Microstructured transdermal systems for intradermal vaccine and drug delivery

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Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-12-01-2006, Volume 18, Issue 12

The needle and syringe have long been the standard delivery technology for vaccines. However, a confluence of market factors is driving new interest in alternative delivery systems that hold the potential to meet one or more of the following goals: improved antigen utilization, higher quality immune response, better stability and improved patient acceptance. Of particular interest are microneedle systems, otherwise referred to as microstuctured transdermal systems (MTS), that provide for targeted delivery of the vaccine formulation directly to antigen-presenting cells within the epidermis. This article provides a brief overview of MTS technology with an emphasis on solid-coated MTS for vaccine delivery.

The vaccine market, once relatively slow growing, has grown 10-fold over the past decade and is expected to exceed $10 billion in global sales in 2006.1 The vast majority of these sales are for injectable vaccines. A combination of technological advances, along with societal and political forces, is likely to lead to further acceleration of global vaccine sales over the next decade. Some of these factors include:

  • the impending market introduction of therapeutic vaccines

  • increasing demand for vaccinations in developing nations

  • preparations for a potential flu pandemic

  • bioterrorism readiness programmes

  • the need for systems to facilitate mass immunizations

  • a desire for more patient-friendly delivery systems.

MTS technologies

Microstructured transdermal systems (MTS) have been attracting increased interest in recent years. The idea of using microstructures to pierce the stratum corneum to enhance drug delivery has been around for many decades in the form of multiple-tine devices for tuberculin testing and vaccine delivery, and in the form of larger numbers of even smaller structures at least since Ganderton was issued a patent on such devices in 1974.2 However, for many years, this idea failed to meet its full potential because the technology to cheaply, accurately and reproducibly manufacture the microstructures was not available. In 1998, Henry disclosed methods of making the microstructures out of silicon, based on processes utilized in the semiconductor industry.3 This disclosure, along with the growth of the biopharmaceuticals market and the difficulty in delivering macromolecules by routes other than injection, has sparked renewed interest in MTS technology. The intact skin, particularly the outermost layer called the stratum corneum, provides an incredibly robust barrier to delivery of all but a small fraction of relatively low molecular weight and lipophilic drugs. It is extremely difficult to achieve delivery of larger molecules through the skin in therapeutically relevant quantities, particularly macromolecules such as proteins, without perturbing the barrier function in some way.

Figure 1 Cross-sectional view (1003) of hairless guinea pig skin after application of an MTS array with microstructures 250 mm in height.

An assortment of alternative active delivery technologies has been proposed based on the use of electric current, ultrasound, thermal ablation, pressure waves and lasers to disrupt the barrier function of the stratum corneum.4–8 MTS offer a comparatively straightforward alternative, which involves a simple mechanical disruption of the barrier (Figure 1).

MTS is particularly well suited to vaccine delivery because it provides a pain-free alternative to injection and unlike subcutaneous (SC) injections, the vaccine can be delivered in close proximity to the Langerhans cells in the epidermis. These two distinctions are responsible for a number of associated advantages (see sidebar).

Types of MTS

MTS can be configured in multiple ways depending on the drug delivery objectives. Microstructures coated with vaccine formulation are a desirable configuration for vaccine applications, but there are other approaches that cover a variety of additional applications.


Pretreatment with MTS. In this configuration, the MTS is applied to the skin, creating temporary channels in the skin. A conventional patch or topical formulation is then applied over the pretreated area. The channels left behind in the skin provide less diffusional resistance than untreated skin, particularly for large, water-soluble drugs.

Advantages of solid-coated MTS for vaccine delivery

Hollow MTS. Microstructures with holes provide a means for delivery of liquid formulations. After microstructure insertion, the liquid formulation either passively diffuses through the needle holes or can be forced through the holes at a controlled rate using a micropump. This is the MTS configuration most amenable to sustained or programmable release.

Erodible MTS. The MTS array itself is made of an erodible material containing the drug. Upon insertion in the skin, the microstructures erode, releasing the drug. The delivery kinetics can be controlled by the rate of erosion.

Solid-coated MTS. In this configuration, the drug or vaccine formulation is coated on the outside of the microstructures. When the microstructures are inserted into the skin, the coated formulation releases from the microstructures and is delivered within the skin (depending on the depth of penetration).

Solid-coated MTS is a particularly advantageous configuration for vaccine delivery. Vaccine formulations coated and dried to a solid state on the microstructures offer the potential of improved vaccine stability compared with injectable formulations. By optimizing system parameters (such as needle size and shape) the vaccine coating can be delivered in very close proximity to the antigen-presenting cells within the skin — often resulting in stimulation of an immune response at much lower doses than injectable formulations. Finally, the solid-coated MTS can be administered without pain during the application and without lingering soreness, making it a very patient-friendly vaccine delivery system. The specific components and attributes of solid-coated MTS are discussed in greater detail.

Solid-coated MTS components

Microstructures. There have been a variety of different shapes and sizes proposed for the microstructures, ranging from conical to blade-like projections. Figure 2 shows a photomicrograph of an MTS array containing pyramidal projections of approximately 250 μm. The projection shape, length and spacing, along with applicator parameters such as force, all play a role in the depth of microstructure penetration within the skin. The projection shape and size also influences the size of the antigen payload that can be carried on the outside surface of the projections. By optimizing these parameters, the delivery of the optimal vaccine payload can be targeted to the desired area within the skin. As previously discussed, the epidermis contains a large number of antigen-presenting Langerhans cells, so for vaccine delivery, it is preferable to target the microstructures to penetrate and release the antigen formulation within the epidermis.

Figure 2 Photomicrographs of MTS arrays coated with fluorescent nanobeads before (a) and after (b) application.

Because the microstructures are so small, they cause comparatively little mechanical trauma to the skin and are painless upon insertion. In one study, human volunteers were unable to discern any difference in pain between applications of a blank (no microstructures) and an MTS array containing more than 1200 microprojections of approximately 250 μm in height.9 To put the relative size of the microstructures in context, the structures shown in Figure 2 have a tip diameter approximately 60 times smaller than the outside diameter of a 31 gauge needle (one of the smallest needles used for injection).

The materials and manufacturing process used to make the microstructures can be quite varied. Numerous array materials have been described, including silicon, metals and even sugars.3,10,11 Although injection molding of microneedle arrays was disclosed at least as early as Gerstel,12 recent advances in manufacturing technology have improved the production of plastic molded arrays that can be manufactured in high volume using very robust and cost-effective injection molding processes.13 The ability to reliably manufacture the arrays at high volume and low cost is essential to the creation of MTS products for the cost conscious, multibillion dose per year vaccine market.

MTS patch. The array is typically held within a patch designed to secure the MTS array against the skin after application. Traditional medical tapes and backing films can be used to construct the patch. Patch wear times are typically short (less than 20 min) to fit within the routine of a normal clinic visit, so the requirements for adhesion, while important to the function of the MTS array, are not particularly stringent. Another important function of the patch is to protect the MTS array from damage during storage, as the microstructures, given their tiny size, can be fragile if exposed to mechanical forces.

Applicator. MTS arrays with a substantial number of microstructures are usually applied with an applicator device (Figure 3). The applicator device serves the function of presenting the array to the skin surface at the right orientation (typically normal to the skin) and with the proper energy to ensure the microstructures penetrate the skin to the desired depth. The applicator includes a means to hold the patch in place prior to and during the application process, and an energy source to provide the energy for insertion of the microstructures within the skin. The energy source can be as simple as a mechanical spring. Applicators can be designed for single or multiple use, however, it is important that the applicator device be consistent in its performance to provide the desired level of dose to dose reproducibility.

Figure 3 Example of MTS components: applicator, patch and array.

Microstructure coatings. In the case of solid-coated microstructures, the vaccine or drug formulation is coated on the exterior surface(s) of the microstructures. A variety of techniques may be used to provide the exterior coating. Preferably, a liquid or solid formulation is applied to the microstructures in a way that results in most of the formulation being located on the microstructures. Because the microstructures do not typically penetrate the skin to their full height, it is important that most of the formulation reside on the microstructures rather than the base of the array. Any coating on the base of the array is much less likely to be delivered.

The liquid vaccine formulations must possess the right concentration, viscosity and surface tension so as to wet the microstructures and provide tip coatings with consistent antigen content. Once the formulation has been coated on the microstructures, they must dry in place to form a coating that is stable for the shelf life of the MTS product. The dried coatings must also be capable of providing rapid release of the antigen once the MTS product has been applied to the skin.

MTS performance requirements

Sterility. Although the microstructures make very shallow penetrations in the skin, it is likely that most MTS products will need to be sterile. Many of the MTS components can be terminally sterilized prior to contact with the vaccine formulation. The vaccine coating and drying operation is then performed in an aseptic environment and the MTS is immediately packaged, resulting in a sterile finished product.

Release. It is desirable to achieve rapid release of the vaccine formulation from the microstructures. The time frame for release should be on the order of minutes, so as to fit within the duration of a typical clinic visit. As an example, formulations prepared with a model fluorescent antigen have been shown to release significant amounts of antigen beneath the stratum corneum in less than 5 min using an in vitro (IV) human cadaver skin model (Figure 4). A visual representation of what happens to the fluorescent coating on the microstructures is shown in Figure 2 — after application most of the fluorescence is removed.

Figure 4 Visualization of antigen release from MTS array (top view).

Stability. As with any pharmaceutical product, the stability of the vaccine formulation is one of the most important performance criteria. Most current vaccines require storage in a refrigerator or freezer. The dried vaccine formulations containing stabilizer used for MTS products should be more robust at higher temperatures than their injectable counterparts. Whether these stability improvements will be substantial enough to enable a break in the cold chain remains to be proven.

Formulation variables impacting the stability of the vaccine-coated MTS include the inherent robustness of the antigen itself, the choice of stabilizer(s) employed within the formulation, the residual water content and the mechanical properties of the dried formulation. By optimizing these variables, solid-coated MTS products can be developed with the best possible stability profile.

Immunogenicity. The bottom line for a vaccine product is its ability to induce a protective immune response. Of course, this is very much dependent on the vaccine formulation itself. Vaccine formulations for MTS are typically modified slightly from the corresponding injectable formulation to facilitate the MTS coating process. However, because MTS products are designed to deliver the vaccine formulation in very close proximity to the antigen-presenting cells within the epidermis, it is possible to achieve excellent immune response with lesser quantities of antigen than is necessary for subcutaneous injection. In many cases, MTS vaccine formulations also require no adjuvation to obtain a robust immune response. Figure 5 shows the antitetanus toxoid immunoglobulin (IgG) response following immunization of White New Zealand rabbits with various MTS formulations containing tetanus toxoid compared with an injectable control. At least one MTS formulation resulted in IgG titers similar to the injectable control after administration of less than one tenth the dose of the control.14

Figure 5 Immune response following administration of MTS formulations containing tetanus toxoid relative to an intramuscular injection.

The future

Aside from tuberculin tines, there are no modern MTS products on the market, but research in this area is accelerating and several products are in the development pipeline. Of these, the solid-coated MTS that are described in this article are the farthest along, but it is still likely to be a number of years before any of these receive regulatory approval and reach the market place. However, the numerous performance advantages of these systems and the ability to eliminate the needle from the vaccination process seem to ensure a healthy market for these systems.

Beyond vaccines, solid-coated MTS products may also be utilized for single dose or pulsatile delivery of other potent macromolecules and small molecules that are currently given by injection.

As the utility of the solid-coated MTS is further proven, additional MTS product configurations are likely to progress farther down the development pathway. For example, the hollow MTS with its potential to deliver liquid formulations of high molecular weight drugs in a manner similar to IV infusion without needle or catheter could have a wide ranging impact on the delivery of biopharmaceuticals. As the technology to reliably and efficiently produce the hollow microstructures reaches the same stage of robustness as the solid MTS, hollow MTS products are likely to emerge. MTS configurations that allow delivery of depot formulations are also a likely prospect for future development. Such systems would enable rapid, needle-less and pain-free application of the depot formulation, followed by removal of the MTS and sustained delivery from the depot formulation.


MTS have a very promising future in drug and vaccine delivery. Multiple configurations of the MTS technology are possible to solve a variety of drug delivery problems. The development of solid-coated MTS vaccine delivery is a leading application, with many advantages compared with the current injectable products. As data emerges from the development of the earliest MTS vaccine products, look for an even greater interest in MTS technology and its broader application.


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2. D. Ganderton and J. McAinsh, "Dressing", US Patent 3,814,097 (1974).

3. S. Henry et al., J. Pharm. Sci., 87(3), 922–925 (1998).

4. P.G. Green, J. Controlled Release, 41, 33–48 (1996).

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6. J.A. Eppstein, H.K. Delcher and M.S. McRae, "A Clinical Feasibility Study for the Transdermal Delivery of Parathyroid Hormone 1–34 through MicroPorsTM," Proc. Int. Symp. Control. Rel. Bioact. Mater., Controlled Release Society, 26, 409 (1999).

7. A.G. Doukas and N. Kollias, Adv. Drug Del. Rev., 56(5), 559–579 (2004).

8. J.Y. Fang et al., J. Controlled Release,100(1), 75–85 (2004).

9. D. Wirtanen, Unpublished Work (2005).

10. D.V. McAllister et al., Proceedings of the National Academy of Sciences of the United States of America, 100(24), 13755–13760 (2003).

11. Y. Tobinaga and S. Sugiyama, "Applicator for applying functional substances into human skin," US Patent Application US20050065463 A1.

12. M.S. Gerstel and V.A. Place, "Drug Delivery Device," US Patent 3,964,482 (1976).

13. J. Raeder-Devens, "Transcutaneous Vaccination Using Microstructured Transdermal Systems," SMI Controlled Release Conference (London, UK, 2005).

14. J. Wolter et al., "Antigen-Adjuvant Dose Response in a Rabbit Model Using 3M's Microstructured Transdermal System," Controlled Release Society (Miami, FL, USA, 2005).

Timothy A. Peterson is technical manager at 3M Drug Delivery Systems, St. Paul (MN, USA).