The present invention relates to fabricating microneedles for transdermal and intradermal drug delivery, particularly, it relates to direct machining of solid and hollow microneedles via conventional machining methods such as CNC machining, wire electro-discharge machining, profile grinding, etc.
Drug is normally administered or brought to contact with a body via topical, enteral (oral) and parenteral (injection) means. In topical administration, the applied drug is supposed to take effect locally, while in enteral and parenteral administration, the drug effect is systemic (entire body). Transdermal drug delivery is a relatively new form of drug administration targeting a systemic delivery by making drugs available on the skin painlessly. This is different than topical method which is intended to target local delivery. This is the first obstacle as the efficacy of the drug is not guaranteed even the drug can be successfully delivered to the body. Solid microneedles are normally chosen for transdermal drug delivery because potent medicinal substances can be coated on the microneedles in dry form and be delivered to the skin by inserting the solid microneedles into the skin. Intradermal drug delivery is injecting medicinal liquid into epidermal layer of skin. It normally involves vaccines as skin contains plenty of antigen-presenting cells. There are only a small number of vaccines that are delivered intradermally, they are namely BCG (against tuberculosis) and anti-rabies vaccines due to a complex procedure that requires skill. One clear advantage of delivering vaccines transdermally or intradermally is that the required volume of the vaccines is significantly less than that required by intramuscular injections.
The second obstacle in transdermal or intradermal delivery is to overcome the outermost layer of the skin, called stratum corneum, which is made up by dead cells that are pushed to the outermost of the body. Stratum corneum forms a formidable layer (20 microns on average) to isolate and protect the body. Because of this formidable layer, only a few small-molecule drugs can be administered via transdermal route. Over two decades, transdermal delivery is complemented by microneedles to overcome stratum corneum to allow faster delivery rate and larger-molecule drugs to be delivered. Since microneedles physically breach or perforate the skin to make way for the drug, the effectiveness is excellent and consistent.
After examining the first two obstacles, there is the last obstacle that is in the way of transdermal delivery, i.e. the cost of microneedles, which includes the initial capital investment and subsequent operational expenditure. Most microneedles developed in the lab lack the capability to scale up with acceptable cost efficiency. The Microneedle technology for transdermal drug delivery has been around for two decades and there is yet any commercial product on the market to date. One major hindrance for commercialization is the production cost and mass manufacturability, which the present invention seeks to address.
There are plenty of microneedles made by various methods in the literature. There are mainly two broad categories, namely direct fabrication approach and moulding approach. In the direct fabrication approach, materials are usually removed from a work piece, e.g. a metal sheet, a silicon wafer and so on to form the microneedles, whereas in the moulding approach, a mould is first constructed which is followed by forming the microneedles taking the shapes of the mould. The direct fabrication approach directly produces metallic or silicon microneedles, from metal sheet with chemical or photo-etching as seen in patent issued to Alza Corp. (U.S. Pat. No. 6,219,574), or from silicon wafer with dry or wet etching process as seen in patents issued to Nanopass Ltd (U.S. Pat. No. 6,533,949). These fabrication methods are not the conventional methods for mass production and the production costs are too high for making disposable microneedles. On the other hand, the moulding approach normally involves forming plastic materials into plastic microneedles, as seen in patents issued to Procter & Gamble (U.S. Pat. No. 6,471,903) and to 3M (U.S. Pat. No. 8,088,321). Since plastic materials are much lower in strength and hardness compared to metals such as stainless steel, moulded plastic microneedles tend to bend or break leaving tiny fractions in the skin after use. Hence, metallic microneedles are strongly preferred over plastic microneedles for this reason. Although moulding approach includes electro-forming of metallic microneedles on a mould, we think it is not a viable manufacturing approach because the electro-forming process takes very long time and involves highly toxic and carcinogenic chemicals.
Only patent '574 issued to Alza Corp. involves fabrication of metallic microneedles. It is learned from the patent that the microneedles are micro-blades that are formed in-plane on a titanium sheet or stainless steel sheet, and the micro-blades are bent 90 degrees perpendicular to the sheet to form protruding micro-blades. The forming of the in-plane micro-blades involves masking the sheet and etching the sheet which involves toxic chemicals. The subsequent bending process, which involves punch and die to push each micro-blade 90 degrees out of plane is technically challenging. The last but not least, the micro-blades sharpness and edges are determined by the thickness of the sheet, as there is no sharpening process to further sharpen the tips and cutting edges. This leaves the tips and edges to be between 50 microns to 100 microns because this is the thinnest sheets (or foils) available with considerable strength. In conclusion, these micro-blades may be hard and expensive to make and too blunt to penetrate skin.
As such, there exists a long-felt need for simple and efficient mass-producible microneedles that are sharp and strong enough for effective skin penetration and drug delivery. The present invention aims to provide a solution to this long-felt need.
The present invention relates to fabricating metallic microneedles using conventional manufacturing methods such as CNC machining, precision electro-discharge-machining, profile grinding and other widely used techniques by first providing a rough cut of the microneedle array and followed by polishing the microneedles to required sharpness and surface finish.
In the preferred embodiment, a metallic block which is substantially planar is machined into long sharp ridges of 300 microns to 700 microns height which are parallel to each other. The parallel ridges are formed through machining on one of the substantial planar surface of the metallic block. The material of the metallic block can be chosen from any bio-compatible metals, including stainless steel, titanium and any other suitable materials. Subsequently, the metallic block is rotated 90 degrees and the similar machining patterns are applied to the same substantially planar surface of the block. In this manner, an array of pyramids with height 300-700 microns are fabricated. Apparently, the height and the width of the ridges are respectively the height and the width of the pyramids. These pyramids are microneedles which is able to penetrate the skin painlessly and effectively.
For the purpose of illustrating the principles of the present invention, reference will now be drawn to the embodiments illustrated herein and specific language will be used to describe the same. It should be understood that no limitation of the scope of the present invention by these embodiments and language is intended. Any alterations and further modifications and applications of the principles of the present invention by a person skilled in the art shall fall in the scope of the present invention.
The last optional process is electro-polishing which removes burrs that build up during the finishing cut process by profile grinding. The building up of burrs may be due to the chips or debris that is cut from the microneedles is fused back on the surface due to extreme heat generated during the grinding process. The electro-polishing process generally removes (oxidizes) metal but the surface irregularities induce high electric field that accelerates the material removal. Normally electro-polishing can be controlled to remove 1-5 microns for achieving de-burring effect, and can even be used to sharpen the tips of the microneedles by deliberately extending the electro-polishing duration. A typical set of parameters for effectively de-burring the microneedles is 8 Volts for 20 seconds. The current varies with the effective area of electro-polishing.
Another optional process is drilling through holes in the microneedles to form hollow microneedles. This process is very straightforward from manufacturing point of view, except that whether to form the microneedles first then drill through holes within them or vice versa is process dependent. The persons skilled in the art should decide whether to drill the through holes first or later once he decides the method of drilling.
Filing Document | Filing Date | Country | Kind |
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PCT/SG2013/000007 | 1/7/2013 | WO | 00 |