Enhancement strategies for transdermal drug delivery systems: current trends and applications

Abstract

Transdermal drug delivery systems have become an intriguing research topic in pharmaceutical technology area and one of the most frequently developed pharmaceutical products in global market. The use of these systems can overcome associated drawbacks of other delivery routes, such as oral and parenteral. The authors will review current trends, and future applications of transdermal technologies, with specific focus on providing a comprehensive understanding of transdermal drug delivery systems and enhancement strategies. This article will initially discuss each transdermal enhancement method used in the development of first-generation transdermal products. These methods include drug/vehicle interactions, vesicles and particles, stratum corneum modification, energy-driven methods and stratum corneum bypassing techniques. Through suitable design and implementation of active stratum corneum bypassing methods, notably microneedle technology, transdermal delivery systems have been shown to deliver both low and high molecular weight drugs. Microneedle technology platforms have proven themselves to be more versatile than other transdermal systems with opportunities for intradermal delivery of drugs/biotherapeutics and therapeutic drug monitoring. These have shown that microneedles have been a prospective strategy for improving transdermal delivery systems.

Keywords: Active; Enhancement methods; Microneedles; Passive; Skin; Transdermal drug delivery.

Fig. 1

Comparison of three different routes of drug administration: oral, intravenous injection and transdermal

Fig. 2

Schematic illustration of the anatomy of the skin

Fig. 3

Schematic representation of epidermis layer of human skin

Fig. 4

Schematic representation of transdermal drug delivery mechanisms

Fig. 5

A timeline illustrating the journey of marketed transdermal products from 1981 until 2013

Fig. 6

Summary of the technologies utilised for enhancing transdermal drug delivery

Fig. 7

A schematic illustration of a variety of different nanovesicles developed for use in transdermal delivery systems

Fig. 8

Classification and mechanisms of action of a variety of different chemical enhancer groups used in the facilitated delivery of drugs transdermally (SC: Stratum corneum)

Fig. 9

Schematic diagram illustrating the delivery mechanism of cationic drugs using iontophoresis. The black arrows in the skin describe the flow of cationic drug moves from drug solution to the cathode. Conversely, the white arrows show the movement of anions from buffer solution under the cathode to the anode

Fig. 10

A schematic illustration of sonophoresis-assisted transdermal drug delivery. Following the application of ultrasound, the drug molecules will be delivered into dermis

Fig. 11

Schematic diagram illustrating transdermal drug delivery using the energy-driven electroporation method. Electroporation helps the drug to permeate into the dermis layer

Fig. 12

Diagram illustrating the process of (a) skin tape-stripping and (b) microscissioning

Fig. 13

A timeline summarising fundamental findings of MNs since the first conceptualisation in 1976 until the invention of the last MN type in 2012

Fig. 14

Drug delivery approach via different type of MN: (a) solid, (b) coated, (c) hollow, (d) dissolving and (e) hydrogel-forming MNs

Fig. 15

Representative images of solid MNs which were made using (a) silicon (reproduced with permission from [228] Copyright 1998, Elsevier), (b) tungsten (reprinted with permission from [239] Copyright 2016, American Vacuum Society), (c) calcium sulfate dihydrate (reprinted with permission from [243] Copyright © 2014, Royal Society of Chemistry) and (d) polylactic acid (reprinted with permission from [244] Copyright © 2017, Royal Society of Chemistry)

Fig. 16

Coated MN with different drug coatings: (a) Desmopressin (reproduced with permission from [230] Copyright 2004, Elsevier). (b) DNA (reprinted with permission from [255] Copyright © 2010, American Chemical Society)

Fig. 17

Hollow MNs made of (a) glass (reproduced with permission from [267] Copyright 2006, Elsevier) and (b) silicon [269] (this is an open access article)

Fig. 18

Micrographs of dissolving MN fabricated from (a) poly(vinylpyrrolidone) (reproduced with permission from [281] Copyright 2008, John Wiley and Sons), (b) poly(vinylpyrrolidone) (reproduced with permission from [277] Copyright 2019, Elsevier) and c pullulan [274] (this is an open access article)

Fig. 19

Hydrogel-forming MN made of (a) poly(methyl vinyl ether-co-maleic acid) crosslinked with polyethylene glycol [291] (this is an open access article), (b) poly(vinyl alcohol) crosslinked-gelatin [289] (this is an open access article) and (c) HEMA-crosslinked EGDMA (reprinted with permission from [290] Copyright © 2016, American Chemical Society). (d) A swollen hydrogel-forming MN post in vitro permeation study [291] (this is an open access article)

Fig. 20

A schematic diagram illustrating all processes involved in photolithography

Fig. 21

Schematic illustration describing a combination of micromoulding method and laser-based fabrication prior MN manufacturing. (a) Silicone elastomer is poured into the aluminium holder with a metal block inside it. (b) The aluminium container is filled with silicone elastomer, then this is centrifuged and cured overnight. (c) The dry silicone elastomer is demoulded from the aluminium holder. (d) A laser-engineered silicone sheet is placed and adhered onto the bottom part of the cast silicone elastomer. (e) Aerial and (f) cross-sectional view of adhered laser-engineered mould

Fig. 22

Schematic representation of MN fabrication using micromoulding method which combined with laser-engineered silicone sheet. (a) An aqueous blend of polymer is poured onto the laser-engineered silicone sheet inside the green silicone elastomer mould. (b) The cast blend is then centrifuged. (c) Cross-sectional view of a silicone mould filled with aqueous polymeric blend during the drying process. (d) The dry MN is removed from the mould. (e) The sidewalls of the MN are cut off using a heated scalpel blade. (f) The MN following removal of the sidewalls