Rheumatoid arthritis (RA) is the most common chronic inflammatory joints disease characterized by progressive joints and bone destruction. It is combined with severe joints pain and disability. It is an autoimune disease in which the immune system attacks body’s own tissue. The disease starts commonly in small joints (hands, feets) and progresses to bigger joints like in shoulders and knees. It is a relapsing disease where swollen, painfull and deformed joints occure. The cause for RA is unclear, whereby genetic factors seems to have impact as well as risk factors like smoking obesity and infections.
Which therapies are being applied?
Currently there is no cure for RA, but the symptoms can be managed in a way that can set the disease dormant. The therapy of RA consists mainly of medication, physical therapy and surgery. Whereby in the medical treatment various anti-inflammatory drugs are used. These are devided into small molecules and biologics (a.o. monoclonal antibodies). While small molecules are mainly applied via oral route, the biologics have to be applied via injection. The utilization of these compounds through the oral and parenteral route can be limited due to low bioavailability, the first-pass, the painful application and adverse effects.
Through The Skin
A transdermal drug delivery system (TDDS) is an appealing alternative due to it can enhance patient compliance, bypass the first-pass effect, avoide gastrointestinal harsh environment and unpleasant effects, reduce dosing frequency, and others. In consideration of biologics transdermal delivery systems can prevent the painful needle based application, prevent infections by contamination and potentially provide an easy use in absense of medical professionals. Because of the advantages mentioned, in research many therapeutic agents have been successfully tested for transdermal treatment of RA.
Challenge skin barrier – stratum corneum
But there are also challenges to the trasdermal route. The main barrier for pharmaceutical compounds is the upper layer of skin which is called the stratum corneum. This skin portion has a barrier function for prevention of harming compounds entering the body. It consists of several layes of cell with different chemical properties which is not easy to overcome. However, there are also strategies to improve those obstacles which are seen in the generational development of transdermal delivery systems.
Transdermal drug delivery systems:
• First-generation TDDS:
First-generation TDDS include compounds that meet the „Lipinski rule of five“ which defines physicochemical requirements (e.g. molecular weight) to predict the skin penetration of a pharmaceutical drug applied by patch, gel or spray. The restriction of the first-generation TDDS is the limited number of drug molecules which meet the „Lipinski rule“ and can be delivered efficiently.
• Second-generation TDDS:
For the second-generation, TDDS strategies were implemented to increase the permeation of the drug across the stratum corneum. The aim is the skin application of drug molecules that do not follow the „Lipinski rule of five“ to enable the transdermal application for more chemical compounds. Most commonly employed techniques in RA therapy include nanoparticles and/or the application of different chemical enhancers. These measures improve the permeation profile for several small molecules but they have very little impact on the permeation of biologics.
• Third-generation TDDS:
The TDDS of the third-generation directly affect the stratum corneum. Techniques which are commmonly used are elecroporation, ultrasound mediated drug delivery and microneedles. For the first two mentioned voltage pulses or ultrasound frequencies enable the permeation of the drug via skin. In opposite microneeles, which contain the drug, are inserted into stratum corneum. This is a new generation of painless application of macromolecules which are usually administered by needle-injection.
Microneedles (MAP) are the future technology for LTS. When you want to know more about it see here.
Sources: Qindeel M, Ullah MH, du-Din F, Ahmed N, Rehman A (2020). Recent trends, challenges and future outlook of transdermal drug delivery systems for rheumatoid arthritis therapy. J Control Release. 2020 327 (2020) 595-615.
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