Designing Fast-Dissolving Orodispersible Films of Amphotericin B for Oropharyngeal Candidiasis

Abstract

Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B’s high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% w/w) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal effect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 w/w) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 ± 3 s), quick release in artificial saliva (>80% in 10 min), high burst strength (2190 mN mm) and high efficacy against several Candida spp. (C. albicans, C. parapsilosis and C. krusei) (>15 mm inhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25 °C) and up to 1 year in the fridge. Although further toxicological and in vivo efficacy studies are required, this novel Amphotericin B orodispersible films is a promising, physicochemically stable formulation with potential wide application in clinical practice, especially for immunocompromised patients suffering from oropharyngeal candidiasis.

Personalised 3D Printed Medicines: Optimising Material Properties for Successful Passive Diffusion Loading of Filaments for Fused Deposition Modelling of Solid Dosage Forms

“…where k is the degradation rate (% remaining drug/day), T is the temperature in Kelvin degrees, a is the collision factor, B is the humidity factor, RH is the relative humidity, Ea is the activation energy in kcal mol −1 , and R is the gas constant (0.00198 kcal K −1 mol −1 ) [30]. In order to calculate the degradation rate, the amount degraded at different time points was fitted at each condition to the following kinetic models: zero-order, first-order, second order, Avrami and diffusion using the following equations (Equations (12)-(16)) [39]:…”

“…The Avrami kinetic model is usually applied to evaluate the growth and the formation of crystals. In this case, the 3DP structure can become heterogeneous over time and as the degradation progresses, the combined effect of physical and chemical degradation can take place simultaneously [39].…”

Poloxamer-188 and d-α-Tocopheryl Polyethylene Glycol Succinate (TPGS-1000) Mixed Micelles Integrated Orodispersible Sublingual Films to Improve Oral Bioavailability of Ebastine; In Vitro and In Vivo Characterization

“…The OSFs have large surface area and thus disintegrate quickly in the oral cavity in the presence of salvia. The released micelles from OSFs might have increased the permeability across the sublingual mucosal layers [ 66 ]. Moreover, small micelles size offers large surface area for drug absorption that could be reason for fast permeability [ 67 , 68 ].…”

Antifungal and Antiparasitic Drug Delivery

“…The originality of the new formulations proposed are usually based on the selection of already approved excipients along with the active components, such as Montanide™ Petgel A as vaccine adjuvant [1], poly(vinyl alcohol) [2], Poloxamer 407™ [3], a combination of Capryol 90™, Peceol™ and Labrasol™ [4], dextran and maltodextrin [5], a combination of modified chitosan nanoparticles with a standardized extract of cultured Lentinula edodes mycelia (AHCC™) [6], ground calcium carbonate [7], poly (d,l-lactide-co-glycolide) 50:50 [8] and Sepigel 305™ [9]. Only in one paper [10], authors have synthesized a new material based on copolymers of poly(ethyleneglycol) and poly(ε-caprolactone) conjugated with retinol as drug vehicle.…”

“…Serrano et al's work focused on the design of fast-dissolving orodispersible films of amphotericin B for oropharyngeal candidiasis [5]. Amphotericin B is a low water soluble antifungal drug.…”