A very promising technology is under development for transdermal delivery of macromolecules such as proteins and vaccines. It involves a minimally invasive technique in which micron-size transport pathways are created in the skin. These micron-size holes are huge compared to drug dimensions but still much smaller than the holes made by hypodermic needles. These micron-size holes can be created in the skin using mechanical microneedles2425 or by using a thermal microporation process.26 The holes will be temporary because the stratum corneum will be replaced through the natural process of desquamation.
Several groups are trying to develop the mechanical microneedles for transdermal delivery, including Alza, Becton Dickinson, Georgia Tech, 3M, Norwood Abbey, and Massachusetts Institute of Technology. The microelectronics industry is making available the microfabrication tools27 needed to make these small microneedles. Microfabrication uses tools employed to make integrated circuits, such as micromachining or microelectromechanical systems (MEMSs), and consists of technologies supporting the core technology of microlithographic pattern transfer.28 It has been reported that insertion of these microneedles in humans is not painful, and no erythema, edema, or other reaction to microneedles was observed.29 These microneedles will typically enter through the stratum corneum and into the epidermis. The stratum corneum barrier has no nerves, which may partly explain the lack of any pain sensation. Nerves are present in the epidermis, but the lack of pain may be attributed to the small size of the needles, which possibly do not encounter or stimulate a nerve to produce a painful sensation.25 In vitro studies using human epidermis have shown that skin permeability may be enhanced by as much as four orders of magnitude using microneedles.29
Microneedles are typically solid. The first microneedles used were etched into a silicon wafer using lithography and reactive ion etching to form a 20-by-20 array in which each needle measured 80 ^m at the base and tapered to a height of 150 ^m with a radius of curvature at the tip of about 1 ^m. Solid metal microneedles have been reported to enable insulin delivery and lower blood glucose levels by as much as 80% in diabetic hairless rats in vivo.30 However, hollow microneedles can also be used, although they are more difficult to make and use.25
Alza Corporation has developed a Macroflux® microprojection array system that incorporates a stainless steel or titanium microprojection array. For example, it may be fabricated from a 30-^m thick foil of stainless steel with a microprojection density of 240 per square centimeter and a length of 430 ^m. In vivo studies using hairless guinea pigs reported that this microprojection patch technology, by itself or in conjunction with iontophoresis, is capable of delivering therapeutically relevant quantities of oligonucle-otides into and through the skin. Similarly, a titanium microprojection array (190 projections per square centimeter of 330 ^m each) was used in hairless guinea pigs for vaccine delivery using a thin dry film coating of ovalbumin as a model protein antigen. The projections penetrated the skin to a depth of 100 ^m with no projections deeper than 300 ^m, and no responses visually assessed for skin tolerability varied from lack of detectable erythema to mild reactions that typically resolved within 24 h.3132
The thermal microporation process involves the application of rapid and controlled pulses of thermal energy by means of tiny resistive elements to a matrix of microscopic sites on the skin surface. A short-duration (milliseconds) electric current is passed through the array. At each site, because of resistive heating, a micropore (around 100 ^m wide and 40 ^m deep) is created by flash vaporization of stratum corneum cells in an area about the width of a human hair. Using thermal microporation, reporter gene expression in mice has been reported to be increased 100-fold following application of an adenovirus vector to microporated skin when compared to intact skin.26 The micropores can stay open for several days if the area is occluded but will seal off quickly once the patch is removed. Clinical data for delivery of insulin and interferon through thermally created micropores is very encouraging, and the technique is also under investigation for vaccine delivery.33 The thermal microporation process is also used for diagnostic applications such as glucose monitoring based on sampling skin interstitial fluid as an alternative method to fingerstick blood glucose monitoring.34
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