Abstract
The present study was designed to develop a thermoreversible gel of Pluronic (P407) loaded amphotericin B (AmB-gel) for the dermal and vaginal treatment of candidiasis. P407 was used as a copolymer to exploit potential advantages related to increasing drug concentration in the tissue layer in order to provide a local effect. Parameters including internal structure, swelling, porosity, and short-term stability were determined. In addition, drug release profile and ex vivo skin and vaginal permeation studies were carried out. Antifungal efficacy was evaluated against strains of Candida spp. and atomic force microscopy (AFM) supported the results. The tolerance of AmB-gel was studied by evaluating biomechanical properties of skin and determining the irritation level in scarified rabbit skin supported by histological analysis. Results confirmed the development of a thermoreversible AmB-gel with high porosity exhibiting Newtonian behavior at 4 °C and pseudoplasticity at 32 °C as well as optimal stability for at least 90 days. The Amb-gel provided a sustained drug release following a Boltzmann sigmoidal model. Non permeation was observed in skin and vaginal mucosa, showing a high retained amount of AmB of 960.0 and 737.3 µg/g/cm2, respectively. In vitro antifungal efficacy showed that AmB-gel was more effective than Free-AmB in inhibiting strains of Candida spp. and these results were corroborated by AFM. Finally, tolerance studies showed that its application did not induce skin irritation nor alter its biophysical properties. Together, these results confirmed that AmB-gel could be proposed as a promising candidate for the clinical status in the treatment of skin and vaginal candidiasis.
Highlights
Cutaneous fungal infections are a significant cause of morbidity and constitute a critical health issue on a global scale
It was able to permeate into the vaginal mucosa without reaching the systemic circulation, which was confirmed with the high amount of drug retained in the tissue and is indicative of the formulation favoring a local effect on the target area with no side effects. This high drug retention capacity in both tissues could be due to the presence of Poloxamer 407 (P407) in the formulation, since the chemical structure of this polymer allows it to act as a surfactant that enhances the diffusion ability of drug, resulting in increased drug concentrations in the tissue layer that leads to efficiently provide a local effect [18]. These results suggest that the amphotericin B (AmB) in this formulation could be successfully implemented in order to achieve a local effect on the skin or vaginal mucosa without adverse systemic effects
The focus of the present study was on the incorporation of AmB in a copolymer P407-based gel designed for application on both the skin and vaginal mucosa, for the treatment of candidiasis
Summary
Cutaneous fungal infections are a significant cause of morbidity and constitute a critical health issue on a global scale. The most identified fungal pathogenesis that affects people worldwide is based on superficial skin, vaginal and nail infections, with approximately 1.7 billion individuals affected This has led to an increase of superficial mycoses higher than 20% in recent decades, especially in patients who are immunocompromised or hospitalized [1,2] as well as in cases of topical burn wound infections [3]. Among these fungal infections, various species of Candida cause superficial complications known as candidiasis [4]. The appearance of these resistance mechanisms leads to the use of other antifungals such as amphotericin B (AmB), especially in immunosuppressed patients [10,11]
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