James Sapirstein, RPh, is CEO of Alliqua Therapeutics., a subsidiary of Alliqua Inc., focusing on the developments of products for wound care dressings and a core transdermal delivery technology platform designed to deliver drugs and other beneficial ingredients through the skin. (Source: Alliqua Inc.)For thousands of years, people have placed substances on the skin for therapeutic effects, and, in the modern era, a variety of topical formulations have been developed to treat local indications. Transdermal drug delivery (TDD) represents an attractive alternative to other drug delivery methods and an increasingly promising player in the $142 billion drug delivery market. Among 15 drug delivery systems surveyed by Frost & Sullivan Inc. (Mountain View, Calif.), it was revealed that most physicians prefer topical delivery — either as a TDD patch or topical gel or cream — and expressed willingness to switch their current mode of therapy to one that is available in these forms.

Historically, many transdermal products have delivered drugs that provide treatment for hormonal deficiencies, help with smoking cessation or pain management. The first TDD system entered the U.S. market in 1979 with the approval of the scopolamine patch by the U.S. Food and Drug Administration to treat motion sickness. A decade later, nicotine patches became the first transdermal blockbuster, raising the profile of TDD in medicine and for the public in general. Today there are more than 20 different types of medical patches available, and researchers are constantly striving to develop additional and improved methods. And one of the more exciting advances in TDD is the development of hydrogel technology that enhances its efficacy.

TDD advantages and design

TDD has a variety of advantages compared with oral drug delivery. In particular, it is used when a significant first-pass effect of the liver that can prematurely metabolize drugs exists. TDD also has advantages over hypodermic injections, which are painful and generate medical waste. In contrast, TDD is non-invasive, can be self-administered, provides controlled release over long periods, lowers the frequency of adverse effects, improves patient compliance and is generally inexpensive.  

The clonidine patch for high blood pressure is one example of a TDD system that offers several of these benefits. Clonidine patches are applied once every seven days, allowing a reduced dosing frequency relative to oral administration of the drug and potentially improving compliance. Furthermore, transdermal clonidine provides steady serum drug concentrations, resulting in lower peak levels of the drug, which may reduce the frequency of adverse effects. When clonidine use is discontinued, a patient receiving transdermal rather than oral therapy is less likely to experience rebound hypertension, since serum levels of clonidine gradually decline over several days once the patch is removed.

The stratum corneum, the outermost layer of the skin, is considered to be the main penetration barrier in TDD; it is approximately 10–20 μm thick in most parts of the body and consists of multiple layers of dead corneocytes embedded in lipid bilayers. Diffusion through the stratum corneum is the rate-limiting step for the transport of drug molecules by the transdermal route.

Factors that control the rate and extent of medication absorption from a TDD system include the size and lipophilicity of the molecule, the site of application, the skin thickness, the drug concentration within the TDD system, the surface area covered by the patch and the hydration status of the skin.Drug entities of low molecular weight (≤500 Daltons) can easily diffuse through the stratum corneum. High lipophilicity and the ability to produce desired effects at small doses are among the factors that make drugs good candidates for transdermal delivery. Effectiveness at small doses is an especially important factor; only a limited amount of medication may be delivered by a TDD system, because the size of the patch limits the amount of medication it can contain.

In general, transdermal patches are composed of several layers, including an impermeable backing, a drug layer that contains the active ingredients and excipients a rate-controlling membrane that controls the rate of drug availability, a contact adhesive layer that provides adhesion to the skin, and a protective cover to be removed before the application of the patch to the skin.

Currently marketed TDD products can be generally classified as reservoir or matrix systems. In a reservoir system, the drug is contained in a reservoir enclosed between the backing and rate-controlling membrane; microreservoir systems have several small reservoirs of medication rather than one large reservoir. In a matrix system, the drug is either dispersed within the adhesive itself or dispersed within a matrix that lies between the backing and a separate adhesive layer.

Hydrogel innovations 

Further innovation to TDD patches may come from the use of hydrogels. These are gel-like or colloidal substances made from water and solids. These compounds can be created chemically — through a combination of ultraviolet cross-linking and chemical interface or by mixing polymer and water and then exposing it to an electron beam, creating a sheet of water.

 Alliqua Inc. (Langhorne, PA.) believes its hydrogel technology can be an effective delivery mechanism for certain molecules for topical drug delivery and TDD. The characteristics of a successful hydrogel-based TDD patch include painless adhesion to the human body, stability of form and composition, purity, reproducibility, compatibility with active ingredients and high water content.

In July 2013, the company announced the initiation of a preclinical proof-of-principle study of an experimental hydrogel patch containing lidocaine. Topical lidocaine is thought to reduce charges of small afferent nerve fibers by blocking voltage-gated sodium channels. It is well tolerated and minimal systemic absorption occurs at the recommended dose.

Safety and tolerability of Alliqua’s lidocaine hydrogel patch will be explored in an animal model. Further, the pharmacokinetic profile will be analyzed to determine the amount of system absorption and local lidocaine concentration in the skin immediately beneath the patch. If successful, these patches could be used for the treatment of localized acute pain, including post-operative pain and back pain as well as pain associated with sports injuries and arthritis. As such, it would offer an interesting alternative to oral opioid medications, whose unwanted side effects — including nausea, constipation and drowsiness — can be debilitating and can slow the recovery process. Alliqua expects to release the results from this study later this year.

The use of hydrogels to enhance TDD may prove useful as an innovative alternative to current drug delivery techniques and could have an increasingly widespread impact on medicine.

 About the author

 James Sapirstein, RPh, is CEO of Alliqua Therapeutics, a subsidiary of Alliqua Inc., focusing on the developments of products for wound care dressings and a core transdermal delivery technology platform designed to deliver drugs and other beneficial ingredients through the skin.