The role of excipients in promoting topical and transdermal delivery: Current limitations and future perspectives
Topical and transdermal delivery has historically offered an attractive and non-invasive route for administration of medicines. However, human skin is known to be a remarkably good barrier to the permeation of substances. The majority of dermatological drug products have been reported to only deliver a portion of the total dose applied, often resulting in low drug bio-availability at the site of action inside the skin. This insufficient formulation performance, coupled with the fact that percutaneous delivery is heavily influenced by the innate physicochemical properties of the active, pose limitations on effective treatment and prevention of diseases by using solely topical formulations. Generally, it is known that the rate and the extent of drug delivery to and through the skin is highly dependent on the formulation components. This work highlights the importance of the vehicle for the design of efficacious skin products, discusses current limitations in dermal delivery and explores recent advances for overcoming these challenges. Novel materials with penetration enhancing properties and innovative formulation strategies are also explored, together with future perspectives and outlooks. The emphasis here is on studies focused on passive skin transport because of clinical limitations associated with disrupting the skin barrier by physical methods. This information is believed to aid in the design and optimization of dermatological drug products for topical and transdermal delivery of actives.
1 Introduction
The therapeutic efficacy of dermatological drug products is characterized by the rate and extent that the active reaches the desired site of action. For topical formulations, this may be located in specific areas inside the viable epidermis and/or the dermis. Additionally, intra-follicular drug disposition is of special significance for the targeted treatment of conditions related to skin appendages, such as hair growth disorders or sebaceous gland-associated disorders. In contrast, for transdermal delivery systems, the active must permeate across the tissue and reach the blood circulation for systemic effects (Lane et al., 2011; Patzelt and Lademann, 2020).
Topical and transdermal drug delivery systems have been approved for clinical use for many years. The last decades have seen a considerable growth of skin formulation development, with the global dermatological drug market projected to reach approximately USD 40 billion by 2030. Yet, to date, only a limited number of drugs are considered as suitable for administration via the percutaneous route, mainly owing to the selective permeability of the skin barrier. Drugs of non-optimal physicochemical properties and potency (e.g., macro-molecules) remain excluded from conventional dermatological drug development, thereby limiting the medical applications of the field (Prausnitz et al., 2004).
Recent technological advances in drug delivery systems have shown promising results in terms of addressing the deficiencies and limitations of conventional means for dermatological drug administration. This review focuses on the utility of film-forming systems (FFS) and ionic liquid (IL) -based systems, as innovative passive permeation enhancement strategies for targeted delivery into and through the skin, and highlights the importance of appropriate excipient selection for the design of efficacious skin products. The selection of studies was based on permeation data using porcine or human skin, since results from these membranes are known to correlate with human in vivo data (Barbero and Frasch, 2009; Huong et al., 2009; Hopf et al., 2020). The use of nano-delivery systems, such as nano-emulsions, nano-fibers and nano-carriers, also included in the passive enhancement category, has been discussed elsewhere in the literature (Prow et al., 2011; Cui et al., 2020; Almeida et al., 2022; Tapfumaneyi et al., 2022) and was not be the focus of the current work. Physical enhancement involves a wide range of invasive methods to disrupt the skin barrier, including the use of microneedles or application of electrical energy. Detailed reviews on novel methods of such delivery have been produced elsewhere (Cross and Roberts, 2004; Larran˜eta et al., 2016; Benson et al., 2019).
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Excipients mentioned in the paper besides other: Eudragit RS, Eudragit E
Iliopoulos F, Sil BC and Evans CL (2022) The role of excipients in promoting topical and transdermal delivery: Current limitations and future perspectives. Front. Drug. Deliv. 2:1049848. doi: 10.3389/fddev.2022.1049848