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Dissolving microneedle patches loaded with amphotericin B microparticles for localised and sustained intradermal delivery: Potential for enhanced treatment of cutaneous fungal infections.
Peng, Ke; Vora, Lalitkumar K; Tekko, Ismaiel A; Permana, Andi Dian; Domínguez-Robles, Juan; Ramadon, Delly; Chambers, Philip; McCarthy, Helen O; Larrañeta, Eneko; Donnelly, Ryan F.
  • Peng K; School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom.
  • Vora LK; School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom.
  • Tekko IA; School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom; Faculty of Pharmacy, Aleppo University, Aleppo, Syria.
  • Permana AD; Department of Pharmaceutics, Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia.
  • Domínguez-Robles J; School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom.
  • Ramadon D; Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia.
  • Chambers P; School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom.
  • McCarthy HO; School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom.
  • Larrañeta E; School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom.
  • Donnelly RF; School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom. Electronic address: R.Donnelly@qub.ac.uk.
J Control Release ; 339: 361-380, 2021 11 10.
Article in English | MEDLINE | ID: covidwho-1454255
ABSTRACT
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. AmB was pulverised with poly (vinyl alcohol) and poly (vinyl 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Amphotericin B / COVID-19 Type of study: Experimental Studies / Randomized controlled trials Limits: Animals / Humans Language: English Journal: J Control Release Journal subject: Pharmacology Year: 2021 Document Type: Article Affiliation country: J.jconrel.2021.10.001

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Amphotericin B / COVID-19 Type of study: Experimental Studies / Randomized controlled trials Limits: Animals / Humans Language: English Journal: J Control Release Journal subject: Pharmacology Year: 2021 Document Type: Article Affiliation country: J.jconrel.2021.10.001