Only skin deep — a detailed look at transdermal drug delivery
In this article Vasiliki Nikolaou and David M. Haddleton from Medherant, The Venture Centre University of Warwick Science Park, detail transdermal drug delivery, a non-invasive option that has the potential to improve patient adherence.
Imagine a drug delivery technology that is more comfortable than an injection, with fewer side effects than pills, capsules or liquids. Imagine a technology convenient enough for patients to use at home but easy to stop at any point. Finally, imagine a system able to maintain a more consistent drug level than either a simple pill or an injectable but still be inexpensive.
These are some of the benefits of transdermal drug delivery (TDD), a non-invasive technology for delivering drugs via the skin, the largest organ of the body. TDD is not a new idea, with a scopolamine patch (for motion sickness) being first launched almost 40 years ago. Despite this pharmaceutical companies have often seen TDD as a niche delivery mechanism, effective only for a limited range of drugs with specific physicochemical characteristics and unable to deliver the required therapeutic levels across the skin.
Today this is changing, thanks to the rapid development in TDD technology and a growing consumer need for non-invasive yet effective drug delivery. With ageing populations, the massive growth in obesity and lifestyle induced ailments placing patients at risk of diseases — cancer, cardiovascular disease, diabetes, Alzheimer’s disease and so on — TDD provides an opportunity to improve outcomes by enhancing patient compliance and minimising undesirable side effects. Additionally, the ability to self-administer drugs circumvents the inconvenience of intravenous injections and avoids the risk of disease transmission by needle reuse, which could have a huge impact on healthcare in the developing world.
Over the past few years a wide range of drugs, including lidocaine, methyl salicylate, hormones, nicotine and fentanyl, have been formulated into a transdermal patch form to treat various conditions. In 2015, the global market for TDD was estimated at $30.3 billion by Research Nester1 and it is expected to reach $81.4 billion by 2024 (Grand View Research).2
Benefits of TDD
Topical drug delivery offers compelling advantages over conventional routes of administration. Apart from the obvious benefits relative to injectables of being self-administered and pain free, these systems deliver a defined dose of drug at a specific site and avoid the problem of first pass metabolism seen with some drugs following oral delivery. Drugs with low bioavailability or those that interact with the gastrointestinal mucosa can be administered via TDD to increase drug exposure, and thus efficacy, and reduce side effects, respectively.
TDD systems also eliminate multiple peaks and troughs in pharmacokinetic profiles as they provide prolonged release of the active with a single application. This can improve patient compliance by reducing the need for multiple daily dosing and potentially improve the safety and/or efficacy profile of the therapy.
Finally, the treatment can easily be terminated by simple removal of the patch from the skin surface. In terms of cost, TDD systems remain generally inexpensive when compared with conventional therapies mainly because they can be worn for extended periods of time (even for a few days).
Rapid technological improvements
The history of TDD can be traced back to China where plasters containing medicinal herbs were applied to the skin. The first TDD product was approved by the US Food and Drug Administration (FDA) in 1979 and was a patch to tackle nausea and vomiting due to motion sickness.
During the 1990s, patches that delivered nicotine to aid smoking cessation became the first TDD blockbuster products. In the following 22 years the FDA has approved 35 transdermal patches covering 13 molecules for applications as varied as birth control to treating Alzheimer’s disease.
The main drawback of TDD systems is that they are frequently unable to convey the desired active ingredient through the skin. The skin is the body’s main line of defence against the environment and consequently it is designed to stop things entering the body.
The main barrier is the stratum corneum, the outermost layer of skin, which provides protection against harmful chemicals and infectious agents entering the body whilst stopping us from dehydrating. The stratum corneum is complex and for a drug to get through and into the tissue or blood-stream it is forced to travel between multiple hydrophilic and hydrophobic domains which hinders the passage of most drug molecules.
Typically, the drugs successfully formulated into TDD patches have had a molecular weight of < 500 Daltons and are of relatively high potency because the amount of drug that can be loaded into most TTD systems is low. These limitations have severely reduced the range of drugs which can be delivered by TDD.
These two factors — the difficulty in getting drugs through the skin, and restrictions in what can be formulated into a TDD patch — led to stagnation in the development of new TDD patch products.
However, over the last 10 to 15 years, TDD technology has seen significant innovation in techniques to improve drug penetration. These range from new formulations, such as nanoparticles, to the addition of chemical permeation enhancers that increase drug solubility or disrupt the stratum corneum on the micron scale. There are also ‘active’ (physical) approaches which use a wide range of energy sources, such as ultrasound or high-voltage electrical pulses, to reduce the barrier properties of the skin and/or increase the penetration of drug molecules.
These innovative techniques aim to expand the range of molecules that can be delivered by TDD to include, for example, proteins and peptides, and to better regulate the rate of drug delivery.
Iontophoresis is an example of an ‘active’ approach; a low-level electrical current is applied to the skin to enhance the penetration of drug molecules. Transdermal iontophoresis can provide continuous drug delivery but it can also be programmed for an on-demand delivery.
Microneedles and systems, which use laser microporation, are also among the ‘active’ technologies that disrupt the barrier function of the skin. Specifically, microneedles painlessly penetrate the stratum corneum to create pores through which drugs can travel and laser systems disrupt the surface of the skin to reduce its resistance to the penetration of drugs.
Research on increasing the energy of drug molecules to improve penetration has focused on testing a variety of energy sources, such as ultrasound, heat and even magnetism. Most of these systems are at various stages of clinical development or they have already been delivered as a marketed product. Although promising, these active systems are less mature and more complex technologies than traditional transdermal patches and challenges remain to be overcome.
Novel adhesive platforms
A typical transdermal patch consists of various components including: (i) a release liner to protect the drug during storage, which is removed prior to use, (ii) the drug (iii) the adhesive matrix which binds the patch to the skin and (iv) a backing which protects the patch from the outer environment. Additional components such as membranes to control the release of the of the drug from the reservoir or permeation enhancers, which increase the delivery of the drug, can also be utilised depending on the type of the TDD system employed.
The effectiveness of the adhesive matrix is one of the most important factors that determines the success of a transdermal patch. The overall performance of the system depends on good skin adhesion under a range of conditions as if the patch becomes detached the amount of drug permeated across the skin is reduced, compromising the efficiency of the therapy. Nevertheless, some of the currently available transdermal patches utilise adhesive matrices that do not provide sufficient adhesion to all body parts or under specific circumstances (e.g., while bathing).
Other issues related to the adhesive matrix which impact the user experience are that patches can be painful to remove and/or leave a residue of adhesive on the skin. One area of innovation has therefore been to improve the adhesive formulations used in patches.
Many polymers are routinely employed as the adhesive matrix including polyacrylates, polyurethanes and silicone based polymers. Among the different adhesive formulations, hot-melt pressure sensitive adhesives (HMPSAs) are of interest due to their low irritation and good adhesion. Moreover, they are solvent-free systems and they can be formulated to contain little or no chemical functionality reducing the possibility of interactions with the active drug.
Medherant’s TEPI Patch technology uses a hot-melt silicone based pressure sensitive adhesive (PSA) as the drug reservoir. This novel polymer adhesive has widened the range of drugs that can be employed in patches and enabled the drug loading to be increased while improving patch adhesion, appearance and comfort. The polymer adhesive can contain up to 30% of a drug by weight, which allows low potency drugs to be used, and releases drug at a steady rate over 24 hours.
Currently, Medherant is developing an ibuprofen TEPI Patch for pain relief, which it plans to license to pharmaceutical companies for commercialisation; it is due to undergo clinical testing in 2018. Furthermore, the company is developing a lidocaine TEPI patch and is working in collaboration with other pharmaceutical companies to develop other novel patch formulations with proprietary drugs. The potential is enormous, the benefits huge for pharmaceutical companies and patients alike.
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