CN109364366A - Template prepares the method and its application of porous polymer micropin - Google Patents
Template prepares the method and its application of porous polymer micropin Download PDFInfo
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- CN109364366A CN109364366A CN201811104132.3A CN201811104132A CN109364366A CN 109364366 A CN109364366 A CN 109364366A CN 201811104132 A CN201811104132 A CN 201811104132A CN 109364366 A CN109364366 A CN 109364366A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/26—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a solid phase from a macromolecular composition or article, e.g. leaching out
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- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
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- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- C08J2201/04—Foams characterised by the foaming process characterised by the elimination of a liquid or solid component, e.g. precipitation, leaching out, evaporation
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- C08J2201/04—Foams characterised by the foaming process characterised by the elimination of a liquid or solid component, e.g. precipitation, leaching out, evaporation
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- C08J2205/00—Foams characterised by their properties
- C08J2205/04—Foams characterised by their properties characterised by the foam pores
- C08J2205/044—Micropores, i.e. average diameter being between 0,1 micrometer and 0,1 millimeter
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- C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
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- C08J2327/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers
- C08J2327/02—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment
- C08J2327/12—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment containing fluorine atoms
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Abstract
The invention discloses the method and its application that a kind of template prepares porous polymer micropin, method includes the following steps: polymer and template are dissolved in preparing in solvent by (1) obtains polymer solution；(2) polymer solution is inserted in micropin mold；(3) solvent in gained micropin mold is removed, solid microneedles are obtained；(4) template in gained solid microneedles is removed, porous polymer micropin can be obtained.The present invention is improved by the integral process flow design to the preparation method, it is cumbersome, expensive can to solve complicated porous polymer micropin preparation process, condition harshness, technique, pore structure, size are difficult to control and the technical problems such as large-scale production and application difficult, resulting porous polymer micropin can be used in tissue fluid extraction and percutaneous dosing, such as the fields such as the extraction of Skin tissue fluid, blood and beauty, hair tonic, percutaneous dosing that is immune, treating the protein in applying, polypeptide and small-molecule drug.
Description
Technical field
The invention belongs to field of biomedical polymer materials, prepare porous polymeric more particularly, to a kind of template
The method and its application of object micropin, the porous polymer micropin obtained by this method can be used in extracting the system of tissue fluid or blood
Agent or the pharmaceutical preparation for preparing percutaneous dosing.
Background technique
Micropin is the three-dimensional matrix structure that the length made of silicon, metal, polymer is 25-2000 μm, needle point is tapered.
Micropin is the novel minimally invasive administration tool of one kind in biomedicine field, can reach increasing through skin epidermis and skin corium
The effect of strong percutaneous drug delivery.In recent years, micropin is obtained in percutaneous dosing field efficiently, safely, without advantages such as pains with it
Extensive concern.
Porous micropin is usually the three-dimensional porous microneedle array structure being prepared by metal, nonmetallic or polymer.With reality
Heart micropin is compared, and the cavity structure of porous micropin makes that it can be applied to transdermal drug transmitting or tissue fluid extracts, be it is a kind of very
Promising medical instrument.Wherein, porous polymer micropin with its good biocompatibility and biodegradability and by
Extensive concern.Porous polymer micropin can be by polymer microballoon by ultrasonic welding or in micropin external sheath porous material
Method obtains.However, these preparation methods process is cumbersome, condition is harsh, higher cost, and the hole knot of conventional porous micropin
Structure, size be difficult to control, be unfavorable for porous polymer micropin large scale preparation and Skin tissue fluid quantitatively extracts and percutaneously
Application in administration.Therefore, it is controllable and low-cost porous that a kind of process simple mildly, pore structure, size and distribution are needed
The preparation method of polymer micro needle, consequently facilitating the resulting porous polymer micropin of this method is applied to Skin tissue fluid, blood
Liquid extracts, nti-freckle, crease-resistant, smoothing wrinkle, hair tonic, immune, treatment, protein or polypeptide drug the fields such as percutaneous dosing.
Summary of the invention
Aiming at the above defects or improvement requirements of the prior art, the purpose of the present invention is to provide a kind of preparation of template is more
The method and its application of pore polymer micropin, wherein improved by the integral process flow design to the preparation method, and
Key condition and parameter (size and template of such as template and the mass ratio of polymer) are optimized, by simple
Template can be prepared on a large scale porous polymer micropin, thus can solve porous polymer micropin preparation process complexity, condition
Harshness, technique are cumbersome, expensive, and pore structure, size are difficult to control and the technical problems such as large-scale production and application difficult,
Resulting porous polymer micropin can be used in tissue fluid extraction and percutaneous dosing, such as Skin tissue fluid, blood extraction and beauty
The fields such as the percutaneous dosing of protein, polypeptide and small-molecule drug in the application such as appearance, hair tonic, immune, treatment；Also, this
Invention further preferably regulates and controls the size of template and content, to regulate and control the pore size and hole of porous polymer micropin
Rate, so that the porous polymer micropin of preparation has the porous structure of pore size and adjustable porosity.
To achieve the above object, according to one aspect of the present invention, providing a kind of template, to prepare porous polymer micro-
The method of needle, which comprises the following steps:
(1) polymer and template are dissolved in prepare in solvent A and obtain polymer solution；
(2) in the polymer solution filling micropin mold obtained the step (1)；
(3) solvent A in micropin mold obtained by the step (2) is removed, solid microneedles are obtained；
(4) template in solid microneedles obtained by the step (3) is removed, porous polymer micropin can be obtained.
As present invention further optimization, in the step (1), the solvent A is n,N-Dimethylformamide, diformazan
Base sulfoxide, DMAC N,N' dimethyl acetamide, N-Methyl pyrrolidone, hexamethyl phosphoramide, 1,4- dioxane, nitromethane, nitre
Base ethane, triethyl phosphate, trimethyl phosphate, tetramethylurea, carbon disulfide, formamide, dibutyl phthalate, tetrahydro furan
Mutter, methylene chloride, acetic acid, carbon tetrachloride, methanol, ethyl alcohol, isopropanol, hexane, hexamethylene, chloroform, acetone, ethylene glycol, methyl ether,
Ether, water, glycerine, 1,2- propylene glycol, n-butanol, octanol, tetrachloro-ethylene, tetrachloroethanes, fluothane hydrocarbon, dichloroethanes, pyridine
One or more of mixture.
As present invention further optimization, the step (4) is specifically using heating, freeze-drying or by solid microneedles
It is immersed in another solvent B to remove the template；The solvent B can dissolve the template and can not dissolve institute
State polymer, specially acid solution, alkaline solution, water, tetrahydrofuran, methylene chloride, methanol, ethyl alcohol, isopropanol, hexane,
One of chloroform, acetone, ethylene glycol, methyl ether, ether, water, glycerine, n-butanol, octanol, dichloroethanes, pyridine or in which
Several mixtures；
The acid solution be preferably sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, acetic acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid,
One of permanganic acid, hydrobromic acid, formic acid, propionic acid, butyric acid, edta solution or in which several mixtures；
The alkaline solution is preferably sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, carbonic acid
One of hydrogen potassium, sodium phosphate, dibastic sodium phosphate, sodium dihydrogen phosphate or in which several mixtures.
As present invention further optimization, in the step (2), material used by the micropin mold is poly- diformazan
Radical siloxane, epoxy resin, polytetrafluoroethylene (PTFE), Kynoar, polypropylene, polyether sulfone, polyether-ether-ketone, hyaluronic acid, poly- second
Enol, polyvinylpyrrolidone, polyethylene glycol, chitosan, sodium alginate, glucose, sodium chloride, mica, glass, silicon, poly- pair
One of ethylene terephthalate, polyvinyl chloride, copper, aluminium, gold, silver, stainless steel and ice or in which several compound
Object.
As present invention further optimization, in the step (1), the polymer is polyacrylonitrile, polylactic acid, poly- cream
Acid-co-glycolic acid, polyarylsulfone (PAS), polyether sulfone, cellulose acetate, polyimides, polyetherimide, gathers Kynoar
Amide, polyether-ether-ketone, polycarbonate, polytetrafluoroethylene (PTFE), polyvinyl chloride, polyacrylic acid, polymethylacrylic acid, polyethyleneimine,
Polyvinylpyridine, polyethylene glycol, poly- isotactic propylene, cellulose esters, polystyrene, polybutadiene, polyphenylene oxide, polyurethane, bromine
Change polyphenylene oxide, polyvinyl alcohol, hyaluronic acid, sodium alginate, carboxymethyl cellulose, agarose, gelatin, one of chitosan or
Several blends or the copolymer being made of above-mentioned polymer.
As present invention further optimization, in the step (1), the template be inorganic salts, oxide, simple substance,
One of organic molecule, ice or in which several mixtures；
The inorganic salts include chloride, sulfate, disulfate, carbonate, bicarbonate, phosphate, hydrophosphate
At least one of, preferably lithium chloride, beryllium chloride, sodium chloride, magnesium chloride, aluminium chloride, potassium chloride, calcium chloride, iron chloride, chlorine
Change copper, nickel chloride, manganese chloride, zinc chloride, barium chloride, lithium sulfate, beryllium sulfate, sodium sulphate, magnesium sulfate, aluminum sulfate, potassium sulfate, sulphur
Sour calcium, manganese sulfate, ferric sulfate, copper sulphate, zinc sulfate, barium sulfate, lithium hydrogen sulfate, hydrogen sulfate beryllium, sodium bisulfate, magnesium bisulfate,
Aluminium hydrogen sulfate, potassium acid sulfate, calcium bisulfate, barium hydrogen sulfate, lithium carbonate, beryllium carbonate, sodium carbonate, magnesium carbonate, aluminium carbonate, carbonic acid
Potassium, calcium carbonate, manganese carbonate, barium carbonate, lithium bicarbonate, bicarbonate beryllium, sodium bicarbonate, magnesium bicarbonate, bicarbonate aluminium, bicarbonate
Potassium, calcium bicarbonate, barium bicarbonate, lithium phosphate, beryllium phosphate, sodium phosphate, magnesium phosphate, aluminum phosphate, potassium phosphate, calcium phosphate, barium phosphate,
Manganese phosphate, ferric phosphate, cupric phosphate, trbasic zinc phosphate, lithium hydrogen phosphate, beryllium hydrophosphate, dibastic sodium phosphate, magnesium monohydrogen phosphate, phosphoric acid hydrogen aluminium, phosphoric acid
One of hydrogen potassium, calcium monohydrogen phosphate, barium hydrogen phosphate or in which several mixtures；
The oxide includes at least one of metal oxide, nonmetal oxide, specially beryllium oxide, oxidation
Magnesium, aluminium oxide, calcium oxide, barium monoxide, manganese oxide, iron oxide, copper oxide, zinc oxide, silica, one in phosphorus pentoxide
Kind or in which several mixtures；
The simple substance includes at least one of metal simple-substance, non-metal simple-substance, specially gold, magnesium, aluminium, silicon, phosphorus, calcium,
One of manganese, iron, copper, zinc, barium or in which several mixtures；
The organic molecule is specially glucose, lactose, galactolipin, fructose, cholesterol, polyvinylpyrrolidone, seaweed
Sour sodium, chitosan, carboxymethyl cellulose, hyaluronic acid, gelatin, agarose, glucan, polyacrylonitrile, polylactic acid, polylactic acid-
Co-glycolic acid, Kynoar, polyarylsulfone (PAS), polyether sulfone, cellulose acetate, polyimides, polyetherimide, polyamides
Amine, polyether-ether-ketone, polycarbonate, polyvinyl chloride, polyacrylic acid, polymethylacrylic acid, polyethyleneimine, polyvinylpyridine,
One of polyethylene glycol, cellulose esters, polystyrene, polybutadiene, polyphenylene oxide, polyurethane, brominated polyphenylether, polyvinyl alcohol
Or in which several mixture.
As present invention further optimization, in the polymer solution that the step (1) obtains, the polymer with
The mass ratio of both templates is 19:1-1:19；The template is preferably particulate powder, and the partial size of particle is 2-
50000nm；
Preferably, the template diameter is 5 μm, and the mass ratio of both the template and described polymer is 3:2, described
Described its pore size of porous polymer micropin that step (4) accordingly obtains is 4.8 μm, porosity 50%；Alternatively, the mould
Plate agent diameter is 10 μm, and template and polymer quality ratio are 5:1, the porous polymer that the step (4) accordingly obtains
Its pore size of micropin is 9.7 μm, porosity 83%.
As present invention further optimization, the step (2) is specifically to use be centrifuged, vacuumize, ultrasound, heating, shaking
Method or several method combination one of are swung to insert the polymer solution in micropin mold；
The step (3) be specifically using be lyophilized, dry, drying, gas drying, one of supercritical fluid extraction just
Method or the combination of a variety of methods are to remove the solvent A.
It is another aspect of this invention to provide that the present invention provides the sides for preparing porous polymer micropin using above-mentioned template
The application for the porous polymer micropin that method is prepared, which is characterized in that specifically be applied to preparation for extract tissue fluid or
The preparation of blood, or preparation have whitening Cosmetic Ingredient, anti-wrinkle cosmetic ingredient, wrinkle removal beauty treatment ingredient, spot-eliminating beauty treatment ingredient, moisturizing
Cosmetic Ingredient, antibiotic, small-molecule drug, protein medicaments or traditional Chinese compound medicine percutaneous drug administration preparation, or preparation is used for
The pharmaceutical preparation for treating the percutaneous dosing of diabetes, psoriasis, alopecia or superficial dermatoma disease.
Contemplated above technical scheme is with conventional ultrasound welding and in micropin outer cladding porous material through the invention
The prior arts such as method compare, polymer and template are made into mixed solution, mixed solution is then filled into micropin mould
In tool, demoulding obtains solid microneedles after the solution is dry, and then removing the template in solid microneedles can be obtained porous gather
Closing object micropin, (removing template using solvent B is acted on using selective dissolution of the solvent B to solid microneedles constituent, molten
Agent B only dissolves these templates；Solvent B is also possible to occur to the course of dissolution of template either physical change occurs
Chemical change)；Porous polymer micropin is made by template in the present invention, and it is numerous to overcome preparation process in traditional preparation methods
It is trivial, condition is harsh, expensive, pore structure, size and distribution poor controllability the disadvantages of.The present invention can be simple, mild, quick
The porous polymer micropin is prepared on ground, is suitable for large scale preparation.The system of porous polymer micropin provided by the invention
The porous polymer micropin that Preparation Method is prepared has the following characteristics that pore structure is coherent, pore size controllability is good, porosity
It is adjustable；Can be used for tissue fluid, blood extracts, nti-freckle, crease-resistant, smoothing wrinkle, hair tonic, immune, treatment, protein or polypeptide drug
The fields such as percutaneous dosing.
Pair the present invention prepares porous polymer micropin using template, and by regulation template, (template is used for pore, i.e.,
Answer pore-foaming agent) size and content, regulate and control porous polymer micropin pore size and its distribution, can prepare pore structure rule
It is whole, pore size distribution is uniform, the good porous polymer micropin of controllability.
In general, through the invention it is designed above technical scheme is compared with the prior art, can obtain down and show
Beneficial effect:
(1) microneedle array mold materials provided by the invention are reusable, save the cost.
(2) Biocompatibility provided by the invention for preparing porous polymer micropin is good, low in cost, is suitable for more
The large scale preparation of pore polymer micropin.
(3) preparation method of porous polymer microneedle array provided by the invention, for conventional porous polymer micro needle battle array
Column preparation process complexity, pore structure, size and distribution poor controllability, the problems such as technique is cumbersome and expensive, by simple
Porous polymer micropin is prepared in template.This method preparation process is simple mild, low in cost, and design is strong, universality
It is good.
(4) preparation method of porous polymer microneedle array provided by the invention, by changing the size of template and containing
Amount can Effective Regulation porous polymer micropin pore size and porosity, and then meet different porous polymer micropins prepares need
It asks.
(5) porous polymer microneedle array provided by the invention, there is bigger cavity compared with solid microneedles, and drugloading rate is higher；
Compared with hollow metal micropin good biocompatibility, no skin irritatin, and preparation is more simple, and pore size and distribution controllability are more preferable.
(6) preparation method of porous polymer microneedle array provided by the invention, the porous polymer micro hole knot of preparation
Structure is regular, pore size and distribution controllability are good, the porous polymer micropin especially obtained compared to other preparation methods, have with
Lower feature: pore size and distribution are easy to regulate and control, and pore size controlled range is wide (a few nanoscale~tens micron), can meet in group
Knit the dosed administration in the percutaneous dosing of liquid, the quantitative extraction of blood and beauty, immune, treatment, protein or polypeptide drug.
To sum up, the method for preparing porous polymer micropin the present invention is based on template is easy to operate, mild condition, at low cost
It is honest and clean, it is easy to large-scale production, obtained porous polymer microneedle configuration is regular, pore structure, pore size and distribution controllability are good, easily
In large-scale production, capable of efficiently solving porous polymer micropin, method is complicated during the preparation process, technique is cumbersome, price is high
High, pore structure, size and distribution are difficult to control, are unable to the problem of large-scale production, can be used for preparing for extracting skin histology
The preparation of liquid or blood, or preparation have whitening Cosmetic Ingredient, anti-wrinkle cosmetic ingredient, wrinkle removal beauty treatment ingredient, spot-eliminating beauty treatment ingredient,
Moisturizing Cosmetic Ingredient, antibiotic, small-molecule drug, protein medicaments or traditional Chinese compound medicine percutaneous drug administration preparation, or preparation
For treating the pharmaceutical preparation of the percutaneous dosing of diabetes, psoriasis, alopecia or superficial dermatoma disease.As it can be seen that the present invention is logical
It crosses simple method i.e. and can be prepared on a large scale porous polymer micropin, overcome porous polymer micropin preparation process complexity, item
The problems such as part is harsh, technique is cumbersome, expensive, and by the content of adjusting template agent and size to regulate and control porous polymer
The pore size and porosity of micropin are made to solve the problems, such as that polymer micro needle pore structure, size and distribution are difficult to control
Porous polymer micropin can be used for tissue fluid extract and percutaneous dosing in.
Detailed description of the invention
Fig. 1 is the flow chart and needle point longitudal section schematic diagram that template prepares porous polymer micropin.
Fig. 2 is the optical microscope of porous polyarylsulfone (PAS) micropin.
Fig. 3 is that micropin has pricked the optical microscope after pigskin.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.As long as in addition, technical characteristic involved in the various embodiments of the present invention described below
Not constituting a conflict with each other can be combined with each other.
The present invention provides a kind of methods for preparing porous polymer micropin based on template.Pass through the ruler of adjusting template agent
Very little and concentration can prepare the good porous polymer microneedle array of regular pore structure, size uniformity, controllability.
The method that template provided by the invention prepares porous polymer microneedle array, comprising the following steps:
(1) polymer and template are dissolved in prepare in solvent A and obtain polymer solution；
(2) in the polymer solution filling micropin mold obtained the step (1)；
(3) solvent in the polymer solution in the step (2) is removed, solid microneedles are obtained；
(4) template in solid microneedles described in the step (3) is removed, porous polymer micropin is obtained.
Can quickly prepare the microneedle array mold according to the method, preparation process is simple, mild condition, at
Sheet is cheap, is suitable for large scale preparation, and the pore size and distribution controllability of resulting porous polymer micropin are good.
Porous polymer micropin provided by the invention improves the loading of drug, reduces administration number of times and wound, both
It can be applied to Skin tissue fluid, blood extracts and biological cutaneous penetration, it can also be used to which nti-freckle, hair tonic, is immunized, controls crease-resistant, smoothing wrinkle
The percutaneous dosing for the treatment of, protein or polypeptide drug.
The present invention obtains the porous polymer of different pore size structure and porosity by the size and content of change template
Micropin.
The following are embodiments:
Embodiment 1
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, passing through laser ablation
Polytetrafluoroethylene (PTFE) former is prepared in method；Then, Kynoar and the calcium carbonate having a size of 500nm are pressed to the mass ratio of 3:7
It is added in dimethyl sulfoxide and is configured to solution, above-mentioned solution is added drop-wise on polytetrafluoroethylene (PTFE) former, vacuumize promotion solution
Into in mold；Heating, drying dimethyl sulfoxide, removing obtain the solid Kynoar micropin containing calcium carbonate；By gained reality
Heart micropin is placed in the dilute nitric acid solution of 2mol/L, removes calcium carbonate nano particle, porous Kynoar micropin can be obtained.
Embodiment 2
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, polysulfones and the calcium carbonate having a size of 2 μm are added to dimethyl sulfoxide by the mass ratio of 3:7
In be configured to solution, above-mentioned solution is added drop-wise on PDMS former, ultrasound promote solution enter in mold；Dry dimethyl Asia
Sulfone, removing obtain the solid polysulfones micropin containing calcium carbonate；Gained solid microneedles are placed in the dilute nitric acid solution of 2mol/L, are removed
Calcium carbonate nano particle is removed, porous polysulfones micropin can be obtained.
Embodiment 3
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, being added by micro electronmechanical
Stainless steel former is prepared in work technology；Then, polysulfones and the sodium chloride having a size of 50 μm are added to N- by the mass ratio of 3:7
It is configured to solution in methyl pyrrolidone, above-mentioned solution is added drop-wise on stainless steel former, vacuumizes and solution is promoted to enter mold
In；Heating, drying N-Methyl pyrrolidone, removing obtain the solid polysulfones micropin containing sodium chloride；Gained solid microneedles are placed in
In pure water, sodium chloride is removed, porous polysulfones micropin can be obtained.
Embodiment 4
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, cellulose acetate and polyethylene glycol are added in dimethyl sulfoxide by the mass ratio of 1:1 and are matched
It is set to solution, above-mentioned solution is added drop-wise on PDMS former, centrifugation promotes solution to enter in mold；Freeze-drying removes dimethyl
Sulfoxide, removing obtain the solid cellulose acetate micropin containing polyethylene glycol；Gained solid microneedles are placed in pure water, are removed poly-
Porous cellulose acetate micropin can be obtained in ethylene glycol.
Embodiment 5
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, polysulfones and the calcium carbonate having a size of 2 μm are added to N- methylpyrrole by the mass ratio of 1:9
It is configured to solution in alkanone, above-mentioned solution is added drop-wise on PDMS former, vacuumizes and solution is promoted to enter in mold；Heating, drying
N-Methyl pyrrolidone, removing obtain the solid polysulfones micropin containing calcium carbonate；Gained solid microneedles are placed in the dilute of 2mol/L
In nitric acid solution, calcium carbonate nano particle is removed, porous polysulfones micropin can be obtained.
Embodiment 6
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, cellulose acetate and polyvinylpyrrolidone are added to dimethyl by the mass ratio of 19:1
It is configured to solution in sulfoxide, above-mentioned solution is added drop-wise on PDMS former, vacuumizes and solution is promoted to enter in mold；Heating, drying
Dimethyl sulfoxide, removing obtain the solid cellulose acetate micropin containing polyvinylpyrrolidone；Gained solid microneedles are placed in
In pure water, polyvinylpyrrolidone is removed, porous cellulose acetate micropin can be obtained.
Embodiment 7
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, cellulose acetate and glucose are added in dimethyl sulfoxide by the mass ratio of 1:19 and are matched
It is set to solution, above-mentioned solution is added drop-wise on PDMS former, vacuumizes and solution is promoted to enter in mold；Heating, drying dimethyl is sub-
Sulfone, removing obtain the solid cellulose acetate micropin containing glucose；Gained solid microneedles are placed in pure water, grape is removed
Porous cellulose acetate micropin can be obtained in sugar.
Embodiment 8
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, polyether sulfone and the silica having a size of 500nm are added to diformazan by the mass ratio of 3:7
It is configured to solution in base sulfoxide, above-mentioned solution is added drop-wise on PDMS former, ultrasound promotes solution to enter in mold；Heating, drying
Dimethyl sulfoxide, removing obtain the solid polyether sulfone micropin containing silica；Gained solid microneedles are placed in the hydrogen of 2mol/L
In sodium hydroxide solution, Nano particles of silicon dioxide is removed, porous polyether sulfone micropin can be obtained.
Embodiment 9
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, polyether sulfone and the silica having a size of 500nm are added to diformazan by the mass ratio of 3:7
It is configured to solution in base sulfoxide, above-mentioned solution is added drop-wise on PDMS former, ultrasound promotes solution to enter in mold；Heating, drying
Dimethyl sulfoxide, removing obtain the solid polyether sulfone micropin containing silica；Gained solid microneedles are placed in 10-4Mol/L's
In sodium hydroxide solution, Nano particles of silicon dioxide is removed, porous polyether sulfone micropin can be obtained.
Embodiment 10
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, polyether sulfone and the silica having a size of 500nm are added to diformazan by the mass ratio of 3:7
It is configured to solution in base sulfoxide, above-mentioned solution is added drop-wise on PDMS former, ultrasound promotes solution to enter in mold；Heating, drying
Dimethyl sulfoxide, removing obtain the solid polyether sulfone micropin containing silica；Gained solid microneedles are placed in the hydrogen of 20mol/L
In sodium hydroxide solution, Nano particles of silicon dioxide is removed, porous polyether sulfone micropin can be obtained.
Embodiment 11
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, polyether sulfone and the calcium oxide having a size of 2 μm are added to N, N- diformazan by the mass ratio of 3:7
It is configured to solution in base formamide, above-mentioned solution is added drop-wise on PDMS former, ultrasound promotes solution to enter in mold；Heating is dried
Dry n,N-Dimethylformamide, removing obtain the solid polyether sulfone micropin containing calcium oxide；Gained solid microneedles are placed in 10- 4In the dilute nitric acid solution of mol/L, calcium oxide nanoparticle is removed, porous polyether sulfone micropin can be obtained.
Embodiment 12
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, polyether sulfone and the barium carbonate having a size of 2 μm are added to N, N- diformazan by the mass ratio of 3:7
It is configured to solution in base formamide, above-mentioned solution is added drop-wise on PDMS former, vacuumizes and solution is promoted to enter in mold；Heating
N,N-Dimethylformamide is dried, removing obtains the solid polyether sulfone micropin containing barium carbonate；Gained solid microneedles are placed in
In the dilute nitric acid solution of 12mol/L, barium carbonate nanoparticle is removed, porous polyether sulfone micropin can be obtained.
Embodiment 13
A kind of porous polymer microneedle array of template preparation, is prepared as follows: firstly, by micro- template
PDMS former is prepared；Then, polyether sulfone and the sodium carbonate having a size of 2nm are added to N, N- diformazan by the mass ratio of 3:7
It is configured to solution in base formamide, above-mentioned solution is added drop-wise on PDMS former, vacuumizes and solution is promoted to enter in mold；Heating
N,N-Dimethylformamide is dried, removing obtains the solid polyether sulfone micropin containing sodium carbonate；Gained solid microneedles are placed in
In the dilute nitric acid solution of 0.1mol/L, sodium carbonate nanoparticle is removed, porous polyether sulfone micropin can be obtained.
Embodiment 14
Porous polyether sulfone micropin is prepared using the method for embodiment 1, inserts it into pre-prepd containing 1mg/
In the agar hydrogel of the 3wt% of mL rhodamine B, observe under the microscope.
Under the microscope it can clearly be seen that the needle point of porous polyether sulfone micropin is white, insertion before being inserted into agar gel
After become red, red is the color of Model Molecule rhodamine B, illustrates that porous polymer micropin can draw model drug and divide
Son.
Embodiment 15
Porous polyether sulfone micropin is prepared using the method for embodiment 1, rhodamine B is loaded into porous micropin, it will
It is inserted on the smooth fresh mouse skin of preprepared depilation, small under the microscope in fluorescence microscopy after a period of time
Mouse skin.
It observes under an optical microscope, the murine skin surface after effect has apparent hole, remaining skin is intact, table
Bright porous polymer micropin can effectively pierce through mouse skin.Similarly, can be observed under fluorescence microscope, it is small after effect
Mouse skin surface has apparent green fluorescence, and other parts show black, illustrate that green fluorescence is porous polymer microneedle
After skin, what rhodamine B was formed at the hole that micropin leaves, illustrate that porous polymer micropin can effectively pierce through skin.
As it can be seen that compared with prior art, porous polymer microneedle array, pore structure made from template of the present invention
It is regular, pore size is uniform, controllability is good；The method can be used for the large-scale production of porous polymer microneedle array；It is resulting
The preparation for extracting tissue fluid or blood can be prepared separately in porous polymer micropin, can also with existing drug or have
The effective component of beauty functions is loaded, and preparation is used for the drug of antibiotic skin test, or prepare and be administered for small-molecule drug,
The drug of protide administration or Chinese medicine compound prescription administration, or preparation have beauty for whitening, crease-resistant, smoothing wrinkle, nti-freckle or moisturizing
The preparation of the percutaneous dosing of Rongcheng point, or preparation is for treating the percutaneous of diabetes, psoriasis, alopecia or superficial dermatoma disease
The drug of administration, so that it is applied to tissue fluid, blood extraction, antibiotic skin test, small-molecule drug administration, protide administration, in
The administration of medicine compound, the percutaneous dosing of the Cosmetic Ingredients such as whitening, crease-resistant, smoothing wrinkle, nti-freckle, moisturizing and diabetes, psoriasis, alopecia
And the percutaneous dosing of the diseases such as superficial dermatoma, it is quantitatively extracted for tissue fluid, blood, nti-freckle, hair tonic, is exempted from crease-resistant, smoothing wrinkle
Epidemic disease, treatment, protein or polypeptide drug the fields such as percutaneous dosing.
As it will be easily appreciated by one skilled in the art that the foregoing is merely illustrative of the preferred embodiments of the present invention, not to
The limitation present invention, any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should all include
Within protection scope of the present invention.
Claims (9)
1. a kind of method that template prepares porous polymer micropin, which comprises the following steps:
(1) polymer and template are dissolved in prepare in solvent A and obtain polymer solution；
(2) in the polymer solution filling micropin mold obtained the step (1)；
(3) solvent A in micropin mold obtained by the step (2) is removed, solid microneedles are obtained；
(4) template in solid microneedles obtained by the step (3) is removed, porous polymer micropin can be obtained.
2. the method that template as described in claim 1 prepares porous polymer micropin, which is characterized in that in the step (1),
The solvent A is N,N-dimethylformamide, dimethyl sulfoxide, DMAC N,N' dimethyl acetamide, N-Methyl pyrrolidone, hexamethyl
Phosphamide, 1,4- dioxane, nitromethane, nitroethane, triethyl phosphate, trimethyl phosphate, tetramethylurea, curing
Carbon, formamide, dibutyl phthalate, tetrahydrofuran, methylene chloride, acetic acid, carbon tetrachloride, methanol, ethyl alcohol, isopropanol,
Hexane, hexamethylene, chloroform, acetone, ethylene glycol, methyl ether, ether, water, glycerine, 1,2- propylene glycol, n-butanol, octanol, tetrachloro
The mixture of one or more of ethylene, tetrachloroethanes, fluothane hydrocarbon, dichloroethanes, pyridine.
3. the method that template as described in claim 1 prepares porous polymer micropin, which is characterized in that step (4) tool
Body is to use heating, freeze-drying or solid microneedles are immersed in another solvent B to remove the template；The solvent
B can dissolve the template and can not dissolve the polymer, specially acid solution, alkaline solution, water, tetrahydrofuran,
It is methylene chloride, methanol, ethyl alcohol, isopropanol, hexane, chloroform, acetone, ethylene glycol, methyl ether, ether, water, glycerine, n-butanol, pungent
One of alcohol, dichloroethanes, pyridine or in which several mixtures；
The acid solution is preferably sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, acetic acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, Gao Meng
One of acid, hydrobromic acid, formic acid, propionic acid, butyric acid, edta solution or in which several mixtures；
The alkaline solution be preferably sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus,
One of sodium phosphate, dibastic sodium phosphate, sodium dihydrogen phosphate or in which several mixtures.
4. the method that template as described in claim 1 prepares porous polymer micropin, which is characterized in that in the step (2),
Material used by the micropin mold is dimethyl silicone polymer, epoxy resin, polytetrafluoroethylene (PTFE), Kynoar, poly- third
Alkene, polyether sulfone, polyether-ether-ketone, hyaluronic acid, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, chitosan, sodium alginate,
Glucose, sodium chloride, mica, glass, silicon, polyethylene terephthalate, polyvinyl chloride, copper, aluminium, gold, silver, stainless steel,
And one of ice or in which several compounds.
5. the method that template as described in claim 1 prepares porous polymer micropin, which is characterized in that in the step (1),
The polymer is polyacrylonitrile, polylactic acid, poly lactide-glycolide acid, Kynoar, polyarylsulfone (PAS), polyether sulfone, vinegar
Acid cellulose, polyetherimide, polyamide, polyether-ether-ketone, polycarbonate, polytetrafluoroethylene (PTFE), polyvinyl chloride, gathers polyimides
Acrylic acid, polymethylacrylic acid, polyethyleneimine, polyvinylpyridine, polyethylene glycol, poly- isotactic propylene, cellulose esters, polyphenyl
Ethylene, polybutadiene, polyphenylene oxide, polyurethane, brominated polyphenylether, polyvinyl alcohol, hyaluronic acid, sodium alginate, carboxymethyl cellulose
One or more of element, agarose, gelatin, chitosan blend or the copolymer being made of above-mentioned polymer.
6. the method that template as described in claim 1 prepares porous polymer micropin, which is characterized in that in the step (1),
The template is one of inorganic salts, oxide, simple substance, organic molecule, ice or in which several mixtures；It is described inorganic
Salt includes at least one of chloride, sulfate, disulfate, carbonate, bicarbonate, phosphate, hydrophosphate, preferably
For lithium chloride, beryllium chloride, sodium chloride, magnesium chloride, aluminium chloride, potassium chloride, calcium chloride, iron chloride, copper chloride, nickel chloride, chlorination
Manganese, zinc chloride, barium chloride, lithium sulfate, beryllium sulfate, sodium sulphate, magnesium sulfate, aluminum sulfate, potassium sulfate, calcium sulfate, manganese sulfate, sulfuric acid
Iron, copper sulphate, zinc sulfate, barium sulfate, lithium hydrogen sulfate, hydrogen sulfate beryllium, sodium bisulfate, magnesium bisulfate, aluminium hydrogen sulfate, hydrogen sulfate
Potassium, calcium bisulfate, barium hydrogen sulfate, lithium carbonate, beryllium carbonate, sodium carbonate, magnesium carbonate, aluminium carbonate, potassium carbonate, calcium carbonate, manganese carbonate,
Barium carbonate, lithium bicarbonate, bicarbonate beryllium, sodium bicarbonate, magnesium bicarbonate, bicarbonate aluminium, saleratus, calcium bicarbonate, bicarbonate
Barium, lithium phosphate, beryllium phosphate, sodium phosphate, magnesium phosphate, aluminum phosphate, potassium phosphate, calcium phosphate, barium phosphate, manganese phosphate, ferric phosphate, phosphoric acid
Copper, trbasic zinc phosphate, lithium hydrogen phosphate, beryllium hydrophosphate, dibastic sodium phosphate, magnesium monohydrogen phosphate, phosphoric acid hydrogen aluminium, potassium hydrogen phosphate, calcium monohydrogen phosphate, phosphoric acid
One of hydrogen barium or in which several mixtures；
The oxide includes at least one of metal oxide, nonmetal oxide, specially beryllium oxide, magnesia, oxygen
Change aluminium, calcium oxide, barium monoxide, manganese oxide, iron oxide, copper oxide, zinc oxide, silica, one of phosphorus pentoxide or
Wherein several mixture；
The simple substance includes at least one of metal simple-substance, non-metal simple-substance, specially gold, magnesium, aluminium, silicon, phosphorus, calcium, manganese,
One of iron, copper, zinc, barium or in which several mixtures；
The organic molecule be specially glucose, lactose, galactolipin, fructose, cholesterol, polyvinylpyrrolidone, sodium alginate,
Chitosan, carboxymethyl cellulose, hyaluronic acid, gelatin, agarose, glucan, polyacrylonitrile, polylactic acid, polylactic acid-glycolic base second
Acid copolymer, Kynoar, polyarylsulfone (PAS), polyether sulfone, cellulose acetate, polyimides, polyetherimide, polyamide, polyethers
Ether ketone, polycarbonate, polyvinyl chloride, polyacrylic acid, polymethylacrylic acid, polyethyleneimine, polyvinylpyridine, poly- second two
One of alcohol, cellulose esters, polystyrene, polybutadiene, polyphenylene oxide, polyurethane, brominated polyphenylether, polyvinyl alcohol or in which
Several mixtures.
7. the method that template as described in claim 1 prepares porous polymer micropin, which is characterized in that the step (1)
To the polymer solution in, the mass ratio of both the polymer and described template is 19:1-1:19；The template
Preferably particulate powder, the partial size of particle are 2-50000nm；
Preferably, the template diameter is 5 μm, and the mass ratio of both the template and described polymer is 3:2, the step
(4) described its pore size of porous polymer micropin accordingly obtained is 4.8 μm, porosity 50%；Alternatively, the template
Diameter is 10 μm, and template and polymer quality ratio are 5:1, the porous polymer micropin that the step (4) accordingly obtains
Its pore size is 9.7 μm, porosity 83%.
8. the method that template as described in claim 1 prepares porous polymer micropin, which is characterized in that step (2) tool
Body is one of to use centrifugation, vacuumize, is ultrasonic, heating, vibrate method or several method combination with the polymer is molten
Liquid is inserted in micropin mold；
The step (3) be specifically using be lyophilized, dry, drying, gas dries up, one of supercritical fluid extraction method or
A variety of method combinations are to remove the solvent A.
9. being prepared using the method that the template as described in claim 1-8 any one prepares porous polymer micropin more
The application of pore polymer micropin, which is characterized in that be specifically applied to prepare the preparation for extracting tissue fluid or blood, or system
It is standby that there is whitening Cosmetic Ingredient, anti-wrinkle cosmetic ingredient, wrinkle removal beauty treatment ingredient, spot-eliminating beauty treatment ingredient, moisturizing Cosmetic Ingredient, antibiosis
Element, small-molecule drug, protein medicaments or traditional Chinese compound medicine percutaneous drug administration preparation, or preparation is for treating diabetes, silver
The pharmaceutical preparation of the percutaneous dosing of bits disease, alopecia or superficial dermatoma disease.
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