Dissolving microneedle patches loaded with amphotericin B microparticles for localised and sustained intradermal delivery: Potential for enhanced treatment of cutaneous fungal infections
Fungal infections affect millions of people globally and are often unreceptive to conventional topical or oral preparations because of low drug bioavailability at the infection site, lack of sustained therapeutic effect, and the development of drug resistance. Amphotericin B (AmB) is one of the most potent antifungal agents. It is increasingly important since fungal co-infections associated with COVID-19 are frequently reported. AmB is only administered via injections (IV) and restricted to life-threatening infections due to its nephrotoxicity and administration-related side effects. In this work, we introduce, for the first time, dissolving microneedle patches (DMP) loaded with micronised particles of AmB to achieve localised and long-acting intradermal delivery of AmB for treatment of cutaneous fungal infections.
Highlights
- • An easy method to fabricate and load amphotericin B microparticles into
dissolving microneedle patches was introduced.- • Fewer steps and no organic solvents are required using this method.
- • The rationalised microneedles patches can deliver amphotericin B into the dermis and
form drug depots.- • Localised and sustained intradermal delivery was achieved for a week
using these patches for 24 h.- • The systemic exposure was much reduced using these patches.
AmB was pulverised with polyvinyl alcohol and polyvinyl pyrrolidone to form micronised particles-loaded gels, which were then cast into DMP moulds to form the tips. The mean particle size of AmB in AmB DMP tips after pulverisation was 1.67 ± 0.01 μm. This is an easy way to fabricate and load microparticles into DMP, as few steps are required, and no organic solvents are needed. AmB had no covalent chemical interaction with the excipients, but the crystallinity of AmB was reduced in the tips. AmB was completely released from the tips within 4 days in vitro. AmB DMP presented inhibition of Candida albicans (CA) and the killing rate of AmB DMP against CA biofilm inside porcine skin reached 100% within 24 h. AmB DMP were able to pierce excised neonatal porcine skin at an insertion depth of 301.34 ± 46.86 μm. Ex vivo dermatokinetic and drug deposition studies showed that AmB was mainly deposited in the dermis. An in vivo dermatokinetic study revealed that the area under curve (AUC0-inf) values of AmB DMP and IV (Fungizone® bolus injection 1 mg/kg) groups were 8823.0 d∙μg/g and 33.4 d∙μg/g, respectively (264-fold higher). AmB remained at high levels (219.07 ± 102.81 μg/g or more) in the skin until 7 days after the application of AmB DMP. Pharmacokinetic and biodistribution studies showed that AmB concentration in plasma, kidney, liver, and spleen in the AmB DMP group was significantly lower than that in the IV group. Accordingly, this system addressed the systemic side effects of intravenous injection of AmB and localised the drug inside the skin for a week. This work establishes a novel, easy and effective method for long-acting and localised intradermal drug delivery.
Ke Peng, Lalitkumar K. Vora, Ismaiel A. Tekko, Andi Dian Permana, Juan Domínguez-Robles, Delly Ramadon, Philip Chambers, Helen O. McCarthy, Eneko Larrañeta, Ryan F. Donnelly,
Dissolving microneedle patches loaded with amphotericin B microparticles for localised and sustained intradermal delivery: Potential for enhanced treatment of cutaneous fungal infections,
Journal of Controlled Release, Volume 339, 2021, Pages 361-380,
ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2021.10.001.