目标聚合物微针阵列芯片具有相同空间特征的微针阵列芯片原 型;
2) 利用步骤 1 ) 制得的金属微针阵列芯片原型和聚合物材料制备阴模;
3 ) 将金属微针阵列芯片原型从阴模中脱出;
4) 将聚丙烯酰胺类聚合物和水混合得到水溶液;
5 ) 将步骤 4) 制得的水溶液浇注到阴模中;
6)进行烘干处理, 使浇注到阴模中的水溶液中的聚丙烯酰胺类聚合物固化成型, 制得 聚合物微针阵列芯片。
进一步地, 步骤 1 ) 中所述金属材料选自下列物质中的一种或多种: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金、 镍合金、 铝合金、 铜合金。
进一步地, 步骤 2) 中所述聚合物材料选自下列物质中的一种或多种: 聚乙烯、 聚丙 烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧垸。
进一步地, 步骤 4) 中, 所述聚丙烯酰胺类聚合物在 10~90°C的温度下与水混合形成水 溶液; 所述聚丙烯酰胺聚合物在水溶液中的质量百分数为 1〜80%; 优选地, 质量百分数为 10-50%; 优选地, 对上述水溶液进行超声处理, 以去除其中的气泡。
进一步地, 步骤 5 ) 中, 在将步骤 4)制备的水溶液浇注于阴模中之前, 使用水对阴模 进行清洗, 然后将阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封 闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封。
进一步地, 步骤 6) 中, 烘干温度为 20〜90°C。 进一步地, 步骤 5) 和步骤 6) 包括如下具体步骤:
Fl、 如果一次浇注到阴模中的水溶液中的聚丙烯酰胺类聚合物满足制备聚合物微针阵 列芯片需要时, 可将注入阴模中的水溶液直接烘干至其中的聚丙烯酰胺类聚合物固化成型, 得到聚合物微针阵列芯片;
Gl、 如果一次浇注到阴模中的水溶液中的聚丙烯胺按类聚合物无法满足制备聚合物微 针阵列芯片需要时, 可以通过烘干处理去除浇注于阴模中的水溶液中的部分水分, 然后进 行二次或多次浇注, 直到阴模中的聚丙烯酰胺类聚合物能够满足制备微针阵列芯片的需要 为止, 最后通过烘干处理使聚丙烯酰胺类聚合物固化成型, 得到聚合物微针阵列芯片。 本发明提供的一种聚合物微针阵列芯片的制备方法, 包括如下步骤:
1 )利用金属材料制得与目标聚合物微针阵列芯片具有相同空间特征的微针阵列芯片原 型;
2) 利用步骤 1 ) 制得的金属微针阵列芯片原型和聚合物材料制备阴模;
3 ) 将金属微针阵列芯片原型从阴模中脱出;
4) 将聚丙烯酰胺类聚合物与生物活性物质或药物混合, 得到混合物;
5 ) 将步骤 4) 制得的混合物与水混合得到混合液;
6) 将步骤 5) 制得的混合液浇注到阴模中;
7) 进行烘干处理; 制得聚合物微针阵列芯片。
进一步地, 步骤 1 ) 中所述金属材料选自下列物质中的一种或多种: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金、 镍合金、 铝合金、 铜合金。
进一步地, 步骤 2)中所述聚合物材料选自下列物质中的一种或多种:聚乙烯、聚丙烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧烷。
进一步地, 步骤 4) 中, 在所述聚丙烯酰胺类聚合物与生物活性物质或药物形成的混 合物中;所述生物活性物质或药物的质量百分数 ¾ 0.1〜50%;优选地,质量百分数为 10~20%。
进一步地, 步骤 5 ) 中, 所述步骤 4) 制得的混合物在 10〜90°C的温度下与水混合形成 混合液; 所述混合物在混合液中的质量百分数为 1~80%; 优选地, 质量百分数为 10~50%; 优选地, 对上述混合液进行超声处理, 以去除其中的气泡。
进一步地, 步骤 6) 中, 在将步骤 5 )制备的混合液浇注于阴模中之前, 使用水对阴模 进行清洗, 然后将阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封 闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封。
进一步地, 步骤 7) 中, 烘干温度为 20〜90°C。
进一步地, 步骤 6) 和步骤 7) 包括如下具体步骤:
H2、 如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物能够满足制备聚合物微针阵列芯片需要时, 可将注入阴模中的混合液直接烘 干至其中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物固化成型, 得到聚合 物微针阵列芯片;
12、如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物构 成的混合物无法满足制备聚合物微针阵列芯片需要时, 可以通过烘干处理去除浇注于阴模 中的混合液中的部分水分, 然后进行二次或多次侥注, 直到阴模中的聚丙烯酰胺类聚合物 与生物活性物质或药物构成的混合物能够满足制备微针阵列芯片的需要时为止, 最后通过 烘干处理使聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物固化成型, 得到聚合 物微针阵列芯片。 本发明提供的一种聚合物微针阵列芯片的制备方法, 包括如下步骤:
1 )利用金属材料制得与目标聚合物微针阵列芯片具有相同空间特征的微针阵列芯片原 型;
2 ) 利用步骤 1 ) 制得的金属微针阵列芯片原型和聚合物材料制备阴模;
3 ) 将金属微针阵列芯片原型从阴模中脱出;
4) 将聚丙烯酰胺类聚合物与生物活性物质或药物混合, 得到混合物;
5 ) 将步骤 4) 制得的混合物与水混合得到混合液;
6) 将步骤 5 ) 制得的混合液浇注到阴模中;
7)进行烘干处理; 浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或 药物构成的混合物固化成型; 制得的聚合物微针阵列芯片的微针阵列部分和与其连接的衬 底薄层;
8) 将聚丙烯酰胺类聚合物和水混合得到水溶液;
9) 将步骤 8) 中制备的水溶液继续浇注到步骤 8 ) 所述的阴模中;
10)将步骤 9)浇注到阴模中的水溶液进行烘干处理; 使浇注到阴模中的水溶液中的聚 丙烯酰胺类聚合物固化成型, 以制得完整的聚合物微针阵列芯片。 进一步地, 步骤 1 ) 中所述金属材料选自下列物质中的一种或多种: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金、 镍合金、 铝合金、 铜合金。
进一步地, 步骤 2)中所述聚合物材料选自下列物质中的一种或多种:聚乙烯、聚丙烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧烷。
进一步地, 步骤 4 ) 中, 在所述聚丙烯酰胺类聚合物与生物活性物质或药物形成的混 合物中;所述生物活性物质或药物的质量百分数为 0.1~50%;优选地,质量百分数为 10〜20%。
进一步地, 步骤 5) 中, 所述步骤 4) 制得的混合物在 10〜90°C的温度下与水混合形成 混合液; 所述混合物在混合液中的质量百分数为 1〜80%; 优选地, 质量百分数为 10~50%; 优选地, 对上述混合液进行超声处理, 以去除其中的气泡。
进一步地, 步骤 6) 中, 在将步骤 5)制备的混合液浇注于阴模中之前, 使用水对阴模 进行清洗, 然后将阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封 闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封。
进一步地, 步骤 7) 中, 烘干温度为 20〜90°C。
进一步地, 步骤 6) 和步骤 7) 包括如下具体步骤:
H3、 如果一次浇注到阴模中的水溶液或混合液中的聚丙烯酰胺类聚合物与生物活性物 质或药物构成的混合物能够满足制备微针阵列芯片的微针阵列部分和衬底薄层的需要时, 将注入阴模中的水溶液或混合液直接烘干至其中的聚丙烯酰胺类聚合物与生物活性物质或 药物构成的混合物固化成型, 得到聚合物微针阵列芯片的微针阵列部分和衬底薄层部分;
13、如果一次浇注到阴模中的水溶液或混合液中的聚丙烯酰胺类聚合物与生物活性物质 或药物构成的混合物无法满足制备微针阵列芯片的微针阵列部分和衬底薄层部分的需要 时, 通过烘干处理去除浇注于阴模中的水溶液或混合液中的部分水分, 然后进行二次或多 次浇注, 直到阴模中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物能够满足 制备微针阵列芯片的微针阵列部分和衬底薄层部分的需要时为止, 最后通过烘干处理使聚 丙烯酰胺类聚合物与生物活性物质或药物构成的 合物固化成型, 得到符合设计要求的聚 合物微针阵列芯片的微针阵列部分和衬底薄层部分部分。
进一步地, 步骤 8 ) 中, 所述聚丙烯酰胺类聚合物在 10~90°C的温度下与水混合形成水 溶液; 所述聚丙烯酰胺聚合物在水溶液中的质量百分数为 20~80%; 优选地, 质量百分数为 40-60%; 优选地, 对上述水溶液进行超声处理, 以去除其中的气泡。
进一步地, 步骤 9) 中: 在水溶液中的聚丙烯酰胺类聚合物的浓度高于步骤 5 ) 中制得 的混合液中聚丙烯酰胺类聚合物的浓度; 以减少通过所述的步骤 1 ) -7)所制备的微针阵列 部分所包含的生物活性物质或药物扩散到衬底部分中来。
进一步地, 步骤 10) 中, 烘干温度为 20〜9(TC。 本发明提供的一种聚合物微针阵列芯片的制备方法, 包括如下步骤:
1 )利用金属材料制得与目标聚合物微针阵列芯片具有相同空间特征的微针阵列芯片原 型;
2) 利用步骤 1 ) 制得的金属微针阵列芯片原型和聚合物材料制备阴模;
3 ) 将金属微针阵列芯片原型从阴模中脱出;
4) 将聚丙烯酰胺类聚合物与水混合得到水溶液;
5 ) 将步骤 4) 制得的水溶液浇注到阴模中;
6) 进行烘干处理; 浇注于阴模中的水溶液中的聚丙烯酰胺类聚合物固化成型, 制得聚 合物微针阵列芯片的微针阵列部分和衬底薄层部分;
7) 将步骤 6) 制备的微针阵列芯片的微针阵列部分和衬底薄层与其他单层或多层薄膜 材料连接在一起, 得到聚合物微针阵列芯片。
进一步地, 步骤 1 ) 中所述金属材料选自下列物质中的一种或多种: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金、 镍合金、 铝合金、 铜合金。
进一步地, 步骤 2)中所述聚合物材料选自下列物质中的一种或多种:聚乙烯、聚丙烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧烷。
进一步地, 步骤 4) 中, 在 10〜90°C的温度下形成混合液; 所述聚丙烯酰胺类聚合物在 水溶液中的质量百分数为 1~80%; 优选地, 质量百分数为 10〜50%; 优选地, 对上述水溶液 进行超声处理, 以去除其中的气泡。
进一步地, 步骤 5 ) 中, 在将步骤 4)制备的水溶液浇注于阴模中之前, 使用水对阴模 .进行清洗, 然后将阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封 闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封。
进一步地, 步骤 6) 中, 烘干温度为 20〜90'C。
进一步地, 步骤 6) 包括如下具体步骤:
F4、 如果一次浇注到阴模中的水溶液中的聚丙烯酰胺类聚合物满足制备微针阵列芯片 的微针阵列部分和衬底薄层部分的需要时, 将注入阴模中的水溶液直接烘干至其中的聚丙 烯酰胺类聚合物固化成型, 得到符合设计要求的聚合物微针阵列芯片的微针阵列部分和衬 底薄层部分;
G4、 如果一次浇注到阴模中的水溶液中的聚丙烯酰胺类聚合物无法满足制备微针阵列 芯片的阵列部分和衬底薄层部分的需要时, 先通过烘干处理去除浇注于阴模中的水溶液中 的部分水分, 然后进行二次或多次浇注, 直到阴模中的聚丙烯酰胺类聚合物能够满足制备 微针阵列芯片的微针阵列部分和衬底薄层部分的需要时为止, 最后通过烘干处理使聚丙烯 酰胺类聚合物固化成型, 得到符合设计要求的聚合物微针阵列芯片的微针阵列部分和衬底 薄层部分。
进一步地, 步骤 7) 中, 所述的其他单层或多层薄膜选自聚乙烯、 聚丙烯、 聚丁二酸丁 二醇酯、 聚二甲基硅氧烷、 橡胶、 聚乳酸、 乳胶、 玻璃、 金属热塑性复合材料中的一种制 备而成或者多种材料分层组合制备而成; 优选地, 所述的其他单层或者多层薄膜通过粘结、 融合、 键合与衬底薄层紧密结合在一起。 本发明提供的一种聚合物微针阵列芯片的制备方法, 包括如下步骤-
1 )利用金属材料制得与目标聚合物微针阵列芯片具有相同空间特征的微针阵列芯片原 型;
2) 利用步骤 1 ) 制得的金属微针阵列芯片原型和聚合物材料制备阴模;
3) 将金属微针阵列芯片原型从阴模中脱出;
4) 将聚丙烯酰胺类聚合物与生物活性物质或药物混合, 得到混合物;
5) 将步骤 4) 制得的混合物与水混合得到混合液;
6) 将步骤 5) 制得的混合液浇注到阴模中;
7)进行烘干处理; 使浇注到阴模中的水溶液或混合液中的聚丙烯酰胺类聚合物与生物 活性物质或药物构成的混合物固化成型, 制得聚合物微针阵列芯片的微针阵列部分和衬底 薄层部分; ,
8)将步骤 7)制备的微针阵列芯片的微针阵列部分和厚度小于 50微米的衬底薄层与其 他单层或多层薄膜材料连接在一起, 得到聚合物微针阵列芯片。
进一步地, 步骤 1 ) 中所述金属材料选自下列物质中的一种或多种: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金、 镍合金、 铝合金、 铜合金。
进一步地, 步骤 2)中所述聚合物材料选自下列物质中的一种或多种:聚乙烯、聚丙烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧烷。
进一步地, 步骤 4 ) 中, 在所述聚丙烯酰胺类聚合物与生物活性物质或药物形成的混 合物中;所述生物活性物质或药物的质量百分数为 0.1~50%;优选地,质量百分数为 10〜20%。
进一步地, 步骤 5 ) 中, 所述混合物与水在 10~90°C的温度下形成混合液; 所述混合物 在混合液中的质量百分数为 1~80%; 优选地, 质量百分数为 10〜50%; 优选地, 对上述混合 液进行超声处理, 以去除其中的气泡。
进一步地, 步骤 6) 中, 在将步骤 5 )制备的混合液浇注于阴模中之前, 使用水对阴模 进行清洗, 然后将阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封 闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封。
进一步地, 步骤 7) 中, 烘干温度为 20〜90°C。 进一步地, 步骤 6 ) 和步骤 7 ) 包括如下具体步骤:
H5、 如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物能够满足制备微针阵列芯片的微针阵列部分和衬底薄层部分的需要时, 将注 入阴模中的水溶液或混合液直接烘干至其中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物固化成型, 制得符合设计要求的聚合物微针阵列芯片的微针阵列部分和衬底 薄层部分;
15、 如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物无法满足制备微针阵列芯片的微针阵列部分和衬底薄层部分的需要时, 通过 烘干处理去除浇注于阴模中的水溶液或混合液中的部分水分, 然后进行二次或多次浇注, 直到阴模中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物能够满足制备微针 阵列芯片的微针阵列部分和衬底薄层部分的需要时为止, 最后通过烘干处理使聚丙烯酰胺 类聚合物与生物生物活性物质或药物构成的混合物固化成型, 制得符合设计要求的聚合物 徵针阵列芯片的微针阵列部分和衬底薄层部分。
进一步地, 步骤 8) 中, 所述的其他单层或多层薄膜选自聚乙烯、 聚丙烯、 聚丁二酸丁 二醇酯、 聚二甲基硅氧烷、 橡胶、 聚乳酸、 乳胶、 玻璃、 金属热塑性复合材料中的一种制 备而成或者多种材料分层组合制备而成; 优选地, 所述的其他单层或者多层薄膜通过粘结、 融合、 键合与衬底薄层紧密结合在一起。 为解决上述第三个技术问题, 本发明所提供的技术方案是:
一种使用聚合物微针阵列芯片的经皮给药贴剂, 包括聚合物微针阵列芯片、 基板、 防 渗垫圈、 防粘层、 粘结胶带和防渗层; 还可以包括微针阵列保护装置; '
所述微针阵列芯片包括微针阵列和微针阵列立于其上的衬底,是微针经皮给药贴剂的核 心元件;
所述微针阵列保护装置是用来保护微针阵列在使用之前不被外界环境破坏的装置; 优 选地, 使用制备聚合物微针阵列芯片的模具作为保护微针阵列的装置;
所述基板是指粘附在聚合物微针阵列芯片衬底背面的一层或者多层薄膜, 施药时可以 使微针阵列方便地刺破皮肤;
所述防渗垫圈是指环绕在微针阵列芯片衬底和微针贴剂基板边缘起保护作用的一层垫 圈
所述防粘层覆盖是指覆盖在微针芯片外部区域的一层保护薄膜, 施药时防粘层可以方 便地剥离;
所述粘结胶带是内外两侧均具有粘性的双面胶带, 其内侧覆盖微针贴剂的基板或微针 阵列芯片的衬底、 防渗垫圈和防粘层, 外侧与防渗层粘结在一起, 粘结胶带施药时主要起 固定作用;
所述防渗层为粘结胶带外侧所覆的一层保护薄膜, 主要为了防止贴剂内部的微针阵列 芯片受到外界环境的影响。
本发明所述的所述利用聚合物微针阵列芯片制备经皮给药贴剂的方法, 主要包括以下 步骤:
1.将基板与微针阵列芯片的衬底粘附在一起;
2.将防渗垫圈固定在微针贴剂的基板周围;
3.将防粘层设置在微针基板或微针阵列芯片衬底的外侧;
4.将双面胶带内侧与微针贴剂的基板、 防渗垫圈和防粘层粘合在一起;
5.将防渗层与粘结胶带的外侧粘附在一起; 制得聚合物经皮给药贴剂。 本发明的有益效果如下: ..
1.本发明所述的聚合物微针阵列芯片中的微针的机械强度高, 针尖锋利, 可以容易地 刺穿皮肤的角质层; 2.本发明所述的聚合物微针阵列芯片中的微针阵列部分采用水溶性的聚丙烯酰胺类聚 合物为基质材料, 可利用其水溶液及其与生物活性物质或药物和水构成的水溶液或混合液 通过模制的方式制备聚合物微针阵列芯片, 避免了高温加工处理步骤, 有利于多肽、 蛋白 质等生物大分子药物保持活性;
3.本发明所述的聚丙烯酰胺聚合物遇含水环境易溶解或溶胀, 有利于药物在皮肤内缓 释;
4.本发明所述的基于聚合物微针阵列芯片的经皮给药贴剂的制备工艺简单, 可以利用 目前已经成熟的加工工艺进行批量生产
附图说明
图 1 : 微针阵列芯片示意图;
图 2-1 : 微针的针体结构示意图;
图 2-2: 微针的针体结构示意图;
图 2-3 : 微针的针体结构示意图;
图 2-4: 微针的针体结构示意图;
图 2-5: 微针的针体结构示意图;
图 3 : 微针中轴线与衬底所在的平面垂直或者倾斜时的结构剖视图;
图 4: 空心微针示意图;
图 5: 微针阵列为长方形, 椭圆形, 三角形和不规则图形的微针阵列芯片示意图。 图 6: 制备聚合物微针阵列芯片的技术路线示意图;
7 : 多个 A类微针原型在同一光滑平整底面 6上排列时的示意图;
图 8: B类微针阵列原型示意图;
图 9: C类微针阵列原型示意图;
图 10: 利用 A类微针阵列芯片原型制备阴模时的立体结构示意图;
..图 11 : 用于制备微针阵列芯片的单个阴模示意图;
图 12: 用于制备微针阵列芯片的包含多个阴模的模板示意图;
图 13 : 微针经皮给药制剂示意图;
图 14: A类微针阵列芯片原型的剖面示意图;
图 15: B类微针阵列芯片原型的剖面示意图;
图 16: C类微针阵列芯片原型的剖面示意图; 图 17 : 本发明实施例中制备的一种实心聚合物微针阵列芯片的整体形貌图。
具体实施方式
具体实施方式是对本发明所述的聚合物微针阵列芯片及制备方法和应用做进一步的详 细说明, 目的是使本领域的技术人员更好地理解本发明。
本发明所述的微针阵列芯片如图 1所示, 包括微针阵列 1和微针阵列 1立于其上的衬 底 2两部分, 所述微针阵列 1的基质材料为聚丙烯酰胺类聚合物;
本发明所述的聚丙烯酰胺类聚合物, 是指一类可医用的聚合物, 由丙烯酰胺单体聚合 而成, 反应方程式为
N H 引发剂 CH2一^
n ^ Y —— - 、 I n
O 0二 C
NH2
本发明所述的聚合物结构可为直链型均聚物、 共聚物或交联聚合物。 优选地, 所述聚 合物为直链型均聚物, 其主要特征在于: 分子量为 1.0X 104~2.0X 105; 维氏硬度为 150~600 (HV); 冲击强度为 5~30J/M; 残余丙烯酰胺单体含量的测量值 0.5ppm, 符合世界卫生组 织规定的医用标准。
本发明所述的聚丙烯酰胺类聚合物具有良好的水溶性, 可与水混合得到质量百分数为 1~80%的水溶液。利用所述聚丙烯酰胺类聚合物制备的厚度为 2毫米,边长为 1厘米的正方 形薄板浸泡在静止放置的生理盐水中时, 经 6小时至少溶解 50%。
本发明所述的聚合物微针阵列芯片的微针阵列 1可由聚丙烯酰胺类聚合物制备而成; 也可由聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物制备而成。
本发明所述的聚合物微针阵列芯片的衬底 2可由纯聚丙烯酰胺类聚合物制备而成; 也 可由聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物制备而成; 还可由也可由聚 乳酸、 聚乙烯、 聚丙烯、 聚丁二酸丁二醇酯、 橡胶、 乳胶、 玻璃或者金属热塑性复合材料 等其中的一种材料制备而成或几种材料分层组合制备而成。
本发明所述的生物活性物质或药物为任意分子量的疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药物、 基因工程药物、 天然产物药物、 中药成分或者营养成分中的一种或者几 种组分的组合; 本发明所述的生物活性物质或药物在其与聚丙烯酰胺类聚合物构成的混合 物中的质量百分数为 0.1~50%; 优选地, 质量百分数为 10~20%; 具体混合比例可根据所需 要的生物活性物质或药物的剂量以及所制备的微针阵列芯片的空间特征进行调整, 所得到 的混合物可以与水混合得到具有流动性的水溶液或混合液, 上述混合物在水溶液或混合液 中的质量百分数为 1~80%; 优选地, 上述质量百分数为 10~50%。
本发明提供了制备上述聚丙烯酰胺类聚合物的合成方法, 主要包括如下步骤:
S-1 , 在配有搅拌装置的反应器内, 按照设定值加入有机溶剂、 水、 丙烯酰胺单体; 本发明所述的有机溶剂以醇类为主, 酮类为辅。 醇类选自甲醇、 乙醇、 正丙醇、 异丙 醇、 正丁醇等组分中的至少一种或者两种以上混合物; 优选地, 醇类溶剂在反应体系中的 体积百分数 60%; 所述酮类选择丙酮、 丁酮、 甲基异丁基酮和环己酮中等组分中的一种 或者两种以上的混合物。优选地, 酮类溶剂在反应体系中的体积百分数 25%; 本发明可以 通过改变所述有机溶剂在反应体系中所占的体积百分比对聚合物的分子量进行控制;
本发明所述的水在反应体系中的体积百分数占应 25%; 本发明可以通过调整所述水 在反应体系中的体积百分比对所得到的聚合物的分子量进行调整;
本发明所述的丙烯酰胺单体在反应体系中的初始浓度为 0.1-3mol/L; 本发明可以通过 改变丙烯酰胺单体在反应体系中的初始浓度对所得到的聚合物的分子量进行调整;
S-2, 向包含上述溶剂和丙烯酰胺单体组成的反应体系的反应器内通高纯氮气以除氧, 保持搅拌, 同时将反应体系加热升温至目标温度; 所述的目标温度为 30-85 °C; 优选地,所 述目标温度为 40-70°C; 本发明可以通过改变合成时的目标温度对所得到的聚合物的分子量 进行调整;
S-3 , 反应体系温度达到目标温度后, 将引发剂加入上述反应体系中, 保持搅拌和氮气 通入;
本发明所述的引发剂可以为偶氮类引发剂, 如偶氮二异丁腈、 偶氮二异庚腈, 偶氮二 异丁脒盐酸盐, 偶氮二丁酸二异丁酯, 偶氮二异丁酸二甲酯中的至少一种或者两种以上的 混合物;
本发明所述的引发剂也可以为无机或有机过氧化物, 如过硫酸铵、 过硫酸钠、 过硫酸 钾、 扭丁基过氧化氢、 过氧化二异丙苯、 过氧化苯甲酰中的至少一种或者两种以上的混合 物, 同时可加入还原剂, 如亚硫酸氢钠或偏亚硫酸钠, 使聚合反应速度更快, 反应更彻底; 本发明所述的引发剂的的用量一般为上述丙烯酰胺单体重量的 0.01~1%。 本发明可以 通过改变引发剂的用量对所得到的聚合物的分子量进行控制;
S-4, 加入引发剂后, 在目标温度下继续恒温一定时间, 并保持搅拌和氮气通入; 本发明所述的反应体系保持恒温的时间为 8~30小时。优选地,所述保持恒温的时间为 12~20小时;
S-5, 反应结束后, 首先将反应器内的固液混合物进行真空过滤, 然后将得到的固体产 物放在真空烘箱内进行干燥, 温度为 30〜70 °C之间;
S-6, 将干燥后的反应产物用适量水溶解, 待完全溶解后, 加入只能溶解丙烯酰胺单体 而不能溶解聚合产物的有机溶剂进行重沉淀, 以去除未反应的丙烯酰胺单体, 所述有机溶 剂为甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇、 丙酮、 丁酮、 甲基异丁基酮和环己酮中的至 少一种或者两种以上的混合物。
重复以上 S-5— S-6三次;
S-7, 将除掉丙烯酰胺单体后的反应产物在真空烘箱中进行干燥, 温度为 30-70 °C, 时 间为 20-50小时。 干燥后的样品在干燥密闭容器内进行保存;
S-8, 利用岛津液相色谱仪(LC-20A/SPD-20AV)测量 S-7所制备的样品中的残余丙烯 酰胺单体含量, 丙烯酰胺单体含量占聚丙烯酰胺总量的测量值均 0.5ppm;
S-9, 按照 GB 17514-2008方法并结合静态光散射方法 (Wyatt DAWN HELEOS-Π)测 量其分子量; 不同合成条件下的聚合物的分子量的测量值在 1.0 X 104~2.0 X 105之间分布;
S-10, 将得到到的聚合物与水混合得到水溶液, 然后浇注于模具中, 通过烘干处理制 得块体材料, 按照 GB/T4340.2标准测得块体材料的维氏硬度约为 150-600HV; 按照美国 ATSM 的 D-256标准测得冲击强度约为 5-30J/m。
本发明所述的聚合物微针阵列芯片的微针阵列 1包括 2个以上的微针; 微针由针杆 3 和针头 4组成; 针杆 3为微针的主体部分, 其后部与微针阵列芯片的衬底 2相连; 微针 4 为微针的顶部, 即针尖部分。
本发明所述的微针的针体结构可为图 2-1〜图 2-5所示的多种类型中的任何一种- 本发明所述的针杆 31和针头 41为一体的圆锥结构;针杆 31与衬底 2连接处的截面圆 的直径为 20-3000微米, 上述针杆 31和针头 41的高度之和为 50-5000微米; 优选地, 上述 截面圆的直径为 50-1000微米, 针杆 31和针头 41的高度 和为 200-2000微米; 针头 41最 尖端处的外接圆的曲率半径为 50纳米 -300微米; 优选地, 上述曲率半径小于 10微米。
本发明所述的针杆 32为圆柱体,针头 42为圆锥体;针杆 32的截面圆的直径为 20-3000 微米, 针杆 32高度为 50-3000微米; 优选地, 上述截面圆的直径为 50-1000微米, 针杆 32 高度为 200-2000微米;针头 42底面的直径与针杆 32的截面圆的直径一致,高度为 50-2000 微米; 优选地, 上述高度为 50-1000微米; 针头 4-2最尖端处的外接圆的曲率半径为 50纳 米 -300微米; 优选地, 上述曲率半径小于 10微米。
本发明所述的针杆 33和针头 43为一体的三棱锥结构; 针杆 35和针头 45为一体的四 棱锥结构; 针杆 37和针头 47为五棱锥结构; 上述棱锥体与衬底 2连接处的截面的外接圆 的直径为 20-3000微米, 上述针杆 3和针头 4的高度之和为 50-3000微米; 优选地, 上述外 接圆的直径为 50-1000微米, 针杆 3和针头 4的高度之和为 200-2000微米; 上述棱锥形针 头 4最尖端处的外接圆的曲率半径为 50纳米 -300微米; 优选地, 上述曲率半径小于 10微 米。
本发明所述的针杆 34为三棱柱, 针头 44为三棱锥体; 针杆 36为四棱柱, 针头 46为 四棱锥体;针杆 38为五棱柱,针头 48为五棱锥;上述棱柱形针杆 3的截面圆的直径为 20-3000 微米, 针杆 3的高度为 50-4000微米; 优选地, 上述截面圆的直径为 50-1000微米, 针杆 3 髙度为 200-2000微米; 上述棱锥体针头 4的底面的外接圆的直径与所连接的棱锥体的外接 圆的直径相同,棱锥体针头 4的高度为 50-2000微米;优选地,上述棱锥体 4的高度为 50-1000 微米; 上述棱锥体针头 4最尖端处的外接圆的曲率半径为 50纳米 -300微米; 优选地, 上述 曲率半径小于 10微米。
本发明所述的针杆 39为圆柱体, 针头 49为一上表面与衬底 2所在的平面成设定锐角 的椭圆形平面; 针杆 310为圆柱体, 针头 410为两个与衬底所在的平面成设定锐角的椭圆 形平面; 类似地, 针杆 3为圆柱体时, 针头 4可为多个与衬底 2所在的平面成设定锐角的 椭圆形或扇形平面构成的尖状结构; 针杆 39和 310的截面圆的直径为 20-3000微米, 针杆 39和 310高度分别为 50-3000微米; 优选地, 上述截面圆的直径为 50-1000微米, 针杆 39 和 310高度分别为 200-2000微米; 针头 49和 410的底面的直径分别与针杆 39和 310的截 面圆的直径一致, 高度为 50-2000微米; 优选地, 上述高度为 50-1000微米; 上述针头 4最 尖端处的刃部的厚度为 50纳米 -300微米; 优选地, 上述针头 4的刃部的厚度为小于 10微 米。
本发明所述的针杆 3和针头 4可由含更多边的棱柱体和棱锥体组合构成; 微针针体可 为其他任何具有尖端状的结构。
如图 3所示, 本发明所述的针杆 3和针头 4的中轴线可以与衬底 2所在的平面保持垂 直或倾斜一定角度; 优选地, 针杆 3和针头 4的中轴线与衬底 2所在的平面保持垂直。
本发明所述的组成微针阵列 1的聚合物微针可以为实心微针, 也可以为空心微针。 如 图 4所示, 空心微针由针杆 3, 针头 4和内孔 5构成; 类似地, 图 2-1〜图 2-5中所示的各 种类型的实心微针均可加工成含内孔的空心微针; 优选地, 聚合物微针为实心微针。
本发明所述的微针阵列 1的空间排列方式可以为线形; 可以为如图 5所示的长方形、 正方形、 平行四边形, 圆形、 椭圆形、 三角形或其他图形。
本发明所述的微针阵列 1可为实心微针阵列 1或者空心微针阵列 1, 或者两者的混合 阵列; 优选地, 微针阵列 1为实心微针阵列 1。
本发明所述的微针阵列芯片中的衬底 2的厚度为 50-5000微米; 优选地, 衬底的厚度 为 100-2000微米。
本发明所述的微针阵列芯片的的空间参数, 包括微针的形状, 长度, 间距、 数量, 微 针阵列 1的排列方式, 衬底 2的厚度等均可根据需要进行调整。 本发明所述的制备聚合物微针阵列芯片的方法如图 6所示, 主要包括如下步骤- F-01, 制备与聚合物目标微针阵列芯片具有同样空间特征的原型
本发明所述的微针阵列芯片原型可由钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金, 镍合金、 铝合金、 铜合金或者其他金属或者合金中的任意一种, 通过数控激光加工或者电火花加工 等微机电加工技术制备而成;
按照空间结构特征的不同, 本发明所述的微针阵列芯片原型可以分为 A、 B和 C三种 类型;
本发明所述的 A类微针阵列芯片原型和图 1所示的微针阵列芯片具有同样的空间特 征, 包括微针阵列 1和衬底 2两部分;
本发明所述的 A类微针阵列芯片原型中的最外侧微针与衬底交界处的截面圆距衬底 2 上表面的外侧的最短距离为 100-5000微米; 优选地, 上述最短距离为 500-2000微米; 本发明所述的多个 A类微针阵列芯片原型可以按照任意拓扑结构在同一光滑平整底面 6上排列, 如图 7所示;
本发明所述的底面 6可由钛、 铜、 铝、 镍、 钨、 不锈 、 钛合金, 镍合金、 铝合金、 铜合金或者其他金属或者合金中的任意一种制备而成, 也可由玻璃、 硅、 二氧化硅等材料 制备而成;
本发明所述的 A类微针阵列原型的空间参数, 包括微针的数量、 高度、 间距、 与衬底 2所在的平面所成的角度; 微针阵列 1的排列方式; 衬底 2的厚度等, 可以根据目标聚合物 微针阵列芯片的需要进行调整; 本发明所述的 B类微针阵列芯片原型如图 8所示, 微针阵列 1、 衬底 2和环绕衬底 2 的凹环 7在底面 6上直接加工而成;
本发明所述的 B类微针阵列芯片原型中的最外侧微针与衬底交界处的截面圆距衬底 2 上表面的外侧的最短距离为 100-5000微米; 优选地, 上述最短距离为 500-2000微米; 本发明所述的 B类微针阵列原型中的凹环 7的截面可以是长方形、 正方形或半圆形等 规则,或不规则形状; 凹环 7截面的最大深度为 100-5000微米,最大宽度为 100-5000微米; 优选地, 凹环 7截面的最大深度为 100-2000微米, 最大宽度为 100-2000微米;
本发明所述的 B类微针阵列芯片原型,可以每次在底面 6上单独加工一个微针阵列 1、 衬底 2和相应的凹环 7, 也可以在同一底面 6上一次加工多个微针阵列 1、 衬底 2和相应的 凹环 7; 多个微针阵列 1、 衬底 2和相应的凹环 7可以按照任意拓扑结构在底面 6上排列; 本发明所述的 B类微针阵列芯片原型的空间参数, 包括微针的数量、 高度、 间距、 与 衬底所在的平面所成的角度; 衬底的厚度; 微针阵列 1、 衬底 1及相应的凹环 7在底面 6上 的排列方式等, 可以根据目标聚合物微针阵列芯片的需要进行调整;
本发明所述的 C类微针阵列芯片原型如图 9所示, 微针阵列 1、 衬底 2, 环绕衬底 2 的凹环 7、 垂直于衬底 2且环绕于凹环 7的侧面 8在底面 6上直接加工而成;
本发明所述的 C类微针阵列芯片原型中的最外侧微针与衬底 2交界处的截面圆距衬底 2上表面的外侧的最短距离为 100-5000微米; 优选地, 上述最短距离为 500-2000微米; 本发明所述的 C类微针阵列芯片原型中的凹环 7的截面可以是长方形、 正方形或半圆 形等规则或不规则形状, 凹环 7截面的最大深度为 100-5000微米, 最大宽度为 100-5000微 米; 优选地, 所述最大深度为 100-2000微米, 最大宽度为 100-2000微米;
本发明所述的 C类微针阵列芯片原型中的凹环 7外侧任意位置距侧面 8的垂直距离为 0-5000微米; 优选地, 距离为 0微米, 即凹环 7外侧与侧面 8内侧重合;
本发明所述的侧面 8的上表面距衬底 2上表面的垂直高度大于微针针头 4尖端处距衬 底 2上奉面的垂直高度 50-5000微米; 优选地, 上述垂直高度的差 200- 2000微米;
本发明所述的 C类微针阵列芯片原型, 可以每次在底面 6上单独加工一个, 也可以在 同一底面 6上一次加工多个微针阵列 1、 衬底 2、 相应的凹环 7和侧面 8 ; 多个微针阵列 1、 衬底 2、 及相应的凹环 7和侧面 8可以按照任意拓扑结构在底面 6上排列;
本发明所述的 C类微针阵列芯片原型的空间参数, 包括微针的数量、 高度、 间距、 与 衬底所在的平面所成的角度; 衬底的厚度; 微针阵列 1、 衬底 1及相应的凹环 7和侧面 8在 底面 6上的排列方式等, 可以根据目标聚合物微针阵列芯片的需要进行调整; F-02, 利用上述微针阵列芯片原型制备阴模'
如图 10所示, 利用所述 A类微针阵列芯片原型制备阴模时, 首先将 F-01制备的单个 或多个微针阵列芯片原型放置在底面 6上; 然后在每一个微针阵列芯片原型周围构建一垂 直于底面 6、 环绕微针阵列原型的封闭侧面 8; 最终形成一个底面 6和侧面 8封闭, 上面开 口的立体结构;
利用所述 A类微针阵列芯片原型制备阴模时, 制备所述侧面 8的材料可以是钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金, 镍合金、 铝合金、 铜合金或者其他金属或者合金中的任意 一种, 也可以是玻璃、 硅、 二氧化硅等材料中的任意一种;
利用所述 A类微针阵列芯片原型制备阴模时, 所述侧面 8与底面 6交界处的内侧的任 意位置与衬底 2与底面 6交界处的最外侧的最短距离为 100-5000微米, 优选地, 上述最短 距离为 500-2000微米;
利用所述 A类微针阵列芯片原型制备阴模时, 所述侧面 8的上表面距底面 6的上表面 的垂直高度大于微针阵列芯片原型的衬底 2和微针的垂直高度之和 50-5000微米; 优选地, 上述垂直高度差为 100-2000微米;
利用所述 A类微针阵列芯片原型制备阴模时, 当所述立体结构制备完成之后, 可将液 态或者熔融状态的聚合物从上面开口处进行浇注至立体结构被注满; 所述聚合物为聚丙烯、 聚乙烯、 聚乳酸、 聚丁二酸丁二醇酯中、 聚二甲基硅氧烷或者其他聚合物中的至少一种; 优选地, 所述用于浇注的液态或者熔融态的聚合物需要比较容易地进行脱模处理; 进一步 优选地, 所述的聚合物在固化成型之后具有合适的硬度, 以方便接下来制备微针阵列芯片; 利用所述 B类微针阵列芯片原型制备阴模时, 首先在底面 6上构建一垂直于底面 6, 环绕凹环 7的封闭侧面 8, 最终形成一如图 9所示, 底面 6和侧面 8封闭, 上面开口的立体 结构;
利用所述 B类微针阵列芯片原型制备阴模时, 制备所 侧面 8的材料可以是钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金, 镍合金、 铝合金、 铜合金或者其他金属或者合金中的任意 一种, 也可以是玻璃、 硅、 二氧化硅等材料中的任意一种;
利用所述 B类微针阵列芯片原型制备阴模时, 所述侧面 8与底面 6交界处的内侧的任 意位置与凹环 7外侧的最短距离为 0-5000微米; 优选地, 上述最短距离为 0微米, 即凹环 7和侧面 8交内侧重合; 利用所述 B类微针阵列芯片原型制备阴模时, 所述侧面 8上表面距衬底 2的上表面的 垂直高度大于微针针头 4的顶端距衬底 2上表面的垂直高度 50-5000微米;优选地,上述垂 直高度差为 100-2000微米;
利用所述 B类微针阵列芯片原型制备阴模时, 当所述立体结构制备完成之后, 可将液 态或者熔融状态的聚合物从上面开口处进行浇注至立体结构被注满。 所述聚合物为聚丙烯、 聚乙烯、 聚乳酸、 聚丁二酸丁二醇酯中、 聚二甲基硅氧垸或者其他聚合物中的至少一种; 优选地, 所述用于浇注的液态或者熔融态的聚合物需要比较容易地进行脱模处理; 进一步 优选地, 所述聚合物在固化成型之后具有合适的硬度, 以方便接下来制备微针阵列芯片; 利用所述 C类微针阵列芯片原型制备阴模时, 可将液态或者熔融状态的聚合物从每个 立体结构的上面开口处进行浇注至至立体结构被注满。 所述聚合物为聚丙烯、 聚乙烯、 聚 乳酸、 聚丁二酸丁二醇酯中、 聚二甲基硅氧烷或者其他聚合物中的至少一种; 优选地, 所 述用于浇注的液态或者熔融态的聚合物需要比较容易地进行脱模处理; 更优选地, 所述聚 合物在固化成型之后具有合适的硬度, 以方便接下来制备微针阵列芯片;
F-03, 将微针阵列芯片原型脱模处理后得到阴模
所述步骤 F-02中注入模具中的聚合物溶液或者熔融态的聚合物固化之后,可进行脱模 处理 F-03。 图 11所示为聚合物模板 9上具有单个阴模, 包括微针腔体 10和衬底腔体 11。 图 12所示为聚合物模板 9上具有多个阴模,每个阴模均由微针腔体 10和衬底腔体 11构成;
F-04, 利用阴模制备微针阵列芯片
根据聚合物微针阵列芯片中的微针阵列 1部分和衬底 2部分所采用的材料类型的不同, 本发明所述的利用聚丙烯酰胺类聚合物或其与生物活性物质或药物构成的混合物制备微针 阵列芯片的方法可分为 Fl, F2和 F3三种类型。
F1型方法制备聚合物微针阵列芯片:
本发明所述的 F1型方法,指制备聚合物微针阵列芯片时,微针阵列 1和衬底 2采用同 一种类型的材料;
本发明所述的同一种类型的材料, 指聚丙烯酰胺类聚合物或其与生物活性物质或药物 构成的混合物。 本发明所述的生物活性物质或药物为任意分子量的疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药物、 基因工程药物、 天然产物药物、 中药成分或者营养成分中 的一种或者几种组分的组合;
具体制备步骤如下: 1、 如果制备材料为聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物时, 则首 先需要将聚丙烯酰胺类聚合物与固态或液态的生物活性物质或药物按照一定比例进行混 合; 所述生物活性物质或药物在其与聚丙烯酰胺类聚合物构成的混合物中的质量百分数为
0.1-50%; 优选地, 质量百分数为 10~20%, 以保证所制备的微针的机械强度可以容易地刺 破皮肤; 聚丙烯酰胺类聚合物与生物活性物质或药物的具体混合比例可根据治疗疾病所需 要的剂量和所制备的聚合物微针阵列芯片的空间特征进行调整;
2、 将聚丙烯酰胺聚合物或其与生物活性物质或药物构成的混合物与水在 10~90°C的温 度下共混以得到水溶液或混合液; 聚丙烯酰胺聚合物或其与生物活性物质或药物构成的混 合物在水溶液或混合液中的质量分数为 1~80%;优选地,上述质量分数为 10〜50%;优选地, 对上述水溶液或混合液进行超声处理, 以去除含有的气泡;
3、 使用水将步骤 F-03制得到的模具进行清洗, 然后放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封闭的体系中, 以确保制备聚合物微针阵列芯片过程中不受 外界环境的影响; 优选地, 水平操作平台与模具之间使用粘性液体密封, 以确保模具紧密 地固定在水平操作平台上, 同时保证实验结束后模具可从操作平台方便的取下;
4、 将步骤 2制备的水溶液或混合液浇注于 F-03制得的, 如图 11或 12所示的阴模中; 所需浇注的水溶液或混合液的体积由微针阵列腔体 10的体积, 衬底腔体 11的体积, 以及 聚丙烯酰胺类聚合物或其与生物活性物质或药物的混合物在水溶液或混合液中的质量分数 决定;
5、 将步骤 4浇注到阴模中的水溶液或混合液进行烘干处理, 烘干温度为 20〜90°C ; 优 选地, 烘干温度为 20-50 °C; 如果一次浇注到阴模中的水溶液或混合液中的聚丙烯酰胺类聚 合物或其与生物活性物质或药物构成的混合物能够满足制备微针阵列芯片需要时, 可将注 入阴模中的水溶液或混合液直接烘干至其中的聚丙烯酰胺类聚合物或其与生物活性物质或 药物构成的混合物固化成型, 得到符合设计要求的聚合物微针阵列芯片; 如果一次浇注到 阴模中的水溶液或混合液中的聚丙烯酰胺类聚合物或其与生物活性物质或药物构成的混合 物无法满足制备微针阵列芯片需要时, 可以通过烘干处理去除浇注于阴模中的水溶液或混 合液中的部分水分, 然后进行二次或多次浇注, 直到阴模中的聚丙烯酰胺类聚合物或其与 生物活性物质或药物构成的混合物能够满足制备微针阵列芯片的需要时为止, 最后通过烘 干处理使聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物固化成型, 得到符合设 计要求的聚合物微针阵列芯片; F2型方法聚合物微针阵列芯片的:
本发明所述 F2型方法, 指制备聚合物微针阵列芯片时, 微针阵列 1部分和衬底 2部分 采用不同类型的材料;
所述微针针体 1部分与所连接的厚度小于 50微米的衬底薄层由聚丙烯酰胺类聚合物与 生物活性物质或药物构成的混合物制备而成; 所述的衬底主体层由聚丙烯酰胺类聚合物制 备而成。 本发明所述的生物活性物质或药物为任意分子量的疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药物、 基因工程药物、 天然产物药物、 中药成分或者营养成分中的一种 或者几种组分的组合;
具体制备步骤如下:
1、 将聚丙烯酰胺类聚合物与固态或液态的生物活性物质或药物按照一定比例进行混 合; 所述生物活性物质或药物在其与聚丙烯酰胺类聚合物构成的混合物中的质量百分数为 0.1-50%; 优选地, 质量百分数为 10~20%, 以保证所制备的微针的机械强度可以容易地刺 破皮肤; 聚丙烯酰胺类聚合物与生物活性物质或药物的具体混合比例根据治疗疾病所需要 的剂量和所制备的聚合物微针阵列芯片的空间特征进行调整;
2、 将聚丙烯酰胺聚合物与生物活性物质或药物构成的混合物与水在 10〜90°C的温度下 共混以得到混合液; 聚丙烯酰胺聚合物与生物活性物质或药物构成的混合物在混合液中的 质量分数为 1~80%之间; 优选地, 上述质量分数为 10~50%之间; 优选地, 对上述混合液进 行超声处理, 以去除含有的气泡。
3、 使用水将步骤 F-03制得到的阴模进行清洗, 然后放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封闭的体系中, 以确保制备聚合物微针阵列芯片过程中不受 外界环境的影响; 优选地, 水平操作平台与模具之间使用粘性液体密封, 以确保模具紧密 地固定在水平操作平台上, 同时保证实验结束后模具可从操作平台方便的取下;
4、 将步骤 2制备的水溶液或混合液浇注于 F-03制得的, 如图 11或 12所示的阴模中; 所需浇注的水溶液或混合液的体积由微针阵列腔体 10的体积, 以及聚丙烯酰胺类聚合物与 生物活性物质或药物的混合物在水溶液或混合液中的质量分数决定;
5、 将步骤 4浇注到阴模中的水溶液或混合液进行烘干处理, 烘干温度为 20〜90°C ; 优 选地, 烘干温度为 20-50。C; 如果一次浇注到阴模中的水溶液或混合液中的聚丙烯酰胺类聚 合物与生物活性物质或药物构成的混合物能够满足制备微针阵列芯片的微针阵列 1部分和 所连接的厚度小于 50微米的衬底 2薄层需要时, 可将注入阴模中的水溶液或混合液直接烘 干至其中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物固化成型, 得到符合 设计要求的聚合物微针阵列芯片的微针阵列 1部分和所连接的厚度小于 50微米的衬底薄 层; 如果一次浇注到阴模中的水溶液或混合液中的聚丙烯酰胺类聚合物与生物活性物质或 药物构成的混合物无法满足制备微针阵列芯片的微针阵列 1部分和所连接的厚度小于 50微 米的衬底 2薄层的需要时, 可以通过烘干处理去除浇注于阴模中的水溶液或混合液中的部 分水分, 然后进行二次或多次浇注, 直到阴模中的聚丙烯酰胺类聚合物与生物活性物质或 药物构成的混合物能够满足制备微针阵列芯片的微针阵列 1部分和所连接的厚度小于 50微 米的衬底 2薄层的需要时为止, 最后通过烘干处理使聚丙烯酰胺类聚合物与生物活性物质 或药物构成的混合物固化成型, 得到符合设计要求的聚合物徼针阵列芯片的微针阵列 1部 分和所连接的厚度小于 50微米的衬底薄层。
6、 将聚丙烯酰胺聚合物与水在 10~90°C的温度下共混以得到水溶液。 聚丙烯酰胺类聚 合物在水溶液中的质量分数为 20~80%; 优选地, 上述质量分数为 40〜60%; 优选地, 一次 浇注到阴模中的水溶液中的聚丙烯酰胺类聚合物能满足制备微针阵列芯片的衬底主体层的 需要; 优选地, 对上述水溶液或混合液进行超声处理, 以去除含有的气泡;
7、 将步骤 6中制备的纯聚丙烯酰胺类聚合物的水溶液浇注于步骤 3~5中所使用的阴模 中; 所浇注的聚合物水溶液的体积由衬底腔体 11的部分体积, 以及聚丙烯酰胺类聚合物在 水溶液中的质量分数决定;
8、 将步骤 7浇注到阴模中的水溶液进行烘干处理; 烘干温度为 20〜90°C; 优选地, 烘 干温度为 20〜50 °C; 通过烘干处理, 使浇注于阴模中的聚丙烯酰胺类聚合物完全固化成型, 以制得聚合物微针阵列芯片中的衬底主体层, 并得到完整的聚合物微针阵列芯片;
F3型方法聚合物微针阵列芯片- 本发明所述的 F3型方法, 指制备聚合物微针阵列芯片时, 微针阵列 1和衬底 2采用不 同类型的材料;
所述微针针体 1与所连接的厚度小于 50微米的衬底薄层由 ¾丙烯酰胺类聚合物或其与 生物活性物质或药物构成的混合物制备而成; 所述衬底主体层由聚乙烯、 聚丙烯、 聚丁二 酸丁二醇酯、 聚二甲基硅氧烷、 橡胶、 聚乳酸、 乳胶等医用聚合物、 玻璃或者金属热塑性 复合材料等的其中一种材料制备而成或几种材料分层组合制备而成;
具体制备步骤如下:
1、 如果制备材料为聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物, 则首先 需要将聚丙烯酰胺类聚合物与固态或液态的生物活性物质或药物按照一定比例进行混合。 所述生物活性物质或药物在其与聚丙烯酰胺类聚合物构成的混合物中的质量百分数为
0.1-50%; 优选地, 质量百分数为 10〜20%, 以保证所制备的微针的机械强度可以容易地剌 破皮肤; 优选地, 聚丙烯酰胺类聚合物与生物活性物质或药物的具体混合比例可根据治疗 疾病所需要的剂量和所制备的聚合物微针阵列芯片的空间特征进行调整;
2、 将聚丙烯酰胺聚合物或其与生物活性物质或药物构成的混合物与水在 10~9(TC的温 度下共混以得到水溶液或混合液; 聚丙烯酰胺聚合物或其与生物活性物质或药物构成的混 合物在水溶液或混合液中的质量分数为 1~80%之间;优选地,上述质量分数为 10~50%之间; 优选地, 对上述水溶液或混合液进行超声处理, 以去除含有的气泡;
3、 使用水将步骤 F-03制得到的模具进行清洗, 然后放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封闭的体系中, 以确保制备聚合物微针阵列芯片过程中不受 外界环境的影响; 优选地, 水平操作平台与模具之间使用粘性液体密封, 以确保模具紧密 地固定在水平操作平台上, 同时保证实验结束后模具可从操作平台方便的取下;
4、 将步骤 2制备的水溶液或混合液浇注于 F-03制得的, 如图 11或 12所示的阴模中; 所需浇注的水溶液或混合液的体积由微针阵列腔体 10的体积, 以及聚丙烯酰胺类聚合物或 其与生物活性物质或药物的混合物在水溶液或混合液中的质量分数决定;
5、 将步骤 4浇注到阴模中的水溶液或混合液进行烘干处理, 烘干温度为 20~90°C ; 优 选地, 烘干温度为 20-50 °C; 如果一次浇注到阴模中的水溶液或混合液中的聚丙烯酰胺类聚 合物或其与生物活性物质或药物构成的混合物能够满足制备微针阵列芯片的微针阵列 1和 所连接的厚度小于 50微米的衬底薄层需要时, 可将注入阴模中的水溶液或混合液直接烘干 至其中的聚丙烯酰胺类聚合物或其与生物活性物质或药物构成的混合物固化成型, 得到符 合设计要求的聚合物微针阵列芯片的微针阵列 1和所连接的厚度小于 50微米的衬底薄层; 如果一次浇注到阴模中的水溶液或混合液中的聚丙烯酰胺类聚合物或其与生物活性物质或 药物构成的 合物无法满足制备微针阵列芯片的需要时, 可以通过烘干处理去除浇注于阴 模中的水溶液或混合液中的部分水分, 然后进行二次或多次浇注, 直到阴模中的聚丙烯酰 胺类聚合物或其与生物活性物质或药物构成的混合物能够满足制备微针阵列芯片的微针阵 列 1和所连接的厚度小于 50微米的衬底薄层的需要时为止, 最后通过烘干处理使聚丙烯酰 胺类聚合物或其与生物活性物质或药物构成的混合物固化成型, 得到符合设计要求的聚合 物微针阵列芯片的微针阵列 1和所连接的厚度小于 50微米的衬底薄层; 6、 将构成衬底主体层的其他单层或多层薄膜材料通过粘结、 融合、 键合或者其他物理 或化学方法与步骤 5制备的聚合物微针阵列芯片的微针阵列 1和所连接的厚度小于 50微米 的衬底薄层紧密地结合在一起, 以制得完整的聚合物微针阵列芯片; 所述单层或多层薄膜 由聚乙烯、 聚丙烯、 聚丁二酸丁二醇酯、 聚二甲基硅氧垸、 橡胶、 聚乳酸、 乳胶等医用聚 合物、 玻璃或者金属热塑性复合材料等的其中一种或者几种材料的分层组合制备而成。
F-05, 微针阵列芯片的保存
制得的聚合物微针阵列芯片, 可从阴模中脱出, 保存在合适的器具中, 也可以继续保 存在阴模中; 优选地, 制得的聚合物微针阵列芯片继续保存在阴模中, 以进行下一步微针 经皮给药贴剂的制备。
一种利用本发明所述的聚合物微针阵列芯片制备的如图 13所示的聚合物微针贴剂, 该 聚合物微针贴剂包括微针阵列 1和微针阵列立于其上的衬底 2组成的微针阵列芯片, 还包 括: 基板 12、 防渗垫圈 13、 防粘层 14、 粘结胶带 15和防渗层 16; 所述基板 12粘贴在衬 底 2背面, 所述防渗垫圈 13环绕在衬底 2和基板 12的边缘; 所述防粘层 14覆盖在防渗垫 圈外侧; 所述粘结胶带 15是内外两侧均具有粘性的双面胶带, 其内侧覆盖基板 12、 防渗垫 圈 13和防粘层 14, 外侧与防渗层 16粘结在一起; 所述粘结胶带 15外侧覆盖防渗层 16; 本发明所述的基板 12是指粘附在微针阵列芯片背面的一层或者多层薄膜, 可由塑料、 聚合物、 合成树脂、 乳胶、 橡胶、 玻璃、 陶瓷、 金属或者复合材料中的至少一种制备而成; 可以为单层薄膜, 也可以为多层薄膜; 当为多层薄膜结构时, 每层之间采用粘结, 融合, 键合或者物理方法紧密结合在一起; 优选地, 构成基板 12的多层薄膜中的至少一层薄膜为 硬质薄膜; 基板 12的尺寸等于或者大于微针阵列芯片衬底 2的尺寸; 基板 12主要用来保 护微针阵列芯片, 使其免受外界环境的影响, 施药时有助于微针阵列方便地刺破皮肤角质 层; 本发明所述的微针经皮给药贴剂可以包括基板 12, 也可以不包括基板 12; 优选地, 微 针阵列芯片衬底 2使用聚丙烯酰胺类聚合物或其与生物活性物质或药物构成的混合物制备 而成时, 微针阵列芯片的衬底 2的背面粘附基板 12, 微针阵列 片的衬底 2采用其他材料 制备, 特别是不溶于水的材料制备而成时, 其背面不粘附基板 12;
本发明所述的防渗垫圈 13环绕在微针经皮给药贴剂基板 12周围, 主要保护微针阵列 芯片免受外部环境的影响, 特别是含水溶液的侵入; 可由乳胶、 橡胶、 医用塑料、 聚合物 中的一种或几种制备而成; 防渗垫圈 13的形状由所包围的微针经皮给药贴剂基板 12的形 状所决定, 即防渗垫圈 13的内侧的形状和基板 12的外侧的形状一致; 防渗垫圈 13的横截 面可矩形, 圆形等形状。 优选地, 防渗垫圈 4的截面为矩形; 防渗垫圈 13的截面的为略大 于或等于微针经皮给药贴剂的基板 12的高度; 优选地, 防渗垫圈 13的高度和基板 12的高 度相等; 防渗垫圈 13的截面的宽度为 20-5000微米; 优选地, 防渗垫圈 13的截面的宽度为 200-2000微米; 本发明所述的微针经皮给药贴剂可以包括防渗垫圈 13, 也可以不包括防渗 垫圈 13 ; 优选地, 如果微针经皮给药贴剂包括基板 12, 则在基板 12的周围环绕防渗垫圈 13, 如果微针经皮给药贴剂不包括基板 12, 则可以不包括防渗垫圈 13。
本发明所述的防粘层 14为覆盖在微针经皮给药制剂的防渗垫圈外侧的一层薄膜,由与 粘结胶带 15不发生粘合的材料制备而成; 施药时防粘层 14可以方便地剥离, 方便粘结胶 带 15用来固定经皮给药贴剂; 防粘层 14的面积和形状由其外侧的粘结胶带 15决定; 如图 13所示, 粘结胶带 15的大小和面积为基板 12, 防渗垫圈 13和防粘层 14的面积之和; 如 果微针经皮给药贴剂不包括基板 12和防渗垫圈 13, 则粘结胶带 15的面积为衬底 2和防粘 层 5的面积之和;
本发明所述的粘结胶带 15的内侧覆微针经皮给药贴剂的基板 12, 防渗垫圈 13和防粘 层粘 14, 外侧与防渗层 16粘结在一起。 施药时将防粘层 14剥离, 粘结胶带 15可以将微针 经皮给药贴剂固定在皮肤表面; 粘结胶带可为任何形状; 优选地, 粘结胶带为长方形。 粘 结胶带的长度为 1-150毫米, 宽度为 1-100毫米。 优选地, 长度为 10-50毫米, 宽度为 5-30 本发明所述的防渗层 16为粘结胶带 15外侧所覆的一层保护薄膜, 大小与形状与粘结 胶带 15—致或稍大; 防渗层 16主要用来防止含水溶液侵入聚合物微针阵列芯片, 可由进 行了疏水处理的各类纤维, 乳胶、 橡胶等其中的一种或者几种的混合物制备而成;
本发明所述的微针阵列芯片使用之前一般需要放置于保护装置中, 以避免微针因受到 外力而折断; 优选地, 微针阵列芯片制备完成后继续保存在如图 11或 12所示的模具中。 制备微针阵列芯片的模具包括模板 9、 微针腔体 10和衬底腔体 11三部分。 进一步优选地, 制备和保存微针经皮给药贴剂时, 微针阵列阵列芯片始终保存在模具中, 直到需要使用微 针经皮给药制剂用于治疗时才将其从模具中取出;
本发明所述的制备微针经皮给药贴剂的方法, 包括如下步骤:
1、 将基板 12与微针阵列芯片的衬底 2粘附在一起; 具体地, 在微针阵列芯片衬底 2 背面粘附粘附基板 12时, 如果基板 12为单层薄膜, 可利用粘结, 融合, 键合或者物理方 法使其与衬底 2紧密结合在一起;优选地,使用粘结的方式将衬底 2与基板 12结合在一起; 如果基板 12为多层薄膜结构, 可以先使多层之间相互粘合, 然后将多层薄膜组成的的基板 12再与微针阵列芯片的衬底 2粘附在一起; 多层膜也可以按照一定顺序逐步粘附在微针阵 列芯片的衬底 2背面; 优选地, 先制备含有多层薄膜结构的基板 12, 然后再与微针阵列芯 片的衬底 2粘附在一起; 如果衬底 2后面不需要粘附基板 12, 则制备方法不包括这一步骤;
2、将防渗垫圈 13固定在微针经皮给药贴剂的基板 12周围; 具体地, 首先加工内径与 基板 12具有相同形状的防渗垫圈 13,然后使用物理方法将防渗垫圈 13固定在基板 12的周 围; 如果微针经皮给药贴剂不包括防渗垫圈 4, 则制备方法不包括这一步骤;
3、 将防粘层 14放置在微针基板 12或微针阵列芯片衬底 2的外侧; 具体地, 首先根 据粘结胶带 15的形状和面积, 以及防渗垫圈 13的形状和面积, 预先加工防粘层 14, 然后 将加工好的防粘层 14放置在防渗垫圈 13的外侧; 如果微针经皮给药贴剂不包括基板 12和 防渗垫圈 13 , 则根据粘结胶带 15和衬底 2的形状和面积, 预先加工防粘层 14, 然后将加 工好的防粘层 14放置在衬底 2的外侧;
4、 将粘结胶带 15与防渗层 16粘和在一起; 具体地, 根据粘结胶带 15的形状和面积 预先加工具有同样形状和面积的防渗层 16, 然后将两者粘合在一起; 也可以先将粘结胶带 15和防渗层 16粘合在一起, 然后再根据形状和面积的要求进行裁剪;
5、将粘结胶带 15内侧与微针经皮给药贴剂的基板 12,防渗垫圈 13和防粘层 14粘合; 具体地, 将已与防渗层 16粘结在一起的粘结胶带 15覆盖于微针经皮给药贴剂的基板 12, 防渗垫圈 13和防粘层 14之上, 并粘合在一起。 如果微针经皮给药贴剂不包括基板 12和防 渗垫圈 13, 则将粘结胶带 15的内侧与衬底 2和防粘层 14粘结在一起;
发明所述步骤 F-04和 F-05, 可根据实际情况对先后顺序进行调整。
为了更好地对本发明的内容进行说明, 下面列举一些具体实施例。
实施例 1-14用于说明利用丙烯酰胺单体合成一种可医用的水溶性聚丙烯酰胺类聚合 物的方法, 合成得到的聚丙烯酰胺类聚合物可用于制备可医用的聚合物微针阵列芯片。
实施例 1-3用于说明水和各种有机溶剂的配比对丙烯酰胺聚食反应的影响。
实施例 1
在配有混流冷凝管、 温度计、 同氮装置的 250ml三口圆底烧瓶中, 按体积比 2:5:10:83 的比例依次加入水、 乙醇、 丙酮和异丙醇共 100ml, 通过磁力搅拌器将其混合均匀; 继续向 本体系加入 10.66g丙烯酰胺单体, 继续搅拌使其溶解; 通入氮气, 通过水浴将反应体系加 热, 设置目标温度为 60 °C; 将 107mg的偶氮二异丁腈溶于 10ml的异丙醇中, 混合均匀, 使其充分溶解, 等反应体系的温度到达目标温度 60 °C后, 向体系中加入 lml溶有偶氮二异 丁腈的异丙醇, 保温反应 15小时, 反应过程中保持搅拌, 并保证高纯氮气不间断通入; 反应结束后, 将体系冷却, 采用真空过滤将反应体系的固液进行分离, 接着将得到的 固体产物放入 55 °C真空干燥箱内干燥; 将千燥后的产物溶解在水中, 待完全溶解后, 使用 体积比为 6:4的乙醇-丙酮的混合液将聚合物进行重沉淀, 以去除未反应的丙烯酰胺单体; 重复以上溶解-沉淀-过滤-干燥过程三次, 将最终得到的样品保持在干燥密闭的容器中。
利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测 量值 0.5ppm。按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II ) 测量其分子量,所得到的聚合物的分子量约为 9.1 χ104。相应的块体材料按 GB/T4340.2标准 测得维氏硬度约为 430HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 20J/m。
实施例 2
同实施例 1, 改变溶剂的中水、 乙醇、 丙酮和异丙醇的配比为 5:5:10:80。 利用岛津液 相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II)测量其分子量, 所得到的聚合物的分子量约为 1.35 X 1 05。 相应的块体材料按 GB/T4340.2标准测得维氏硬 度约为 300HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 25J/m。
实施例 3
同实施例 1, 改变溶剂的中水、 乙醇、 丙酮和异丙醇的配比为 10:5:10:80。 利用岛津液 相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II)测量其分子量, 所得到的聚合物的分子量约为 2.0χ105。相应的块体材料按 GB/T4340.2标准测得维氏硬度约 为 150HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 30J/m。
实施例 1, 4-6用于说明丙烯酰胺单体在反应体系中的初始浓度对丙烯酰胺聚合反应的 影响。 ..
实施例 4
同实施例 1, 改变丙烯酰胺单体的质量为 3.56g。 利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II)测量其分子量, 所得到 的聚合物的分子量约为 6.3χ104。 相应的块体材料按 GB/T4340.2标准测得维氏硬度约为 550HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 9J/m。
实施例 5
同实施例 1, 改变丙烯酰胺单体的质量为 7.11g。 利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II )测量其分子量, 所得到 的聚合物的分子量约为 7.6χ104。 相应的块体材料按 GB/T4340.2标准测得维氏硬度约为 510HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 14J/m。
实施例 6
同实施例 1, 改变丙烯酰胺单体的质量为 14.22g。 利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II)测量其分子量, 所得到 的聚合物的分子量约为 1.2χ105。 相应的块体材料按 GB/T4340.2标准测得维氏硬度约为 330HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 24J/m。
实施例 1, 7-9用于说明反应温度对丙烯酰胺聚合反应的影响。
实施例 7
同实施例 1, 改变设置的恒温阶段的目标的温度为 55 °C。 利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II )测量其分子量, 所得到 的聚合物的分子量约为 9.5χ104。 相应的块体材料按 GB/T4340.2标准测得维氏硬度约为 410HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 21J/m。
实施例 8
同实施例 1, 改变设置的恒温阶段的目标的温度为 65 °C。 利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II) .测量其分子量, 所得到 的聚合物的分子量约为 8.7 X 1 04。 相应的块体材料按 GB/T4340.2标准测得维氏硬度约为 450HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 19J/m。
实施例 9
同实施例 1, 改变设置的恒温阶段的目标的温度为 70。C。 利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II )测量其分子量, 所得到 的聚合物的分子量约为 7.8χ 104。 相应的块体材料按 GB/T4340.2标准测得维氏硬度约为 490HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 16J/m。
实施例 1, 10-13用于说明引发剂的用量对丙烯酰胺聚合反应的影响。
实施例 10
同实施例 1, 改变溶于 10ml的异丙醇中的引发剂偶氮二异丁腈的量为 53.5mg。 利用 岛津液相色谱仪 (LC-20A/SPD-20AV ) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II )测量 其分子量,所得到的聚合物的分子量约为 1.6xl05。相应的块体材料按 GB/T4340.2标准测得 维氏硬度约为 250HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 28J/m。
实施例 11
同实施例 1, 改变溶于 10ml的异丙醇中的引发剂偶氮二异丁腈的量为 214mg。利用岛 津液相色谱仪(LC-20A/SPD-20AV)检测聚合物中残余丙烯酰胺单体含量,测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II )测量其分子量, 所得到的聚合物的分子量约为 4.3χ 104。相应的块体材料按 GB/T4340.2标准测得维氏硬度约 为 600HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 10J/m。
实施例 12
同实施例 1, 称取引发剂偶氮二异丁腈的量为 53.5mg, 直接加入反应器中, 同时加入 lml的异丙醇以保持和实施例 1 中的气体反应条件一致。 利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法(Wyatt DAWN HELEOS-II )测量其分子量, 所得到 的聚合物的分子量约为 1.0χ 104。 相应的块体材料按 GB/T4340.2标准测得维氏硬度约为 500HV。 按照美国 ATSM 的 D-256标准测得冲击强度约为 5J/m。
实施例 1, 1.3-14说明引发剂的种类对丙烯酰胺聚合反应的影响。
实施例 13
同实施例 1, 改变引发剂为 107mg过硫酸铵, 将溶解引发剂的溶剂异丙醇改变为 10ml 的水。 利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法 ( Wyatt DAWN HELEOS-II ) 测量其分子量, 所得到的聚合物的分子量约为 7.7χ 104。 相应的块体材料按 GB/T4340.2标准测得维氏硬度约为 500HV。按照美国 ATSM 的 D-256标准测得冲击强度 约为 15J/m。
实施例 14
同实施例 1, 改变引发剂为 107mg过氧化十二酰, 将溶解引发剂的溶剂异丙醇改变为 10ml的水。 利用岛津液相色谱仪 (LC-20A/SPD-20AV) 检测聚合物中残余丙烯酰胺单体含 量, 测量值 0.5ppm。 按照 GB 17514-2008方法并结合静态光散射方法 (Wyatt DAWN HELEOS-II ) 测量其分子量, 所得到的聚合物的分子量约为 8.2χ104道尔顿。 相应的块体材 料按 GB/T4340.2标准测得维氏硬度约为 470HV。 按照美国 ATSM 的 D-256标准测得冲 击强度约为 18J/m。
实施例 15
该实施例用于说明本发明所述 A类微针阵列芯片原型的制备方法。
选用镍铬不锈钢合金作为制备微针阵列原型的材料; 先利用电火花精密加工技术进行 线切割, 然后利用电化学腐蚀的方法进行抛光处理, 得到如图 14所示的 8 X 8微针阵列芯 片原型; 针杆 3和针头 4为一体化结构的五棱锥体, 针杆 3底部与衬底 2交界处的外接圆 的直径为 250微米, 邻针杆 3与衬底 2交界处的两外接圆的最短距离为 500微米, 微针的 高度为 1000微米, 微针尖端的曲率半径小于 10微米, 微针阵列芯片原型的衬底 2的厚度 为 500微米; 微针衬底 2的外侧的任意位置距微针阵列 1的最短距离为 1000微米; 上述 A 类微针阵列芯片原型的空间参数, 包括微针的数量、 高度、 间距、 衬底的厚度、 衬底最外 侧与微针阵列的最短距离等根据需要进行调整;
上述 A类微针阵列芯片原型可以通过激光数控微加工结合电化学腐蚀的方法制备; 上述 A类微针阵列芯片原型可采用钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金, 镍合金、 铝合金、 铜合金或者其他金属或者合金中的任意一种, 通过数控激光加工或者电火花加工 等微机电加工技术制备而成;
实施例 16 ..
该实施例用于说明本发明所述 B类微针阵列芯片原型的制备方法。
选用镍铬不锈钢合金作为制备微针阵列原型的材料; 先利用电火花精密加工技术进行 线切割, 然后利用电化学腐蚀的方法进行抛光处理, 得到如图 15所示的 8 X 8微针阵列芯 片原型; 针杆 3和针头 4为一体化结构的三棱锥体, 针杆 3底部与衬底 2交界处的外接圆 的直径为 300微米, 针杆 3与衬底 2交界两最近邻外接圆的最短距离为 750微米, 微针的 高度为 1200微米, 微针尖端的曲率半径小于 10微米, 微针阵列芯片原型生物衬底 2的厚 度为 800微米; 环绕微针阵列的凹环 7的截面为矩形, 凹环 7的截面的高度为 500微米, 宽度为 600微米, 凹环 7上表面内侧的任意位置距微针矩阵的最短距离为 1000微米;
上述 B类微针阵列芯片原型的空间参数, 包括微针的数量、 高度、 间距、 衬底 2的厚 度、 凹环 7的高度和宽度、 凹环 7的上表面最外侧的任意位置与微针阵列 1的最短距离等, 可以根据目标微针阵列芯片的需要进行调整;
上述 B类微针阵列芯片原型可以通过激光数控微加工结合电化学腐蚀的方法制备; 上述 B类微针阵列芯片原型可采用钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金, 镍合金、 铝合金、 铜合金或者其他金属或者合金中的任意一种, 通过数控激光加工或者电火花加工 等微机电加工技术制备而成。
实施例 17
该实施例用于说明本发明所述 C类微针阵列芯片原型的制备方法。
选用镍铬不锈钢合金作为制备微针阵列原型的材料; 先利用电火花精密加工技术进行 线切割, 然后利用电化学腐蚀的方法进行抛光处理, 得到如图 16所示的 8 X 8微针阵列芯 片原型; 微针为针杆 3和针头 4为一体化结构的四棱锥体, 针杆 3底部与衬底 2交界处的 外接圆的直径为 200微米, 针杆 3与衬底 2交界两最近邻外接圆的最短距离为 600微米, 微针的高度为 900微米, 微针尖端的曲率半径小于 10微米, 微针阵列芯片原型衬底的厚度 为 1000微米。 环绕微针阵列的凹环 7的截面为矩形。 凹环 7截面的高度为 600微米, 宽度 为 500微米, 凹环 7上表面内侧的任意位置距微针阵列 1的最短距离为 1000微米, 凹环 7 外侧与侧面 8和衬底 2交界处的内侧重合。 侧面 8上表面距衬底 2上表面的垂直高度大于 微针针头 4顶端距衬底 2上表面的垂直高度 500徼米;
上述 C类微针阵列芯片原型的空间参数, 包括微针的数量、 高度、 间距、 衬底 2的厚 度、 凹环 7的高度和宽度、 凹环 7的上表面最外侧的任意位置与微针阵列 1的最短距离, 侧面 8的高度等, 以根据需要进行调整;
上述 C类微针阵列芯片原型可以通过激光数控微加工结合电化学腐蚀的方法制备; 上述 C类微针阵列芯片原型可采用钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金, 镍合金、 铝合金、 铜合金或者其他金属或者合金中的任意一种, 通过数控激光加工或者电火花加工 等微机电加工技术制备而成。
实施例 18 该实施例用于说明利用实施例 1制备的 A类微针阵列芯片原型制备阴模的方法; 具体 步骤如下:
1、 如图 10所示, 首先将实施例 1中制备的 A类微针阵列芯片原型固定在玻璃底面 6 上, 并在玻璃底面 6上构建一垂直于底面 6, 环绕微针阵列原型的封闭玻璃侧面 8, 最终形 成一个底面 6和侧面 8封闭, 上面开口的立体结构。 侧面 8与底面 6交界处内侧的任意位 置与微针阵列芯片原型的衬底 2外侧的最短距离保持相等, 均为 3000微米, 侧面 8的高度 为 1500微米;
2、 将聚二甲基硅氧烷 AB胶按照 10:1混合, 并通过磁力搅拌器将其混合均匀; 将混合 均勾的聚二甲基硅氧垸 AB胶进行超声波处理, 以除去其中的气泡;
3、 将超声波处理后的聚二甲基硅氧垸 AB胶从立体结构的上面开口处进行浇注, 至立 体结构基本被注满;
4、将注满了聚二甲基硅氧垸 AB胶的立体结构在 100。C进行烘干处理, 时间为 5小时;
5、 将烘干处理后固化成型的聚二甲基硅氧烷 AB胶从所构建的立体结构中取出, 即可 得到如图 11或 12所示的单个或多个制备聚合物微针阵列芯片的阴模。
上述制备底面 6和侧面 8的玻璃板, 可由钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金, 镍 合金、 铝合金、 铜合金或者其他金属或者合金中的任意一种替代;
上述浇注于立体结构中的聚二甲基硅氧垸 AB胶的烘干温度可以在 20-150。C之间, 烘 干时间随着烘干温度的升高而减少;
上述浇注于立体结构中的聚二甲基硅氧烷 AB胶可由液态或熔融态的聚丙烯、聚乙烯、 聚乳酸、 聚丁二酸丁二醇酯中的一种或其他聚合物替代。
实施例 19
该实施例用于说明利用实施例 2制备的 B类微针阵列芯片原型制备阴模的方法: 具体步骤如下:
1、 首先利用不锈钢在衬底上构建一垂直于衬底 2, 环绕凹环 7外侧的封闭侧面 8, 最 终形成一衬底 2和侧面 8封闭, 上面开口的立体结构 (如图 9所示); 侧面 8与衬底 2交界 处的内侧与凹环 7的外侧重合, 侧面的高度为 1500微米;
2、 将熔融的聚乙烯从立体结构的上面开口处进行浇注, 至立体结构基本被注满; 注入 的聚乙烯冷却至室温后, 可将其从立体结构中取出, 即可得到如图 11或 12所示的单个或 多个制备聚合物微针阵列芯片的阴模。 上述制备侧面的不锈钢, 可由钛、 铜、 铝、 镍、 钨、 钛合金, 镍合金、 铝合金、 铜合 金或者其他金属或者合金中的任意一种替代, 也可由玻璃、 硅、 二氧化硅等半导体材料中 的任何一种替代;
上述浇注于立体结构的聚乙烯可由液态或熔融态的聚丙烯、聚二甲基硅氧烷、聚乳酸、 聚丁二酸丁二醇酯中的一种或其他聚合物替代。
实施例 20
该实施例用于说明利用实施例 3制备的 C类微针阵列芯片原型制备阴模的方法: 具体步骤如下:
将高温熔融的聚乳酸从立体结构的上面开口处进行浇注, 至立体结构基本被注满; 注 入的聚乳酸冷却至室温后, 可将其从立体结构中取出, 即可得到如图 11或 12所示的单个 或多个制备聚合物微针阵列芯片的阴模;
上述浇注于立体结构的聚乳酸可由液态或熔融态的聚丙烯、聚乙烯、聚二甲基硅氧烷、 聚丁二酸丁二醇酯中的一种或其他聚合物替代。
实施例 21
该实施例用于说明利用实施例 18-20所制得的阴模制备聚合物微针阵列芯片的方法; 该实施例中制备微针阵列 1和衬底 2所采用的材料均为分子量约为 1.0 X 105的聚丙烯 酰胺类聚合物;
具体步骤如下-
1、 首先聚丙烯胺类聚合物与水按照质量比 35:65进行混合, 待聚合物完全溶解后, 用 超声波将聚合物的水溶液处理 5分钟, 以消除其中的气泡;
2、 将步骤 1制得的聚合物的水溶液, 实施例 4-6中制得的的阴模和水平操作平台放置 于手套箱内; 将润滑油均匀地涂抹在水平操作平台的表面, 然后将阴模固定在水平操作平 台的表面上;
3、 将上述聚合物的水溶液注入如图 11或 12所示的阴模中; 制备聚合物微针阵列芯片 所需浇注的聚合物水溶液的体积由微针阵列腔体 10的体积、 衬底腔体 11的体积, 以及聚 合物在其水溶液中的质量分数决定; 对所浇注的聚合物的水溶液进行烘干处理, 烘干温度 为 40 °C; 若一次浇注到阴模中的聚合物水溶液无法满足制备微针阵列芯片的需要时, 可在 部分浇注到模具中的聚合物的水溶液中的部分水分蒸发后进行二次或者更多次浇注, 然后 继续进行烘干处理, 最终使所有浇注到模具中的水溶液中的聚合物固化成型, 得到满足设 计要求的聚合物微针阵列芯片;
4、 将固化成型后的聚丙烯酰胺类聚合物从阴模中取出, 即可得到如图 17所示的聚合 物微针阵列芯片。
上述聚丙烯酰胺类聚合物的分子量可为 5.0X 104 ~2.0X 105之间某一值; 也可为分子量 在 5.0 X 104~2.0 X 105之间的不同分子量的聚丙烯酰胺按照一定比例混合构成的混合物; 上述聚丙烯酰胺类聚合物在水溶液中的质量分数, 可以在 1-80%之间变化; 上述烘干温度, 可在 30-90 °C之间变化;
上述烘干时间, 可根据温度及其他条件的变化进行调整。
实施例 22
同实施例 21, 改变所采用的材料改变为聚丙烯酰胺类聚合物和目标药物构成的混合 物; 该实施例中的目标药物为牛血清蛋白, 按照质量比 20:80与聚丙烯酰胺类聚合物共混后 使用;
上述牛血清蛋白在其与聚丙烯酰胺类聚合物构成的混合物中的质量分数可以在 0.5~50%之间变化;
上述牛血清蛋白可由任意分子量的疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药 物、 基因工程药物、 天然产物药物、 中药成分或者营养成分中的一种或者几种组分的组合 替代。
实施例 23
该实施例用于说明利用实施例 18-20所制得的阴模制备聚合物微针阵列芯片的方法: 该实施例中制备微针阵列 1使用聚丙烯酰胺类聚合物和目标药物构成的混合物; 该实 施例中的聚丙烯酰胺类聚合物的分子量约为 8.0 X 104; 该实施例中的目标药物为胰岛素,按 照质量比 15:85与聚丙烯酰胺类聚合物共混后使用;该实施例制备微针阵列芯片的衬底 2所 采用的材料为纯聚丙烯酰胺类聚合物;
具体步骤如下:
1、 首先将上述聚丙烯胺类聚合物和胰岛素构成的混合物与水按照质量百分比 20:80混 合, 并使用振荡计使其混合均匀, 然后利用超声波将混合液处理 5分钟, 以消除其中的气 泡;
2、将步骤 1配制好的混合液, 实施例 4-6中制得的阴模和水平操作平台放置于手套箱 内; 将润滑油均匀地涂抹在水平操作平台的表面, 将阴模固定在水平操作平台的表面上; 3、 将步骤 1中制得的混合液浇注于如图 11或 12所示的阴模中。 制备聚合物微针阵列 1和衬底 2薄层所需浇注的混合液的体积由微针阵列腔体 10的体积、衬底腔体 11的部分体 积, 以及聚丙烯酰胺类聚合物和其与胰岛素构成的混合物在混合液中的质量百分决定。 对 所浇注的聚合物的水溶液进行烘干处理, 烘干温度为 40 °C; 烘干处理至聚合物和目标药物 构成的混合物的水溶液失去流动性后停止;
4、 按照上述步骤 1将纯聚丙烯酰胺类聚合物与水按照质量比 40:60进行混合。 待聚合 物完全溶解后, 用超声波将聚合物的水溶液处理 5分钟, 以消除其中的气泡;
5、 将上述步骤 4中制得的聚合物的水溶液浇注于已浇注了步骤 3所使用的阴模中; 制 备微针阵列芯片所需浇注的聚合物的水溶液的体积由衬底腔体 11的部分体积, 以及聚丙烯 酰胺类聚合物在水溶液中的质量分数决定; 对所浇注的聚合物的水溶液进行烘干处理, 烘 干温度为 40 °C; 若一次浇注到阴模中的聚合物水溶液无法满足制备微针阵列芯片的衬底 2 的需要时, 可在部分浇注到模具中的聚合物的水溶液中的部分水分蒸发后进行二次或者更 多次浇注, 然后继续进行烘干处理, 最终使所有浇注到模具中的水溶液中的聚合物和目标 药物均固化成型, 得到满足设计要求的聚合物微针阵列芯片;
6、 将固化的聚丙烯酰胺类聚合物及其与胰岛素所构成的混合物从阴模中取出, 即可得 到如图 15所示的聚合物微针阵列芯片。
上述聚丙烯酰胺类聚合物的分子量可为 5.0 X 104~2.0 X 105之间某一值; 也可为分子量 在 5.0 X 104~2.0 X 105之间的不同分子量的聚丙烯酰胺按照一定比例混合构成的混合物; 上述胰岛素在其与聚丙烯酰胺类聚合物构成的混合物中的质量分数可以在 0.1~50%之 间变化;
上述聚丙烯酰胺类聚合物与胰岛素构成的混合物的在混合液中的质量分数, 可在 1-80%之间变化;
上述纯聚丙烯酰胺类聚合物在其水溶液中的质量分数, 可在 30~80%之间变化; 上述烘干温度, 可在 30-90。C之间变化;
上述烘干处理的时间, 可根据温度及其他条件的变化进行调整;
上述胰岛素可由任意分子量的疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药物、 基因工程药物、 天然产物药物、 中药成分或者营养成分中的一种或者几种组分的组合替代。
实施例 24
该实施例用于说明利用实施例 18-20所制得的阴模制备聚合物微针阵列芯片的方法; 该实施例中制备微针针体使用聚丙烯酰胺类聚合物和目标药物构成的混合物; 该实施 例中的目标药物为胰岛素, 按照质量比 10:90与聚丙烯酰胺类聚合物共混后使用; 该实施例 制备微针阵列芯片的衬底 2所采用的材料为聚乳酸薄膜;
具体步骤如下:
1、 首先将上述聚丙烯胺类聚合物和胰岛素构成的混合物与水按照质量百分比 15:85混 合, 并使用振荡计使其混合均匀, 然后利用超声波将混合液处理 5分钟, 以消除其中的气 泡;
2、 将步骤 1配制好的混合液, 实施例 4-6中制得的阴模和水平操作平台放置于手套箱 内; 将润滑油均匀地涂抹在水平操作平台的表面, 然后将阴模固定在水平操作平台的表面 上;
3、 将步骤 1中制得的混合液浇注于如图 11或 12所示的阴模中; 制备聚合物微针阵列 1及所连接的衬底薄层所需浇注的混合液体积由微针阵列腔体 10的体积、衬底腔体 11的部 分体积, 以及聚丙烯酰胺类聚合物与胰岛素构成的混合物在混合液中的质量百分比决定; 对所浇注的混合液进行烘干处理, 烘干温度为 40 °C; 烘干处理至所浇注的混合液中的聚丙 烯酰胺类聚合物和胰岛素完全固化后停止;
4、 将预制好的聚乳酸薄膜粘结在微针阵列芯片衬底层的背面;
5、 将粘结了聚乳酸薄膜的微针阵列芯片从从阴模中取出, 即可得到如图 15所示的聚 合物微针阵列芯片。
上述胰岛素在其与聚丙烯酰胺类聚合物构成的混合物中的质量分数可以在 0.1~50%之 间变化;
上述聚丙烯酰胺类聚合物的分子量可为 5.0 X 104~2.0 X 105之间某一值; 也可为分子量 在 5.0 X 104~2.0 X 105之间的不同分子量的聚丙烯酰胺按照一定比例混合构成的混合物; 上述聚丙烯酰胺类聚合物与胰岛素构成的混合物的在混合液中的质量分数, 可在 1-80%之间变化; ,
上述烘干温度, 可在 30-90。C之间变化;
上述烘干处理的时间, 可根据温度及其他条件的变化进行调整;
上述胰岛素可由任意分子量的疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药物、 基因工程药物、 天然产物药物、 中药成分或者营养成分中的一种或者几种组分的组合替代。
实施例 25 该实施例用于说明利用实施例 21所制得的聚合物微针阵列芯片制备微针经皮给药贴 剂的方法;
具体步骤如下-
1、 利用医用塑料加工成和衬底 2具有同样形状, 即边长为 7.5毫米的正方形, 厚度为 200微米的基板 3, 然后将基板 3粘结在衬底 2的背面;
2、 利用天然橡胶制得防渗垫圈 4; 防渗垫圈 4内侧的形状和所包围的基板 3的形状一 致, 即边长为 7.5毫米; 防渗垫圈 4的横截面为矩形, 高度和所包围的基板 3的高度一致, 即 200微米, 宽度为 500微米;
3、将防渗层 Ί与粘结胶带 6结合在一起,裁剪成长为 25毫米,宽为 10毫米的长方形; 防渗层为已进行了疏水处理的棉花纤维;
4、 将 25毫米长, 10毫米宽的防粘层 6居中部分裁掉, 裁掉部分形状与面积和防渗垫 圈 4的外侧的形状和面积一致; 将裁剪好的防粘层 6放置在防渗垫圈 4的周围;
5、 将已与防渗层 7结合在一起的粘结胶带的内侧覆盖在基板 3, 防渗垫圈 4和防粘层 5之上, 并使其粘合在一起。
制备好的聚合物微针经皮贴剂的微针阵列 1部分继续保存在制备聚合物微针阵列芯片 的模具中;
上述微针阵列芯片的空间参数, 包括微针的数量、 高度、 间距、 衬底 2的厚度、 衬底 2最外侧任意位置与微针阵列 1的最短距离等, 可以根据需要进行调整;
上述基板 12可由医用聚合物、 合成树脂、 乳胶、 橡胶、 玻璃、 陶瓷、 金属或者复合材 料中的至少一种制备而成;基板 12可为上述材料制备而成的多层薄膜,每层之间采用粘结, 融合, 键合或者物理方法使其紧密结合在一起;
上述防渗垫圈 4可由乳胶、 橡胶、 医用塑料、 聚合物中的中的至少一种制备而成; 上述防渗层 7可由任何具有疏水性的纤维, 乳胶、 橡胶等其中的一种制备而成。
实施例 26 ,
该实施例用于说明利用实施例 22所制得的聚合物微针阵列芯片制备微针经皮给药贴 剂的方法;
同实施例 25, 改变制备微针阵列芯片的材料为聚丙烯酰胺类聚合物和目标药物构成的 混合物; 本实施例中的目标药物为牛血清蛋白, 质量分数为 20%;
上述牛血清蛋白在其与聚丙烯酰胺类聚合物构成的混合物中的质量分数可以在 0.5~50%之间变化;
上述牛血清蛋白可由任意分子量的疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药 物、 基因工程药物、 天然产物药物、 中药成分或者营养成分中的一种或者几种组分的组合 替代。
实施例 27
该实施例用于说明利用实施例 23所制得的聚合物微针阵列芯片制备微针经皮给药贴 剂的方法;
同实施例 25, 改变制备微针阵列芯片中的微针阵列 1的材料为聚丙烯酰胺类聚合物与 目标药物构成的混合物; 本实施例中的目标药物为胰岛素, 质量分数为 15%;
上述胰岛素在其与聚丙烯酰胺类聚合物构成的混合物中的质量分数可以在 0.5~50%之 间变化;
上述胰岛素可由任意分子量的疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药物、 基因工程药物、 天然产物药物、 中药成分或者营养成分中的一种或者几种组分的组合替代。
实施例 28
该实施例用于说明利用实施例 24所制得的聚合物微针阵列芯片制备微针经皮给药贴 剂的方法;
改变制备微针阵列芯片中的微针阵列 1的材料为聚丙烯酰胺类聚合物与目标药物构成 的混合物;制备衬底 2的材料为聚乳酸;本实施例中的目标药物为胰岛素,质量分数为 10%; 制备该贴剂时, 衬底 2后面不需要再粘合基板 12, 周围不再环绕防渗垫圈 13 ;
具体步骤如下:
1、 防粘层 14居中部分裁掉的形状和面积与衬底 2的形状和面积一致, 然后将裁剪好 的防粘层 14放置在衬底 2的周围; .
2、将与防渗层 16结合在一起的粘结胶带 6的内侧直接覆盖在衬底 2和防粘层 14之上, 并使其粘合在一起。 ,
上述胰岛素在其与聚丙烯酰胺类聚合物构成的混合物中的质量分数可以在 0.5~50%之 间变化;
上述胰岛素可由任意分子量的疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药物、 基因工程药物、 天然产物药物、 中药成分或者营养成分中的一种或者几种组分的组合替代。
实施例 29-31用于说明上述实施例 25-28所制备的聚合物微针经皮给药贴剂的使用方 法。
实施例 29
将用于模拟人体皮肤的冰冻猪皮解冻; 解冻好之后对施药部位进行清洗和消毒处理; 将实施例 25制备的微针经皮给药贴剂从模具中取出,放在放大镜下进行观察,发现断 针数量小于 /等于 2个;
将防粘层 14撕去, 通过轻按的方式将微针阵列刺入解冻后的猪皮内, 一分钟后移开; 将混有荧光标记染料 FITC的流感疫苗涂覆在被微针阵列刺破的猪皮表面, 然后放在 温度不高于 36°C, 相对湿度不低于 40%的环境中, 静止半小时;
将涂覆了流感疫苗的猪皮置于荧光显微镜观察, 发现表面具有明显的微孔, 染料可以 透入猪皮的内部;
上述施药方法适合于其他疫苗类, 或者其他使用量较少且对用量无严格要求的药品的 用药。
实施例 30
将用于模拟人体皮肤的冰冻猪皮解冻; 解冻好之后对施药部位进行清洗和消毒处理; 将实施例 26制备的微针经皮给药贴剂从模具中取出,放在放大镜下进行观察,发现断 针数量小于 /等于 2个;
将防粘层 14撕去,通过轻按的方式将微针阵列 1刺入解冻后的猪皮内,并通过粘结胶 带 6将微针经皮给药贴剂固定在皮肤表面;将上述猪皮和微针贴剂放置于温度不高于 36°C, 相对湿度不低于 40%的环境中。 1小时后将微针经皮给药贴剂从猪皮上移开;
将移除微针经皮给药贴剂的猪皮置于放大镜下进行观察, 发现表面具有明显的微孔, 牛血清蛋白可以透入猪皮的内部;
上述施药方法适合于药品比较便宜, 用量较多且对用量无严格要求的药品的用药。 实施例 31
同实施例 30, 改变墩针经皮给药贴剂为实施例 27或 28中制备的微针经皮给药贴剂; 上述施药方法适合于药品比较昂贵, 对用量有严格要求的药品的用药。 以上具体实施方式和实施例对本发明进行了详细描述。 以上详细描述是为了使本领域 的技术人员可以更好的理解本发明。'本领域的技术人员, 在本发明的基础上可以对技术方 案做适当的变化或者变型, 因此所有等同的技术方案也属于本发明的范畴。 本发明的专利 保护范围由权利要求限定

Claims

权利要求书
1、 一种聚合物微针阵列芯片, 其包括微针阵列和微针阵列立于其上的衬底; 其特征在 于:
制备所述微针阵列的材料采用聚丙烯酰胺类聚合物;
所述聚丙烯酰胺类聚合物的分子量为 1.0 X 104〜2.0 X 105
所述聚丙烯酰胺类聚合物的维氏硬度在 150~600HV之间;
所述聚丙烯酰胺类聚合物的冲击强度在 5~30J/m之间。
2、 根据权利要求 1所述的聚合物微针阵列芯片, 其特征在于: 利用所述聚丙烯酰胺类 聚合物制备的厚度为 2毫米、 边长为 1厘米的正方形薄板浸泡在静止放置的生理盐水中时, 经 6小时至少溶解 50%。
3、根据权利要求 1~2所述的聚合物微针阵列芯片, 其特征在于: 所述聚丙烯酰胺类聚 合物是由丙烯酰胺单体聚合而成的聚合物; 所述聚丙烯酰胺类聚合物中残余丙烯酰胺单体 含量 0.5ppm。
4、 根据权利要求 1所述的聚合物微针阵列芯片, 其特征在于: 所述聚丙烯酰胺类聚合 物中混合有生物活性物质或药物, 所述生物活性物质或药物在混合物中的质量百分数为 0.1-50%; 优选地, 质量百分数为 10~20%。
5、 根据权利要求 4所述的聚合物微针阵列芯片, 其特征在于: 所述生物活性物质或药 物选自下列物质中的一种或多种: 疫苗、 多肽、 蛋白质、 多糖、 核酸、 激素、 抗癌药物、 基因工程药物、 天然产物药物、 中药成分或者营养成分。
6、 根据权利要求 1〜5中任一所述的聚合物微针阵列芯片, 其特征在于: 所述微针阵 列由至少 2个以上的微针组成; 所述微针包括针杆和针头两部分; 所述针杆为微针的主体 部分, 其一端固定在微针阵列芯片的衬底上; 所述针头为微针的顶部, 其一端与针杆相连 接, 针头的形状为任意尖端状结构。
7、根据权利要求 1或 6所述的聚合物微针阵列芯片, 其特征在于: 所 微针的最大截 面圆或外接圆的直径为 50-1000微米; 所述微针的长度为 100~5000微米; 所述衬底的厚度 为 50~5000微米。
8、 根据权利要求 1或 7所述的聚合物微针阵列芯片, 其特征在于: 所述衬底包括衬底 薄层和衬底主体层,所述衬底薄层是指与微针阵列部分相连的厚度小于 50微米的薄膜结构, 衬底主体层与衬底薄层相连构成整个衬底。
9、 根据权利要求 1所述的聚合物微针阵列芯片, 其特征在于: 所述衬底采用的材料为 聚丙烯酰胺类聚合物。
10、 根据权利要求 4所述的聚合物微针阵列芯片, 其特征在于: 所述衬底采用的材料 为聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物, 所述生物活性物质或药物在 混合物中的质量百分数为 0.1~50%; 优选地, 质量百分数为 10~20%
11、 根据权利要求 8所述的聚合物微针阵列芯片, 其特征在于: 所述聚合物微针芯片 的微针阵列和衬底薄层采用的材料是聚丙烯酰胺类聚合物与生物活性物质或药物构成的混 合物, 所述生物活性物质或药物在混合物中的质量百分数为 0.1〜50%; 优选地, 质量百分数 为 10~20%; 所述衬底主体层由聚丙烯酰胺类聚合物制备而成。
12、 根据权利要求 8所述的聚合物微针阵列芯片, 其特征在于: 所述微针阵列和衬底 薄层采用的材料是聚丙烯酰胺类聚合物, 所述衬底主体层采用的材料是聚乳酸、 聚乙烯、 聚丙烯、 聚丁二酸丁二醇酯、 橡胶、 乳胶、 玻璃、 金属热塑性复合材料中的一种或两种以 上材料的分层组合。
13、 根据权利要求 8所述的聚合物微针阵列芯片, 其特征在于: 所述微针阵列和衬底 薄层釆用的材料是聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物, 所述生物活 性物质或药物在混合物中的质量百分数为 0.1〜50%; 优选地, 质量百分数为 10~20%; 所述 衬底主体层釆用的材料是聚乳酸、 聚乙烯、 聚丙烯、 聚丁二酸丁二醇酯、 橡胶、 乳胶、 玻 璃、 金属热塑性复合材料中的一种或两种以上材料的分层组合。
14、 根据权利要求 1、 2、 4、 9〜13中任一所述的聚合物微针阵列芯片, 其特征在于, 所述聚丙烯酰胺类聚合物制备方法如下:
合成反应体系包括以醇类为主的有机溶剂、 水、 丙烯酰胺单体和引发剂四部分; 反应 过程中不间断地对反应体系通高纯氮气进行保护、 保持搅拌、 在温度升高至目标温度后进 行保温; 反应结束后, 先对反应产物进行去除丙烯酰胺单体的处理, 然后进行烘干以得到 聚丙烯酰胺类聚合物。
15、 根据权利要求 14所述的聚合物微针阵列芯片, 其特征在于, 所述聚丙烯酰胺类聚 合物制备方法包括如下具体步骤:
S-l, 在配有搅拌装置的反应器内, 按照设定值加入有机溶剂、 水、 丙烯酰胺单体; 所述的有机溶剂包括醇类有机溶剂和酮类有机溶剂; 醇类有机溶剂选自甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇等组分中的至少一种或者两种以上混合物; 醇类溶剂在反应体系 中的体积百分数 60%; 所述酮类有机溶剂选自丙酮、丁酮、 甲基异丁基酮和环己酮中等组 分中的一种或者两种以上的混合物, 所述酮类溶剂在反应体系中的体积百分数 25%; 所述水在反应体系中的体积百分数占应 25%;
所述的丙烯酰胺单体在反应体系中的初始浓度为 0.1-3md/L;
S-2, 向包含上述溶剂、水和丙烯酰胺单体组成的反应体系的反应器内通高纯氮气以除 氧, 搅拌, 同时将反应体系加热升温至目标温度; 所述的目标温度为 30-85 °C;
S-3 , 反应体系温度达到目标温度后, 将引发剂加入上述反应体系中, 保持搅拌和氮气 通入; 所述的引发剂为偶氮类引发剂, 或过氧化物; 所述偶氮类引发剂选自下列物质中的 一种或多种: 偶氮二异丁腈、 偶氮二异庚腈、 偶氮二异丁脒盐酸盐、 偶氮二丁酸二异丁酯、 偶氮二异丁酸二甲酯; 所述过氧化物选自下列物质中的一种或多种: 过硫酸铵、 过硫酸钠、 过硫酸钾、 叔丁基过氧化氢、 过氧化二异丙苯、 过氧化苯甲酰; 更优选地, 所述的引发剂 还包括还原剂; 优选地, 所述还原剂选自下列物质中的一种或两种: 亚硫酸氢钠、 偏亚硫 酸钠; 引发剂的的用量为上述丙烯酰胺单体重量的 0.01~1%;
S-4, 加入引发剂后, 在目标温度下继续恒温 8~30小时, 并保持搅拌和氮气通入; 所 述目标温度为 30-85。C;
S-5 , 反应结束后, 首先将反应器内的固液混合物进行真空过滤, 然后将得到的固体产 物放在真空烘箱内进行干燥, 温度为 30~70 °C之间;
S-6, 将干燥后的反应产物用水溶解, 待完全溶解后, 加入只能溶解丙烯酰胺单体而不 能溶解聚合产物的有机溶剂进行重沉淀, 以去除未反应的丙烯酰胺单体, 所述有机溶剂为 甲醇、 乙醇、 正丙醇、 异丙醇、 正丁醇、 丙酮、 丁酮、 甲基异丁基酮和环己酮中的至少一 种或者两种以上的混合物;
重复以上 S-5— S-6两个步骤 2~4次;
S-7, 将除掉丙烯酰胺单体后的反应产物在真空烘箱中进行干燥, 温度为 30-70 °C, 时 间为 20-50小时, 得到聚丙烯酰胺类聚合物。 ,
16、 如权利要求 9所述的聚合物微针阵列芯片的制备方法, 其特征在于, 包括以下步 骤:
1 )利用下列金属材料中的一种或多种制得与目标聚合物微针阵列芯片具有相同空间特 征的微针阵列芯片原型: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金, 镍合金、 铝合金、 铜合 金; 2) 利用步骤 1 ) 制得的金属微针阵列芯片原型和下列聚合物材料中的一种或多种制备 阴模: 聚乙烯、 聚丙烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧烷。
3 ) 将金属微针阵列芯片原型从阴模中脱出;
4) 将聚丙烯酰胺类聚合物和水在 10~90°C的温度下混合得到水溶液; 所述聚丙烯酰胺 聚合物在水溶液中的质量百分数为 1~80%; 优选地, 质量百分数为 10〜50%;
5) 将步骤 4) 制得的水溶液进行超声处理, 以去除其中的气泡;
6) 将步骤 5 ) 制得的水溶液浇注到已被进行了清洗处理的阴模中, 然后将浇注了水溶 液的阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封;
7) 将步骤 6) 浇注到阴模中的水溶液在 20〜90°C下进行烘干处理; 使浇注到阴模中的 水溶液中的聚丙烯酰胺类聚合物固化成型, 制得聚合物微针阵列芯片。
17、 根据权利要求 16所述的方法, 其特征在于: 步骤 6) 和步骤 7) 包括如下具体步 骤:
A 如果一次浇注到阴模中的水溶液中的聚丙烯酰胺类聚合物满足制备聚合物微针阵 列芯片需要时, 可将注入阴模中的水溶液直接烘干至其中的聚丙烯酰胺类聚合物固化成型, 得到聚合物微针阵列芯片;
Bl、 如果一次浇注到阴模中的水溶液中的聚丙烯胺按类聚合物无法满足制备聚合物微 针阵列芯片需要时, 可以通过烘干处理去除浇注于阴模中的水溶液中的部分水分, 然后进 行二次或多次浇注, 直到阴模中的聚丙烯酰胺类聚合物能够满足制备微针阵列芯片的需要 为止, 最后通过烘干处理使水溶液中的聚丙烯酰胺类聚合物固化成型, 得到聚合物微针阵 列芯片。
18、 如权利要求 10中所述的聚合物微针阵列芯片的制备方法, 其特征在于, 包括以下 步骤:
1 )利用下列金属材料中的一种或多种制得与目标聚合物微针阵列芯片具有相同空间特 征的微针阵列芯片原型: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金、 镍合金、 铝合金、 铜合 金;
2)利用步骤 1 )制得的金属微针阵列芯片原型和下列聚合物材料中的一种或制备阴模: 聚乙烯、 聚丙烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧烷;
3 ) 将金属微针阵列芯片原型从阴模中脱出; 4)将聚丙烯酰胺类聚合物与生物活性物质或药物混合, 得到混合物; 所述生物活性物 质或药物在混合物中的质量百分数为 0.1~50%; 优选地, 质量百分数为 10〜20%。
5 ) 将步骤 4) 制得的混合物在 10~90°C的温度下与水混合得到混合液; 所述混合物在 混合液中的质量百分数为 1~80%; 优选地, 质量百分数为 10~50%;
6) 将步骤 5 ) 制得的混合液进行超声处理, 以去除其中的气泡;
7) 将步骤 6) 制得的混合液浇注到已被进行了清洗处理的阴模中; 然后将浇注了混合 液的阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封。
8 ) 将步骤 7) 浇注到阴模中的混合液在 20〜90°C下进行烘干处理; 使浇注到阴模中的 混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物固化成型, 制得聚合 物微针阵列芯片。
19、根据权利要求 18所述的方法, 其特征在于: 步骤 7和步骤 8)包括如下具体步骤: A2、 如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物能够满足制备聚合物微针阵列芯片需要时, 可将注入阴模中的混合液直接烘 干至其中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物固化成型, 得到聚合 物微针阵列芯片;
B2、 如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物无法满足制备聚合物微针阵列芯片需要时, 可以通过烘干处理去除浇注于阴 模中的混合液中的部分水分, 然后进行二次或多次浇注, 直到阴模中的聚丙烯酰胺类聚合 物与生物活性物质或药物构成的混合物能够满足制备微针阵列芯片的需要时为止, 最后通 过烘干处理使混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物固化成 型, 得到聚合物微针阵列芯片。
20、 如权利要求 11中所述的聚合物微针阵列芯片的制备方法, 其特征在于, 包括以下 步骤: ,.
1 )利用下列金属材料中的一种或多种制得与目标聚合物微针阵列芯片具有相同空间特 征的微针阵列芯片原型: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金、 镍合金、 铝合金、 铜合 金;
2) 利用步骤 1 ) 制得的金属微针阵列芯片原型和下列聚合物材料中的一种或多种制备 阴模: 聚乙烯、 聚丙烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧垸; 3 ) 将金属微针阵列芯片原型从阴模中脱出;
4) 将聚丙烯酰胺类聚合物与生物活性物质或药物混合, 得到混合物; 所述生物活性物 质或药物在混合物中的质量百分数为 0.1~50%; 优选地, 质量百分数为 10~20%;
5) 将步骤 4) 制得的混合物在 10~90Ό的温度下与水混合得到混合液; 所述混合物在 混合液中的质量百分数为 1〜80%; 优选地, 质量百分数为 10~50%;
6) 将步骤 5 ) 制得的混合液进行超声处理, 以去除其中的气泡。
7) 将步骤 6) 制得的混合液浇注到已被进行了清洗处理的阴模中; 然后将浇注了混合 液的阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封。
8) 将步骤 7浇注到阴模中的混合液在 20~90°C下进行进行烘干处理; 浇注到阴模中的 混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物固化成型; 制得聚合 物微针阵列芯片的微针阵列和与其连接的厚度小于 50微米的衬底薄层;
9) 将聚丙烯酰胺类聚合物和水在 10~90°C的温度下混合得到水溶液; 所述聚丙烯酰胺 聚合物在水溶液中的质量百分数较高, 为 20~80%; 优选地, 质量百分数为 30~50%; 优选 地, 一次浇注于于阴模中的水溶液能够满足制备聚合物微针阵列芯片的衬底的需要;
10) 将步骤 9) 制得的水溶液进行超声处理, 以去除其中的气泡。
11 ) 将步骤 10中制备的水溶液继续浇注到步骤步骤 7) 和 8) 所述的阴模中;
12) 将步骤 11 ) 浇注到阴模中的水溶液 20~90°C下进行烘干处理; 使浇注到阴模中的 水溶液中的聚丙烯酰胺类聚合物固化成型, 制得完整的聚合物微针阵列芯片。
21、 根据权利要求 20所述的方法, 其特征在于: 步骤 7 ) 和步骤 8) 包括如下具体步 骤:
A3、 如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物能够满足制备微针阵列芯片的微针阵列部分和衬底薄层的需要时, 将注入阴 模中的混合液直接烘干至其 的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物 固化成型, 得到聚合物微针阵列芯片的微针阵列部分和衬底薄层部分;
Β3、 如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物无法满足制备微针阵列芯片的微针阵列部分和衬底薄层部分的需要时, 通过 烘干处理去除浇注于阴模中的混合液中的部分水分, 然后进行二次或多次浇注, 直到阴模 中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物能够满足制备微针阵列芯片 的微针阵列部分和衬底薄层部分的需要时为止, 最后通过烘干处理使混合液中的聚丙烯酰 胺类聚合物与生物活性物质或药物构成的混合物固化成型, 得到符合设计要求的聚合物微 针阵列芯片的微针阵列部分和衬底薄层部分。
22、 如权利要求 12中所述的聚合物微针阵列芯片的制备方法, 其特征在于, 包括以下 步骤:
1 )利用下列金属材料中的一种或多种制得与目标聚合物微针阵列芯片具有相同空间特 征的微针阵列芯片原型: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钛合金、 镍合金、 铝合金、 铜合 金。
2) 利用步骤 1 ) 制得的金属微针阵列芯片原型和下列聚合物材料中的一种或多种制备 阴模: 聚乙烯、 聚丙烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧烷;
3 ) 将金属微针阵列芯片原型从阴模中脱出;
4) 将聚丙烯酰胺类聚合物与水混合得到水溶液; 将聚丙烯酰胺类聚合物和水在 10~90 °C的温度下混合得到水溶液; 所述聚丙烯酰胺聚合物在水溶液中的质量百分数为 1〜80%; 优选地, 质量百分数为 10~50%;
5 ) 将步骤 4) 制得的水溶液进行超声处理, 以去除其中的气泡;
6) 将步骤 5 ) 制得的水溶液浇注到巳被进行了清洗处理的阴模中, 然后将浇注了水溶 液的阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封;
7) 将步骤 6) 浇注到阴模中的水溶液在 20~90°C下进行烘干处理; 使浇注到阴模中的 水溶液中的聚丙烯酰胺类聚合物固化成型, 制得聚合物微针阵列芯片的微针阵列和与其连 接的衬底薄层;
8) 将步骤 7) 制备的微针阵列芯片的微针阵列和衬底薄层与下列单层或多层薄膜材料 中的一种或多种制作的衬底部分连接在一起得到聚合物微针阵列芯片: 自聚乙烯、 聚丙烯、 聚丁二酸丁二醇酯、 聚二甲基硅氧垸、 橡胶、 聚乳酸、 乳胶、 玻璃、 金属热塑性.复合材料; 所述单层或者多层薄膜制作的衬底主体层通过粘结、 融合、 键合与衬底薄层紧密结合在一 起;
23、 根据权利要求 22所述的方法, 其特征在于: 步骤 6) 和步骤 7 ) 包括如下具体步 骤:
F4、 如果一次浇注到阴模中的水溶液中的聚丙烯酰胺类聚合物满足制备微针阵列芯片 的微针阵列部分和衬底薄层部分的需要时, 将注入阴模中的水溶液直接烘干至其中的聚丙 烯酰胺类聚合物固化成型, 得到聚合物微针阵列芯片的微针阵列部分和衬底薄层部分;
G4、 如果一次浇注到阴模中的水溶液中的聚丙烯酰胺类聚合物无法满足制备微针阵列 芯片的阵列部分和衬底薄层部分的需要时, 先通过烘干处理去除浇注于阴模中的水溶液中 的部分水分, 然后进行二次或多次浇注, 直到阴模中的聚丙烯酰胺类聚合物能够满足制备 微针阵列芯片的微针阵列部分和衬底薄层部分的需要时为止, 最后通过烘干处理使聚丙烯 酰胺类聚合物固化成型, 得到聚合物微针阵列芯片的微针阵列部分和衬底薄层部分。
24、 如权利要求 13中所述的聚合物微针阵列芯片的制备方法, 其特征在于, 包括以下 步骤:
1 )利用下列金属材料中的一种或多种制得与目标聚合物微针阵列芯片具有相同空间特 征的微针阵列芯片原型: 钛、 铜、 铝、 镍、 钨、 不锈钢、 钕合金、 镍合金、 铝合金、 铜合 金;
2) 利用步骤 1 ) 制得的金属微针阵列芯片原型和下列聚合物材料中的一种或多种制备 阴模: 聚乙烯、 聚丙烯、 聚乳酸、 聚丁二酸丁二醇酯、 聚二甲基硅氧垸;
3) 将金属微针阵列芯片原型从阴模中脱出;
4) 将聚丙烯酰胺类聚合物与生物活性物质或药物混合, 得混合物; 所述生物活性物质 或药物在混合物中的质量百分数为 0.1~50%; 优选地, 质量百分数为 10~20%;
5)将步骤 4)制得的混合物在 10〜90°C的温度下与水混合得到混合液; 所述混合物在混 合液中的质量百分数为 1~80%; 优选地, 质量百分数为 10~50%;
6) 将步骤 5) 制得的混合液进行超声处理, 以去除其中的气泡;
7) 将步骤 6) 制得的混合液浇注到已被进行了清洗处理的阴模中; 然后将浇注了混合 液的阴模放置在水平操作平台上; 优选地, 将模具和水平操作平台放置在封闭的体系中; 优选地, 水平操作平台与模具之间使用粘性液体密封。
8) 将步骤 7) 浇注到阴樺中的混合液在 20~90°C下进行烘干处理; 使浇注到阴模中的 混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物固化成型, 制得聚合 物微针阵列芯片的微针阵列部分和衬底薄层部分。
9) 将步骤 7) 制备的微针阵列芯片的微针阵列部分和衬底薄层与下列单层或多层薄膜 材料中的一种或多种制作的衬底部分连接在一起得到聚合物微针阵列芯片: 自聚乙烯、 聚 丙烯、 聚丁二酸丁二醇酯、 聚二甲基硅氧垸、 橡胶、 聚乳酸、 乳胶、 玻璃、 金属热塑性复 合材料; 所述单层或者多层薄膜制作的衬底主体层通过粘结、 融合、 键合与衬底薄层紧密 结合在一起。
25、 根据权利要求 24所述的方法, 其特征在于: 步骤 7 ) 和步骤 8 ) 包括如下具体步 骤-
A5、 如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物能够满足制备微针阵列芯片的微针阵列部分和衬底薄层部分的需要时, 将注 入阴模中的混合液直接烘干至其中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混 合物固化成型, 制得聚合物微针阵列芯片的微针阵列部分和衬底薄层部分;
B5、 如果一次浇注到阴模中的混合液中的聚丙烯酰胺类聚合物与生物活性物质或药物 构成的混合物无法满足制备微针阵列芯片的微针阵列部分和衬底薄层部分的需要时, 通过 烘干处理去除浇注于阴模中的混合液中的部分水分, 然后进行二次或多次浇注, 直到阴模 中的聚丙烯酰胺类聚合物与生物活性物质或药物构成的混合物能够满足制备微针阵列芯片 的微针阵列部分和衬底薄层部分的需要时为止, 最后通过供干处理使聚丙烯酰胺类聚合物 与生物生物活性物质或药物构成的混合物固化成型, 制得符合设计要求的聚合物微针阵列 芯片的微针阵列部分和衬底薄层部分。
26、 如权利要求 9-13中任一所述的聚合物微针阵列芯片的微针经皮给药贴剂, 其特征 在于: 包括聚合物微针阵列芯片、 基板、 防渗垫圈、 防粘层、 粘结胶带和防渗层; 所述微 针阵列芯片包括微针阵列和微针阵列立于其上的衬底; 所述基板是指粘附在聚合物微针阵 列芯片衬底背面的一层或者多层薄膜; 所述防渗垫圈环绕在微针阵列芯片衬底和基板的边 缘一层垫圈; 所述防粘层覆盖在防渗垫圈外部的区域; 所述粘结胶带是内外两侧均具有粘 性的双面胶带, 其内侧覆盖基板、 防渗垫圈和防粘层, 外侧与防渗层粘结在一起; 所述粘 结胶带外侧覆盖防渗层; 所述防渗层为粘结胶带外侧所覆的一层保护薄膜。 '
27、如权利要求 26所述的微针经皮给药贴剂的制备方法, 其特征在于,包括如下步骤:
1 ) 将基板与微针阵列芯片的衬底粘附在一起;
2 ) 将防渗垫圈固定在微针贴剂的基板周围;
3 ) 将防粘层设置在微针基板或微针阵列芯片衬底的外侧;
4) 将双面胶带内侧与微针贴剂的基板、 防渗垫圈和防粘层粘合在一起;
5 ) 将防渗层与粘结胶带的外侧粘附在一起; 制得聚合物经皮给药贴剂。
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