## 3 The Skin's Role
### Transdermal Drug Delivery (TDD)  
Transdermal drug delivery is considered an effective and innovative method for delivering substances through the skin. The process consists of the passage of a substance through the skin, passing through the tissues and into the blood circulation. The passage of therapeutic quantities of substances or drugs through the skin and into blood circulation allows obtaining speed in its effects. However, the skin is still a barrier. Most of the research work carried out focuses on the ease with which drugs or other substances can pass through the skin and in controlled concentrations. TDD has become a viable and market valued drug delivery method, allowing the administration of controlled doses and with demonstrated clinical benefits, and is probably the safest form of controlled drug delivery [10].  
The topical application of therapeutic substances facilitates the patient's adherence to the treatment because it is easy to apply and remove. It avoids the risks associated with intravenous therapies and eliminates any variables that the treatment depends on, such as gastrointestinal absorption, mobility and intestinal transit or empty stomach [11].  
Topically applied drugs have an absorption sequence: first, the drug is released by TDD, absorbed by the first skin barrier, the stratum corneum, then the epidermis and dermis to the bloodstream and transported to the site where it is expected to have a therapeutic effect [10].  
The term TDD is used for all therapeutic formulations that are administered topically and whose transmission is done through the skin until the systemic circulation. There are numerous plasters of various types and sizes on the market for the treatment and prevention of systemic diseases, mostly of a medicinal nature.  
The drugs administered topically through the skin fall into two categories of application: (i) local action, through skin application and (ii) exerting action on the stratum corneum or systemic, modulating the function of the epidermis and/or dermis [33].  
Topical application systems allow a controlled action on the drug dose in plasma, thus reducing the possibility of overdosing or low dosage. It also allows a reduction in the substance frequency administration. On the other hand, if intolerance or toxicity reactions occur, treatment is easily finished [11], which is why its effectiveness and safety must be supported by in vitro and in vivo trials.  
Despite TDD limitations regarding skin permeability, age, application spot and skin diseases, the advantages are notorious when compared with other forms of drug administration, as following [10]:  
* The skin represents a relatively large and accessible surface for absorption and prevention of overdose or unwanted effects;
* Reduces gastric adverse drug reactions (ADRs) and increases tolerance;
* First-pass metabolism of the drug is prevented (liver metabolism);
* Reduces pharmacokinetic peaks and troughs, for example, peak drug concentration in plasma;
* Suitable for drugs with a short life cycle, high lipophilicity, and narrow therapeutic index drug;
* Increased performance time;
* Easy to apply and remove in case of toxicity;
* Drug absorption is not affected by pH, enzyme activity and interactions between the drug and food;
* Reduced dose or frequency of administration and increased patient adherence;
* Improves drug stability and solubility, reducing response delay and increasing transmission rate.  
The passage through the different layers of the skin until it reaches the systemic circulation, can occur through the trans-epidermal route (transcellular and intercellular), through the sweat glands and through the hair follicles [25; 30; 34].