CN103386164B - The method of solid array of microneedles device medicine carrying and device - Google Patents
The method of solid array of microneedles device medicine carrying and device Download PDFInfo
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- CN103386164B CN103386164B CN201210140545.3A CN201210140545A CN103386164B CN 103386164 B CN103386164 B CN 103386164B CN 201210140545 A CN201210140545 A CN 201210140545A CN 103386164 B CN103386164 B CN 103386164B
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- solid array
- microneedles
- microneedles device
- medicine carrying
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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
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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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 present invention relates to method and the device of solid array of microneedles device medicine carrying.The present invention utilizes the thin liquid layer of the adhesion of drug solution and groove base plate and micro-meter scale to weaken capillarity, thus the medicine carrying that the needle point realizing the micropin on solid array of microneedles device is accurate, even, economic.The method of described solid array of microneedles device medicine carrying is the gravity relying on solid array of microneedles device self, the needle point of the micropin on solid array of microneedles device is placed among thin liquid layer that thickness is the drug solution of micro-meter scale, drug solution is adsorbed on the needle point of micropin, thus realizes the medicine carrying of solid array of microneedles device.Device of the present invention is the device of the solid array of microneedles device medicine carrying of principle design a kind of manual and a kind of automatization out according to the method for solid array of microneedles device medicine carrying, the formation of thin liquid layer, the placement of solid array of microneedles device and switching can realize automatization, avoid the error that manual operation brings, make drug incorporation have homogeneity.
Description
Technical field
The present invention relates to the method for solid array of microneedles device medicine carrying and the device of solid array of microneedles device medicine carrying, specifically, utilize the thin liquid layer of the adhesion of drug solution and groove base plate and micro-meter scale to weaken capillarity, thus the medicine carrying that the needle point realizing the micropin on solid array of microneedles device is accurate, even, economic.
Background technology
Percutaneous dosing mode is subject to cuticular inhibition, causes the medicine that may be used for percutaneous dosing to be very restricted.In order to overcome cuticular inhibition, there is a lot of method at present, active mode and the large class of passive mode two can be divided into.In various active mode, solid array of microneedles device have use simple, without the need to advantages such as outside resources, therefore seem more attractive.Drug administration based on solid array of microneedles device mainly contains four kinds of patterns.Wherein there is most the mode of administration of application prospect to be: the needle point of the micropin of Drug absorbability on solid array of microneedles device to be formed medicine film skin puncture (being called for short: solid array of microneedles device medicine carrying) again, be adsorbed on medicine dissolution on the needle point of the upper micropin of solid array of microneedles device in skin.The solid array of microneedles device of medicine carrying can make paster, so can realize patient's automedication.And, the needle point of the micropin of Drug absorbability on solid array of microneedles device is solid-state, in this state, even the stability of long period also can be kept under normal temperature condition.In this context, many scientists are had to study the medicine-carrying method of solid array of microneedles device.The difficult point of the medicine carrying of solid array of microneedles device is how to weaken capillarity, and makes medicine can not pollute the substrate of solid array of microneedles device.
At present, the medicine-carrying method of the solid array of microneedles device reported: (the Coatedmicroneedles for transdermal delivery such as Harvinder S.Gill, Journal of Controlled Release 117 (2007) 227 – 237), (the Microneedle device such as Oshiyuki Matsudo, and (the Methods and systems forcoating a microneedle with a dosage of a biologically active compound such as Alexander K.Andrianov Pub.No.:US2010/0221314A1Pub.Date:Sep.22010), Pub.No:US 2009/0017210A1) MP method invented, namely the microwell array matched with the micropin on solid array of microneedles device is made, by toward injection of medicine solution in micropore or with pressure, drug solution is pressed in micropore, then the micropin on solid array of microneedles device is made to insert the medicine-carrying method of micropore, micropin on the every root solid array of microneedles device in the accurate location of the method needs and the position of each micropore, the precise requirements operated under micro-meter scale is high, the micropin on solid array of microneedles device is easily made to suffer damage.(the AEROSOL COATING OF MICRONEEDLES such as BIRCHALJames, International ApplicationNo.:PCT/GB2008/004205) aeroponics invented, namely in closed cavity, pharmaceutical aerosol is formed, maintain high temperature, solid array of microneedles device is placed in one and adsorbs, the method temperature height easily causes protein medicaments inactivation, and extremely wastes medicine.(the Dry-coatedmicroprojection array patches for targeted delivery of immunotherapeutics to theskin such as Xianfeng Chen; Journal of Controlled Release 139 (2009) 212 – 220) and (Determination of parameters for successful spray coating of siliconmicroneedle arrays, the Int J Pharm.2011Aug 30 such as McGrath Marie G.; 415 (1-2): 140-9.) spurt method invented, adopt air gun drug solution to be ejected on the needle point of the micropin on solid array of microneedles device, drug solution is not only uneven on needle point, and easily causes the waste of medicine.(the Maskingmethod for coating a microneedle array such as Peter R.Johnson, US Patent Pub.No:US2008/0102192) mask method invented, namely in the substrate of micropin device solid array of microneedles device, one deck mask is first covered, add drug solution again, make on the needle point of the micropin of Drug absorbability on solid array of microneedles device, the method length consuming time, easily causes drug waste.(the Method of contact coating a microneedlearray such as Choi, US Patent Pub.No:US2011/8057842) invent be stained with painting method, namely adopt on the needle point picking the micropin of plastic tab on solid array of microneedles device of medicine and drag, the method easily makes the needle point of the micropin on solid array of microneedles device suffer damage, and medicine carrying is uneven.The roller method that Michel J NCormier etc. (Method and apparatus for coating skin piercing microprojections.ALZA February 2005:US 6855372) invent, namely from drug solution pond, solution is taken by roller out of, the thickness of the drug solution layer on roller is controlled by scraping blade, the needle point of the micropin on solid array of microneedles device is made to contact this drug solution layer, the needle point of micropin on the control solid array of microneedles device that the method needs are accurate and the contact of drug solution layer, otherwise easily make the needle point of the micropin on solid array of microneedles device suffer damage.The medicine-carrying method of the solid array of microneedles device of current exploitation has many defects, limits the development of medicine carrying solid array of microneedles device administering mode, develops a kind of new medicine-carrying method significant.
Summary of the invention
An object of the present invention is that the restriction of method in order to overcome existing solid array of microneedles device medicine carrying (as: needs accurately to control, easily make drug inactivation, medicine carrying is uneven, causes drug waste etc.), a kind of method of solid array of microneedles device medicine carrying is provided.
Two of object of the present invention is to provide a kind of device (as shown in Figure 1) being applicable to the simple manual solid array of microneedles device medicine carrying of the method for solid array of microneedles device medicine carrying, makes the process of solid array of microneedles device medicine carrying become easy, accurate, economical.
Three of object of the present invention is to provide a kind of device (as shown in Figure 2) being applicable to automatization's solid array of microneedles device medicine carrying of the method for solid array of microneedles device medicine carrying, realizes the automatization of above-mentioned solid array of microneedles device medicine-carrying method.
The method of solid array of microneedles device medicine carrying of the present invention is the gravity relying on solid array of microneedles device self, micropin on solid array of microneedles device is placed among thin liquid layer that thickness is the drug solution of micro-meter scale, and the length of the needle point of micropin on described solid array of microneedles device is higher than the thickness of the thin liquid layer of described drug solution, drug solution is adsorbed on the needle point of the micropin on solid array of microneedles device, thus realizes the medicine carrying of solid array of microneedles device.
Described micro-meter scale is preferably 75 μm ~ 500 μm.
In order to better realize method of the present invention, the invention provides a kind of device (as shown in Figure 1) being applicable to the manual solid array of microneedles device medicine carrying of said method, the device of this manual solid array of microneedles device medicine carrying comprises groove base plate and frame scraper plate.
Described frame scraper plate is installed on described groove base plate, and described frame scraper plate and the groove of described groove base plate form a liquid storage tank jointly.
Described liquid storage tank is for storing drug solution.
The degree of depth of described groove is micro-meter scale.Described micro-meter scale is preferably 75 μm ~ 500 μm.
The method utilizing the device of the manual solid array of microneedles device medicine carrying of the invention described above to realize solid array of microneedles device medicine carrying is: drug solution is placed in the liquid storage tank jointly formed by the groove of described frame scraper plate and described groove base plate, described frame scraper plate and described groove base plate are done relative motion, the thin liquid layer that a layer thickness thickness identical with the degree of depth of the groove of described groove base plate is the drug solution of micro-meter scale is formed in the groove of described groove base plate, rely on the gravity of solid array of microneedles device self, the needle point of the micropin on solid array of microneedles device is placed among the thin liquid layer formed by described drug solution that (time that the needle point of the micropin on general solid array of microneedles device stops at drug solution is short, such as about 1 second), and the length of described needle point is higher than the thickness of described thin liquid layer, described drug solution is made to be adsorbed on the needle point of the micropin on described solid array of microneedles device, because the length of needle point is higher than the thickness of thin liquid layer, solution can not pollute the substrate of microneedle array, thus realize the medicine carrying of solid array of microneedles device.
In order to better realize method of the present invention, present invention also offers a kind of device (as shown in Figure 2) being applicable to automatization's solid array of microneedles device medicine carrying of said method, the device of this automatization's solid array of microneedles device medicine carrying comprises groove base plate, frame scraper plate, solid array of microneedles device, solid array of microneedles device fixed disc, solid array of microneedles device locking cap, rolling disc, the first motor, the second motor, the 3rd motor, digital control panel and climatic chamber.
In described climatic chamber, described groove base plate 1 is fixed at the bottom of the case of described climatic chamber, described frame scraper plate is installed on described groove base plate, and described frame scraper plate and the groove of described groove base plate form a liquid storage tank jointly; Described frame scraper plate is provided with rotary screw, the machine shaft being arranged on the first described motor in climatic chamber is a rotary screw, and the rotary screw on described frame scraper plate is connected by the rotation screw thread on rotary screw with the rotary screw on the first described motor; Described solid array of microneedles device fixed disc is that a center is porose, and the cogged disk of outward flange band, described solid array of microneedles device fixed disc is connected with the rotation screw thread be arranged on a rotary screw being fixed at the bottom of the case of climatic chamber by the rotation screw thread on centre bore surface, and described solid array of microneedles device fixed disc is positioned at the oblique upper of described groove base plate; Described solid array of microneedles device locking cap is arranged on described solid array of microneedles device, and described solid array of microneedles device locking cap hangs on described solid array of microneedles device fixed disc; The machine shaft being arranged on the second described motor in climatic chamber is a rotary screw, the outward flange of the rotation screw thread on this rotary screw and described solid array of microneedles device fixed disc with gear be connected; The machine shaft being arranged on the 3rd described motor in climatic chamber is a rotary screw, and the rotation screw thread on this rotary screw is connected with the gear of the cogged rolling disc of outward flange band.
The second described motor, the 3rd motor can be fixed on a metallic plate, and this metallic plate is fixed on the tank wall of described climatic chamber; The digital control panel carrying out described in working state control for the first described motor, the second described motor and the 3rd described motor is installed outside described climatic chamber.
Described liquid storage tank is for storing drug solution.
The degree of depth of described groove is micro-meter scale.Described micro-meter scale is preferably 75 μm ~ 500 μm.
The method utilizing automatization's solid array of microneedles device medicine carrying of the invention described above to realize solid array of microneedles device medicine carrying is: hang on solid array of microneedles device fixed disc by multiple (being generally designed to about 10 as required) the solid array of microneedles device connected one to one on multiple (being generally designed to about 10 as required) solid array of microneedles device locking cap, described solid array of microneedles device fixed disc installs described multiple solid array of microneedles devices, drug solution is placed in the liquid storage tank jointly formed by the groove of frame scraper plate and groove base plate, after shutting the cabinet door of climatic chamber, switch on power, temperature and humidity needed for adjustment, by digital control panel, recall medicine carrying program, click the medicine carrying automatically running and carry out automatization's solid array of microneedles device, carry out moving to high order end or low order end to left or right by the frame scraper plate described in the first stepping driven by motor, then turn back to initial position, in the groove of described groove base plate, form the thin liquid layer that a layer thickness thickness identical with the degree of depth of the groove of described groove base plate is the drug solution of micro-meter scale, moved downward by the solid array of microneedles device fixed disc described in the second stepping driven by motor, the described solid array of microneedles device faced above described thin liquid layer is allowed slowly to drop on described thin liquid layer, rely on the gravity of solid array of microneedles device self, the needle point of the micropin on first solid array of microneedles device is placed in (needle point of the micropin on general solid array of microneedles device stops about 1 second at drug solution) among the thin liquid layer formed by described drug solution, described drug solution is made to be adsorbed on the needle point of the micropin on first described solid array of microneedles device, thus realize the medicine carrying of first solid array of microneedles device, and then to be moved upward by the solid array of microneedles device fixed disc described in the second stepping driven by motor and get back to initial position, and the gear of rolling disc is connected with the gear of solid array of microneedles device fixed disc, rolling disc is driven by the 3rd motor, described solid array of microneedles device fixed disc is done clockwise or is rotated counterclockwise that (gear of rolling disc is connected with the gear of solid array of microneedles device fixed disc, thus realize the 3rd motor to the control of solid array of microneedles device fixed disc), the solid array of microneedles device described in next is made to be positioned at above described thin liquid layer, the switching between the solid array of microneedles device described in realization, then the medicine carrying operation repeating to start to carry out automatization's solid array of microneedles device, till making to be arranged on the described solid array of microneedles device on described solid array of microneedles device fixed disc all medicine carrying complete.This device can realize the medicine carrying of solid array of microneedles device by the first described motor, the second described motor and the 3rd described motor and program, improve precision and the accuracy of medicine carrying, and can realize batch medicine carrying.
The control of the duty of the first described motor, the second described motor and the 3rd described motor is that the instruction sent by described digital control panel is controlled.
The length of described needle point is higher than the thickness of described thin liquid layer.
The thickness of described thin liquid layer is micro-meter scale.Described micro-meter scale is preferably 75 μm ~ 500 μm.
Wherein, the shape of described solid array of microneedles device locking cap can be shape for hat, sheet type or column type, the top at the support position of described solid array of microneedles device can be connected to easily, and it is for convenience detach between the support of solid array of microneedles device, when described solid array of microneedles device relies on the gravity of self to make the needle point of the micropin on solid array of microneedles device be placed among thin liquid layer, solid array of microneedles device locking cap can by solid array of microneedles device jack-up, realizing solid array of microneedles device relies on the gravity of self to make the vertical lowering of the needle point of the micropin on solid array of microneedles device among thin liquid layer.
Wherein, the combination of described solid array of microneedles device fixed disc and described solid array of microneedles device locking cap, the fixing of described solid array of microneedles device can be realized, and the needle point of the micropin on described solid array of microneedles device is when immersing thin liquid layer, described solid array of microneedles device locking cap upwards jack-up, described solid array of microneedles device can be realized and vertically rely on the gravity of self to place.
Wherein, the position that the combination of described rolling disc and described solid array of microneedles device fixed disc can realize between described solid array of microneedles device switches.Solid array of microneedles device fixed disk is used for fixing solid array of microneedles device, the support of solid array of microneedles device through on described solid array of microneedles device fixed disc for after hanging hole that solid array of microneedles device opens, be combined with solid array of microneedles device locking cap again, described solid array of microneedles device can freely be moved up and down in hole, and rolling disc drive solid array of microneedles device fixed disk realizes the switching between solid array of microneedles device position.
Wherein, described motor is 3, realizes respective function respectively: the frame scraper plate described in realization and the side-to-side movement of described groove base plate, form thin liquid layer; Solid array of microneedles device described in realization from top to bottom, the action of the thin liquid layer of immersion from bottom to top; The position realized between different solid array of microneedles device switches.
Wherein, described digital control panel controls 3 motors, realize the loading parameter (time of staying of needle point in drug solution, cycle-index etc. of the micropin on the speed of service of frame scraper plate, medicine carrying number of times, solid array of microneedles device) of various described solid array of microneedles device, realize full auto-programs management.
Wherein, described climatic chamber controls the temperature humidity of whole system.Temperature in described climatic chamber is adjustable at 4 ~ 37 DEG C, and humidity is adjustable 50% ~ 95%.
The surface of described groove needs certain hydrophilic, the material of groove base plate described is thus selected from simple glass, aluminum, zinc, one (the described hydrophilic process of surface through the rustless steel of hydrophilic process and surface in the copper etc. of hydrophilic process, can at room temperature, rustless steel or copper are put into hydrophilizing agent (the HCl aqueous solution, the 1 volume mass concentration that are 36% by 1 volume mass concentration be 0.5% ethylenediaminetetraacetic acid (EDTA) aqueous solution and 2 volume mass concentration be the H of 30%
2o
2composition, and be as the criterion with the volume unit of HCl aqueous solution) in process one minute), or be selected from surface by the material of a kind of modification in above-mentioned material.The material of described frame scraper plate can be glass, rustless steel or politef.
Described solid array of microneedles device is as the object of medicine carrying, and the cross sectional shape of solid array of microneedles device is conical or polyhedral cone shaped.The material of the micropin on described solid array of microneedles device is selected from the one in monocrystal silicon, titanium, rustless steel and macromolecular material (described macromolecular material is selected from the one in polylactic acid, polyglycolic acid, polyethylene, polyvinyl alcohol, Merlon, polyacrylamide, polypropylene and nylon).The length of the needle point of the micropin on described solid array of microneedles device is between 100 ~ 1000 microns; The diameter of the needle point of the micropin on described solid array of microneedles device is between 100 nanometer ~ 10 micron; The cone angle of the needle point of the micropin on described solid array of microneedles device is 20 ~ 60 degree.
Described drug solution needs to form uniform thin liquid layer with groove base plate, and has certain adhesion, thus realizes weakening capillarity, avoids drug solution to pollute the substrate of solid array of microneedles device, carries out the object of even medicine carrying.So, medicine (comprising all medicines being applicable to micropin medicine carrying) and the aqueous solution containing thickening agent should be comprised in the formula of described drug solution.Described thickening agent, there is thickening property and film property, thickening property is the binding ability in order to the needle point and medicine improving the micropin on solid array of microneedles device, thus raising drug loading, film property is that the thin liquid layer in order to make drug solution be formed is even, thus improve the uniformity of medicine carrying, meanwhile, strengthen the adhesion of drug solution and groove base plate, capillarity can be weakened, avoid drug solution to pollute the substrate of solid array of microneedles device, realize the needle point medicine carrying of the micropin on solid array of microneedles device, save medicine.Frame scraper plate and groove base plate are done relative (or left and right) and are moved, form the thin liquid layer that a layer thickness is identical with the degree of depth of the groove of groove base plate, the thickness of this thin liquid layer is micro-meter scale, capillarity can be weakened further, thus avoid drug solution to pollute the substrate of solid array of microneedles device, and save medicine.Then solid array of microneedles device relies on the gravity of self, among the thin liquid layer needle point of the micropin on solid array of microneedles device being placed in drug solution, drug solution is adsorbed on the needle point of the micropin on solid array of microneedles device, thus realizes the medicine carrying of solid array of microneedles device.
According to different drug loading requirements, described drug solution consist of medicine and containing the aqueous solution of thickening agent.
The concentration preferences of the medicine in described drug solution is 0.1% ~ 50%(w/v), more preferably scope is 0.5% ~ 5%(w/v).
The concentration preferences of the thickening agent in described drug solution is 0.1% ~ 50%(w/v), more preferably scope is 1% ~ 10%(w/v).
Described thickening agent is selected from one or more in sodium alginate, gelatin, hyaluronic acid, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, carbomer, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, starch, xanthan gum, polyacrylic acid, Radix Acaciae senegalis and chitosan etc.
In method of the present invention, solid array of microneedles device is the gravity relying on self, the surface needle point of the micropin on solid array of microneedles device being placed in the thin liquid layer of drug solution is very significant, overcomes the shortcoming that the medicine-carrying method used at present in the world mentioned in background technology needs accurately to control.If method of the present invention is without the need to aiming at the micropin on solid array of microneedles device the process that corresponding micropore carries out medicine carrying exactly, so do not need accurate control, whole process is at room temperature carried out, and can not impact because of high temperature to pharmaceutically active.
Device of the present invention is according to the principle design of the method for solid array of microneedles device medicine carrying out, the formation of thin liquid layer, the placement of solid array of microneedles device and switching can realize automatization, avoid the error that manual operation brings, make drug incorporation have homogeneity.Add climatic chamber simultaneously, the temperature and humidity of casing can be controlled, effectively can keep the activity of protein medicaments.After realizing automatization, various parameter: as the time of staying of needle point in drug solution of the micropin on time of staying of the speed of service of the degree of depth of the groove of groove base plate, frame scraper plate, frame scraper plate, medicine carrying number of times, solid array of microneedles device, cycle-index realize regulation and control, the combination of various parameter can realize the controllable of the degree of depth of the medicine carrying of the needle point of the micropin on solid array of microneedles device, medicine carrying thickness and drug loading.
The method of solid array of microneedles device medicine carrying of the present invention relies on gravity to be placed in a kind of method of carrying out medicine carrying on thin liquid layer solid array of microneedles device.Method And Principle of the present invention is completely different from the medicine-carrying method mentioned in above-mentioned background technology, weaken capillarity by the thin liquid layer of micro-meter scale and the adhesion between drug solution and the groove of groove base plate, the method does not need accurate control, and (needs as mentioned in the introduction are aimed at corresponding micropore exactly micropin and are carried out medicine carrying, this process need accurately controls, and method of the present invention does not relate to the process that micropin aims at micropore, so do not need accurate control), drug inactivation can not be made, medicine carrying is even, the substrate that solid array of microneedles device drug incorporation does not pollute solid array of microneedles device can be realized, thus save medicine and accurate quantitative analysis.
The device of solid array of microneedles device medicine carrying of the present invention is according to the principle design of the method for solid array of microneedles device medicine carrying out, achieve full-automation (utilizing the operation that three motors and program realize), optimize the personal error that manual medicine carrying brings further, make the drug incorporation of solid array of microneedles device more accurate, accurately, economy is easy.
Accompanying drawing explanation
Fig. 1. the schematic diagram of the device of a kind of manual solid array of microneedles device medicine carrying of the present invention; Wherein: Fig. 1 a is top view; Fig. 1 b is left view.
Fig. 2. the schematic diagram of the device of the solid array of microneedles device medicine carrying of a kind of automatization of the present invention.
Reference numeral
1. groove base plate 2. groove 3. frame scraper plate
4. liquid storage tank 5. thin liquid layer 6. solid array of microneedles device
7. the solid array of microneedles device after solid array of microneedles device 8. medicine carrying before medicine carrying
9. solid array of microneedles device fixed disc 10. solid array of microneedles device locking cap
11. rolling disc 12. first motor 13. second motors
14. the 3rd motor 15. digital control panel 16. climatic chambers
Detailed description of the invention
Below with reference to drawings and Examples, the present invention is described further, and embodiments of the invention are only used for technical scheme of the present invention is described, and non-limiting the present invention.
Embodiment 1.
Refer to Fig. 1 (adopting the medicine carrying manually carrying out solid array of microneedles device), the device of manual solid array of microneedles device medicine carrying comprises the frame scraper plate 3 that the groove base plate 1 adopting simple glass to make is the rustless steel making of 304 with employing model; Described frame scraper plate 3 is installed on described groove base plate 1, and the groove 2 of described frame scraper plate 3 and described groove base plate 1 forms a liquid storage tank 4 jointly.The degree of depth of groove 2 is 75 μm, and width is 10mm, and length is 30mm.Frame scraper plate 3 is square-shaped frame, and the length of side is 10mm, is highly 10mm.
What the material of the micropin on solid array of microneedles device 6 used adopted is single crystal silicon material, and array is 6 × 6, and array area is 0.25cm
2, be made up of 36 micropins, the length of often propping up micropin is 100 μm, and the diameter of needle point is 100nm, and the maximum cone angle of needle point is 20 °.The back of solid array of microneedles device adheres in cylindrical substrate and forms solid array of microneedles device as the support of solid array of microneedles device, is convenient to pick and place.
Using the aqueous solution containing hydroxypropyl emthylcellulose as thickening agent in drug solution, in drug solution, the concentration of hydroxypropyl emthylcellulose is 1%(w/v); Using fluorescein sodium as model drug in drug solution, in drug solution, the concentration of fluorescein sodium is 3%(w/v).
The device of above-mentioned manual solid array of microneedles device medicine carrying is utilized to carry out solid array of microneedles device medicine carrying: drug solution to be placed in the common liquid storage tank 4 formed of groove 2 by described frame scraper plate 3 and described groove base plate 1, described frame scraper plate and described groove base plate are done relative motion, the thin liquid layer 5 of a layer thickness drug solution identical with the degree of depth of the groove of described groove base plate is formed in the groove 2 of described groove base plate 1, rely on the gravity of solid array of microneedles device self, the needle point often propping up micropin of the solid array of microneedles device 7 before medicine carrying is placed among the thin liquid layer formed by described drug solution, stop 1 second, what make described drug solution be adsorbed on described solid array of microneedles device often props up on the needle point of micropin, obtain the solid array of microneedles device 8 after medicine carrying, thus realize the medicine carrying of solid array of microneedles device.
Embodiment 2
Refer to Fig. 1 (adopting the medicine carrying manually carrying out solid array of microneedles device), the device of manual solid array of microneedles device medicine carrying comprises the groove base plate 1 adopting aluminium sheet to make and the frame scraper plate 3 adopting politef to make; Described frame scraper plate 3 is installed on described groove base plate 1, and the groove 2 of described frame scraper plate 3 and described groove base plate 1 forms a liquid storage tank 4 jointly.The degree of depth of groove 2 is 300 μm, and width is 14mm, and length is 30mm.Frame scraper plate 3 is square-shaped frame, and the length of side is 14mm, is highly 10mm.
What the material of the micropin on solid array of microneedles device 6 used adopted is polyphosphazene polymer lactate material, and array is 9 × 9, and array area is 0.64cm
2, be made up of 81 micropins, the length of often propping up micropin is 500 μm, and the diameter of needle point is 200nm, and the maximum cone angle of needle point is 26 °.The back of solid array of microneedles device adheres in cylindrical substrate and forms solid array of microneedles device as the support of solid array of microneedles device, is convenient to pick and place.
Using the aqueous solution containing hydroxypropyl emthylcellulose as thickening agent in drug solution, in drug solution, the concentration of hydroxypropyl emthylcellulose is 5%(w/v); Using fluorescein sodium as model drug in drug solution, in drug solution, the concentration of fluorescein sodium is 0.1%(w/v).
The device of above-mentioned manual solid array of microneedles device medicine carrying is utilized to carry out solid array of microneedles device medicine carrying: drug solution to be placed in the common liquid storage tank 4 formed of groove 2 by described frame scraper plate 3 and described groove base plate 1, described frame scraper plate and described groove base plate are done relative motion, the thin liquid layer 5 of a layer thickness drug solution identical with the degree of depth of the groove of described groove base plate is formed in the groove 2 of described groove base plate 1, rely on the gravity of solid array of microneedles device self, the needle point often propping up micropin of the solid array of microneedles device 7 before medicine carrying is placed among the thin liquid layer formed by described drug solution, stop 1 second, what make described drug solution be adsorbed on described solid array of microneedles device often props up on the needle point of micropin, obtain the solid array of microneedles device 8 after medicine carrying, thus realize the medicine carrying of solid array of microneedles device.
Embodiment 3.
Refer to Fig. 1 (adopting the medicine carrying manually carrying out solid array of microneedles device), the device of manual solid array of microneedles device medicine carrying comprises the frame scraper plate 3 that the groove base plate 1 adopting corrosion resistant plate to make is the rustless steel making of 304 with employing model; Described frame scraper plate 3 is installed on described groove base plate 1, and the groove 2 of described frame scraper plate 3 and described groove base plate 1 forms a liquid storage tank 4 jointly.The degree of depth of groove 2 is 500 μm, and width is 14mm, and length is 30mm.The surface of groove through hydrophilic process (be as the criterion with the volume unit of HCl aqueous solution, at room temperature, HCl aqueous solution, 1 volume mass concentration that to be put into by rustless steel by 1 volume mass concentration be 36% be 0.5% EDTA aqueous solution and 2 volume mass concentration be the H of 30%
2o
2process one minute in the hydrophilizing agent of composition).Frame scraper plate 3 is square-shaped frame, and the length of side is 14mm, is highly 10mm.
What the material of the micropin on solid array of microneedles device 6 used adopted is stainless steel material, and array is 9 × 9, and array area is 0.64cm
2, be made up of 81 micropins, the length of often propping up micropin is 1000 μm, and the diameter of needle point is 10 μm, and the maximum cone angle of needle point is 60 °.The back of solid array of microneedles device adheres in cylindrical substrate and forms solid array of microneedles device as the support of solid array of microneedles device, is convenient to pick and place.
Using the aqueous solution containing polyvinylpyrrolidone as thickening agent in drug solution, in drug solution, the concentration of polyvinylpyrrolidone is 50%(w/v); Using fluorescein sodium as model drug in drug solution, in drug solution, the concentration of fluorescein sodium is 5%(w/v).
The device of above-mentioned manual solid array of microneedles device medicine carrying is utilized to carry out solid array of microneedles device medicine carrying: drug solution to be placed in the common liquid storage tank 4 formed of groove 2 by described frame scraper plate 3 and described groove base plate 1, described frame scraper plate and described groove base plate are done relative motion, the thin liquid layer 5 of a layer thickness drug solution identical with the degree of depth of the groove of described groove base plate is formed in the groove 2 of described groove base plate 1, rely on the gravity of solid array of microneedles device self, the needle point often propping up micropin of the solid array of microneedles device 7 before medicine carrying is placed among the thin liquid layer formed by described drug solution, stop 1 second, what make described drug solution be adsorbed on described solid array of microneedles device often props up on the needle point of micropin, obtain the solid array of microneedles device 8 after medicine carrying, thus realize the medicine carrying of solid array of microneedles device.
Embodiment 4.
Refer to Fig. 2 (adopting the mode of automatization to carry out the medicine carrying of solid array of microneedles device), the device of automatization's solid array of microneedles device medicine carrying comprises groove base plate 1, frame scraper plate 3, solid array of microneedles device 6, solid array of microneedles device fixed disc 9, solid array of microneedles device locking cap 10, rolling disc 11, first motor 12, second motor 13, the 3rd motor 14, digital control panel 15 and climatic chamber 16.
In described climatic chamber 16, described groove base plate 1 is fixed at the bottom of the case of described climatic chamber 16, described frame scraper plate 3 is installed on described groove base plate 1, and the groove 2 of described frame scraper plate 3 and described groove base plate 1 forms a liquid storage tank 4 jointly; Described frame scraper plate 3 is provided with rotary screw, the machine shaft being arranged on the first described motor 12 in climatic chamber 16 is a rotary screw, and the rotary screw on described frame scraper plate 3 is connected by the rotation screw thread on rotary screw with the rotary screw on the first described motor 12; Described solid array of microneedles device fixed disc 9 is that a center is porose, and the cogged disk of outward flange band, described solid array of microneedles device fixed disc 9 is connected with the rotation screw thread be arranged on a rotary screw being fixed at the bottom of the case of climatic chamber by the rotation screw thread on centre bore surface, and described solid array of microneedles device fixed disc 9 is positioned at the oblique upper of described groove base plate 1; Described solid array of microneedles device locking cap 10 is arranged on described solid array of microneedles device 6, and described solid array of microneedles device locking cap 10 hangs on described solid array of microneedles device fixed disc; The machine shaft being arranged on the second described motor 13 in climatic chamber 16 is a rotary screw, the outward flange of the rotation screw thread on this rotary screw and described solid array of microneedles device fixed disc 9 with gear be connected; The machine shaft being arranged on the 3rd described motor 14 in climatic chamber 16 is a rotary screw, and the rotation screw thread on this rotary screw is connected with the gear of the cogged rolling disc 11 of outward flange band.
The second described motor 13, the 3rd motor 14 can be fixed on a metallic plate, and this metallic plate is fixed on the tank wall of described climatic chamber 16; The digital control panel 15 carrying out described in working state control for the first described motor 12, the second described motor 13 and the 3rd described motor 14 is installed outside described climatic chamber 16.
Described groove base plate 1 and described frame scraper plate 3 all adopt corrosion resistant plate to make.
The degree of depth of described groove 2 is 100 μm, and width is 10mm, and length is 30mm.The surface of groove through hydrophilic process (be as the criterion with the volume unit of HCl aqueous solution, at room temperature, HCl aqueous solution, 1 volume mass concentration that to be put into by rustless steel by 1 volume mass concentration be 36% be 0.5% EDTA aqueous solution and 2 volume mass concentration be the H of 30%
2o
2process one minute in the hydrophilizing agent of composition).Frame scraper plate 3 is square-shaped frame, and the length of side is 10mm, is highly 10mm.
What the material of the micropin on solid array of microneedles device 6 used adopted is single crystal silicon material, and array is 6 × 6, and array area is 0.25cm
2, be made up of 36 micropins, the length of often propping up micropin is 260 μm, and the diameter of needle point is 2 μm, and the maximum cone angle of needle point is 26 °.The back of solid array of microneedles device adheres in cylindrical substrate and forms solid array of microneedles device as the support of solid array of microneedles device, is convenient to pick and place.
Using the aqueous solution containing sodium carboxymethyl cellulose as thickening agent in drug solution, in drug solution, the concentration of sodium carboxymethyl cellulose is 1%(w/v); Using L-carnitine as model drug in drug solution, in drug solution, the concentration of L-carnitine is 50%(w/v).
The method utilizing the device of above-mentioned automatization solid array of microneedles device medicine carrying to realize solid array of microneedles device medicine carrying is: hang on solid array of microneedles device fixed disc by 10 the solid array of microneedles devices 6 connected one to one on 10 solid array of microneedles device locking caps 10; Described solid array of microneedles device fixed disc 9 installs 10 described solid array of microneedles devices 6, drug solution is placed in the common liquid storage tank 4 formed of groove 2 by frame scraper plate 3 and groove base plate 1, after shutting the cabinet door of climatic chamber 16, switch on power, temperature and humidity needed for adjustment, by digital control panel 15, recall medicine carrying program, click the medicine carrying automatically running and carry out automatization's solid array of microneedles device; Described frame scraper plate 3 is driven to carry out moving to high order end or low order end to left or right by the first motor 12, then turn back to initial position, in the groove 2 of described groove base plate 1, form the thin liquid layer 5 of a layer thickness drug solution identical with the degree of depth of the groove of described groove base plate; Described solid array of microneedles device fixed disc is driven to move downward by the second motor 13, the described solid array of microneedles device faced above described thin liquid layer is allowed slowly to drop on described thin liquid layer, rely on the gravity of solid array of microneedles device self, the needle point of first solid array of microneedles device is placed among the thin liquid layer formed by described drug solution and stops 1 second, described drug solution is adsorbed on the needle point of first described solid array of microneedles device, thus realizes the medicine carrying of first solid array of microneedles device; And then to be moved upward by the solid array of microneedles device fixed disc described in the second stepping driven by motor and get back to initial position, and the gear of rolling disc 11 is connected with the gear of solid array of microneedles device fixed disc 9; Rolling disc 11 is driven by the 3rd motor 14, described solid array of microneedles device fixed disc is done clockwise or is rotated counterclockwise that (gear of rolling disc 11 is connected with the gear of solid array of microneedles device fixed disc 9, thus realize the control of the 3rd motor 14 pairs of solid array of microneedles device fixed discs), the solid array of microneedles device described in next is made to be positioned at above described thin liquid layer, the switching between the solid array of microneedles device described in realization; Then the medicine carrying operation repeating to start to carry out automatization's solid array of microneedles device, till making to be arranged on the solid array of microneedles device described in 10 on described solid array of microneedles device fixed disc all medicine carrying complete.This device can realize the medicine carrying of solid array of microneedles device by the first described motor 12, the second described motor 13 and the 3rd described motor 14 and program, improve precision and the accuracy of medicine carrying, and can realize batch medicine carrying.
The control of the duty of the first described motor 12, the second described motor 13 and the 3rd described motor 14 is that the instruction sent by described digital control panel 15 is controlled.
Embodiment 5.
Adopt the mode of automatization to carry out the medicine carrying of solid array of microneedles device, the device of automatization's solid array of microneedles device medicine carrying is substantially with embodiment 4, and difference is: described groove base plate 1 and described frame scraper plate 3 all adopt zine plate to make.The degree of depth of described groove 2 is 75 μm, and width is 14mm, and length is 30mm.Frame scraper plate 3 is square-shaped frame, and the length of side is 14mm, is highly 10mm.What the material of the micropin on solid array of microneedles device 6 used adopted is single crystal silicon material, and array is 11 × 11, and array area is 1cm
2, be made up of 121 micropins, the length of often propping up micropin is 150 μm, and the diameter of needle point is 2 μm, and the maximum cone angle of needle point is 38 °.The back of solid array of microneedles device adheres in cylindrical substrate and forms solid array of microneedles device as the support of solid array of microneedles device, is convenient to pick and place.
Using the aqueous solution containing sodium carboxymethyl cellulose as thickening agent in drug solution, in drug solution, the concentration of sodium carboxymethyl cellulose is 4%(w/v); Using interferon as model drug in drug solution, in drug solution, the concentration of interferon is 1%(w/v).
The device of above-mentioned automatization solid array of microneedles device medicine carrying is utilized to realize the method for solid array of microneedles device medicine carrying with embodiment 4.
Embodiment 6.
Adopt the mode of automatization to carry out the medicine carrying of solid array of microneedles device, the device of automatization's solid array of microneedles device medicine carrying is substantially with embodiment 4, and difference is: the degree of depth of described groove 2 is 500 μm, and width is 14mm, and length is 30mm.Frame scraper plate 3 is square-shaped frame, and the length of side is 14mm, is highly 10mm.What the material of the micropin on solid array of microneedles device 6 used adopted is poly-lactic acid material, and array is 9 × 9, and array area is 0.64cm
2, be made up of 81 micropins, the length of often propping up micropin is 1000 μm, and the diameter of needle point is 2 μm, and the maximum cone angle of needle point is 38 °.The back of solid array of microneedles device adheres in cylindrical substrate and forms solid array of microneedles device as the support of solid array of microneedles device, is convenient to pick and place.
Using the aqueous solution containing sodium alginate as thickening agent in drug solution, in drug solution, the concentration of sodium alginate is 10%(w/v); Using riboflavin as model drug in drug solution, in drug solution, the concentration of riboflavin is 3%(w/v).
The device of above-mentioned automatization solid array of microneedles device medicine carrying is utilized to realize the method for solid array of microneedles device medicine carrying with embodiment 4.
Claims (12)
1. the method for a solid array of microneedles device medicine carrying, it is characterized in that: the method for described solid array of microneedles device medicine carrying utilizes the device of manual solid array of microneedles device medicine carrying or utilizes the device of automatization's solid array of microneedles device medicine carrying, rely on the gravity of solid array of microneedles device self, the needle point of the micropin on solid array of microneedles device is placed among thin liquid layer that thickness is the drug solution of micro-meter scale, and the length of the needle point of micropin on described solid array of microneedles device is higher than the thickness of the thin liquid layer of described drug solution, drug solution is made to be adsorbed on the needle point of the micropin on solid array of microneedles device, realize the medicine carrying of solid array of microneedles device,
The device of described manual solid array of microneedles device medicine carrying comprises groove base plate and frame scraper plate;
Described frame scraper plate is installed on described groove base plate, and described frame scraper plate and the groove of described groove base plate form a liquid storage tank jointly; The degree of depth of described groove is micro-meter scale;
The device of described automatization's solid array of microneedles device medicine carrying comprises groove base plate, frame scraper plate, solid array of microneedles device, solid array of microneedles device fixed disc, solid array of microneedles device locking cap, rolling disc, the first motor, the second motor, the 3rd motor, digital control panel and climatic chamber;
In described climatic chamber, described groove base plate is fixed at the bottom of the case of described climatic chamber, described frame scraper plate is installed on described groove base plate, and described frame scraper plate and the groove of described groove base plate form a liquid storage tank jointly; Described frame scraper plate is provided with rotary screw, the machine shaft being arranged on the first described motor in climatic chamber is a rotary screw, and the rotary screw on described frame scraper plate is connected by the rotation screw thread on rotary screw with the rotary screw on the first described motor; Described solid array of microneedles device fixed disc is that a center is porose, and the cogged disk of outward flange band, described solid array of microneedles device fixed disc is connected with the rotation screw thread be arranged on a rotary screw being fixed at the bottom of the case of climatic chamber by the rotation screw thread on centre bore surface, and described solid array of microneedles device fixed disc is positioned at the oblique upper of described groove base plate; Described solid array of microneedles device locking cap is arranged on described solid array of microneedles device, and described solid array of microneedles device locking cap hangs on described solid array of microneedles device fixed disc; The machine shaft being arranged on the second described motor in climatic chamber is a rotary screw, the outward flange of the rotation screw thread on this rotary screw and described solid array of microneedles device fixed disc with gear be connected; The machine shaft being arranged on the 3rd described motor in climatic chamber is a rotary screw, and the rotation screw thread on this rotary screw is connected with the gear of the cogged rolling disc of outward flange band;
The digital control panel carrying out described in working state control for the first described motor, the second described motor and the 3rd described motor is installed outside described climatic chamber;
The degree of depth of described groove is micro-meter scale.
2. the method for solid array of microneedles device medicine carrying according to claim 1, is characterized in that: described thickness is the thin liquid layer of the drug solution of micro-meter scale, and its micro-meter scale is 75 μm ~ 500 μm.
3. the method for solid array of microneedles device medicine carrying according to claim 1, it is characterized in that: the described device utilizing manual solid array of microneedles device medicine carrying, realize the medicine carrying of solid array of microneedles device, drug solution is placed in the liquid storage tank jointly formed by the groove of frame scraper plate and groove base plate, described frame scraper plate and described groove base plate are done relative motion, the thin liquid layer that a layer thickness thickness identical with the degree of depth of the groove of described groove base plate is the drug solution of micro-meter scale is formed in the groove of described groove base plate, rely on the gravity of solid array of microneedles device self, the needle point of the micropin on solid array of microneedles device is placed among the thin liquid layer formed by described drug solution, and the length of the needle point of micropin on described solid array of microneedles device is higher than the thickness of described thin liquid layer, described drug solution is made to be adsorbed on the needle point of the micropin on described solid array of microneedles device, realize the medicine carrying of solid array of microneedles device.
4. the method for solid array of microneedles device medicine carrying according to claim 1, it is characterized in that: the described device utilizing automatization's solid array of microneedles device medicine carrying, realize the method for solid array of microneedles device medicine carrying, be that the multiple solid array of microneedles devices connected one to one on multiple solid array of microneedles device locking cap are hung on solid array of microneedles device fixed disc, described solid array of microneedles device fixed disc installs described multiple solid array of microneedles devices, drug solution is placed in the liquid storage tank jointly formed by the groove of frame scraper plate and groove base plate, after shutting the cabinet door of climatic chamber, switch on power, temperature and humidity needed for adjustment, pass through digital control panel, recall medicine carrying program, click the medicine carrying automatically running and carry out automatization's solid array of microneedles device, carry out moving to high order end or low order end to left or right by the frame scraper plate described in the first stepping driven by motor, then turn back to initial position, in the groove of described groove base plate, form the thin liquid layer that a layer thickness thickness identical with the degree of depth of the groove of described groove base plate is the drug solution of micro-meter scale, moved downward by the solid array of microneedles device fixed disc described in the second stepping driven by motor, the described solid array of microneedles device faced above described thin liquid layer is allowed slowly to drop on described thin liquid layer, rely on the gravity of solid array of microneedles device self, the needle point of the micropin on first solid array of microneedles device is placed among the thin liquid layer formed by described drug solution, described drug solution is made to be adsorbed on the needle point of the micropin on first described solid array of microneedles device, thus realize the medicine carrying of first solid array of microneedles device, and then to be moved upward by the solid array of microneedles device fixed disc described in the second stepping driven by motor and get back to initial position, and the gear of rolling disc is connected with the gear of solid array of microneedles device fixed disc, rolling disc is driven by the 3rd motor, described solid array of microneedles device fixed disc is made to do clockwise or be rotated counterclockwise, the solid array of microneedles device described in next is made to be positioned at above described thin liquid layer, the switching between the solid array of microneedles device described in realization, then the medicine carrying operation repeating to start to carry out automatization's solid array of microneedles device, till making to be arranged on the described solid array of microneedles device on described solid array of microneedles device fixed disc all medicine carrying complete,
The length of the needle point of the micropin on described solid array of microneedles device is higher than the thickness of described thin liquid layer;
The control of the duty of the first described motor, the second described motor and the 3rd described motor is that the instruction sent by described digital control panel is controlled.
5. the method for solid array of microneedles device medicine carrying according to claim 1, is characterized in that: the degree of depth of described groove is micro-meter scale, and its micro-meter scale is 75 μm ~ 500 μm.
6. the method for solid array of microneedles device medicine carrying according to claim 1, it is characterized in that: the material of described groove base plate is selected from simple glass, aluminum, zinc, surperficial rustless steel and the surface one in the copper of hydrophilic process through hydrophilic process, or is selected from surface by the material of a kind of modification in above-mentioned material; The material of described frame scraper plate is glass, rustless steel or politef.
7. the method for the solid array of microneedles device medicine carrying according to claim 1,3 or 4, is characterized in that: the length of the needle point of the micropin on described solid array of microneedles device is between 100 ~ 1000 microns; The diameter of the needle point of the micropin on described solid array of microneedles device is between 100 nanometer ~ 10 micron; The cone angle of the needle point of the micropin on described solid array of microneedles device is 20 ~ 60 degree; The material of the micropin on described solid array of microneedles device is selected from the one in monocrystal silicon, titanium, rustless steel and macromolecular material.
8. the method for solid array of microneedles device medicine carrying according to claim 7, is characterized in that: described macromolecular material is selected from the one in polylactic acid, polyglycolic acid, polyethylene, polyvinyl alcohol, Merlon, polyacrylamide, polypropylene and nylon.
9. the method for the solid array of microneedles device medicine carrying according to claim 1,3 or 4, is characterized in that: described drug solution consist of medicine and containing the aqueous solution of thickening agent;
Described thickening agent is selected from one or more in sodium alginate, gelatin, hyaluronic acid, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, carbomer, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone, starch, xanthan gum, polyacrylic acid, Radix Acaciae senegalis and chitosan.
10. the method for solid array of microneedles device medicine carrying according to claim 9, is characterized in that: the concentration of the medicine in described drug solution is 0.1% ~ 50% (w/v), and the concentration of thickening agent is 0.1% ~ 50% (w/v).
The method of 11. solid array of microneedles device medicine carryings according to claim 10, is characterized in that: the concentration of the medicine in described drug solution is 0.5% ~ 5% (w/v).
The method of 12. solid array of microneedles device medicine carryings according to claim 10, is characterized in that: the concentration of the thickening agent in described drug solution is 1% ~ 10% (w/v).
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| US3470011A (en) * | 1967-02-07 | 1969-09-30 | American Cyanamid Co | Process for applying liquid biologicals to applicators for intracutaneous injection |
| CN101076409A (en) * | 2004-11-18 | 2007-11-21 | 3M创新有限公司 | Method of contact coating a microneedle array |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3470011A (en) * | 1967-02-07 | 1969-09-30 | American Cyanamid Co | Process for applying liquid biologicals to applicators for intracutaneous injection |
| CN101076409A (en) * | 2004-11-18 | 2007-11-21 | 3M创新有限公司 | Method of contact coating a microneedle array |
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Effective date of registration: 20181227 Address after: Room 1103, Building No. 22, Tianrong Street, Daxing Biomedical Industry Base, Zhongguancun Science and Technology Park, Daxing District, Beijing 102600 Patentee after: Zhongke Microneedle (Beijing) Technology Co., Ltd. Address before: No. 29 East Zhongguancun Road, Haidian District, Beijing 100190 Patentee before: Technical Institute of Physics and Chemistry, CAS |
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