CN101507857A - Micro-needle array chip, percutaneous administration device, percutaneous administration patch and preparation method thereof - Google Patents
Micro-needle array chip, percutaneous administration device, percutaneous administration patch and preparation method thereof Download PDFInfo
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- CN101507857A CN101507857A CN 200910080758 CN200910080758A CN101507857A CN 101507857 A CN101507857 A CN 101507857A CN 200910080758 CN200910080758 CN 200910080758 CN 200910080758 A CN200910080758 A CN 200910080758A CN 101507857 A CN101507857 A CN 101507857A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Abstract
The invention relates to a micro-needle array chip, a transdermal delivery device, a transdermal delivery patch and a preparation method thereof, wherein a micro-needle is obliquely fixed on a substrate at a set angle, the upper surface of the needle is an elliptic plane parallel to the substrate or obliquely provided with an acute angle, the needle is further treated to have more edge angles, a metal wire bar or tube penetrates a non-metallic material substrate such as polymer and the like along a certain angle, and then a nick of the metal wire bar or tube on the substrate is grinded and polished; and photosensitive resist patterns are formed nearby the nick at one end by adopting photoetching and etching technology, then the metal wire bar or tube is subjected to chemical or electrochemical corrosion to form a needle point and the photosensitive resist is removed, the surface of the manufactured solid micro-needle array chip can be covered with drugs, and the manufactured solid micro-needle array chip can deliver liquid medicine or extract body fluid. The method avoids the skin plugging a transfusion hole, is easy to adjust and control the maximum penetrating depth of the micro-needle, and is suitable for percutaneous transportation of biological macromolecular drugs and cosmetics and skincare and new percutaneous preparation of the prior drugs.
Description
Technical field
The present invention relates to medical treatment and beauty treatment instrument, biological medicine and Micrometer-Nanometer Processing Technology field, be specifically related to a kind of micro-needle array chip, transdermal delivery device, percutaneous administration patch and preparation method.
Background technology
The therapeutical effect of medicine not only depends on medicine itself, and the drug delivery system also has crucial influence for the performance of drug effect.For the biopharmaceutical macromolecular drugs such as polypeptide, protein, DNA, vaccine that with the insulin are representative, owing to influenced by the Degradation of enzyme in the gastrointestinal tract, the first pass effect of liver etc., its oral administration bioavailability is very low and can not reach curative effect.Subcutaneous injection can conveniently inject heavy dose of medicine human body and can remedy the shortcoming of oral administration, but its limitation is to people's pain, exist injection point damage, injection to need know-how and be difficult to realize and continue medication, patient especially child patient has probably pin consciousness usually, is not suitable for long term administration.Transdermal delivery system claims Transcutaneous Therapeutic System again, is meant that medicine enters a class preparation that body circulation produce drug effect by skin through the blood capillary absorption with certain speed.Compare with traditional administering mode, percutaneous dosing has many advantages: can produce lasting, constant and controlled blood drug level, make because the body intracellular metabolic rapidly and very short pharmaceutically active of half-life obviously improves, avoided the first pass effect of liver and the interference of gastrointestinal factors, toxic and side effects has been dropped to minimum; Have painless, noinvasive or invasive, but patient's self-medication is easy to use, at any time interruption of the administration.Though percutaneous dosing is very tempting, but when the medicine that advances into percutaneous dosing market, the world has only about 20 kinds, this mainly is because about 30～50 microns cuticular barrier effects of human body skin outermost bed thickness, cause the transdermal penetration speed of most medicines too low, can not satisfy the needs of treatment.Medicine that now can percutaneous dosing is subjected to many restrictions, for example molecular weight less than 500D, fat-solubility, fusing point less than 150 ℃, therapeutic dose less than 20 milligrams/day etc., macromolecule and polar medicine are difficult to realize passive percutaneous dosing.The biopharmaceutical macromolecular drug of researching and developing in the world at present has thousands of kinds, and can lacks suitable drug-supplying system have become it and bring into play optimum curative effect and enter clinical and significant obstacle that put on market smoothly.
In order to increase the permeability of skin, people have adopted several different methods such as chemical penetrating agent, iontherapy and electroporation method.All there is in various degree limitation in these methods to the medicine that is transmitted, and some may also can cause bigger toxic and side effects.1998, U.S. Prausnitz professor seminar is used for the percutaneous dosing field with the miniature solid silicon pin array of MEMS (MEMS) technology preparation first, find that it can improve 4 orders of magnitude with the percutaneous permeation of biomacromolecule model drug calcein, has from then on started the tide of microneedle transdermal delivery research in the world.
Microneedle array in certain sense is a kind of administering mode between subcutaneous injection and percutaneous patch.The skin of human body has three-layer weave: horny layer, active epidermal area and skin corium.Outermost cuticle thickness is about 30～50 microns, is made up of the horn cell of densification, and its permeability to most medicines is very low, is the major obstacle that these medicines are carried by percutaneous; Be epidermal area below the horny layer, thickness is about 50～100 microns, contains competent cell and very a spot of nervous tissue, but does not have blood vessel; Be skin corium below the epidermal area, it is the key component of skin, contains a large amount of living cells, nervous tissue and vascular tissue.The syringe needle external diameter that the tradition hypodermic injection uses is generally 0.4～3.4 millimeter, the syringe needle transdermal must be deep in the muscle during injection, will touch blood vessel undoubtedly and damage a large amount of nervous tissues, therefore except meeting was hemorrhage, the patient tended to experience comparatively violent pain.Adopt the MEMS technology can produce short and small and sharp microneedle array low-costly and in high volume, by pushing the mode of executing pin can moment obviously improves medicine in the duct that keratodermatitis and epidermal area produce a large amount of micron dimension sizes permeability, should be applicable to any medicine that comprises biopharmaceutical macromolecular drug in theory and be not subjected to the restriction of molecular weight size, medicine polarity, fusing point etc.Because the micropin medicine-feeding part does not touch nervous tissue and blood vessel at body surface, therefore can not produce pain and bleeding; Adopt the micropin administration not need the professional to operate, flexible and convenient to use, interruption of the administration at any time is so accepted by the patient easilier.
With percutaneous dosing in like manner because cuticular barrier effect, adopt general traditional method to use cosmetics and skincare product, most active nutrients wherein are difficult to enter active epidermal area and skin corium, so cosmetic result is not remarkable.If have the microneedle array of cosmetics and skincare product to thrust skin surface applied, or microneedle array thrusts and removes repaste behind the skin and apply cosmetics and skincare product, all can obviously improve active nutrient and pass through the penetrating power that horny layer enters epidermal area and skin corium cell, thereby significantly improve the looks improving and the skin nourishing effect.In addition, tatoo, will make the process of tatooing become painless, safe and faster undoubtedly if replace cosmetics and skincare product to carry out micropin with dyestuff.
Micropin has two types of solid needle and hollow needles.In use, adopt following two kinds of administering modes usually: 1) earlier microneedle array is thrust skin and form hole, again medicated patches is applied on therapentic part for solid microneedles; 2) behind microneedle array surface-coated medicine, thrust skin and continue release.Normally adopt the form of microinjection to carry medicine for empty micropin, be applicable to liquid and the bigger medicine of therapeutic dose requirement.In addition, empty micropin can also be used for extraction and the detection that percutaneous carries out trace body fluid.
The material of making micropin has polymer, monocrystal silicon and metal etc.The outstanding problem that existing polymer micro needle exists is that the strength of materials is not enough, is difficult for piercing through the horny layer of skin.Hard, the easy brittle failure of monocrystal silicon material, it has bio-compatibility preferably though bibliographical information is arranged, and does not also belong to conventional medical material now, whether can be applicable to that the biological medicine aspect is still waiting further textual criticism.Metal is used for manufacturing needles acupuncture needle or existing thousand one-hundred-year histories of injection needle, though its safety is unquestionable, adopts traditional precision machining method to be difficult to process low-costly and in high volume solid, hollow metal micro-needle array chip.
At present, reported both at home and abroad that some are solid, hollow metal micro-needle array chip structure and manufacture method thereof, comprised following document:
1) array chip of minitype needles of administration through skin and manufacture method thereof, CN 1415385A;
2) Metal Micro-Needle Array Chips, Their Preparation Method and Usage, CN 100402107C;
3)Coated?Microstructures?and?Method?of?Manufacture?Thereof.WO?2006138719?A2；
4)High-aspect-ratio?microdevices?and?methods?for?transdermaldelivery?and?sampling?of?active?substances.US?20050261632?A1；
5)Device?for?enhancing?transdermal?agent?flux.WO?1999029365A1；
6)Hollow?Metal?Microneedles?for?Insulin?Delivery?to?Diabetic?Rats.IEEE?Tran.Biomedical?Eng.，52(5)：909-914，2005。
In above-mentioned document, all be on a nugget genus, to form the solid or empty micropin array of different shape and perpendicular to its substrate, preparation method comprises following several: 1) adopt mode cutting metal plates such as chemical attack or cut also to form various planes micropin figure thereon, utilize method such as punching press with these plane micropin perks and final vertical with this metallic plate then, this method is only applicable to the manufacturing of solid microneedles array chip; 2) metal sheet surface is carried out optionally electrolysis or electrochemical corrosion to form the micropin of projection, the solid microneedles structure that this method is prepared all has much room for improvement at aspects such as depth-to-width ratio and robustnesses; 3) adopt plating to combine with methods such as moulding casting and make the hollow metal micropin, the syringe needle shape of these micropins all is similar to the bottleneck of common daily bottle, if can thrust the obstruction that skin also very easily causes pin oral pore road.
Summary of the invention
The purpose of this invention is to provide a kind of micro-needle array chip, transdermal delivery device, percutaneous administration patch and preparation method, the microneedle configuration of preparing is firm, needle point is sharp, be convenient to puncture; Empty micropin has the side perforate that is similar to traditional injection needle, thereby can effectively avoid skin to stop up the phenomenon of infusion hole; The maximum that is easy to regulate and control micropin is thrust the degree of depth, and the planar shaped syringe needle can obviously increase the contact area of syringe needle and skin, more helps the rapid diffusion and the absorption of medicine; Micropin high conformity in the array, safe and reliable, evident in efficacy.
For achieving the above object, the present invention adopts following technical scheme:
The present invention at first provides micro-needle array chip, comprises micropin and substrate, wherein,
Described micropin is made up of syringe needle, shank and needle stand, and described needle tip is a needle point, and described micropin is fixed on the substrate by needle stand;
The shank of described micropin is cylinder or cone, and described shank is vertical with substrate, and it is conical that syringe needle is; Or described shank is to the substrate set angle that tilts, and the upper surface of needle point is parallel with substrate or tilts to set the elliptic plane of acute angle.
Preferably, described needle point place elliptic plane is cut one section arc surface at least and makes it have more corner angle.
Preferably, constitute microneedle array by at least two micropins, described microneedle array is solid or empty micropin array, or both mixing array, and described micropin is arranged by setting spacing on substrate.
Preferably, described micropin is solid microneedles or empty micropin, the shank of described micropin and needle stand to substrate inclination set angle separately, exist groove or pit respectively on the syringe needle of described solid microneedles or the shank, have through hole between the needle stand of described empty micropin and the syringe needle.
Preferably, the set angle that described needle stand tilts is 15～90 degree, and the set angle that described shank tilts is 15～150 degree.
Preferably, the material that described micropin adopts is rustless steel, titanium alloy, aluminium alloy, copper alloy, tungsten metal bar or metal tube, described micropin surface or be coated with one deck in addition or several layers dielectric material thin film or gold, titanium, platinum thin film.
Preferably, the material that described substrate adopts is medical plastic, polymer, glass, rubber, latex or nonmetal thermoplastic composite, or form or combine by different materials layering wherein by a kind of material preparation wherein, binding agent or fixed structure are arranged between each layer.
Preferably, the radius of curvature of needle point, thickness and width are 5 nanometers～350 micron;
The external diameter of described shank is 20～1000 microns, highly is 50～5000 microns;
The through hole internal diameter of described empty micropin is 5～800 microns;
Described needle stand is fixed in one deck baseplate material or penetrates one deck baseplate material at least;
The thickness of described substrate is 20 microns～8000 microns, is surface plate or curved slab.
The present invention also provides a kind of preparation method of above-mentioned micro-needle array chip, comprises step:
S101 vertically or along set angle tilts to insert or penetrate described substrate with metal thread bar or metal capillary;
S102 cuts off described metal thread bar or metal capillary, and fracture surface is formed oval needle point along direction grinding and polishing parallel with substrate or that tilt;
S103 immerses micro-needle array chip in chemistry or the electrochemical polish liquid, and chemistry or electrochemical polish are carried out in the micropin surface.
Preferably, between step s102 and step s103, also comprise step:
S102a applies photoresist in substrate one side that is fixed with metal thread bar or metal capillary, utilizes the figure transfer techniques in the microelectronic technique to form the photoresist pattern that designs at an end of metal thread bar or metal capillary;
S102b; metal thread bar or metal capillary that chemistry or electrochemical corrosion are not protected by photoresist; prepare syringe needle with pit or groove, have the groove that leads to syringe needle or pit shank, have the solid metal micropin of more multangular needle point; or after preparing hollow metal micropin, remove photoresist with more multangular needle point.
The present invention also provides a kind of transdermal delivery device that utilizes above-mentioned micro-needle array chip, it is characterized in that, this device comprises:
Pedestal, the permanent or dismountable front that is fixed on described pedestal of micro-needle array chip;
The size in described pedestal front is equal to or greater than the size of described micro-needle array chip;
The described pedestal back side has manipulation, as to have plane or curved surface shaped hands handle;
The size in described pedestal front is during greater than the size of micro-needle array chip, and described micro-needle array chip is embedded in the center in described pedestal front, and the edge in pedestal front is higher than the substrate of the micro-needle array chip of center, but is lower than syringe needle.
Preferably, when the micropin in described micro-needle array chip is empty micropin,
The size in described pedestal front is greater than the size of micro-needle array chip, and described micro-needle array chip is embedded in the center that can form the described pedestal of inner chamber front, the edge in pedestal front be higher than the center micro-needle array chip substrate and be lower than syringe needle;
At the passage and the interface that have intracavity interpolation medicinal liquid in described on the pedestal, the element that the medicinal liquid of intracavity packing punctures in maybe will placing.
Preferably be fixed with the propulsion plant that inner chamber is pushed by pipeline connection or integration mode at the pedestal back side;
Described pedestal is prepared by plastics, polymer, glass, rubber, latex, metal or composite, or is formed by wherein a kind of material manufacture or multiple combination of materials, and multiple storeroom has binding agent or fixed structure.
The present invention also provides a kind of preparation method of above-mentioned transdermal delivery device, comprises step:
S201 adopts die casting, cutting, machining or bonding way to produce the pedestal that positive size is equal to or greater than the micro-needle array chip size;
S202 adopts bonding, fusion, bonding, mechanical pressing mode that micro-needle array chip is permanent or dismountablely be fixed on center positive on the pedestal, the edge in pedestal front be higher than the center micro-needle array chip substrate and be lower than syringe needle.
Preferably, when the micropin in described micro-needle array chip is empty micropin,
Among the step s201, has the passage from medicinal liquid to formed inner chamber and the interface that add on the pedestal of making, the element that the medicinal liquid of intracavity packing punctures in maybe will placing.
Preferably, between step s201 and step s202, also comprise step:
S201a connects by pipeline at the pedestal back side or integration mode is fixed with the propulsion plant that inner chamber is pushed.
The present invention also provides a kind of percutaneous administration patch that is applied on the above-mentioned micro-needle array chip, wherein,
This percutaneous administration patch is made of the thin film that one or more layers comprises one or more materials;
At least include a kind of medicine or cosmetics and skincare product in the described material with treatment, diagnosis or preventive effect.
Preferably, described material is solid, liquid, microgranule, colloidal sol, gel or wherein several mixtures.
The present invention also provides a kind of application process of above-mentioned percutaneous administration patch, comprises step:
S301 covers percutaneous administration patch by dipping, coating, physical property or chemical deposition process on solid microneedles even substrate;
S302 will have the substrate of micro-needle array chip of solid microneedles or the centre that glue one side is arranged that the pedestal back side is bonded in medical adhesive tape or adhesive plaster, and medical adhesive tape or adhesive plaster cover with strippable material film at the remainder glue face of this side.
Utilize the present invention, can obtain following beneficial effect:
1) microneedle configuration is firm, needle point is sharp, be convenient to puncture;
2) the planar shaped syringe needle can obviously increase the contact area of syringe needle and skin, more helps the rapid diffusion and the absorption of medicine;
3) empty micropin has the side perforate that is similar to traditional injection needle, thereby has effectively avoided skin to stop up the infusion hole phenomenon;
4) maximum that is easy to regulate and control micropin is thrust the degree of depth;
5) adopt conventional medical material to make micro-needle array chip and related equipment thereof, and utilize sophisticated processing technique to realize the batch manufacturing of its low cost, high finished product rate, high duplication;
6) the micropin high conformity in the array is safe and reliable, durable in use;
7) percutaneous that is highly suitable for biopharmaceutical macromolecular drugs such as polypeptide, protein, vaccine, DNA, cosmetics and skincare product transports and has now the exploitation of medicine percutaneous novel form, has boundless application prospect.
Description of drawings
Fig. 1 be in the embodiment of the invention cylindrical shank and needle stand all perpendicular to the solid microneedles array chip structure sketch map of substrate;
Fig. 2 be in the embodiment of the invention conical shank and needle stand all perpendicular to the solid microneedles array chip structure sketch map of substrate;
Fig. 3 is the vertical view of Fig. 1 or Fig. 2 substrate back;
Fig. 4 is the needle point plane a kind of solid microneedles array chip structure sketch map parallel with substrate in the embodiment of the invention;
Fig. 5 is the needle point plane a kind of empty micropin array chip structural representation parallel with substrate in the embodiment of the invention;
Fig. 6 has more multi-angular and parallel with substrate solid microneedles array chip structure sketch map for needle point place in the embodiment of the invention;
Fig. 7 is more multi-angular for needle point place in the embodiment of the invention has, groove and the solid microneedles array chip structure sketch map parallel with substrate.
Fig. 8 is the solid microneedles array chip structure cutaway view that needle point plane and shank all tilt with substrate in the embodiment of the invention;
Fig. 9 is the vertical view of Fig. 4,6～8 substrate backs.
Figure 10 has more multi-angular and parallel with substrate empty micropin array chip structural representation for needle point place in the embodiment of the invention;
Figure 11 is the vertical view of Fig. 5,10 substrate backs;
Figure 12 be in the embodiment of the invention a kind of shank perpendicular to the solid microneedles array chip structure sketch map of substrate;
Figure 13 be in the embodiment of the invention a kind of shank perpendicular to the solid microneedles array chip structure cutaway view of substrate
Figure 14 is a kind of structural representation that is used for the transdermal delivery device of solid microneedles array chip in the embodiment of the invention.
Figure 15 is a kind of structural representation that is used for the transdermal delivery device of solid microneedles array chip in the embodiment of the invention.
Figure 16 is the another kind of structural representation that is used for the transdermal delivery device of solid microneedles array chip in the embodiment of the invention
Figure 17 is the structural representation of transdermal delivery device of the solid microneedles array chip of curved slab for the invention process spr substrate.
Figure 18 A～Figure 18 E is the sketch map of preparation technology's flow process of micro-needle array chip in the embodiment of the invention.
The specific embodiment
Micro-needle array chip, transdermal delivery device, percutaneous administration patch and preparation method that the present invention proposes are described as follows in conjunction with the accompanying drawings and embodiments.
Micro-needle array chip and preparation method thereof
Micro-needle array chip comprises micropin and substrate 4, micropin is made up of syringe needle 1, shank 2 and needle stand 3, needle tip is a needle point 5, micropin is fixed on the substrate 4 by needle stand 3, shank 2 and needle stand 3 are cylinder or cone, micropin is vertically fixed on the substrate 4, and as depicted in figs. 1 and 2, it is conical that syringe needle 1 is; Or micropin inclination set angle is fixed on the substrate 4, set angle preferably adopts 15～90 degree, as shown in Figure 4 to 7, the upper surface of needle point 5 is parallel with substrate 4 or tilts to set the elliptic plane of acute angle, therefore this needle point 5 is further handled for oval needle point 5 or to this ellipse needle point and is made it have sharper keen wedge angle 5a, promptly to the edge of oval needle point 5 through further handle exist more multi-angular; Or shank 2 and needle stand 3 be respectively to tilt separately set angle of substrate, and shown in Figure 11,12, the upper surface of needle point 5 be and substrate 4 tilts to set the elliptic plane of acute angles, and the sharper keen wedge angle 5a of its existence is further handled and made to this ellipse needle point.
At least two micropins constitute microneedle array in the micro-needle array chip, and microneedle array is solid or empty micropin array, or both mixing array, and micropin is arranged by setting spacing on substrate.According to micropin is that solid microneedles or empty micropin can be divided into solid microneedles array chip and empty micropin array chip.Structure of solid microneedles array chip and empty micropin array chip and preparation method thereof is described in detail in detail below.
1) solid microneedles array chip
In the present embodiment, the shank 2 of solid microneedles and needle stand 3 are cylinder or the cones that are respectively 15～90 degree and 15～150 degree with the angle of substrate 4.When the angle of shank 2 and needle stand 3 and substrate 4 is 90 when spending, syringe needle 1 is needle point 5 directions and substrate 4 vertical taper shapes.When the shank 2 of solid microneedles is spent less than 90 with the angle of substrate 4, may there be pit that leads to syringe needle or groove 6 on the shank 2 as medicine storage pool; Syringe needle 1 place has and substrate 4 parallel or plane inclined 7, and syringe needle 1 has oval-shaped needle point 5 or this ellipse needle point is further handled the wedge angle 5a (it is more multi-angular to claim that also the needle point plane has) that makes its existence sharper keen on this plane 7; In addition, on syringe needle, also may there be pit or groove 6 as medicine storage pool.
The preparation method of above-mentioned solid microneedles comprises step:
(1) metal thread bar vertically or along the certain angle inclination is inserted or penetrates the substrate 4 that is prepared by medical plastic, polymer, glass, rubber, latex or nonmetal thermoplastic composite;
(2) cut off metal thread bar and with its at least one end fracture surface along parallel with substrate 4 or have the direction grinding and polishing at certain inclination angle to form oval needle point 5;
(3) when the micropin needle point of design preparation has the needle point 5a structure of sharper keen wedge angle and pit or groove 6, apply photoresist in substrate 4 one sides that have metal thread bar, utilize the figure transfer techniques in the microelectronic technique to form above-mentioned designed photoresist pattern then at an end of metal thread bar;
(4) metal thread bar do not protected of chemistry or electrochemical corrosion by photoresist, after forming required needle point, hole and groove, remove photoresist, prepare the needle point 5 that has as the pit of medicine storage pool or groove 6, as the pit that leads to syringe needle of medicine storage pool or the shank 2 of groove 6, the solid metal micropin of more multangular needle point 5a;
(5) the above-mentioned micro-needle array chip of preparing is immersed in chemistry or the electrochemical polish liquid, chemistry or electrochemical polish are carried out in the solid microneedles surface.
(6), can utilize baffle plate to promote the angle of shank 2 adjustment itself and substrate 4 when the shank 2 of design when having different angles with substrate 4 with needle stand 3.
2) empty micropin array chip
The shank 2 of empty micropin and needle stand 3 are cylindrical tube or the conical tubes that are respectively 15～90 degree and 15～150 degree with the angle of substrate 4; Syringe needle 1 place have through hole 8 ovalizes and with substrate 4 parallel or plane inclined 7, syringe needle 1 has oval-shaped needle point 5 or this ellipse needle point further handled on this plane 7 makes it have more multangular wedge angle 5a.
The preparation method of above-mentioned empty micropin comprises step:
(1) metal capillary is inserted or penetrates the substrate 4 that is prepared by medical plastic, polymer, glass, rubber, latex or nonmetal thermoplastic composite along the certain angle inclination;
(2) cut off metal capillary and with its fracture surface along parallel with substrate 4 or have the direction grinding and polishing at certain inclination angle to form oval needle point 5;
(3) when the micropin needle point of design preparation has the needle point 5a of sharper keen wedge angle, need apply photoresist in substrate 4 one sides that have metal capillary, utilize the figure transfer techniques in the microelectronic technique on an end tube wall of metal capillary, to form above-mentioned designed photoresist pattern then;
(4) metal capillary do not protected of chemistry or electrochemical corrosion by photoresist, form required needle point after, remove photoresist, prepare hollow metal micropin with more multangular needle point 5a;
(5) the above-mentioned micro-needle array chip of preparing is immersed in chemistry or the electrochemical polish liquid, chemistry or electrochemical polish are carried out in the empty micropin surface.
(6), can utilize baffle plate to promote the angle of shank 2 adjustment itself and substrate 4 when the shank 2 of design when having different angles with substrate 4 with needle stand 3.
In the present embodiment, the material that micro-needle array chip is made the micropin employing is the silk rod or the capillary tube of rustless steel, titanium alloy, aluminium alloy, copper alloy, tungsten or other metal, its smooth surface or have groove and pit, its surface also may be coated with metallic films such as one deck or which floor dielectric material thin film or gold, titanium, platinum.The material of making substrate 4 comprises medical plastic, polymer, glass, rubber, latex or nonmetal thermoplastic composite, can be formed or the different materials layering combines by a kind of material preparation wherein, has binding agent or fixed structure between each layer.
Preferably, the radius of curvature of syringe needle 1 place's needle point 5 is 5 nanometers～350 micron, or thickness is that 5 nanometers～350 micron, width are 5 nanometers～350 micron; The external diameter of shank 2 is 20～1000 microns, highly is 50～5000 microns.The through hole internal diameter of hollow needle tubing is 5～800 microns.Needle stand 3 is fixed in one deck baseplate material or penetrates one deck baseplate material at least.The thickness of substrate 4 is 20 microns～8000 microns, is surface plate or curved slab.
The manufacturing of solid or hollow rustless steel micro-needle array chip
In each hole of via-hole array mould, insert an external diameter and be 350 microns stainless steel silk rod or capillary tube, then with these rods or capillary tube simultaneously along certain angle inserts or to penetrate thermoplastic thickness be 2mm polymethyl methacrylate base plate.In water, after the cooling, adopt cutting machine these rods or capillary tube being cut off, thereby form silk rod or capillary array chip apart from 1～8 millimeter place of this plate.Adopt grinder that substrate one side grinding of this chip is flat, if need electrochemical polish must guarantee that this side group plate surface exposes all rods or capillary tube in the subsequent technique; The stainless steel silk of opposite side rod or fracture capillaceous polished be polished to required micropin height.At last chip is immersed and polished in stainless steel chemical polishing solution or the electrochemical polish liquid 2～10 minutes.Comprise 80～120g/L hydrochloric acid, 50～60g/L nitric acid and 150～200g/L phosphoric acid in the chemical brightening solution.Comprise 600mL/L phosphoric acid and 300mL/L sulphuric acid in the electrochemical polish liquid.During electrochemical polish, need the microneedle array one side immersion of chip substrate is connected in the electrochemical polish liquid of plumbous anelectrode, the opposite side of chip substrate immerses and is connected in 0.1～0.5wt%NaCl conductivity water solution of plumbous negative electrode, adds 8～10V DC voltage between two electrodes.Form solid or hollow rustless steel micro-needle array chip as shown in Figure 5 as shown in Figure 4 at last.
The manufacturing of solid or hollow rustless steel micro-needle array chip
In each hole of via-hole array mould, insert an external diameter and be 350 microns stainless steel silk rod or capillary tube, then with these stainless steel silk rods or capillary tube simultaneously along certain angle inserts or to penetrate thermoplastic thickness be 2mm polymethyl methacrylate base plate.In water, after the cooling, adopt cutting machine these rods or capillary tube being cut off, thereby form silk rod or capillary array chip apart from 1～8 millimeter place of this substrate.Adopt grinder that substrate one side grinding of this chip is flat, if need electrochemical corrosion or polishing must guarantee that this side group plate surface exposes all rods or capillary tube in the subsequent technique; The micropin height that the stainless steel silk rod or the capillary tube fracture of opposite side polished the demand of being polished to is shown in Figure 18 A.Array one side in said chip applies the photoresist 12 of one deck shown in Figure 18 B, and utilize figure transfer techniques in the conventional microelectronic technique that photoresist 12 is optionally exposed and develop, thereby on silk rod or capillary tube, form the photoresist figure, shown in Figure 18 C.As masking film silk rod or capillary tube on the chip are carried out optionally chemistry or electrochemical corrosion with photoresist 12, thereby have more multangular needle point, groove or pit, shown in Figure 18 D at silk rod or an end capillaceous formation.The chemical corrosion liquid that uses is that the Baume relative density is 35～45 liquor ferri trichloridi, and etching time is 20～60min.During electrochemical corrosion, need microneedle array one side of chip substrate is immersed in the electrochemical corrosive liquid, this corrosive liquid comprises 16～38wt% ferric chloride 1000mL, 1～10vol% hydrochloric acid, 1～10vol% nitric acid, 0.1～0.5wt% potassium dichromate; The opposite side immersion of chip substrate is included in the conductivity water solution of 0.1～0.5wt%NaCl; All insert graphite electrode in above-mentioned two solution, add 5～25 volts of DC voltages therebetween, at first in the electrode of corrosive liquid, connect positive potential 2～10 minutes, then it is connect nagative potential 20～50 minutes.Shown in Figure 18 E, chip is immersed polished in stainless steel chemical polishing solution or the electrochemical polish liquid 2～10 minutes again behind the employing acetone removal photoresist.Comprise 80～120g/L hydrochloric acid, 50～60g/L nitric acid and 150～200g/L phosphoric acid in the chemical brightening solution.Comprise 600mL/L phosphoric acid and 300mL/L sulphuric acid in the electrochemical polish liquid.During electrochemical polish, need the microneedle array one side immersion of chip substrate is connected in the electrochemical polish liquid of plumbous anelectrode, the opposite side of chip substrate immerses and is connected in 0.1～0.5wt%NaCl conductivity water solution of plumbous negative electrode, adds 8～10V DC voltage between two electrodes.Form the solid or hollow rustless steel micro-needle array chip as shown in figure 10 shown in Fig. 1,2,6,7,12 at last.
Transdermal delivery device and preparation method thereof
In the present embodiment, for the solid microneedles array chip, on the permanent or dismountable front that is fixed on pedestal 9 of solid microneedles array chip, size and chip substrate that a kind of possible structure is the pedestal front are measure-alike; Another kind of possible structure is the center that chip is embedded in the pedestal front, and the projection 10 of pedestal front edge is higher than the micro-needle array chip substrate 4 of center but is lower than syringe needle 1.By regulating the height that this projection 10 protrudes from the substrate 4 of micro-needle array chip, can limit the depth capacity that Shi Zhenshi thrusts skin.The back side of pedestal 9 is to be convenient to manipulation, as to have plane or curve form handle 11.Be a kind of structural representation that is used for the transdermal delivery device of solid microneedles array chip in the present embodiment as Figure 14,15, a side that is used for fixing micro-needle array chip in this transdermal delivery device on the pedestal is the plane, certainly, this base plane also can be made adjustment according to the back side shape of substrate in the micro-needle array chip, to adjust the direction that syringe needle inserts skin, as shown in figure 16, be the another kind of structural representation that is used for the transdermal delivery device of solid microneedles array chip in the present embodiment, base plane is an inclined-plane.In addition, as shown in figure 17, can earlier chip substrate be added thermal bending deformation, and then bond on the pedestal 9.
In the present embodiment, for empty micropin array chip, the empty micropin chip is embedded in the center in pedestal 9 fronts that can form inner chamber, and the projection 10 of pedestal front edge is higher than the micro-needle array chip substrate 4 of center but is lower than syringe needle 1.By regulating the height that this projection 10 protrudes from the substrate 4 of micro-needle array chip, can limit the depth capacity that Shi Zhenshi thrusts skin.The inner chamber that micro-needle array chip and pedestal are 4 is used to store medicine, has passage and interface that inside intracavity adds medicinal liquid on pedestal 9, or the medicinal liquid in the inner chamber is packed structure or the element that punctures.The back side at pedestal 9 may be fixed with the propulsion plant that the medicinal liquid in the inner chamber is pushed by pipeline connection or integration mode, its operation principle is based on the propulsion plant that modes such as electricity, heat, reed mechanical movement or conventional syringe promote the change of piston position or elastic diaphragm shape, also may be based on the micropump of modes such as piezoelectricity, electronic, electromagnetism.
In the present embodiment, for the solid microneedles array chip, the preparation method of transdermal delivery device may further comprise the steps:
(1) adopt die casting, cutting, machining or bonding way to produce the pedestal 9 that positive size is equal to or greater than solid microneedles array chip size, this pedestal is made up of medical materials such as plastics, polymer, glass, rubber, latexes, preferably, the edge in pedestal front be higher than the center micro-needle array chip substrate and be lower than syringe needle.
(2) adopt modes such as bonding, fusion, bonding, mechanical pressing with the solid microneedles array chip permanent or dismountable being fixed on the pedestal 9.
In the present embodiment, for empty micropin array chip, the preparation method of transdermal delivery device may further comprise the steps:
(1) adopt die casting, cutting, machining or bonding way to produce the pedestal 9 that positive size is equal to or greater than the empty micropin array chip size, this pedestal 9 is made up of plastics, polymer, glass, rubber, latex, metal or composite, and have concave surface, inner chamber or through hole, on pedestal, have and inject medicine to the passage of inner chamber and interface or structure or element that the drug packages of inner chamber is punctured, preferably, the edge in pedestal front be higher than the center micro-needle array chip substrate and be lower than syringe needle;
(2) adopt modes such as bonding, bonding, screw socket or bayonet socket, screw be fixing to connect by pipeline or the fixing propulsion plant that pedestal inner chamber medicinal liquid is pushed of integration mode at the back side of pedestal, the operation principle of propulsion plant is based on the change that modes such as electricity, heat, reed mechanical movement or conventional syringe promote piston position or elastic diaphragm shape, also may be based on the micropump of mode work such as piezoelectricity, electronic, electromagnetism;
(3) adopt modes such as bonding, bonding, fusion, mechanical pressing with hollow metal micropin chip permanent or dismountable center that is fixed on the pedestal front that can form inner chamber.
The preparation method of the transdermal delivery device of solid microneedles array chip
At first adopt plastic-injection moulding machine to produce polyethylene pedestal 9 shown in Figure 14～17 and top handle 11 thereof, and the chip size that utilizes conventional cutting tool that the substrate cut of solid microneedles array is become to need.For structure shown in Figure 14～16, can be directly with die bonding to pedestal 9, the rubber layer 10 of the bonding suitable thickness of susceptor edges around the chip depth capacity of thrusting skin then with the restriction micropin.For structure as shown in figure 17, can earlier chip substrate be added thermal bending deformation, and then bond on the pedestal 9.
Percutaneous administration patch and application process thereof
The structure of microneedle transdermal delivery patch is as follows: this percutaneous administration patch is made of the thin film that one or more layers comprises one or more materials; At least include a kind of medicine or cosmetics and skincare product in the described material with treatment, diagnosis or preventive effect.Described material is solid, liquid, microgranule, colloidal sol, gel or wherein several mixtures, wherein may include adjunct ingredients such as viscosifier, solvent.
The substrate 4 that is coated with the micropin chip of medicine can be embedded in the center in pedestal 9 fronts, and the projection 10 of pedestal front edge is higher than the chip substrate 4 of center but is lower than syringe needle 1.By regulating the height that this part 10 protrudes from chip substrate 4, can limit the depth capacity that Shi Zhenshi thrusts skin.The substrate or the pedestal back side are bonded in the centre that glue one side is arranged of medical adhesive tape or adhesive plaster, and medical adhesive tape or adhesive plaster cover with strippable material film at the remainder glue face of this side.
The preparation method of percutaneous administration patch may further comprise the steps:
(1) on solid microneedles even substrate, covers percutaneous administration patch by dipping, coating, physical property or chemical deposition process, in order to improve infiltration and the cementability of metal micro-needle, may need at first to have the surfactant of dependent interaction during preparation in the solid microneedles surface coverage to these materials;
(2) centre that glue one side is arranged that the substrate or the pedestal back side of micropin chip is bonded in medical adhesive tape or adhesive plaster, medical adhesive tape or adhesive plaster cover with strippable material film at the remainder glue face of this side.
Above embodiment only is used to illustrate the present invention; and be not limitation of the present invention; the those of ordinary skill in relevant technologies field; under the situation that does not break away from the spirit and scope of the present invention; can also make various variations and modification; therefore all technical schemes that are equal to also belong to category of the present invention, and scope of patent protection of the present invention should be defined by the claims.
Claims (19)
1, micro-needle array chip comprises micropin and substrate, it is characterized in that,
Described micropin is made up of syringe needle, shank and needle stand, and described needle tip is a needle point, and described micropin is fixed on the substrate by needle stand;
The shank of described micropin is cylinder or cone, and described shank is vertical with substrate, and it is conical that syringe needle is; Or described shank is to the substrate set angle that tilts, and the upper surface of needle point is parallel with substrate or tilts to set the elliptic plane of acute angle.
2, micro-needle array chip according to claim 1 is characterized in that, the elliptic plane of described needle point is cut one section arc surface at least makes it have more corner angle.
3, micro-needle array chip according to claim 1 and 2, it is characterized in that, constitute microneedle array by at least two micropins, described microneedle array is solid or empty micropin array, or both mixing array, described micropin is arranged by setting spacing on substrate.
4, micro-needle array chip according to claim 3, it is characterized in that, described micropin is solid microneedles or empty micropin, the shank of described micropin and needle stand are respectively to substrate inclination set angle separately, there are groove or pit on the syringe needle of described solid microneedles or the shank, have through hole between the needle stand of described empty micropin and the syringe needle.
5, micro-needle array chip according to claim 1 and 2 is characterized in that, the set angle that described needle stand tilts is 15～90 degree, and the set angle that described shank tilts is 15～150 degree.
6, micro-needle array chip according to claim 1 and 2, it is characterized in that, the material that described micropin adopts is rustless steel, titanium alloy, aluminium alloy, copper alloy, tungsten metal bar or metal tube, described micropin surface or be coated with one deck in addition or several layers dielectric material thin film or gold, titanium, platinum thin film.
7, micro-needle array chip according to claim 1 and 2, it is characterized in that, the material that described substrate adopts is medical plastic, polymer, glass, rubber, latex or nonmetal thermoplastic composite, or form or combine by different materials layering wherein by a kind of material preparation wherein, binding agent or fixed structure are arranged between each layer.
8, micro-needle array chip according to claim 3 is characterized in that, the radius of curvature of described needle point, thickness and width are 5 nanometers～350 micron;
The external diameter of described shank is 20～1000 microns, highly is 50～5000 microns;
The through hole internal diameter of described empty micropin is 5～800 microns;
Described needle stand is fixed in one deck baseplate material or penetrates one deck baseplate material at least;
The thickness of described substrate is 20 microns～8000 microns, is surface plate or curved slab.
9, the preparation method of the described micro-needle array chip of a kind of claim 1 comprises step:
S101 vertically or along set angle tilts to insert or penetrate described substrate with metal thread bar or metal capillary;
S102 cuts off described metal thread bar or metal capillary, and fracture surface is formed oval needle point along direction grinding and polishing parallel with substrate or that tilt;
S103 immerses micro-needle array chip in chemistry or the electrochemical polish liquid, and chemistry or electrochemical polish are carried out in the micropin surface.
10, preparation method according to claim 9 is characterized in that, also comprises step between step s102 and step s103:
S102a applies photoresist in substrate one side that is fixed with metal thread bar or metal capillary, utilizes the figure transfer techniques in the microelectronic technique to form the photoresist pattern that designs at an end of metal thread bar or metal capillary;
S102b; metal thread bar or metal capillary that chemistry or electrochemical corrosion are not protected by photoresist; prepare syringe needle with pit or groove, have the groove that leads to syringe needle or pit shank, have the solid metal micropin of more multangular needle point; or after preparing hollow metal micropin, remove photoresist with more multangular needle point.
11, a kind of transdermal delivery device that utilizes the described micro-needle array chip of claim 1 is characterized in that, this device comprises:
Pedestal, the permanent or dismountable front that is fixed on described pedestal of micro-needle array chip;
The size in described pedestal front is equal to or greater than the size of described micro-needle array chip;
The described pedestal back side has manipulation, as to have plane or curved surface shaped hands handle;
The size in described pedestal front is during greater than the size of micro-needle array chip, and described micro-needle array chip is embedded in the center in described pedestal front, and the edge in pedestal front is higher than the substrate of the micro-needle array chip of center, but is lower than syringe needle.
12, transdermal delivery device according to claim 11 is characterized in that, when the micropin in described micro-needle array chip is empty micropin,
The size in described pedestal front is greater than the size of micro-needle array chip, and described micro-needle array chip is embedded in the center that can form the described pedestal of inner chamber front, the edge in pedestal front be higher than the center micro-needle array chip substrate and be lower than syringe needle;
At the passage and the interface that have intracavity interpolation medicinal liquid in described on the pedestal, the element that the medicinal liquid of intracavity packing punctures in maybe will placing.
13, transdermal delivery device according to claim 12 is characterized in that,
Be fixed with the propulsion plant that inner chamber is pushed at the pedestal back side by pipeline connection or integration mode;
Described pedestal is prepared by plastics, polymer, glass, rubber, latex, metal or composite, or is formed by wherein a kind of material manufacture or multiple combination of materials, and multiple storeroom has binding agent or fixed structure.
14, the preparation method of the described transdermal delivery device of a kind of claim 11 comprises step:
S201 adopts die casting, cutting, machining or bonding way to produce the pedestal that positive size is equal to or greater than the micro-needle array chip size;
S202 adopts bonding, fusion, bonding, mechanical pressing mode that micro-needle array chip is permanent or dismountablely be fixed on center positive on the pedestal, the edge in pedestal front be higher than the center micro-needle array chip substrate and be lower than syringe needle.
15, preparation method according to claim 14 is characterized in that, when the micropin in described micro-needle array chip is empty micropin,
Among the step s201, has the passage from medicinal liquid to formed inner chamber and the interface that add on the pedestal of making, the element that the medicinal liquid of intracavity packing punctures in maybe will placing.
16, preparation method according to claim 15 is characterized in that, also comprises step between step s201 and step s202:
S201a connects by pipeline at the pedestal back side or integration mode is fixed with the propulsion plant that inner chamber is pushed.
17, a kind of percutaneous administration patch that is applied on the described micro-needle array chip of claim 1 is characterized in that,
This percutaneous administration patch is made of the thin film that one or more layers comprises one or more materials;
At least include a kind of medicine or cosmetics and skincare product in the described material with treatment, diagnosis or preventive effect.
18, percutaneous administration patch according to claim 17 is characterized in that, described material is solid, liquid, microgranule, colloidal sol, gel or wherein several mixtures.
19, the application process of the described percutaneous administration patch of a kind of claim 17 comprises step:
S301 covers percutaneous administration patch by dipping, coating, physical property or chemical deposition process on solid microneedles even substrate;
S302 will have the substrate of micro-needle array chip of solid microneedles or the centre that glue one side is arranged that the pedestal back side is bonded in medical adhesive tape or adhesive plaster, and medical adhesive tape or adhesive plaster cover with strippable material film at the remainder glue face of this side.
Priority Applications (2)
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| CN 200910080758 CN101507857A (en) | 2009-03-27 | 2009-03-27 | Micro-needle array chip, percutaneous administration device, percutaneous administration patch and preparation method thereof |
| CN2010101809034A CN101829396B (en) | 2009-03-27 | 2010-03-26 | Micro-needle array chip and percutaneous administration patch using same and preparation method thereof |
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| CN 200910080758 CN101507857A (en) | 2009-03-27 | 2009-03-27 | Micro-needle array chip, percutaneous administration device, percutaneous administration patch and preparation method thereof |
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