CN101254326A - Preparation of micro-needle array injection syringe - Google Patents
Preparation of micro-needle array injection syringe Download PDFInfo
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- CN101254326A CN101254326A CN200810023352.3A CN200810023352A CN101254326A CN 101254326 A CN101254326 A CN 101254326A CN 200810023352 A CN200810023352 A CN 200810023352A CN 101254326 A CN101254326 A CN 101254326A
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- 238000002347 injection Methods 0.000 title claims description 33
- 239000007924 injection Substances 0.000 title claims description 33
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- 239000007787 solid Substances 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000000463 material Substances 0.000 claims description 34
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- 238000004528 spin coating Methods 0.000 claims description 16
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- 238000005516 engineering process Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 6
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 16
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- 229940079593 drug Drugs 0.000 description 6
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- 239000004205 dimethyl polysiloxane Substances 0.000 description 4
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- CXQXSVUQTKDNFP-UHFFFAOYSA-N octamethyltrisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 4
- 239000012188 paraffin wax Substances 0.000 description 4
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
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- 102000004877 Insulin Human genes 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Media Introduction/Drainage Providing Device (AREA)
Abstract
The invention discloses a method for preparing a micro-needle array syringe, and belongs to the field of biomedical apparatus. The method takes a micron and sub-micron solid micro-needle array as a template, and uses the imprinting and pulling modes for preparing the hollow high-quality polymer micro-needle array syringe with adjustable length. The preparation method has the advantages of cheap price, no need of complicated devices and technologies, mass rapid production, etc. The technology is applicable to the industrial production, the micro-needle array syringe with high-quality and cheap-price can be industrially produced, so the expensive transdermal drug delivery technology in the biomedical field can go to the mass market by the low cost of the micro-needle array syringe.
Description
Technical field
The present invention relates to the preparation method of the preparation method, particularly a kind of micro-needle array injection syringe of a kind of nanometer and micron fine structure material.
Background technology
Along with the appearance of newtype drug, to the requirements at the higher level of human comfort and drug controllable release, a kind of in recent years new route of administration----transdermal administration begins to enter clinical practice.Transdermal administration is meant the skin surface administering mode of breaking through skin surface horny layer inhibition, and medicine is entered the systemic blood circulation and reached effective blood drug concentration by skin absorbs realizes disease treatment or prevention.The advantage of transdermal administration is clearly: overcome oral administration to gastrointestinal stimulation and liver, gastrointestinal first-pass effect effect; Overcome it and skin damage has been caused the shortcoming of pain; Overcome the slow shortcoming of percutaneous dosing speed.Simultaneously can not cause wound, particularly can not bring pain, therefore can improve patient's adaptability to skin; Release is steady, can keep constant effective blood drug concentration for a long time, avoids peak valley phenomenon, reduces the toxic and side effects of medicine, and administration for a long time is to improve curative effect; Safe, can stop administration at any time when side effect occurring.
The key of transdermal administration is how to make medicine break through keratodermatitis.Because the empty micropin array transdermal administration to medicine almost without limits, and on the basis of common transdermal administration advantage, have own special advantages: can transmit macromolecule, supermolecule even drug particles; Can control the transfer rate of medicine arbitrarily; The medicine that is transmitted there is not specific (special) requirements; But long-time continuous constant rate of speed administration; Can two-way fluid exchange, not only can see through the keratodermatitis administration, but also extracting interstitial fluid.Therefore except that can be used as conventional painless administration, have more advantage in some special fields, as the human body of the transporting of the long term administration of insulin, the synthetic hmw protein of modern biotechnology, drug microcapsule get involved, vaccine inoculation or the like.Crowd to needs administration steady in a long-term is afraid of that with having an injection painful child is especially suitable, has very big market potential.
At present more the preparation method of solid microneedles adopts and relies on the semiconductor microactuator process technology directly to prepare, and as reactive ion beam etching (RIBE) (RIE), focused-ion-beam lithography (FIB) etc., but the cost of solid microneedles can duplicate on a large scale by methods such as little castings and reduces.The far super solid microneedles of the performance of empty micropin, but its preparation is much more difficult.Empty micropin also mainly relies on three-dimensional fine process technology (LIGA), reactive ion beam etching (RIBE) (RIE), inductive couple plasma etching micro-processing technologies such as (ICP) directly to prepare at present, but be difficult to duplicate as solid microneedles is extensive, manufacturing cost is high.And for prevention infection, stain etc., syringe needs disposable use usually, and its use cost is also very high.Therefore, the empty micropin array administering mode does not enter ordinary populace consumer groups so far, only uses in some special industries at present, as beauty culture etc.In addition, the selected material of empty micropin array of preparation is suitable micro-machined semi-conducting materials such as silicon substantially at present.The typical feature of these materials is hard and crisp, and superfine micropin fractures in skin easily.Consider the mechanics requirement, in conjunction with biocompatibility, macromolecule is undoubtedly microneedle array material preferably.
Walk close to masses for the empty micropin array transdermal administration mode that makes integrated plurality of advantages, its cost must drop under the cost of common disposable medical syringe.Therefore, need exploitation to be suitable for the new technology of preparing that enterprise produces in batches, obtain cheap, practical hollow micro-needle array injection syringe.
Summary of the invention
Goal of the invention: the purpose of this invention is to provide that a kind of technology is simple, the micron that is suitable for suitability for industrialized production and the preparation method of submicron micro-needle array injection syringe.
Technical scheme: the present invention prepares described micro-needle array injection syringe by two kinds of methods.
First method may further comprise the steps:
(1) polymer I is carried out surface-functionalized processing, obtain the rete of 1nm～500 μ m thickness on the surface;
(2) at the polymeric material II of polymer I surface preparation 10～500 μ m thickness;
(3) utilization is heated or solvent processing polymeric material I and II;
(4) regulation and control are pressed into speed and the degree of depth is utilized the solid microneedles array roller roll extrusion or directly is pressed into polymeric material I and II;
(5) peel off micropin, behind the removal polymer II, promptly get the empty micropin array of polymer I;
(6) make empty micropin array SMD or the syringe-type micro-needle array injection syringe.
Second method may further comprise the steps:
(7) polymer I is carried out surface-functionalized processing, obtain the rete of 1nm～500 μ m thickness on the surface;
(8) at the polymeric material II of polymer I surface preparation 10～500 μ m thickness;
(9) utilization is heated or solvent processing polymeric material I and II;
(10) under uniform temperature or solvent processing condition, the solid microneedles array is pressed into polymeric material I and II with appropriate speed;
(11) under uniform temperature or solvent environment, lift micropin with appropriate speed;
(12) take out micropin, behind the removal polymer II, promptly get the empty micropin array of polymer I;
(13) make empty micropin array SMD or the syringe-type micro-needle array injection syringe.
In step (1) and (7), said polymer I is a natural macromolecular material, or synthesized polymer material, perhaps the combination of above material; Polymer II is a natural macromolecular material, or synthesized polymer material, perhaps the combination of above material; The method of said surface-functionalized processing is coating, or sputter, or chemical plating, or electroplates, or PVD, or CVD, or above method combination in any; Material therefor is metal, inorganic matter or Organic substance and combination in any thereof.
In step (2) and (8), said polymer II is a natural macromolecular material, or synthesized polymer material, perhaps the combination of above material; Said method at polymer I surface preparation polymer II is spin coating, or membrane, or pad pasting, or spraying, or above method combination in any.
In step (3) and (9), said temperature is 0～100 ℃ of the temperature that is higher than processed polymer softening point, and the time is 0.1min～24h; Solvent is CHCl
3, CHCl
2, acetone, toluene, benzene, oxolane equal solvent or its combination in any, the processing time is 0.1min～12h.
In step (4), the said speed that is pressed into is 0.01～100cm/s; Compression distance is 1～2000 μ m.
In step (10), (11), said temperature is 30～200 ℃, and the time is 0.1min～24h; Solvent is CHCl
3, CHCl
2, in the acetone, toluene, benzene, oxolane equal solvent one or more, the processing time is 0.1min～12h; The said rate of pulling is 0.01cm/s～100m/s; Lifting highly is 10 μ m～1cm.
Beneficial effect: the present invention compared with prior art has following outstanding advantage:
1, greatly reduced the preparation cost of micro-needle array injection syringe.
2, do not need expensive complex technology and equipment such as little processing.
3, technology is simple, and the place environment is had no special requirements.
4, simple to operate, manufacturing cycle is short.
5, be suitable for suitability for industrialized production.
Description of drawings
Accompanying drawing is the sketch map of preparation process of the present invention.The preparation process of (a)-(d) method for expressing 1 wherein: (a) the solid microneedles array is pressed into polymeric matrix; (b) be pressed into solid microneedles surface, back and form polymer; (c) remove the solid microneedles array and form the polymer empty micropin array; (d) obtain hollow micro-needle array injection syringe.(e)-(h) preparation process of method for expressing 2: (e) the solid microneedles array is pressed into polymeric matrix; (f) lift solid microneedles and form the polymeric tubular structure; (g) remove the solid microneedles array and form the polymer empty micropin array; (h) obtain hollow micro-needle array injection syringe.
The specific embodiment
The industrialized process for preparing of a kind of micro-needle array injection syringe of the present invention comprises determining of surface of polymer material treatment process and parameter; Impress and lift determining of parameter; Determining etc. of microneedle array syringe needle and syringe incorporating parametric.
Embodiment 1: at the paraffin layer of PMMA surface spin coating 50 micron thickness as the functionalization rete, and then attach the PMMA of 400 μ m thickness, place 100 ℃ of baking oven heat treatment 30min, speed with 50cm/s is pressed into the silicon dioxide solid microneedles then, the degree of depth is 700 μ m, and micropin is extracted in cooling, two-layer PMMA peels off up and down then, promptly gets the empty micropin array of PMMA.Then microneedle array is bonded in the disposable syringe end, promptly forms the syringe-type micro-needle array injection syringe.
Embodiment 2: as the functionalization rete, and then the polystyrene of spin coating 300 μ m thickness is at CHCl at the paraffin layer of PMMA surface spin coating 50 micron thickness
3Handle 20min in the steam, the speed with 30cm/s is pressed into the silicon dioxide solid microneedles then, and the degree of depth is 600 μ m, and solid microneedles is extracted in cooling, and two layers of polymers is peeled off up and down then, promptly gets the empty micropin array of polystyrene.Then microneedle array is bonded in the disposable syringe end, promptly forms the syringe-type micro-needle array injection syringe.
Embodiment 3: at the gold layer of PDMS surface sputtering 100 nano thickness as the functionalization rete, and then the PMMA of spin coating 300 μ m thickness, place 90 ℃ of baking oven heat treatment 20min, speed with 0.1cm/s is pressed into the silicon solid microneedles then, the degree of depth is 600 μ m, and solid microneedles is extracted in cooling, two layers of polymers is peeled off up and down then, promptly gets the empty micropin array of polystyrene.Then with the microneedle array hot melt in the disposable syringe end, promptly form the syringe-type micro-needle array injection syringe.
Embodiment 4: at the polyvinyl alcohol of PDMS surface spin coating 5 micron thickness as the functionalization rete, and then the PMMA of spin coating 200 μ m thickness, place 140 ℃ of baking oven heat treatment 20min, speed with 1cm/s is pressed into the silicon dioxide solid microneedles then, and the degree of depth is 400 μ m, and then the speed with 10m/s lifts 300 μ m with the silicon dioxide solid microneedles, cooling, micropin is extracted, be placed on then and make in the water up and down that two-layer PMMA peels off, promptly get the empty micropin array of PMMA.Then microneedle array is bonded in the disposable syringe end, promptly forms the syringe-type micro-needle array injection syringe.
Embodiment 5: as the functionalization rete, and then the polystyrene of spin coating 300 μ m thickness places CHCl at the polyvinyl alcohol of PDMS surface spin coating 5 micron thickness
2Handle 20min in the steam, speed with 30cm/s is pressed into the silicon dioxide solid microneedles then, the degree of depth is 600 μ m, then the speed with 50m/s lifts 500 μ m with the silicon dioxide solid microneedles, cooling, solid microneedles is extracted, and two layers of polymers is peeled off up and down then, promptly gets the empty micropin array of polystyrene.Then microneedle array is encapsulated on the thin polymer film, promptly forms SMD micro-needle array injection syringe.
Embodiment 6: at the gold layer of PDMS surface sputtering 100 nano thickness as the functionalization rete, and then the PMMA of spin coating 300 μ m thickness, place 90 ℃ of baking oven heat treatment 20min, speed with 0.1cm/s is pressed into the silicon solid microneedles then, and the degree of depth is 500 μ m, and then the speed with 10m/s lifts 1000 μ m with the silicon dioxide solid microneedles, cooling, solid microneedles is extracted, and two layers of polymers is peeled off up and down then, promptly gets the empty micropin array of polystyrene.Then microneedle array is encapsulated on the thin polymer film, promptly forms SMD micro-needle array injection syringe.
Embodiment 7: at the paraffin layer of PMMA surface spin coating 10 micron thickness as the functionalization rete, and then the PMMA of spin coating 300 μ m thickness, place 130 ℃ of baking oven heat treatment 30min, the roller rolled that to adhere to the silicon dioxide solid microneedles with the speed of 50cm/s was pressed then, two-layer PMMA peels off about inciting somebody to action after the cooling, promptly gets the empty micropin array of PMMA.Then microneedle array is bonded in the disposable syringe end, promptly forms the syringe-type micro-needle array injection syringe.
Embodiment 8: at the paraffin layer of PMMA surface spin coating 50 micron thickness as the functionalization rete, and then the polystyrene of spin coating 300 μ m thickness, in toluene and acetone (volume ratio 1: 1) mixed vapour, handle 30min, with the speed of 30cm/s the roller rolled of adhesion metal solid microneedles was pressed then, two layers of polymers is peeled off about inciting somebody to action after the cooling, promptly gets the empty micropin array of polystyrene.Then microneedle array is encapsulated on the thin polymer film, promptly forms SMD micro-needle array injection syringe.
Embodiment 9: basic step is same as embodiment 1, and the thickness that different is attaches PMMA is 200um.
Embodiment 10: basic step is same as embodiment 1, and different is that compression distance is 500um.
Embodiment 11: basic step is same as embodiment 1, and different is, and to be pressed into speed be 50cm/s.
Embodiment 12: basic step is same as embodiment 1, and different is that heat treatment temperature is 140 ℃.
Claims (8)
1, a kind of preparation method of micro-needle array injection syringe is characterized in that this method may further comprise the steps:
(1) polymeric material I is carried out surface-functionalized processing, obtain the rete of 1nm～500 μ m thickness on the surface;
(2) at the polymeric material II of polymer I surface preparation 10～500 μ m thickness;
(3) utilize temperature or solvent processing polymeric material I and II;
(4) regulation and control are pressed into speed and the degree of depth is utilized the solid microneedles array roller roll extrusion or directly is pressed into polymeric material I and II;
(5) peel off micropin, behind the removal polymer II, promptly get the empty micropin array of polymer I;
(6) make empty micropin array SMD or the syringe-type micro-needle array injection syringe;
Described polymeric material I, polymeric material II are natural macromolecular materials, or synthesized polymer material, perhaps the combination of above material;
In the step (3), said temperature is 0～100 ℃ of the temperature that is higher than processed polymer softening point, and the time is 0.1min～24h; Solvent is CHCl
3, CHCl
2, in the acetone, toluene, benzene, oxolane any one or a few, the processing time is 0.1min～12h;
In the step (4), the said speed that is pressed into is 0.01～100cm/s; Compression distance is 1～2000 μ m.
2, the preparation method of a kind of micro-needle array injection syringe according to claim 1, it is characterized in that in step (1), the method of said surface-functionalized processing is for applying, or sputter, or chemical plating, or electroplate, or PVD, or CVD, or above method combination in any, material therefor is metal, inorganic matter or Organic substance and combination in any thereof.
3, the preparation method of a kind of micro-needle array injection syringe according to claim 1 is characterized in that in step (2), and said method at polymer I surface preparation polymer II is spin coating, or membrane, or pad pasting, or spraying, or above method combination in any.
4, the preparation method of a kind of micro-needle array injection syringe according to claim 1 is characterized in that in step (6) method that said empty micropin array is made hollow micro-needle array injection syringe is a hot melt, or bonding, or its combination in any.
5, a kind of preparation method of micro-needle array injection syringe is characterized in that this method may further comprise the steps:
(1) polymer I is carried out surface-functionalized processing, obtain the rete of 1nm～500 μ m thickness on the surface;
(2) at the polymeric material II of polymer I surface preparation 10～500 μ m thickness;
(3) utilize temperature or solvent processing polymeric material I and II;
(4) under uniform temperature or solvent processing condition, the solid microneedles array is pressed into polymeric material I and II with appropriate speed;
(5) under uniform temperature or solvent environment, lift micropin with appropriate speed;
(6) take out micropin, behind the removal polymer II, promptly get the empty micropin array of polymer I;
(7) make empty micropin array SMD or the syringe-type micro-needle array injection syringe;
Described polymeric material I, polymeric material II are natural macromolecular materials, or synthesized polymer material, perhaps the combination of above material;
In the step (3), said temperature is 0～100 ℃ of the temperature that is higher than processed polymer softening point, and the time is 0.1min～24h; Solvent is CHCl
3, CHCl
2, in the acetone, toluene, benzene, oxolane any one or a few, the processing time is 0.1min～12h;
In step (4), (5), said temperature is 30～200 ℃, and the time is 0.1min～24h; Solvent is CHCl
3, CHCl
2, in the acetone, toluene, benzene, oxolane any one or a few, the processing time is 0.1min～12h; The said rate of pulling is 0.01cm/s～100m/s; Lifting highly is 10 μ m～1cm.
6, the preparation method of a kind of micro-needle array injection syringe according to claim 5, it is characterized in that in step (1), the method of said surface-functionalized processing is for applying, or sputter, or chemical plating, or electroplate, or PVD, or CVD, or above method combination in any, material therefor is metal, inorganic matter or Organic substance and combination in any thereof.
7, the preparation method of a kind of micro-needle array injection syringe according to claim 5 is characterized in that in step (2), and said method at polymer I surface preparation polymer II is spin coating, or membrane, or pad pasting, or spraying, or above method combination in any.
8, the preparation method of a kind of micro-needle array injection syringe according to claim 5 is characterized in that in step (7) method that said empty micropin array is made hollow micro-needle array injection syringe is a hot melt, or bonding, or its combination in any.
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| CN101347652B (en) * | 2008-09-09 | 2011-01-12 | 南京大学 | Method for preparing hollow micro-needle array injection syringe |
| CN102887477A (en) * | 2012-10-11 | 2013-01-23 | 无锡英普林纳米科技有限公司 | Polymer surface nanowire array and preparation method thereof |
| WO2013131215A1 (en) | 2012-03-06 | 2013-09-12 | 中国科学院理化技术研究所 | Polymer micro-needle array chip, preparation process and use thereof |
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| CN102039000B (en) * | 2009-10-20 | 2015-08-26 | 苏州纳通生物纳米技术有限公司 | A kind of transdermal administration kit |
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| US6611707B1 (en) * | 1999-06-04 | 2003-08-26 | Georgia Tech Research Corporation | Microneedle drug delivery device |
| US6256533B1 (en) * | 1999-06-09 | 2001-07-03 | The Procter & Gamble Company | Apparatus and method for using an intracutaneous microneedle array |
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| CN118383761B (en) * | 2024-06-26 | 2024-10-11 | 北京大学 | Graphene electrode microneedle biosensor and construction method |
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