Solid Microneedles

The simplest subset of out-of-plane microneedle arrays are solid-type, and are simply sharp microstructures capable of breaking through the stratum corneum. Unlike hypodermic needles, they lack the internal bore required for direct injection of drugs, and cannot be used for bloodletting. Instead, drugs can be applied in a topical form, as either a cream or a patch, with the microneedle array creating micro-sized pores in the epidermis through which the drug can be absorbed. This process can increase the skin permeability by several orders of magnitude [33-35].

Figure 6.7 – Permeability of human skin treated with different microneedle protocols in vitro. Increases of 3 to 4 orders of magnitude were observed for microneedles (1) inserted and left in skin, (2) inserted for 10 s and then removed, and (3) inserted for 1 h and then removed. Such large increases in skin permeability have the potential to significantly increase the number and types of drugs which can be delivered across the skin. Each data point represents the average of 7 to 9 experiments. Standard deviation bars are shown. Taken from Henry et al[33].

As mentioned previously, the first example of solid microneedles can be found in Henry et al [33], the first study to demonstrate microneedles for transdermal drug delivery. The structures (seen in Figure 5 above) were designed to be pressed into the skin, either with the topical cream already applied, or inserted and removed before the cream was applied. Permeability data,

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collected in vitro using human cadaver skin as the membrane in a Franz diffuser chamber, can be seen in Figure 6.7. Similar devices were later produced, along with a number of other microneedle structures, by McAllister et al [34] of the same group at the Georgia Institute of Technology. The structures can be seen in Figure 6.8, and were fabricated from silicon, metal and polymer materials by a combination of RIE and micromachining, electrodeposition and micromoulding respectively. Similar diffusion tests were carried out as in Henry et al [33], showing a major increase in skin permeability of a range of high molecular weight molecules including insulin, calcein and bovine serum albumin (BSA).

Figure 6.8 – Solid microneedles fabricated out of silicon, polymer, and metal imaged by scanning electron microscopy. (A) Silicon microneedle 150 µm tall from a 400-needle array etched out of a silicon substrate. (B) Section of an array containing 160,000 silicon microneedles (25 µm tall). (C) Metal microneedle (120 µm tall) from a 400-needle array made by electrodepositing onto a polymeric mould. (D–F) Biodegradable polymer microneedles with bevelled tips from 100-needle arrays made by filling polymeric moulds. (D) Flat-bevel tip made of polylactic acid (400 µm tall). (E) Curved-bevel tip made of polyglycolic acid (600 µm tall). (F) Curved- bevel tip with a groove etched along the full length of the needle made of polyglycolic acid (400 µm tall). Taken from McAllister et al 2003 [34].

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Mikszta et al [35-37] produced arrays of what they termed “microenhancer arrays”, or MEAs. These structures were scraped across, rather than pressed into, the upper layers of the skin, disrupting the cellular organisation and allowing the passage of DNA vaccine into the basal epithelium and the supporting layers. Gene expression reported after topically-applied gene transfer was found to be 1,000-2,800-fold higher after MEA treatment in a mouse model, when compared to purely topical treatment. Where 12 passes of the MEAs were applied, gene expression actually outstripped that found when using intravenous and intramuscular macroscale injection [35].

Figure 6.9 – (a) Scanning electron micrograph of solid metal microneedles shown next to the tip of a 27- gauge hypodermic needle. The complete microneedle array contains 105 needles, each measuring 1000 µm in length, 50 µm by 200 µm in cross section at the base, and tapering to a sharp tip with an angle of 20°. (b) Changes in blood glucose level in diabetic, hairless rats after insulin delivery using microneedles (), subcutaneous hypodermic injection of 0.05 U (), 0.5 U (), or 1.5 U () of insulin, or passive delivery across untreated skin ( ×). Microneedles were inserted into skin for 10 min and then removed. Insulin solution was applied to the skin immediately after microneedle insertion and left on the skin for 4 h (as shown by arrow). Subcutaneous injections took a few seconds to perform. The pharmacodynamic effect of insulin delivery by microneedles was bounded by that of 0.05-0.5 U injected subcutaneously. Data are expressed as mean values (n ≥ 3) with average standard deviation associated with each data point of 14%. Blood glucose levels have been normalised relative to average pretreatment levels. From Martanto et al

[38].

Another paper, again from Georgia Tech, demonstrated laser cut metal microneedles [38]. As shown in Figure 6.9a, the structures produced were simply triangle-cut sections of the 50 µm-thick stainless steel sheet, bend upwards to create the needle array. In Figure 6.9b, the results of in vivo tests in a hairless rat model are shown. Hairless rats were given type 1 diabetes,

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using an injection of streptozotocin, which is toxic to the pancreatic cells, which normally produce insulin. A topical insulin solution was applied to skin treated with the microneedles, and the fall in glucose levels were compared with injected insulin of varying concentration. The microneedle delivery route was found to reduce the concentration of glucose in the rat’s bloodstream by around 80%, 6.5 hours after the treatment. This was around 4 times the drop seen in the control, and comparable to the effect seen in the intravenous route. However, it should be noted that the microneedles were left in place for around 10 minutes, and the topical solution was left in place for around 4 hours. Although this may sound excessive, it is possible in treatment that a patch containing the insulin could be used instead of a loose solution.