Transdermal Drug Delivery System (TDDS): Research Overview and Methods for Enhancing Skin Permeability

The skin, the largest organ in the human body, covers approximately 2m² in adults. Upon transdermal administration, drugs permeate various layers of the skin, eliciting therapeutic effects. Transdermal drug delivery systems (TDDS) ¹, which induce systemic therapeutic effects, constitute the third major drug delivery route after oral and injection administrations. Compared to the first two routes, transdermal administration has the following advantages^2-5:

1. It circumvents the first-pass effect of the liver and degradation of drugs in the gastrointestinal tract, thereby reducing inter-individual variability in drug response;

2. It maintains a constant, effective blood drug concentration, avoiding peak-trough fluctuations induced by oral administration and reducing toxic side effects;

3. It is both convenient and possesses a sustained-release effect (suitable for drugs with a short biological half-life that requires frequent oral or parenteral route administration). This can reduce the frequency of administration, and allow for flexibility for discontinuation at any time. It is particularly useful in improving patient compliance in some subgroups experiencing difficulties.

TDDS is rapidly developing and has broad market prospects. This blog will introduce the research status and related guiding principles of transdermal formulations, their limitations, as well as methods to enhance transdermal permeation.

Progress in transdermal drug delivery system (TDDS)

Creams, ointments, sprays, and gels are common forms that people apply on the skin. Some exert local effects, referred to as topical medications, and some exert systemic effects – they are often referred to as transdermal drug delivery systems or TDDS. The global transdermal drug delivery market will reach 7.358 billion US dollars by the end of 2024⁶.

The scopolamine transdermal patch (Transderm Scop), approved by the FDA in 1979, opened the chapter of modern TDDS. Since then many TDDS products have been approved (Table 1). The indications include but are not limited to, neurology, anti-inflammatory, and sedation. With the development and innovation of technology and the increase in clinical demand, transdermal - has been gaining more extensive development in Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, anti-inflammatory analgesia, etc. To provide better regulatory support for TDDS product marketing applications, both the US and the EU have issued TDDS guidelines. Table 2 lists some of the major TDDS guidelines issued by the FDA and the EMA over the years. They help gradually improve regulatory requirements of the research and production of novel and generic transdermal drug formulations, quality and safety evaluations, and product packaging.

Table 1. FDA/EMA/NMPA approved TDDS products⁷

TDDS, transdermal drug delivery system; NMPA, Chinese National Medical Products Administration; FDA, Food and Drug Administration; EMA, European Medicines Agency

Table 2. FDA and EMA guidelines for TDDS⁸

Methods of enhancing transdermal drug delivery

Skin, as a protective layer, is designed to prevent the traverse of xenobiotics. When delivering drugs, the natural barrier of the skin makes it difficult for most drugs to permeate across. The properties of the drug, such as their molecular weights and lipophilicity , also limit their use in TDDS. For example, hydrophilic large molecules are difficult to penetrate through the skin ^8,9. Chemical enhancers and/or physical permeation enhancing methods are utilized to enhance the transdermal permeation, especially for small molecule drugs.¹⁰

Can large molecules be delivered via the transdermal route?

Higher molecular weights (larger size), complex conformations, as well as their labile stability often pose some of the challenges for large molecule delivery.

With the emergence of new materials, technologies, and equipment, advancements in physical permeation methods are rapidly developed. In some ways, they effectively overcome the obstacles in the development process of large molecule TDDS. One of these methods is micro needling. This technology uses microneedles to puncture the outermost layer of the skin and epidermis, delivering drugs directly to the dermis by producing reversible microchannels. This has been used more widely for peptides, proteins, and other larger molecule drugs. especially in the fields of oligonucleotide , vaccine delivery, and skin care products. ^11-13

Two research teams from Sun Yat-sen University and Guangzhou Women and Children’s Medical Center have jointly developed a microneedle patch carrying growth hormone (GH) that can be used for the treatment of growth hormone deficiency¹³. In this study, the researchers used rats with pituitary removal as an animal model and administered recombinant growth hormone (rhGH) to the animals through a microneedle patch or subcutaneous injection (SC). The results indicate that the microneedle patch can indeed deliver rhGH well and can achieve sustained release of rhGH, reduce the frequency of injection administration, maintain the biological activity of rhGH, and represent a promising approach for the delivery of macromolecular drugs, such as peptides.

A final word on transdermal drugs

In conclusion, as a novel drug delivery mechanism, transdermal formulations have high technical barriers and potential market advantages. The selection of appropriate formulation evaluation models is crucial in the development process and can provide a powerful impetus for the research and development of transdermal formulations. The variety of animal skin assessment strategies (as referenced in the article “Evaluating In Vivo Pharmacokinetics for Transdermal Drugs: Strategies and Methods”) developed by the WuXi AppTec DMPK team can more accurately predict the effectiveness of formulation drug delivery, undoubtedly facilitating the development and optimization of transdermal drug delivery systems more quickly. In the future, with the continuous advancement of technology and the deepening of research, we have every reason to believe that transdermal formulations will play an even larger role in drug delivery, bringing better therapeutic effects to patients.

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Authors: Linlin Pei, Huan He, Chao Zhang, Zhihai Li, Shoutao Liu