Cover Story

Low Risk, Patient Friendly Microneedle Arrays: An Emerging
Medical Device for Enhanced Local/Systemic, Transdermal Drug Delivery

ABSTRACT :

There exist distinct pathways for drug delivery to body to achieve maximum therapeutic effects. Transdermal drug delivery system has been recognized as one of the potential alternative to conventional injection methods because, skin is easily accessible for drug administration. The Stratum corneum acts as a major barrier in systemic or topical delivery of the drug via skin. Transdermal administration of drugs is feasible only for low molecular weight and moderately lipophilic drugs. The biomolecules-based bio-therapeutics market is expanding with the development of genetic engineering and proteomics. Delivery of biomolecules-based bio-therapeutics by achieving controlled disruption of the skin without losing protective function of the skin is the current need. Microneedles (MNs) based transdermal drug delivery system can enhance the skin permeability of hydrophilic drug substances and bio-therapeutics by temporarily rupturing the skin barrier layer physically. Various types of MNs have been designed and evolved. The present review article would focus on the application of low risk, patient friendly microneedle arrays as an emerging medical device for enhanced local /systemic, transdermal drug delivery.

INTRODUCTION :

Background

The pathway for drugs to achieve therapeutic effects comprises distinct phases of delivery in the body. Currently, most biopharmaceuticals are administered by parenteral route using hypodermic needle based injection systems. However, treatment by injection requires a visit to the hospital or clinic for the administration. In addition, hypodermic needles should be disposed of under specific protocols because reuse can be another path for disease infection. Also the injection based systems have not received patient acceptability till date. To resolve these problems, pharmaceutical companies are currently focused on the design of biopharmaceutical delivery by non-conventional routes such as transdermal drug delivery systems.1-5 Development of a transdermal drug delivery system has been of interest as one of the alternatives to conventional injection methods because skin is the most easily accessible site for drug administration, transdermal formulations are easy and convenient to use and they would likely have better patient compliance than hypodermic needles.

The role of the integumentary system which is composed of the skin is the regulation of interactions between the body and the external environment for the purpose of protecting the body. The protective function of the integumentary system composed of skin resides in the outer layer of the skin, the stratum corneum. Stratum corneum prevents entry of noxious chemicals, dangerous microorganism and dehydration of the body by controlling water loss. Thus Stratum corneum acts as a major barrier in systemic or topical delivery of the drug via skin. It is observed that transdermal administration of drugs is feasible only for low molecular weight and moderately lipophilic drugs. It is difficult to deliver high molecular weight and hydrophilic biomolecules drugs into the body without using hypodermic needles.

The barrier properties of skin

Transdermal drug delivery systems have been investigated for a long time due to the advantages described above. However, the skin is exposed to external environments and has become evolved into an efficient barrier to prevent entry of harmful chemicals and microorganisms. These barrier properties of the skin result from the histological layers: the subcutaneous tissue, the dermis layer, and the epidermis layer as shown in Figure 1.

The skin consists of two main parts; the outermost layer, epidermis, and the inner connective tissue layer, dermis, as shown in Figure 1. The dermis layer is 3-5 mm thick and the major component of skin. It is composed of mostly collagen fibrous protein providing the mechanical properties of skin. The vascular structures, such as blood or lymphatic vessels, nerve endings, and various glands, are in this layer to perform nutrient/waste exchange, create sensation, and regulate body temperature controlling, and so forth. From the standpoint of transdermal drug delivery, the vasculature elements in the dermis layer are the absorption sink causing the concentration gradient of drug diffusion from the exterior into skin and are the driving force for drug permeation.

Figure 1 Schematic illustrations of skin, stratum corneum and viable layer of skin

The epidermis layer creates the barrier function against transdermal drug delivery. It has complex multiple layers of cells in the differentiation processes with the changes of structure and the lipid content of skin. While cells in the lower layers of epidermis, the viable epidermis, contain typical organelles like mitochondria, the outermost epidermis layer, the stratum corneum, is a horny layer with approximately 10-15 μm thickness and composed of dead cells, which are the final product of the differentiation process. A typical horny cell has an amorphous structure, created by dead keratinized cells with approximately 30-40 μm of diameter encompassed by multiple lipid bilayers.

This envelope structure, in which keratinized cell and lipids are continuously overlapped with each other. Because of this ‘brick and mortar‘ structure of stratum corneum , stratum corneum is the key layer of the skin barrier for regulating the flux of molecules from the inside to the outside of the body and vice versa. Due to the stratum corneum barrier, only small molecular weight and moderately lipophilic drugs are able to diffuse through the skin at a therapeutic rate. Consequently, various transdermal methods have been designed for enhanced transdermal delivery of hydrophilic or large molecular weight drugs by modulating the barrier properties of stratum corneum or disrupting it or breaking it or removing.

Transdermal drug delivery systems

Historically, a primitive type of transdermal drug delivery patch was used in the form of a medicated plaster several hundred years ago. This prototype of a transdermal drug patch simply contained herb extracts composed of small molecules such as menthol and methyl salicylate used to soothe inflammation in muscle or to help healing of bone fractures by inducing a local analgesic effect.

While the barrier properties of skin have been a subject of scientific debate since the early 1900’s, it was shown that these properties reside in stratum corneum and drugs can or cannot permeate stratum corneum depending on their water/oil partition coefficient around 1950’s. These scientific findings triggered development of transdermal drug delivery systems for systemic therapy. In early 1970’s, the first transdermal drug delivery system for 3 days of systemic effect of scopolamine against motion sickness, Transderm-Scop® was developed by Alza and approved for the USA market in 1979. Since then, various types of transdermal drug patches have been designed for systemic effect at controlled rates.

For patch types of drug formulations, it has been suggested that transdermal administration for systemic effects might be limited to small and moderately lipophilic drugs because patches are based on the passive diffusion of drugs from the reservoir of a patch to skin. Thus, an active transdermal drug delivery system has been sought to deliver hydrophilic or large size drugs which are bio-therapeutics that cannot permeate through intact stratum corneum. These active delivery systems should bring an integrity change of stratum corneum or the physical removal and breakage of stratum corneum to increase the permeability of the skin.

To create an integrity change in stratum corneum, chemical treatment of the skin surface or the use of energy application was studied such as chemical enhancement. with various chemicals, sonophoresis with ultrasound, and Iontophoresis or electroporation with electrical energy. For the removal or breakage of stratum corneum, minimally invasive methods were designed, such as the jet injector, microneedle and skin ablation treatment.

However, the use of chemical enhancers has been limited due to skin irritation and the inability to deliver large size drugs. Sonophoresis uses ultrasonic energy to increase the permeation of drugs through skin. Iontophoresis uses an electrical gradient for the transport of charged drugs. Electroporation applies a relatively higher voltage (~100 V) pulse to skin than iontophoresis does, but the electric field lasts for a shorter time, usually 10 μs –10 ms.