Bilayer mucoadhesive buccal films with prolonged release of ciclopirox olamine for the treatment of oral candidiasis: In vitro development, ex vivo permeation testing, pharmacokinetic and efficacy study in rabbits.

The incidence of fungal infections has increased in recent decades not only in patients with predisposing and risk factors, but it has also spread up due to the widespread use of broad-spectrum antibiotics, immunosuppressants and corticosteroids. A limited number of drugs are currently used to treat oral candidiasis (OC). There is an emerging need to look for new antifungals, to rework or to explore the already known molecules. Ciclopirox olamine (CPX), a broad-spectrum antifungal agent, is currently used for topical dermatologic treatment. In this study, bilayer mucoadhesive buccal films (MBFs) containing poly(ethylene oxide) (PEO) and Eudragit® NM 30D (EU) with the prolonged release of ciclopirox olamine, were developed for the treatment of oral candidiasis. During ex vivo testing it was found that CPX does not pass through the porcine buccal tissue but it accumulates in it, which may be beneficial for the treatment of candidiasis in the oral cavity. In a pharmacokinetic study, the drug release from mucoadhesive films was prolonged with the maximum plasma concentration at 3.4 (1.4; 5.5) h. All rabbits with stomatitis showed progressive healing after the treatment with CPX bilayer mucoadhesive buccal films without organ pathologies.

Pharmacokinetics of Ciclopirox Olamine after Buccal Administration in Rabbits.

BACKGROUND: Prevalence of oral mucosal fungal infections increases with the frequent administration of antibiotics, corticosteroids and immunosuppressive drugs. Therapeutically used antifungals are usually associated with a variety of drug interactions. Furthermore, there has been a noticeable increase in microorganisms resistant to these preparations. Mucoadhesive buccal films represent a modern therapeutic system for the treatment of oral mucosal fungal infection paired with a high degree of patient compliance. Ciclopirox olamine applied directly onto the oral mucosa offers an attractive alternative to treatment with systemic antifungals thanks to its low incidence of resistance and side effects. OBJECTIVE: The aim of this work was to evaluate the pharmacokinetic parameters of ciclopirox olamine after the buccal application of mucoadhesive film prepared by the solvent casting method. METHOD: A chromatographic method using an internal standard was developed and validated for evaluation of ciclopirox olamine plasma concentrations. Method accuracy was 88.5-104.6% and 89.5-99.7% for interday and intraday assays, respectively. RESULTS: The pharmacokinetic properties of ciclopirox olamine were studied in New Zealand White rabbits. The mucoadhesive films containing ciclopirox olamine in a total dose of 34.4 (33.0; 35.9) mg kg-1 were applied to all the rabbits. Plasma ciclopirox olamine concentrations were determined during the 12 h following application. The time taken to reach maximum plasma concentration was 1.7 (1.1; 2.2) h after the drug administration with cmax 5.73 (4.18; 7.28) µg mL-1. Overall elimination half-life was 3.8 (1.9; 10.8) h. CONCLUSION: The experiment suggests that oral mucoadhesive film may be a valuable alternative ciclopirox olamine administration.

The influence of hyaluronan addition on thickness, weight, uniformity of mass and water content of mucoadhesive films.

Characteristics of the buccal mucoadhesive films (film thickness, film weight, uniformity of mass and moisture content) prepared by solvent casting method were tested in this experimental study. The formulations consisted either of one mucoadhesive polymer (sodium hyaluronate of two different molecular weights and sodium carboxymethylcellulose) or combinations thereof. On the basis of the aforementioned tests, it was determined that water content was influenced by the molecular weight of sodium hyaluronate as well as by the ratio of mucoadhesive polymers in the composition. The composition of the films influences also other tested parameters.Key words: buccal mucoadhesive films solvent casting method sodium hyaluronate sodium carboxymethylcellulose water content.

Molecular-Level Control of Ciclopirox Olamine Release from Poly(ethylene oxide)-Based Mucoadhesive Buccal Films: Exploration of Structure-Property Relationships with Solid-State NMR.

Mucoadhesive buccal films (MBFs) provide an innovative way to facilitate the efficient site-specific delivery of active compounds while simultaneously separating the lesions from the environment of the oral cavity. The structural diversity of these complex multicomponent and mostly multiphase systems as well as an experimental strategy for their structural characterization at molecular scale with atomic resolution were demonstrated using MBFs of ciclopirox olamine (CPX) in a poly(ethylene oxide) (PEO) matrix as a case study. A detailed description of each component of the CPX/PEO films was followed by an analysis of the relationships between each component and the physicochemical properties of the MBFs. Two distinct MBFs were identified by solid-state NMR spectroscopy: (i) at low API (active pharmaceutical ingredient) loading, a nanoheterogeneous solid solution of CPX molecularly dispersed in an amorphous PEO matrix was created; and (ii) at high API loading, a pseudoco-crystalline system containing CPX-2-aminoethanol nanocrystals incorporated into the interlamellar space of a crystalline PEO matrix was revealed. These structural differences were found to be closely related to the mechanical and physicochemical properties of the prepared MBFs. At low API loading, the polymer chains of PEO provided sufficient quantities of binding sites to stabilize the CPX that was molecularly dispersed in the highly amorphous semiflexible polymer matrix. Consequently, the resulting MBFs were soft, with low tensile strength, plasticity, and swelling index, supporting rapid drug release. At high CPX content, however, the active compounds and the polymer chains simultaneously cocrystallized, leaving the CPX to form nanocrystals grown directly inside the spherulites of PEO. Interfacial polymer-drug interactions were thus responsible not only for the considerably enhanced plasticity of the system but also for the exclusive crystallization of CPX in the thermodynamically most stable polymorphic form, Form I, which exhibited reduced dissolution kinetics. The bioavailability of CPX olamine formulated as PEO-based MBFs can thus be effectively controlled by inducing the complete dispersion and/or microsegregation and nanocrystallization of CPX olamine in the polymer matrix. Solid-state NMR spectroscopy is an efficient tool for exploring structure-property relationships in these complex pharmaceutical solids.