Transdermal drug delivery system (TDDS) is one of the widely studied non-invasive delivery system alternative to invasive parenteral delivery. It is also a preferred route for drugs having poor or inconsistent oral bioavailability due to extensive pre-systemic metabolism/elimination. TDDS overcomes the problems associated with painful parenteral drug delivery as well as unsuccessful oral drug delivery. It decreases adverse effects, improves efficacy and patient compliance. However, a very few number of drugs with low dose, low molecular weight and high octanol-water partition coefficients can only be successfully delivered by transdermal route, because of the anatomical structure of the barrier layer of skin. To achieve successful transdermal drug delivery, enhancement of skin permeability is of prime concern. Recently several physical, electrical, chemical and biochemical techniques have been proposed to increase the permeability of the skin. Among these, modification of permeability by chemical method is most widely used as it is economical, simple and rapid. Chemical permeation enhancers either improve the solubility or partition coefficient or increase the diffusion of drugs across the skin. However, these may be toxic and irritants to skin. Therefore, natural compounds such as essential oils, terpenes, fatty acids and alcohols has been proposed as safe and non-irritant skin permeation enhancers to improve the effectiveness of transdermal delivery systems.

Keywords: Transdermal Drug Delivery; Non-Invasive Technique; First Pass Effect

Transdermal Drug Delivery Systems: Opportunities and Challenges

Oral route of drug administration is the simplest and widely used route of drug therapy owing to ease of administration, possibility of self-administration, high degree of patient compliance [1-3]. however, it is not always feasible, as a large proportion of drugs are poorly water soluble thus requiring special technique to deliver the drug per oral [4-8]. Furthermore, many oral drugs fail to achieve sufficient plasma concentration which is clinically significant for therapeutic actions owing to gastric/intestinal degradation [9-11], poor intestinal absorption / permeability [12-14], pre-systemic gut/intestinal metabolism of drugs [15-20], counter-transport processes [21-24] or extensive hepatic first-pass elimination [25- 30]. Consequently, incomplete or poor bioavailability necessitates frequent dosing leading to various adverse effects [31]. Such drug candidates which have poor performance upon oral administration usually belong to either class II or IV as per biopharmaceutical classification systems [32,33]. The drug candidates in these classes are well known as problematic drugs and these can be delivered successfully only when formulated as parenteral dosage forms [34-36]. Parenteral dosage forms are not only a valuable means to deliver problematic drugs successfully but are also the fastest acting dosage forms therefore are lifesaving and very valuable in emergency situations [37,38]. However, unfortunately, it is also one of the least acceptable dosage forms owing to its invasiveness nature and several associated complications. Pain / abscess formation at the site of injection, cross infections, chances of thrombophlebitis, embolism, acute idiosyncratic reactions, chances of improper dosing, adverse reactions, inability of dosage withdrawal are some of the problems associated with parenteral therapy [39-53].

Currently the pharmaceutical industries are focusing on the development of transdermal drug delivery systems (TDDS) due to several advantages including its site–specificity, non- invasiveness, dosage withdrawal capacity, zero first – pass effect and constant drug levels in the blood [54-58]. All of the above features help in ease of administration, reducing adverse effects, improving efficacy and patient compliance leading to cost effective treatment [59-62]. Therefore, transdermal delivery has emerged as one of the best alternatives of invasive parenteral delivery and unsuccessful oral delivery of drugs due to associated problems such as extensive first pass metabolism, instability in gastrointestinal tract and incomplete absorption etc.. However, it is interesting to note that all drug candidates cannot be delivered successfully through transdermal route due to anatomical and physiological constraints of skin [63]. The appropriate drug features for TDDS includes low dose, low molecular weight and high octanol-water partition coefficients [64]. All of these limitations or preconditions result in relatively less number of approvals of transdermal products thus less market shares in comparison to the oral drug products [65-67]. The first generation of transdermal delivery systems included transdermal patches which were generally composed of either a simple matrix of drug reservoir in adhesive layer which rest on skin or a rate limiting semi permeable membrane separating the drug reservoir and adhesive layer. Some of the transdermal patches approved for clinical use includes drugs such as buprenorphine, clonidine, estradiol, fentanyl, nitroglycerine, scopolamine, selegeline, testosterone, lidocaine, epinephrine, menthol, diclofenac, capsaicin etc [51]. These systems were able to deliver incorporated drugs at controlled rates for prolonged durations such over days or weeks thus these were preferred over oral drugs requiring frequent dosing.

Barrier nature of skin’s stratum corneum was main challenge for transdermal delivery of variety of drug molecules. Several techniques to enhance the permeability of stratum corneum in order to deliver different drug molecules, lead to development of the second generation of transdermal delivery systems. Strategies to combat the barrier nature of skin to increase its permeability include physical / electrical, chemical and biochemical techniques. Iontophoresis (application of electrical current to enhance delivery small charged molecules via electrophoresis) and sonophoresis (application of ultrasound to the skin that causes cavitations, thermal effects, and mechanical perturbation of the stratum corneum) are some of the popular physical methods along with use of chemical permeation enhancers (application of chemicals that intercalate with the lipid bilayers thus change the fluidity of skin) to enhance the skin permeability of the drugs [55,68-78]. Both physical as well as chemical methods of enhancing permeability of stratum corneum suffers with limitations such as skin irritation, pain, and injury to deeper tissues. However latter method finds wider acceptability as it is economical, simple, rapid, and several natural non-irritating penetration enhancers such as essential oils, terpenes and peptides have been employed as safe penetration enhancers [79-81]. Transdermal delivery of macromolecules and hydrophilic molecules warranted development of third generation transdermal delivery techniques such as microneedles (hollow microneedle carriers fabricated from silicon, metal, sugar, or plastic in groups of 150-650 microneedles/ cm2 called arrays), [82-84] skin electroporation (application of high voltage pulses to cause temporary structural perturbation of lipid bilayer in the skin), [85] and thermal ablation (application of heat to the skin for very short periods of time like for micro- to milliseconds that forms painless, reversible microchannels in the stratum corneum without damaging the underlying tissue) [86].

Conclusion

Transdermal drug delivery has emerged as viable alternative to invasive parenteral drug delivery systems and drugs having extensive first pass metabolism, however, barrier nature of staratum corneum and pre-requisite physicochemical properties of drug candidates has been main challenges to commercialization of products based on transdermal drug delivery. Nevertheless ongoing extensive research into active technologies such as iontophoresis, sonophoresis, skin electroporation, thermal ablation, micro needles and combinations of natural penetration enhancers to overcome the barrier nature of skin, has great potential for growth and commercialization of transdermal delivery market.

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