Revolutionizing Treatment Through the Skin with Transdermal Drug Delivery Systems

Explore how Transdermal Drug Delivery Systems are paving the way for more effective, patient-friendly treatments.

Revolutionizing Treatment Through the Skin with Transdermal Drug Delivery Systems

Revolutionizing Treatment Through the Skin with Transdermal Drug Delivery Systems

The human skin, often perceived as a passive barrier to the external environment, holds potential as a route for drug administration. Transdermal drug delivery (TDD) systems offer a novel approach to drug delivery, by increasing therapeutic efficacy and increasing adherence to chronic disease management. It has gained significant attention due to its advantages over traditional routes of administration such as oral and intravenous administration. 

TDD Systems

TDD systems come in a variety of wearable designs optimized for individual drug types and release profiles. The most prevalent design is the reservoir patch, consisting of a drug reservoir sandwiched between a pressure-sensitive adhesive layer that attaches to the skin and a rate-controlling membrane. This membrane regulates the diffusion of the drug from the reservoir into the skin. Reservoir patches can be fabricated from various materials, including polymers, silicones, and hydrogels. Estrogen patches, a common form of hormone replacement therapy, often utilize a silicone reservoir and a semi-permeable membrane to deliver a constant dose of estrogen over several days. Another example are glucose responsive insulin patches that can deliver medication according to real-time monitoring of blood glucose levels. These novel wearable TDD systems are transforming disease management by providing a new and effective way to deliver medication directly through the skin.

Improved Therapeutic Efficacy

Controlled and sustained release of medication through the skin with TDD systems offers a distinct advantage over oral medication. A major challenge with oral medications is the fluctuation in drug levels within the body. This can occur because the medication is absorbed inconsistently or is significantly metabolized, or broken down, by the liver before it reaches its intended site of action. These fluctuations can lead to unwanted side effects or compromise the effectiveness of the treatment. This can lead to reduced bioavailability of the medication, necessitating higher doses to achieve therapeutic efficacy. TDD systems bypass this, allowing more drug to reach its target site. 

Chronic Disease Management and Enhanced Patient Adherence 

Studies show that up to 30% of chronic disease patients do not stick to their treatment regimen. Daily pill routines can be easily forgotten or disrupted by busy schedules. Injections, while effective, can be painful and intimidating which further reduces patient adherence. Applying a TDD system offers a simple, convenient alternative that integrates seamlessly into the daily life of patients. This is made possible by the sustained-release technology of TDD systems, where medication is released steadily over time, eliminating the need for frequent dosing.

Novel Technologies and Advancements in TDD 

Microneedles offer a novel approach for painless delivery through the skin. Unlike traditional needles that pierce deep into the skin, microneedles are small and typically less than a millimeter in length. They painlessly pierce the stratum corneum (the outermost layer of the epidermis). This creates temporary channels that allow medication to reach the viable layers of the skin. Upon insertion, the medication gradually dissolves or diffuses into the microchannels, allowing for a sustained release over a predetermined period. This optimizes therapeutic efficacy by maintaining consistent drug concentrations within the target tissue.

Recently, a phase 3 clinical trial (NCT04064411) was conducted to compare the efficacy of a microneedle TDD system compared to regular subcutaneous injection of abaloparatide. This is a synthetic analog of the parathyroid hormone used for the treatment of postmenopausal osteoporosis. Results showed that the TDD system resulted in higher bone mineral density and reduced incidence of new fractures compared to the traditional subcutaneous injection method in women with postmenopausal osteoporosis.  

Chemical Penetration Enhancers
Another strategy involves using formulations called chemical penetration enhancers. These treatments modify the structure of the stratum corneum, allowing for improved passage of drugs. These enhancers work by disrupting the tight lipid layer within the stratum corneum, altering epidermis density, and inducing the formation of transient pores, leading to improved drug permeation and bioavailability. 

Preclinical studies have utilized choline-based microemulsions to supplement the TDD of insulin in diabetic mice. The study showed that microemulsion co-administration with insulin significantly lowered blood glucose levels and increased systemic bioavailability of insulin in diabetic mice compared to conventional subcutaneous injection. Choline has high hydrophobicity allowing it to easily cross membranes, as well as high hygroscopicity allowing it to loosen the tight corneocyte structure of the skin which increases drug permeability.  While preclinical studies show encouraging results, clinical trials are crucial to evaluate the safety and efficacy of chemical penetration enhancers for human TDD.

Iontophoresis for Targeted Delivery

Iontophoresis devices utilize a low-intensity electric current to facilitate the improved passage of medication through the skin. The electric current forms aqueous pores within the lipid bilayers of the stratum corneum in a process known as electroporation. This allows selective passage of drugs according to their size and charge. This targeted approach offers several advantages. Firstly, iontophoresis allows for the delivery of ionic drugs that might otherwise struggle to penetrate through layers. Secondly, the controlled application of the electric current ensures a localized effect at the application site, minimizing systemic exposure and potential side effects. 

Iontophoresis was utilized in a preclinical porcine model which demonstrated the increased bioavailability of cetuximab – an approved inhibitor of the endothelial growth factor receptor for treatment of squamous cell carcinoma. Cetuximab is traditionally given intravenously, where patients have irritating side effects such as skin dryness and diarrhea. Iontophoresis resulted in the targeted delivery of cetuximab to the tumor site without systemic circulation of the drug. 

Sonophoresis for Enhanced Diffusion of Therapeutics 

Sonophoresis represents another innovative physical approach for enhanced TDD. This technique employs ultrasound waves, typically in the low-frequency range, applied to the target skin area. The ultrasound waves interact with the stratum corneum, increasing its permeability. Additionally, sonophoresis enhances drug penetration by promoting localized vasodilation, which can increase blood flow to the application site and potentially improve drug delivery through the perfused capillaries.

Sonophoresis has emerged as a promising strategy to enhance the transcranial delivery of therapeutic agents across the blood-brain barrier. Researchers have successfully administered edaravone – a neuroprotective antioxidant used to treat amyotrophic lateral sclerosis. Mutated mice were administered edaravone in their motor cortex by sonophoresis, resulting in a two-fold increase in drug concentration at the target tissue. Mice that received both sonophoresis and drug treatment also showed improvements in neuromuscular function and muscle atrophy demonstrating improved transfer of drug across the blood-brain barrier.


Future TDDs will leverage the unique properties of nanoparticles – microscopic particles typically ranging from 1-100 nanometers in diameter. Nanoparticles offer a versatile platform for drug delivery, where their size and surface properties can be engineered to optimize interaction with the skin. Encapsulating drugs within nanoparticles brings several advantages for TDD. Firstly, nanoparticles can serve as protective carriers, shielding the medication from degradation within the complex environment of the skin. Secondly, the size and surface characteristics of nanoparticles can be strategically designed to enhance their penetration through the skin. This controlled release profile allows for a more prolonged therapeutic effect, minimizing the need for frequent dosing and potentially improving patient compliance.

Chitosan, a natural polymer derived from chitin (a component of the hard shells of crustaceans) has recently been used to engineer novel nanoparticles. Studies have shown that coating nanoparticles with a chitosan matrix allows drugs to be gradually released in a more controlled and sustained manner. This ensures consistent therapeutic drug concentrations within the target tissue, minimizing potential fluctuations and associated side effects. An antimalarial agent called artemether has been encapsulated into chitosan sulfate nanoparticles and subsequently loaded into transdermal patches to treat acute malaria. These nanoparticles offer less toxicity, high stability, encapsulation efficiency, and increased drug permeability. 

Smart and Biodegradable Systems

Researchers are creating "smart" TDD systems that can respond to external stimuli, such as changes in temperature or pH, to control the release of medication. This is demonstrated by recent research surrounding the use of guanidinium oleate as a pH sensor for the TDD of anti-cancer medications. This allows for a more personalized and dynamic approach to treatment. Additionally, biodegradable systems such as the construction of gelatin-composite biodegradable microneedles that dissolve into the skin are being designed to deliver medication and then safely dissolve within the skin layer. This eliminates the need for removal and disposal of a separate patch and reduces waste generated by the TDD system. By eliminating the requirement for continuous self-monitoring and frequent patch changes, these TDD systems help to simplify drug management for patients. 

TDD on the Horizon 

TDD systems offer a distinct advantage over traditional methods like pills and injections, providing a novel and convenient drug delivery approach. These systems ensure improved drug bioavailability and reduce potential side effects. Additionally, TDD offers a painless, and autonomous delivery method for controlled drug release. TDD has the potential to modernize the management of various diseases, from chronic pain and diabetes to cancer immunotherapy. As research in TDD continues, we can expect to see more technologies that will improve current drug delivery methods and patient care.

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