Transdermal drug delivery skin irritation

Drugs chosen for delivery via a transdermal drug-delivery system must adequately penetrate the skin in such a way that the system determines the delivery rate that should be fairly constant. In addition, the drug must not irritate or sensitize the skin. It is hoped that in the future more drugs will be developed for transdermal delivery. This could become an alternative route for drug delivery to children who have difficulty with oral administration. 

The cosmetics and transdermal drug delivery fields are also expected to further benefit from the formulation of microemulsions from mild sugarbased surfactants. Lehmann et al. have studied the effect of such a microemulsion on dermal and corneal irritation, and hydrocortisone incorporation [105]. A microemulsion containing commercially available sucrose esters, isopropyl myristate, and propylene glycol and water was prepared as a water continuous system, and 16.5% hydrocortisone was loaded into the anhydrous base mixture. The formulation spread well on the skin due to the low surface tension of the system at 26 mN/m. While the microemulsion provided greater drug penetration, it also resulted in irritation and barrier compromise. The authors make the point that the formulation may be better suited to drugs that do not induce an irritation themselves. 

Localized tissue irritation can be seen from the intramuscular (IM) route. This is especially an issue when the formulation pH differs from the pH of the surrounding tissue or when precipitation of poorly soluble drugs occurs. Incorrect administration of IM injections is probably the most important factor that causes local adverse effects. Local skin irritation can also be seen with transdermal delivery systems due to the alcohols, nonionic surfactants, and adhesives. 

The principal distinction between transdermal and topical drugs is that only the former is intended for systemic delivery. Both are subject to the same skin irritancy testing prior to human exposures precli-nical and clinical skin irritancy testing is reasonably stereotypical and commodity priced. 

Skin irritation and sensitization, referred to as the Achilles heel of dermal and transdermal delivery. The skin as an immunological barrier may be provoked by exposure to certain stimuli this may include drugs, excipients or components of delivery devices, resulting in erythema, oedema, etc. [22-25]... 

The chitosan and its derivatives show no acute toxicity and are not absorbed via transdermal route. The European pharmacopoeia contains a single monograph on chitosan hydrochloride. In the United States, chitosan is currently being included in the US Pharmacopoeia [Sarmento and das Neves, 2012]. The chitosan and its derivatives are deemed safe for use as permeation enhancer for transmucosal delivery of hydrophilic drugs and offer promising prospects for novel pharmaceutical applications [Junginger and Verhoef, 1998]. Despite the chitosan and its derivatives interact with lipids and proteins of the membranes of stratum corneum, they may not penetrate into deeper layers of the skin. This can be inferred from the absence of skin irritation by chitosan and its derivatives in Draize test [Aoyagi et al., 1991]. 

A major factor in the clinical acceptability of electrically enhanced transdermal delivery is its effect on the skin. The pig is a widely accepted animal model for assessing electrically assisted transdermal delivery (Mon-teiro-Riviere, 1990 Riviere and Monteiro-Riviere, 1991). Preliminaiy studies using electroporation (Riviere et al, 1995) conducted with pigs had two objectives. The first was to identify any unique skin changes associated with electroporation and to determine the effect of pulses on iontophoresis-induced irritation. The second objective was to define a pulse/iontophoresis protocol for drug delivery that was minimally irritating. 

Transdermal Slow absorption, rate may vary Transdermal delivery system (patch) is easy to use Some irritation by patch or drug Permeability of skin variable with condition, anatomic site, age, and gender... 

Dermac SR-38 is one of a series of oxazolidinones, cyclic urethane compounds, evaluated as transdermal enhancers. The compound was designed to mimic natural skin lipids (such as ceramides), to be nonirritating, and to be rapidly cleared from the systemic circulation following absorption. In animal and human safety studies, Dermac SR-38 demonstrated a good skin tolerance (no observed irritancy or sensitization at levels of 1-10 wt% moderate to severe irritation in rabbit at 100%), and a low degree of acute toxicity (LD50(rat oral) > 5.0g/kg). The compound was evaluated for its ability to enhance the human skin permeation of diverse drugs from dermal and transdermal delivery systems. Data for minoxidil indicated an enhancer concentration-dependent effect for permeation enhancement. Dermac SR-38 was also found to enhance the skin retention of both retinoic acid when applied in Retin A cream, and dihydroxyacetone when applied in a hydrophilic cream. ... 

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