Transdermal antimalarial drug delivery to improve poor adherence to antimalarials: A new light at the end of the tunnel

INTRODUCTION

Malaria is the deadliest parasitic disease, with 247 million cases and 619,000 deaths worldwide in 2021, including 274,030 children under the age of 5, yet available treatments are prone to drug resistance and lack palatability. The majority of malaria cases were recorded on the African continent.^[1] Current antimalarials medications are administered either orally, intramuscularly, or intravenously. However, the drug efficacy and patient compliance of these conventional antimalarials therapies are hindered by emerging resistance by the parasite as well as lack of palatability, especially for the oral medications, negatively impacting efforts toward prevention, control, and utmost eradication of malaria. A study showed that more than 90% of the respondents following an antimalarial therapy felt that the medications had an unpleasant taste and that taking them was an uncomfortable experience. As a result, patients are more likely to stop taking their medication,^[2] leading to poor adherence and development of drug resistance.^[3]

Herein, our study intends to harness the potential benefits of the transdermal administered antimalarial solutions in addressing issues with palatability, adherence, and antimalarial drug resistance. We aim to explore the successful preclinical trials done so far on transdermal antimalarial therapies and suggest the possible commencement of clinical trials in humans.

TRANSDERMAL ROUTE AS A SOLUTION

Transdermal drug delivery system (TDDS, patch) is a promising, alternative, and innovative route to the conventional drug delivery routes of oral ingestion and parenteral administration. Its unique advantages include noninvasiveness, prolonged duration of action, avoidance of the first pass effect, reduced dosing frequency, and improved patient compliance, the flexibility of terminating drug administration by removing the patch among others.^[13] Regardless of its few disadvantages which include the skin’s low permeability due to the barrier offered by the stratum corneum and local irritation at the site of application,^[13] notable success has been recorded with the TDDS since the commercial use of Transderm-Scop^® patch in the United States of America (US) – the first widely recognized TDDS indicated for motion sickness.^[14]

Several other drugs have been formulated into a patch to mitigate against the limitations of their traditional forms [Table 1]; the Nitro-Dur I^® (developed by Key Pharmaceuticals), Transderm-Nitro^® (by Ciba Pharmaceuticals Company), and Nitrodisc^® (Searle Laboratories) were all introduced in 1981 for the prevention and treatment of angina pectoris with an advantage of reduced dosing frequency;^[14] transdermal clonidine for the treatment of hypertension with an advantage of reduced side effects and improved patient compliance;^[14] and nicotine patches such as Habitrol^®, Nicotrol^®, Nicoderm^®, and Prostep^® developed for smoking cessation. This was popularly regarded as the first transdermal blockbuster due to its outstanding milestone where over 1 million smokers quit smoking.^[14] In all these transdermal products, the advantages necessitate their delivery as patches. The different techniques for the enhancement of transdermal drug delivery also hold promise for these advantages.

These techniques gave rise to three generations of TDDS [Figure 1].^[15]

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Figure 1:

Techniques utilized for enhancing transdermal drug delivery.

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TOXICOLOGICAL STUDIES OF THE TRANSDERMAL ROUTE

The transdermal route is considered generally safe but not devoid of possible toxicities. Volpe-Zanutto et al. showed that the S3AL formulation, out of other formulations used in the study, was found to be the most promising option for a transdermal system based on surfactants in the toxicological investigations.^[23] In this formulation, LUM and ART are combined in a liquid crystal system. At concentrations of 1.95 µg/mL of the formulation, almost 80% of human keratinocyte cells were still alive, demonstrating its low toxicity and promise as a drug candidate.^[22] In Ananda et al.’s preclinical study involving a combination of transdermal patch and solid microneedles for the transdermal delivery of Primaquine, histopathological analyses confirmed the results of in vitro hemolytic and in vivo irritation tests, which were used to assess the safety of the transdermal patch. Results show hemolysis of less than 5% and no significant damage, which highlights the safety of this approach.^[24] In addition, a skin tolerance test was conducted for the nanogel transdermal formulation of ART, and following a 5-day treatment period, no signs of skin reaction, including redness/erythema, wrinkles, papules, and/or dermatitis, were noted.^[25] The transdermal antimalarial route has shown to be safe and less toxic. However, it could have common complications faced by the general transdermal route, namely, skin irritation and hypersensitivity and drug accumulation on the skin and patch residue; thus, human clinical trials could offer further perspective on the toxicity profile of these potential transdermal antimalarials.

CONCLUSION

Transdermal delivery offers a viable alternative to oral administration of drugs. Unlike oral delivery, it does not pose adherence issues and can be self-administered. This method enables the sustained release of medications over extended periods, leading to improved patient adherence. In addition, transdermal systems are cost-effective. Numerous drugs have been successfully formulated into patches, overcoming the limitations associated with their traditional forms. However, antimalarials face various challenges when administered orally, even the most widely used antimalarial agents. To address these limitations, formulating antimalarial drugs as transdermal patches, especially while integrating the characteristics of third-generation delivery systems, presents a potential solution as suggested in successful preclinical studies. By doing so, some of the side effects associated with certain antimalarial agents can be mitigated. Transdermal patches offer several advantages, including enhanced safety, improved bioavailability, affordability, and easy accessibility for individuals. This approach has the potential to provide a safe and convenient option for delivering antimalarial medications; thus, clinical trials could be the route to seeing the light at the end of the malaria tunnel.