Review
Microneedle technologies for (trans)dermal drug and vaccine delivery

https://doi.org/10.1016/j.jconrel.2012.01.042Get rights and content

Abstract

Microneedles have been used for the dermal and transdermal delivery of a broad range of drugs, such as small molecular weight drugs, oligonucleotides, DNA, peptides, proteins and inactivated viruses. However, until now there are no microneedle-based (trans)dermal drug delivery systems on the market. In the past decade various types of microneedles have been developed by a number of production processes. Numerous geometries of microneedles have been designed from various materials. These microneedles have been used for different approaches of microneedle-based (trans)dermal drug delivery. Following a brief introduction about dermal and transdermal drug delivery, this review describes different production methods for solid and hollow microneedles as well as conditions that influence skin penetration. Besides, the four microneedle-based (trans)dermal drug delivery approaches are discussed: “poke and flow”, “poke and patch”, “poke and release”, and “coat and poke”. A separate section of this review is devoted to the use of microneedles for the delivery of therapeutic proteins and vaccines. Finally, we give our view on research and development that is needed to render microneedle-based (trans)dermal drug delivery technologies clinically useful in the near future.

Introduction

The field of microelectronics and micromachinery is becoming more and more applicable for medical purposes, because nowadays it is possible to accurately make nano-scaled geometries by techniques developed for the computer industry. One application of these techniques is the production of microneedles for dermal and transdermal drug delivery, i.e., the delivery of drugs into and through the skin, respectively (see Table 1 for terminology). Microneedles are needle-like structures with diameters in the size order of microns and lengths up to 1 mm. These structures are used to pierce the upper layer of the skin to enable (trans)dermal drug delivery. Scientists are now able to produce microneedles made of different materials with different geometries and sizes, and with or without a bore. Microneedles have been used for (trans)dermal drug delivery and for taking biological samples via the skin. The major advantage of microneedles is their ability to pierce the skin in a non-invasive and painless way. Furthermore, microneedles can be integrated into “lab-on-a-chip” systems, whereby hollow microneedles are combined with either microsensors, micropumps, or both. Such systems can be used as health monitoring systems for diseases, such as diabetes. The ultimate goal of “lab-on-a-chip” approaches is to create minimally invasive, fully automated modules for constantly extracting and analyzing biological fluid and directly responding on the analytical results by the delivery of drugs [1], [2], [3], [4], [5]. However, until now there are no microneedle-based drug delivery systems on the market for (trans)dermal delivery.

After a short introduction about (trans)dermal drug delivery, this review describes different production methods for microneedles as well as factors that influence skin penetration, such as microneedle geometry and the use of an applicator. Then different (trans)dermal drug delivery approaches by microneedles are described for solid and hollow microneedles. Subsequently, the (trans)dermal delivery of specific drug categories, namely vaccines and therapeutic proteins, by microneedles is discussed. Finally, perspectives are given for the clinical application of microneedle-based (trans)dermal drug delivery.

Section snippets

The skin and its implications for drug delivery

The skin is the largest organ in the human body and is of great importance for the protection of the body against excessive water loss and to offer a protective barrier against unwanted influences, such as pathogens. The skin owes its protective function to its efficient physical barrier, the stratum corneum, which is 15–20 μm thick and is indispensible for a proper barrier function as it complicates foreign compounds, including drugs, to penetrate the skin [6], [7]. The viable epidermis is

Production of microneedles

Numerous types of microneedles composed of various materials have been used for the (trans)dermal delivery of a broad range of compounds in a painless manner, a selection of which is shown in Fig. 2. The first produced microneedles for drug delivery were made from silicon wafers by photolithography and deep reactive ion etching [13], [20], [21]. The used microfabrication technologies were initially developed for the production of integrated circuits and turned out to be very suitable for the

Drug delivery methods via the skin by microneedles

There are four general approaches of (trans)dermal drug delivery by microneedles, as schematically depicted in Fig. 4. The limitations, advantages and disadvantages of each of these approaches are summarized in Table 2. Furthermore, examples of the four different approaches are shown in figure 5.

Vaccine and protein delivery by microneedles

In this review we dedicate a separate section to the delivery of therapeutic proteins and antigenic proteins for vaccination by microneedles, because these types of drugs are more difficult to deliver (trans)dermally and because of stability challenges. The different methods of drug delivery by microneedles, as described above, all have their own advantages and disadvantages with respect to (trans)dermal protein delivery. This is dependent on the type of protein that needs to be delivered,

Perspectives

Microneedle technologies offer a way to deliver drugs via the skin in a non-invasive and painless manner and have been used to deliver drugs (trans)dermally by several approaches. However, “the microneedle” does not exist, and the ideal one is yet to be determined and may depend on the type of drug and the type of application.

Microneedles have been produced by different production methods from a variety of materials with a broad range of geometries and have been produced as solid and hollow

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