WO2014142749A1 - Micro-aiguilles intégrées dans des nanotubes - Google Patents
Micro-aiguilles intégrées dans des nanotubes Download PDFInfo
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- WO2014142749A1 WO2014142749A1 PCT/SG2014/000116 SG2014000116W WO2014142749A1 WO 2014142749 A1 WO2014142749 A1 WO 2014142749A1 SG 2014000116 W SG2014000116 W SG 2014000116W WO 2014142749 A1 WO2014142749 A1 WO 2014142749A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- 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
-
- 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
- A61M2037/0061—Methods for using microneedles
Definitions
- the invention relates to a microneedle for transdermal drug delivery; a composite comprising a plurality of said microneedles; and a method for the manufacture of said microneedles.
- drugs can be delivered into a human body via several routes, such as injection and oral delivery.
- routes such as injection and oral delivery.
- administration by injection cannot be easily conducted by patients as it often requires training and, if carried out incorrectly, may result in pain.
- oral delivery may be inappropriate for the administration of certain drugs as the pharmacological action of medicines can be affected by digestive enzymes, with protein and DNA targeting drugs having poor absorption rates when administered in this way.
- MEMS micro- electromechanical system
- MEMS devices have evolved from the process technology used in semiconductor device fabrication, i.e. the basic techniques involve the deposition of material layers, patterning by photolithography and etching to produce the required shapes.
- Lithography in an MEMS context is typically the transfer of a pattern into a photosensitive material by selective exposure to a radiation source such as light.
- nano- imprint lithography is used, which refers to a method of fabrication on nanometre scale patterns.
- nanometer scale filters of high chemical selectivity and high flux are highly desired.
- pore size matching is one of the most critical fabrication challenges.
- a good pore size that is selective for desired molecules can allow molecular sieving and force interactions between those bound to the pore.
- Many approaches regarding the fabrication of nano-scale filters of pore size ranging from 1 to 10 nm have been investigated these include functionalized polymer affinity membranes, block copolymers, mesoporous macromolecular architectures and hollow carbon nanotubes (CNTs).
- CNTs are allotropes of carbon with a cylindrical nanostructure, possessing unusual strength and flexibility which lends them for use in nanotechnology devices.
- Vertically aligned CNT forests can be grown from a macro or micro- patterned catalyst layer.
- CNT growth techniques when compared with other nanofabrication technologies, are easier, cheaper and more suitable for mass fabrication.
- the surface of inner channel of CNTs is smooth and uniform at the atomic level over large distance, which is not achievable by other nanofabrication technologies. We consider this atomic level smoothness and uniformity lead to frictionless motion for mass transport.
- novel microneedles ideally fabricated from a stretchable, biocompatible and inexpensive polymer-based membrane layer, comprising nano-filter tips based on small arrays of nanotubes such as, in one example only, vertically grown CNT bundles.
- the microneedles have improved properties for transdermal-based delivery of molecules or drugs, with particular utility for the selective delivery of nano-scale particles and molecules with applications in protein and vaccine therapy.
- a microneedle for transdermal drug delivery comprising a nano-filter including a plurality of nano-tubes whose longitudinal axis is aligned with that of said needle for the selective delivery of nano-scale molecules or particles.
- references herein to a nano-filter is reference to a filter that allows the passage of nano-scale or nano-sized molecules or particles typically understood to be in the order of a nm size and/or blocks the passage of molecules or particles with a size larger than the inner tube diameter of said nanotubes.
- W 201
- references herein to a drug is intended to include any agent to be delivered by said microneedle, in particular a drug having a therapeutic or even a preparatory property such as an anaesthetic, but it may also include agents of a diagnostic, prognostic or cosmetic nature. Further, reference herein to a drug includes a gas, liquid or a number of small particles.
- Reference herein to a drug is reference to any molecular structure that can be administered transdermal ⁇ and so, without limitation, includes reference to conventional pharmaceuticals and therapeutics but also DNA technologies and vaccine technologies.
- a microneedle contains at least one and, ideally, a plurality of fluidic channels or microtubes.
- said nano-filter is located at or adjacent either end of the microneedle and ideally at the needle tip.
- said nano-filter is located within the microneedle.
- said nano-filter is integrated with said microneedle, ideally, integration is achieved by said nano-tubes being grown in or on, or assembled on, said microneedle and/or sealed thereto using either adhesive or the use of at least one plastics material and/or at least one polymer and a heat-cooling cycle.
- the provision, and ideally the integration, of a nano-filter in or on a microneedle is advantageous because the use of a microneedle as a base for the nano-filter enhances the strength of the whole needle and so ensures it does not break during penetration.
- nano-tubes have a limited length and so the provision of same especially at either end of the microneedle, and ideally on the tip of a microneedle, ensures the whole needle is long enough to penetrate deep into the skin and ideally through the stratum corneum of the skin.
- the use of the microneedle with the nano-tubes, the disclosed microneedle achieves particle selectivity such that only particles of nano-scale can traverse.
- this reduces the incidence of cross-contamination and transfer of pathogens during injection.
- the nano-tubes are made from carbon. Due to the unique property of carbon nanotubes, which have at the atomic level a smooth inner channel wall, the transportation efficiency of the microneedles disclosed herein is much higher than other nano-scale fluid channel. Moreover, through incorporation of multiple CNTs at the tip, the efficiency of drug delivery is improved.
- said microneedle is made from one or more of the following materials: silicon, stainless steel, titanium, tantalum, nickel, a ceramic, a biodegradable material and a polymer-based material such as SU-8, polymethyl meth-acrylate (PMMA), polycarbonates (PC) and polylactic acid (PLA).
- the microneedle is made from a polymer-based material and so has the advantage of improved whole needle strength and flexibility of the tip. More ideally still, said microneedle is a SU-8 needle.
- the microneedle is made from a biodegradable material such as starch and so has the advantage of being biodegradable.
- microneedle is fabricated into a sharp shape for ease of penetration, preferably having an ultra-sharp tip.
- said nano-tubes are made from carbon, however, they may also be made from silicon or indeed any other chosen material provided they have the requisite nano- scale size and so have an internal diameter that restricts the passage of particles or molecules whose size is greater than a nano-scale.
- said microneedle has a dissolvable member, ideally, in the form of a dissolvable tip which, preferably is fashioned into a sharp-shape for ease of penetration.
- said dissolvable tip is bio-compatible and, more ideally, is in the form of a carbohydrate-based tip, such as a sugar based tip for example a maltose tip or a glucose tip, or indeed a tip made from any other sugar.
- a sugar based tip for example a maltose tip or a glucose tip, or indeed a tip made from any other sugar.
- Maltose based microtips are preferred because of their unique features i.e. high mechanical strength and biodissolvability.
- said tip is made from a polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- the use of a dissolvable tip is a preferred feature of the invention because after the sugar tip has melted, the micro- tubes of the microneedle efficiently allow the flow of a large volume of a desired drug into the nano-filter.
- said microneedle further comprises either an integrated or removable electric field driven member and/or a pressure driven member for facilitating the passage of said drug through the nano-filter of said microneedle.
- an integrated or removable electric field driven member and/or a pressure driven member for facilitating the passage of said drug through the nano-filter of said microneedle.
- the former uses an electric field gradient whilst the latter uses a pressure gradient for the purpose of forcing said drug through said microneedle.
- gas, liquid and small particles are passed through said microneedle using said pressure driven member, whereas proteins, nucleic acid e.g. DNA such as double-stranded or single- stranded and charged particles are passed through said microneedle using said electric field driven member.
- a conventional pressure driven member and/or electric field driven member is used in the production of the invention as herein described. More ideally still, where an electric field driven member is used to drive molecules through the nano-tubes electrodes are positioned, or ideally patterned, onto the nano-tubes to enable an electric field to be applied.
- a microneedle provided with the afore pressure and/or electric field assisted delivery can be used to deliver large molecular drugs such as insulin since this microneedle can apply force in the form of pressure and/or voltage on the drug solution to facilitate the large molecular drug diffusion process.
- continuous delivery with the microneedle is expected to release large volumes. In this way, the device can support those drugs, including vaccines, that require large doses.
- a composite comprising:
- each microneedle comprises a nano-filter including a plurality of nano-tubes whose longitudinal axis is aligned with that of said needle for the delivery of nano-scale molecules or particles; and b) a supporting membrane for supporting said microneedles.
- a grid layer including a plurality of holes some of which are aligned with the microneedles
- a sealant layer which seals those holes not aligned with said microneedles.
- said nano-filter is located at or adjacent either end of the microneedle and ideally at the needle tip.
- said nano-filter is located within the microneedle.
- each microneedle is provided with a dissolvable tip, ideally made of a carbohydrate such as maltose.
- the maximum loading force on the individual microneedle can be as large as 7.36 ⁇ 0.48N and after 9 minutes of the penetration, all the maltose tips were dissolved in the tissue. Drugs could then be delivered via these open biocompatible SU-8 microtubes in a continuous flow manner.
- our microneedle array comprises microtubes of approximately 350pm height and 1000pm spacing between adjacent microtubes.
- a skin patch for transdermal drug delivery comprising:
- each microneedle comprises a nano-filter including a plurality of nano-tubes whose longitudinal axis is aligned with that of said needle for the delivery of nano-scale molecules or particles;
- a skin contact layer for attaching to said skin.
- said skin contact layer is made from a material that sealingly engages with skin, especially when pressure is applied. Additionally, or alternatively, said skin contact layer comprises an adhesive suitable for attaching said patch to said skin.
- At least one, ideally the majority, and more ideally still all of said microneedles contain at least one selected drug.
- said nano-filter is located at or adjacent the needle tip. Alternatively, said nano-filter is located within the microneedle.
- a method of treatment involving the use of said microneedle(s) or the use of said patch wherein said microneedle(s) loaded with a suitable medicament is/are applied to the skin, ideally using pressure, whereby said microneedle(s) is forced through the skin and said medicament is administered.
- the skin patch can advantageously be used for vaccination purposes in either humans or animals.
- microneedle patches containing influenza vaccine provide a simple patch-based system that enables delivery of said vaccine to the skin's antigen-presenting cells.
- Most preferably said microneedles are provided with dissolvable tips.
- a microneedle for use in transdermal drug delivery comprising:
- microneedles wherein said mask is positioned such that
- microneedles are made beneath or above said nano-tubes and the nano-tube are located at or adjacent a microneedle tip with their longitudinal axis aligned with that of the microneedle;
- said nano-tubes are held in a vertical position by the use of a polymer film such as parylene.
- said mounted nano-tubes are attached to said substrate by heating the assembly to a temperature that melts said polymer substrate, causing it to flow and so mix with a first contact end of said nano- tubes and then cooling the assembly so that said polymer hardens.
- said nano-tubes are made from carbon or silicon and, more ideally still, said nano-tubes are grown on said substrate. Ideally, said nano-tubes are carbon. In a preferred method of the invention, optionally, a sub-layer is applied to said assembly.
- a method for the manufacture of a microneedle for use in transdermal drug delivery comprising fixedly mounting a plurality of nano-tubes on or in at least one microneedle wherein the longitudinal axis of said nano-tubes is aligned with that of said needle.
- said nano-tubes are located at or adjacent either end of the microneedle and ideally at the needle tip. Alternatively, said nano-tubes are located within the microneedle.
- said nano-tubes are made from carbon, however, they may also be made from silicon or indeed any other chosen material provided they have the requisite nano-scale size and so have an internal diameter that restricts the passage of particles or molecules whose size is greater than a nano-scale.
- any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose.
- Figure 1 (a) 3D schematic drawing of detailed layer structure of a composite according to the invention; (b) SEM picture taken from the rear of the SU-8 layer showing a hole under a CNT bundle on SU-8 layer, (c) 3D schematic drawing of the assembled composite (d) SEM picture of the CNT bundle with exposed CNT fibers and a parylene sidewall; (e) 3D schematic drawing of the CNT bundle with exposed CNT fibers and parylene sidewall.
- FIG. 1 3D illustration of the composite.
- the whole composite excluding PDMS bonding part comprises four layers; CNT bundle array [1], SU-8 needle array [2], supporting the CNT bundle array, a grid layer [3] comprising plurality of holes, and a sealing layer [4], which will seal all the grid holes with the exception of those positioned beneath the SU-8 needles.
- solution is able to pass through these four layers via the CNT bundle-SU-8 channels.
- Figure 5 Fabrication process for stretchable membrane based microneedles using patterned array of vertically grown carbon nanotubes.
- FIG. 6 An individual CNT bundle grows from catalyst layer, the diameter of the CNT bundle is 50 ⁇ , the height of the CNT bundle is 50pm; (b) An individual CNT bundle reinforced by parylene, the thickness of the parylene layer is 10pm; (c) catalyst layer seals the bottom of the CNT bundle; (d) The catalyst layer is etched by oxygen plasma; (e) TEM picture showing the inner diameter of the CNT is 10nm.
- Figure 7. Electric field driven member and pressure driven member, (a) Preloading test solution in the tube and assembling Ti electrode; (b) Connecting long tube with syringe and air pressure sensor for exerting air pressure; (c) Illustration of the ion depletion in the PDMS chamber in the dash line box in (b).
- Figure 8. (a) The ionic current through the CNTs as a function of time in different NaCI concentrations; (b) The ionic current as a function of time under square wave bias in different NaCI concentrations. The green line and pink line indicate the difference between peak values of ionic current, (c) The pH value of the NaCI solution with different concentrations as a function of time; (d) The pH value of the HCI solution under different driving pressure as a function of time.
- Figure 9 (a) IR spectra of ss-DNA in the beaker after applying 25kPa pressure and after applying both 25kPa pressure and 5V bias; (b) IR spectra of haemagglutinin in the beaker after applying 25kPa pressure and after applying both 25kPa pressure and 5V bias.
- Figure 10 Dissolvable sharp tip upon a SU-8-CNT microneedle as shown in Fig 2 or 3.
- FIG 11. Schematic illustration of a SU-8 microneedle including a carbohydrate tip.
- Figure 12. (a) Schematic illustration of the stage to ensure flat SU-8 membrane surface, (b) SU-8 membrane bends after development, (c) After bonded with PDMS and clamped in the stage, the membrane becomes flat.
- FIG. 13 Fabrication process for maltose tips, (a) Expelling water at 140 °C. (b) Immersing micro-tubes into the maltose at 140 °C. (c) Drawing the tips at end of the micro-tubes when the temperature increases up to 60 °C. (d) Increasing drawing speed to form sharp tips.
- Figure 14 Optical image of the finished SU-8 microneedles with a carbohydrate tip.
- Figure 15. Penetration testing results on a porcine cadaver skin.
- Figure 16. Maltose tips dissolving process, (a) The original sharp maltose tip. (b) Maltose tip after inserted into skin for 3minutes. (c) Maltose tip after inserted into skin for 6 minutes, (d) Maltose tip after inserted into skin for 9 minutes.
- Figure 17 (a) cross-section of an alternative microtube or microneedle for working the invention, (b) The manufacture of a carbohydrate tip using the microneedle of part (a), (c) The manufacture of an alternative carbohydrate tip using the microneedle of part (a).
- FIG. 18 Schematic illustration of the manufacture of a starch microneedle.
- Figure 19 Microfluidic testing of manufactured SU-8 microtubes.
- FIG. 20 An alternative fabrication process I for making SU-8 microneedle tubes.
- Figure 21 (a) 3D schematic drawing of the microneedle device integrated with CNT nanofilters; (b) Optical image of the microneedle array with gold surface electrode, scale bar is 1000pm; (c) SEM image of single SU-8 microneedle with four-beam sidewalls and a sharp tip, scale bar is 80pm; (d) SEM picture of a CNT bundle embedded inside the microneedle, scale bar is 10 ⁇ .
- FIG. 22 Working principle of the microneedle array integrated with CNT nanofilters for transdermal drug delivery.
- Figure 23 Alternative fabrication process II for microneedle array integrated with CNT nanofilters.
- Figure 24 (a) Process for single step drawing lithography; (b) Process for double drawing lithography.
- FIG. 25 Insulin delivery test result: (a) IR spectra of insulin by applying different pressure; (b) The peak value of IR spectra by applying different pressure and bias of electric field.
- Figure 26 (a) Result of bacterium culture of the solution sampled from the device chamber, bacterial colonies were observed; (b) Result of bacterium culture of the solution loaded in the beaker, no bacterial colony was found.
- FIG. 27 Schematic illustration of the SU-8 microneedles, (a) Overview of the whole device; (b) SU-8 supporting structures made of 4 SU-8 pillars; (c) Enlarge view of a single SU-8 microneedle.
- the top side of CNTs was covered with parylene-C, and the discrete CNTs were bound together by parylene-C ( Figure 4(c) and 6(b)).
- This step was the most critical process for forming the mechanical supporting layer for CNT bundles.
- the thickness of the flexible parylene-C layer was determined by the CVD process. To achieve reliable mechanical strength for following handling and process, 10 ⁇ thick parylene layer was deployed. The parylene layer was peeled off together with CNT bundles from the substrate. Since the catalyst layer blocked the bottom ends of CNTs, the catalyst layer at the bottom of CNT bundles ( Figure 6(c)) was etched by oxygen plasma from the rear side ( Figure 4(d)).
- Figure 6(d) shows the SEM picture taken from the rear side of the parylene layer for the opening of CNT bundle. Then a prebaked SU-8 layer of 200pm thickness on PET was prepared.
- PET is a kind of transparent soft film having low adhesion with SU-8. The PET film was fixed on glass slide by tapes to provide a rigid substrate for processing.
- the sticky kapton film applied along the edges of samples to tightly fix with PET film can be easily removed after the device developed in SU-8 developer.
- the PET film with the SU-8 layer is separated from the Si substrate. Then SU-8 layer could be dry released from the PET film just by slightly bending the PET film.
- the film was then spun at 2,000rpm for 30 seconds coated and pre-baked at 65°C for 10 minutes and 95°C for 30 minutes to form the first SU-8 layer (figure 5b), of thickness 100pm. This formed the grid layer. This component was then exposed under 40mJ/cm 2 UV energy and baked 65 °C for 5 minutes and 95 °C for 15 minutes, but not developed (figure 5c). If the first layer is developed to get patterns, the surface will not be smooth enough to achieve a uniform second SU-8 layer on it. A second layer was then spun and pre-baked to form the second SU-8 layer, of thickness greater than 100pm. This layer forms the SU-8 microneedle, and therefore its thickness determines length of needle (figure 5d).
- Parylene was then attached to the second layer surface, upon which the CNT bundles were present.
- the film was then re-baked to make the SU-8 reflow, and cooled to permit strong bonding between parylene and SU-8 (figure 5e), and exposed to 650 mJ/cm2 energy with a mask to form the shape of the SU-8 needle (figure 5f).
- the grid underneath the SU-8 needle and within the SU-8 channel is not developed as they are sealed by the parylene layer and sidewall of the SU-8 needle.
- the material was then post-baked at 65 °C for 10 minutes and 95 °C for 30 minutes, and the SU-8 developed, to generate the shape of the needles and the grid layer.
- the SU-8 component is then dry-released from the substrate (figure 5g).
- a layer of SU-8 was then spun on PET film, which has low adhesion to SU-8 that has not been post- baked (figure 5h).
- the SU-8 layers were then bonded together at 65°C, and cooled to permit bonding (figure 5i).
- FIG. 1 (b) shows the SEM picture taken from rear side of the SU-8 layer for the micro-channel. After UV lithography, the sample was post baked at 65 °C for 10 min and 95 °C for 30 min (figure 5k).
- the PET film together with SU-8 and parylene layer was released from glass slide by removing the tapes.
- the SU-8 layer together with the parylene layer was dry released from PET by slightly bending the PET film. This was post baked and developed to form the micro-channels on the final layer, the holes on the grid layer and the hollow SU-8 needle.
- Oxygen plasma etching was used to etch the parylene film between needles. Due to the anisotropic etching, the parylene sidewall around CNT bundles was not etched. By having this parylene sidewall, CNT bundles could still be assembled onto SU-8 needles.
- a thin PDMS film of 200 ⁇ thickness with a centre space larger than the dimension of the microneedle CNT bundle array cut off was prepared (figure 51).
- the surface of this PDMS layer was treated with nitrogen plasma to introduce amino groups on one side.
- interfacial amine-epoxide chemical reaction takes place at an elevated temperature (figure 5m) permitting attachment to the SU-8 layer.
- the sample was therefore baked at 120 °C for 30 min to achieve a permanent bonding between SU-8 and PDMS (figure 5m).
- the thickness of PDMS must be kept low enough to avoid the poor quality bonding, which is due to the non-conductivity and the low plasma efficiency of the PDMS layer.
- This flat surface is important for the following maltose tips drawing process.
- O2 plasma is performed on the opposite side of the first PDMS layer and one side of the second PDMS layer. After attaching these two surfaces together, two PDMS layers are bonded firmly together to form a fluidic chamber for a drug to flow into microneedles.
- the parylene layer was etched by oxygen plasma to open the sealed top ends (figure 5m).
- the whole parylene layer was etched away except the parylene sidewall around the CNT bundles due to the anisotropic property of RIE ( Figure 1 (d) and 1 (e)).
- the adhesion between parylene and SU-8 was good enough to hold suspended CNT bundles as mentioned above.
- the plasma generated large amount of heat.
- the temperature of SU-8 layer would rise to several hundred °C during the long period of the 10 ⁇ thick parylene etching. This high temperature would degenerate the bonding between SU-8 and PDMS.
- the whole etching process was divided into several periods to avoid over heating for samples.
- the product array was bonded with a thick PDMS layer (figure 5n).
- This process is a conventional bonding between PDMS surfaces. Both PMDS surfaces were treated with oxygen plasma and bonded together. This thick PDMS layer allows us to connect tubes for further fluidic tests.
- SU-8 microtubes fabrication starts from a layer of Polyethylene Terephthalate (PET, 3M USA) film pasted on the Si substrate by sticking the edge area with kapton tape (Fig. 2 (a)).
- PET film a kind of transparent film not sticky on both sides, is used as a sacrificial template to dry release the final device from the Si substrate because of the poor adhesion between PET film and SU-8. [The sticky kapton film just applied along the edges of samples to tightly fix with PET film can be easily removed after the device developed in SU-8 developer].
- the PET film with the SU-8 layer is separated from the Si substrate. Then SU-8 layer could be dry released from the PET film just by slightly bending the PET film.
- a 140 ⁇ thick SU-8 layer is deposited on the fixed PET film (Fig. 20(b)). To ensure a smooth SU-8 surface, this deposition is conducted in two steps of coating with 70 ⁇ layer each. In each step, SU-8 2050 is spun at 2000 rpm for 30 seconds, followed by prebaking steps at 65 °C for 10 minutes and 95 °C for 30 minutes. After the prebaking steps, this SU-8 layer is exposed under 450 mJ/cm2 ultraviolet (UV) energy to define the membrane structure on this layer (Fig. 20(c)). After exposure baking steps at 65 °C for 5 minutes and 95 °C for 15 minutes, another 350 m SU-8 layer is directly deposited on this layer in two steps without development (Fig. 20(d)).
- UV ultraviolet
- the surface will not be smooth enough to achieve a uniform second SU-8 layer on it.
- an exposure of 650 mJ/cm2 energy is performed on the second layer to get the pattern of SU-8 microtubes, which are precisely above the holes patterned on the first layer (Fig. 20(e)).
- the SU-8 device with PET film is released from the silicon substrate by the same method described before (Fig. 20(f, g)).
- the SU-8 microtubes array on the membrane is developed (Fig. 20(h)).
- the microneedle array is fabricated by an innovative double drawing lithography process.
- Fig. 21 The design of the microneedle array integrated with CNT nanofilters is shown in Fig. 21.
- An array of SU-8 microneedles was patterned above a SU-8 membrane(Fig. 21 (a)). Every SU-8 microneedle has two parts: four-beam sidewalls at the bottom and a sharp tip at the top as shown in Fig. 21 (c). The four-beam sidewalls are patterned by photo lithography. The gaps along the sidewalls are the outlets of the microneedles.
- the sharp tips above the four- beam structure (shown in Fig. 21 (a)) are assembled and patterned by double drawing lithography. Above them, a layer of gold surface electrode was deposited onto the whole surface. This surface electrode allows us to apply electric field in the test.
- FIG. 21 (d) shows the SEM image of the CNT bundle.
- PDMS layers the base part in Fig. 21 (a)
- Solution could be loaded in the chamber under the CNT bundles, pass through the CNT bundles and finally through the SU-8 microneedle into the tissue.
- the optical image of the microneedle array with gold surface electrode is shown in Fig. 21(b).
- one electrode will be bonded onto the surface electrode and another electrode will be inserted into the PDMS chamber as shown in Fig. 22.
- two electrodes would be connected by solution and an electric field is generated across the CNT nanofilters.
- Fig. 23 illustrates the fabrication process.
- the process began with thermal oxidation of single crystal silicon substrate to form a etch stop oxide layer.
- a 5 nm thickness of pattered Fe film which acted as the catalyst film for the selective growth of CNTs, was prepared onto the silicon substrate (Fig. 23(a)).
- the vertical aligned CNT bundles of 50 pm in height were grown via pyrolysis of acetylene at 800°C with an Ar/NH3 flow for 15 min.
- the CVD parylene-C was employed to fill into vertically aligned CNTs and then to reinforce the inter-tube binding at room temperature.
- the top side of CNTs was covered with parylene-C, and the discrete CNTs were bound together by parylene-C.
- This step was the most critical process for forming the mechanical supporting layer for CNT bundles.
- the thickness of the flexible parylene-C layer was determined by the CVD process. To achieve reliable mechanical strength for following handling and use, 10 pm thick parylene layer was deployed. The parylene layer was peeled off together with CNT bundles from the substrate. As shown in Fig. 23(d), the parylene film was attached onto a thin glass slide. Then a layer of 50pm SU-8 was deposited onto the parylene layer. The thickness of this SU-8 layer was the same as the height of CNT bundles.
- the SU-8 layer was exposed from the back side of glass slide.
- the catalyst layer under the CNT bundles could act as mask in this lithography step.
- the SU-8 above the CNT bundles would not be exposed.
- the parylene top of CNT bundles would not be covered by SU-8 as shown in Fig. 23(e).
- Such SU-8 layer deposited above the parylene layer could act as hard mask for plasma etching.
- the sealed parylene top of CNT bundles could be etched by oxygen plasma as shown in Fig. 23(f).
- a thin PDMS layer as shown in Fig. 23(i).
- the PDMS layer should be treated with nitrogen plasma then be attached onto the SU-8 layer and baked at 120°C for 30 minutes. Then a 30pm thick SU-8 membrane was patterned on the front layer of sample as shown in Fig. 23(j) to reinforce the structure. On this membrane layer, holes aligned with the CNT bundle array were patterned. As shown in Fig. 23(k), array of SU-8 four-beam sidewalls array was further aligned and patterned above the membrane layer. As shown in Fig.
- a thick PDMS layer with a center hole was bonded at the backside. This PDMS layer was used for tubing purpose. The centre hole was for the insertion of tube. Then SU-8 sharp tips were assembled onto the four-beam sidewalls array by double drawing lithography as shown in Fig. 23(m). Finally, a gold surface electrode was deposited onto the whole surface by evaporation as shown in Fig. 23(n). The detailed structure of a single microneedle integrated with CNT nanofilter is shown in Fig. 23(o).
- the process for drawing lithography is as shown is Fig24(a).
- a pre-baked SU-8 layer was prepared on Si substrate.
- a four beam structure is mounted above the SU-8 layer and the SU-8 layer is baked to make it melt as shown in step (I).
- the four beam structure is inserted into the melted SU-8 layer to a depth d as shown in step(ll).
- the four beam structure is drawn out of the melted SU-8 layer.
- Some Su-8 will attach onto the top of the four beam structure and a Su-8 bridge will be formed between the melted SU-8 layer and the four beam structure as shown in step(lll).
- the four beam structure is further drawn out the pillar to break the SU-8 bridge and form the sharp tip as shown in step(IV).
- the new double drawing lithography is developed to create sharp SU-8 tips on the top of four SU-8 pillars for penetration purpose. Drugs can flow through the sidewall gaps between the pillars and enter into the tissues.
- the experiment results indicate that the new device can have larger than 1 N planar buckling force and be easily penetrated into skin for drugs delivery purpose.
- the delivery rate of the microneedles can be as high as 71% when the single microneedle delivery speed is lower than 0.002mL/min.
- FIG. 27(a) An array of 3x3 SU-8 supporting structures was patterned on a 140 ⁇ thick, 6mmx6mm SU-8 membrane (Fig. 27(a)). Each SU-8 supporting structure included four SU-8 pillars and was 350 ⁇ high. The four pillars were patterned into a tube like shape on the membrane (Fig. 27(b)). The inner diameter of the tube was 150 ⁇ , while the outer diameter was 300 ⁇ . SU- 8 needles of 700 ⁇ height were created on the top of SU-8 supporting structures to ensure the ability of transdermal perforation. Considering that the total SU-8 supporting structure is only 350 ⁇ high, we choose 125 °C as baking temperature for proper SU-8 flow-in speed and easier SU-8 flow-in depth control.
- the SU-8 could flow inside the sidewall gaps between the pillars to form anchors. These anchors could enhance the microneedles' mechanical strength and overcome any planar shear force problems.
- Two PDMS layers were bonded with SU-8 membrane to form a sealed chamber for storing drugs from a connection tube. Once the microneedles penetrated into the tissue, drugs could be delivered into the body through the sidewall gaps between the pillars (Fig. 27(c)).
- Hydrogel can be used with eth device.
- An array of 5x5 SU-8 microtubes is patterned on a 140 ⁇ thick, 2.5cmx2.5cm SU-8 membrane ( Figure 11 (a)). Each SU-8 microtube is 350 ⁇ high. The inner diameter of the SU-8 microtube is 150 ⁇ , while the outer diameter is 300 ⁇ ( Figure 11 (d)). Maltose needles of around ⁇ ⁇ height are integrated on the SU-8 microtubes to ensure the ability of transdermal perforation. Two PDMS layers and the 2.5cmx2.5cm SU-8 membrane are bonded together to form a sealed chamber for retaining drugs from the connection tube during delivery process. The 2.5cmx2.5cm size of the device is designed on purpose in order to conceptualize a skin patch kind of drug delivery device.
- the critical area comprising the SU-8 microneedles at the centre is only 6mmx6mm.
- the large marginal space offers sufficient area to achieve good bonding between SU-8 layer and PDMS layer, i.e., tolerating higher pressure to drive drugs into tissues during the delivery process.
- Maltose needles are integrated on the SU-8 micro-tubes by a drawing lithography technology (figure 10). In our device, drugs are delivered through SU-8 microtubes and the maltose is just used as sharp tips for skin penetration.
- Fig. 13 (c) the temperature of the liquid maltose is gradually increased and we start drawing SU-8 microneedle composite away from the liquid maltose and air interface. Finally, when the temperature rises up to 160 °C, the drawing speed is increased. Since the maltose liquid is less viscous at higher temperature, the connection between the SU-8 microneedle composite and the surface of the liquid maltose creates individual maltose bridges which shrink gradually, and then break. The end of each shrunken maltose bridge forms a sharp tip on top of each SU-8 microneedle (Fig. 13 (d)).
- Fig. 14 shows the final drug delivery device containing SU-8 microneedles integrated with maltose tips and microfluidics, e.g. channels and the chamber formed by PDMS.
- FIG. 17a-b An alternative embodiment of a Maltose tip is shown in Figure 17a-b.
- the microneedle comprising a number of up-standing but disconnected pillars is made from our preferred polymer, SU-8.
- a maltose tip is added to the microneedle using a first lithography drawing, the microneedle and maltose tip are then heated until the maltose tip dissolves and so flows into the central cavity of the microneedle and into the side gaps between adjacent pillars.
- the microneedle is then subjected to a second lithography drawing, as above, to provide a final maltose tip on the microneedle.
- a microneedle made in this fashion has a maltose tip with improved adhesion to the remainder of the microneedle.
- FIG 17c there is shown an alternative method for manufacturing a microneedle with a maltose tip.
- a microneedle comprising a number of up-standing but disconnected pillars is made from our preferred polymer, SU-8.
- a maltose tip is added to the microneedle using a first lithography drawing, the microneedle and maltose tip are then heated until the maltose tip dissolves and so flows into the central cavity of the microneedle and into the side gaps between adjacent pillars and also over the entire outer surface of the microneedle.
- the microneedle is then subjected to a second lithography drawing, as above, to provide a final maltose tip on the microneedle.
- sufficient maltose must be deposited on the microneedle, relative to the size of the microneedle, for this method to be undertaken.
- FIG 18 there is illustrated a method for the manufacture of a microneedle made from a biodegradable material such as starch.
- the manufacture of a starch microneedle involves the deposition of starch on a substrate using conventional techniques, the use of a mask (shown as a solid image in the figure but in reality having the requisite features to enable a microneedle to be manufactured) followed by the deployment of a suitable etching process such as etching with oxygen plasma.
- Microtubes 150 ⁇ to 350 ⁇ in height require a 100 ⁇ interval spacing whereas microtubes 300pm to 1200pm in height require a 300pm interval spacing.
- Table 1 shows the observed data for the ratio of formed individual maltose tips:formed clustered tips in 48 samples.
- individual maltose tips are successfully derived from samples of microtubes with the height beyond 350pm and the spacing larger than 900pm.
- the mechanical strength of the microneedle was studied.
- the SU-8 microtubes are strong enough to withstand considerable pressure: after characterization of 20 samples, the average pressure threshold value is 7.36 ⁇ 0.48N for the microneedles (300pm apart at the microneedle base and 1000 m high). Since the minimal force required for a successful penetration is reported to be less than 1 N for a similar microneedle array, the device is reliable during the penetration process.
- test setup is shown in Figure 7.
- a short tube was inserted in the hole on the PDMS layer.
- a Ti electrode penetrated the PDMS layer and connected the solution inside the PDMS chamber. Bias could be applied via this electrode.
- Test solution of very small volume was pre-loaded in the PDMS chamber and part of the short tube. This preloading is necessary to get rid of the air in the PDMS chamber and make the solution contact the surface of CNT bundles.
- a longer tube and a syringe were connected to the short tube. The air in the long tube and syringe were compressed when the syringe was driven by a syringe pump to supply a constant air pressure on the solution in the short tube.
- NaCI solution was loaded in both the beaker and the tube.
- the solution volume in the beaker was 60 ml and in the tube was about 0.2 ml.
- a bias of 5 V was applied between the two Ti electrodes for 160 min.
- the electrode in the beaker was grounded and the electrode in the tube was positively biased. No air pressure was applied. No obvious electrolysis of water was observed.
- Two concentrations of NaCI solution, 1mol/L and 0.1 mol/L, were employed to study the relation between the ion concentration and ionic current. The experiments were carried out at room temperature ( ⁇ 26°C).
- the solution in the beaker was sampled for pH measurement at 10, 20, 40, 80 and 160 min.
- NaCI and HCI solutions were prepared using deionized (Dl) water from a water purification system (Millipore SAS 67120 MOISHEIM). DNA synthesis
- Single strand DNA was prepared by the following steps: Bordetella pertussis genomic DNA was used as a template to synthesize a PCR fragment of 805 base pair using Go Taq Green Master Mix (Promega) kit protocol. Primers used for the PCR were from Sigma Aldrich, HPLC purified vipC forward primer (5TTGAATTCGAGTTCGAGCCGGTGCTGG3') and vipC reverse primer (5'TTAAGCTTTTGCTGGTAAGGAATGCGCTG3'). Annealing temperature of 64.5°C was used and the denaturation, annealing and extension cycle was repeated 25 times. Final elongation step was carried out at 72°C for 10 min.
- ds-DNA generated was then kept at 95°C for 5 min to separate the two DNA strands to generate ss-DNA.
- PCR reaction was set up using Bio-Rad iCycler-thermal cycler PCR.
- Haemagglutinin was purchased from Zuellig Pharma.
- Other chemical reagents were purchased from Sigma Aldrich and used without a further purification.
- Patterned CNT bundles were transferred and assembled on SU-8 substrate and micro-channels were patterned under CNT bundles as shown in Figure 1(a).
- CNTs are grown vertically from silicon substrates, making it very difficult to pattern well aligned fluidic channels under patterned CNT bundles.
- patterned CNT bundles grown on silicon substrate were reinforced by parylene first. Then the parylene layer together with the CNT bundles were peeled off from a silicon substrate and transferred to the SU-8 substrate.
- SU-8 is pronounced of a negative photoresist commonly used during the fabrication of microfluidic devices.
- Well aligned channels were created under the CNT bundles on SU-8 ( Figure 1(a) and (b)).
- FIG. 2 shows the 3D illustration of the device.
- the whole device excluding PDMS bonding part has four layers.
- the top layer is CNT bundle array. Beneath the CNT bundle array is the SU-8 needle array supporting the CNT bundle array.
- the third layer is a grid layer. On this grid layer there are many holes.
- the last layer is the sealing layer, which will seal all the grid holes but just let holes under the SU-8 needles open. Then solution could pass through these four layers. SEM images of the SU-8 needles with CNT tips can be seen in Figure 3.
- the large peak value difference suggests that the main transport mechanism under electric field is electrophoresis.
- the drop of the ionic current is due to the depletion of the ions at the PDMS chamber.
- the high peak values of the ionic currents represent fast ion transport. This fast ion transport may cause depletions which cannot be compensated by the ion diffusion from other regions.
- the geometry of PDMS chamber connecting to the CNT bundles is very limited. We hypothesized that ions cannot efficiently diffuse from other places to this region where ions quickly pass through the CNT bundles. Thus the depletion of ions in the DPMS chamber causes the drop of the ionic current. We carried out an experiment to prove this.
- the 5 V bias was applied in a square wave mode with duty cycle of 1 min on and 1 min off. This square wave mode bias was applied for several cycles and the recorded ionic current is shown in Figure 8(c).
- the ionic current dropped when bias was on.
- bias was not off the solution in the PDMS chamber was replenished with ions by diffusion from other regions.
- the peak value of ionic current recovered to a certain level. But after a 1 min time duration was again depleted.
- the green line shows the drop of peak values from about 1.5*10 "5 A to about 1.4*10 "5 A for 1 mol/L NaCI concentration.
- the ratio of H + concentration was almost the same as the ratio of pressure level. This result suggests a linear relation between mass transport rate and pressure level, which is consistent with the reported results.
- ss-DNA and Haemagglutinin were employed to study CNT bundles' function as a filter.
- the inner diameter of the CNT in this study is 10 nm ( Figure 6(e)).
- the ss- DNA whose cross sectional dimension is smaller than 10nm was expected to pass through CNTs just by applying pressures.
- a combination of pressure and electric field driven methods could drive ss-DNA through CNTs.
- the test result shows that permeability decreases with the increase of dimension of molecule.
- Insulin is a peptide hormone and central for regulating carbohydrate and fat metabolism in the body. Due to the poor absorption or enzymatic degradation of insulin in the gastrointestinal tract and liver, the transdermal delivery has been so far the preferred method of insulin administration.
- the molecular radius of insulin is 1.34nm which is smaller than the inner diameter of the CNTs in the device. It could pass through the CNTs just by applying pressure. And also the insulin molecules are positively charged in solution, and so the transport rate could be tuned by applying electric field.
- the insulin solution of 1mg/ml concentration was preloaded in the drug reservoir. Air pressure levels range from 5kPa to 20kPa were applied for 30mins.
- the resultant solution samples were analyzed by FTIR as shown in Fig 25(a). The peak value indicates the concentration of insulin in sampled solutions. From the test results, the concentration of insulin is proportional to the pressure level which means the transport rate of insulin through CNTs is linear to the pressure level.
- the solution sampled in the beaker was cultured on blood agar plates for 5 days to see whether bacteria passed through the CNTs nanofilters.
- Solution with bacteria loaded in the device chamber was also cultured as control group for comparison.
- Figure 26(a) shows the result of bacterial culture of the solution sampled from the device chamber. After 5 days of culture, bacterial colonies were observed.
- Figure 26(b) shows the result of bacterial culture of the solution sampled in the beaker. No bacterial colony was found which confirms a perfect bacterium blockage.
- Dissolvable microneedles have been shown to encapsulate bioactive molecules and deliver their cargo into skin when microneedles are dissolved in body fluid. Such results showed that dissolvable microneedles offer an attractive and effective mean to administer drugs while providing safety and immunogenicity. However, so far, there are no published data reporting the use of dissolvable microneedles integrated with microfluidics. To continuously provide a large volume of drugs via the perforated skin using a dissolvable microneedle system, a novel dissolvable microneedles device comprising fluidic channels or micro-tubes connected with individual dissolvable tips is highly desired.
- Figure 15 (a) shows the insertion result of a 5*5 microneedles array into a porcine cadaver skin. After the insertion, maltose tips were rapidly dissolved once inserted in the tissue. Methylene blue was added into the maltose for inspection purpose. Ten minutes after insertion, 25 blue traces were easily found, which matched the pattern of the microneedle array.
- the optical microscope image in Figure 15 (b) shows a hole perforated in the skin after the skin surface was cleaned. During the insertion experiment, it was important to avoid the shear force influence caused by deformed skin surface on the individual maltose tip in order to get successful microneedle penetration for the whole array. We used precision stages to hold the microneedle device substrate and control the relative position of device substrate and skin sample. Dissolving of Maltose Tips and Demonstration of Injection via SU-8 Microneedles
- the device can endure high pressure.
- the functionality is optionally improved by pumping drugs through the nano-tubes either by applying pressure or applying an electric field.
- the test results prove that the nano-tubes can be deployed as a nano-filter working at high pressure.
- the nano-filters provided on or in a flexible polymer or biodegradable material enables integration with other microfluidics for chemical and pharmaceutical applications.
- the microneedles may be provided with dissolvable tips to enhance their performance, in particular their penetration function.
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Abstract
L'invention concerne une micro-aiguille pour une administration de médicament transdermique, comprenant, à sa pointe ou adjacent à celle-ci, un nanofiltre sous la forme d'un ensemble de nanotubes verticaux ; un composite comprenant une pluralité desdites micro-aiguilles ; un timbre transdermique comprenant une pluralité desdites micro-aiguilles ; un procédé de traitement comprenant lesdites micro-aiguilles ou ledit timbre transdermique, et un procédé pour la fabrication desdites micro-aiguilles.
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US20090118672A1 (en) * | 2002-10-07 | 2009-05-07 | Gonnelli Robert R | Microneedle array patch |
US20100196446A1 (en) * | 2007-07-10 | 2010-08-05 | Morteza Gharib | Drug delivery and substance transfer facilitated by nano-enhanced device having aligned carbon nanotubes protruding from device surface |
US20120089117A1 (en) * | 2009-04-23 | 2012-04-12 | National University Of Singapore | Apparatus that includes nano-sized projections and a method for manufacture thereof |
US20120220980A1 (en) * | 2011-02-28 | 2012-08-30 | Kimberly-Clark Worldwide, Inc. | Transdermal Patch Containing Microneedles |
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US20090118672A1 (en) * | 2002-10-07 | 2009-05-07 | Gonnelli Robert R | Microneedle array patch |
US20100196446A1 (en) * | 2007-07-10 | 2010-08-05 | Morteza Gharib | Drug delivery and substance transfer facilitated by nano-enhanced device having aligned carbon nanotubes protruding from device surface |
US20120089117A1 (en) * | 2009-04-23 | 2012-04-12 | National University Of Singapore | Apparatus that includes nano-sized projections and a method for manufacture thereof |
US20120220980A1 (en) * | 2011-02-28 | 2012-08-30 | Kimberly-Clark Worldwide, Inc. | Transdermal Patch Containing Microneedles |
Non-Patent Citations (1)
Title |
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STRASINGER, C L ET AL.: "Carbon nanotube membranes for use in the transdermal treatment of nicotine addiction and opioid withdrawal symptoms", SUBSTANCE ABUSE: RESEARCH AND TREATMENT, vol. 3, 2009, pages 31 - 39, Retrieved from the Internet <URL:http://www.la-press.com/redirect_file.php?fileld=1872&filename=SART.3-Stinchcomb-et-al&filéType=pdt> [retrieved on 20140505] * |
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