Mucoadhesive Itraconazole Nanocrystals With Precise Control of Surface Charge Incorporated to Chitosan Films for Buccal Drug Delivery

Drug delivery to mucosal tissues presents considerable challenges related to the complex nature of the mucus layer protecting such tissues. This aggravates when delivering hydrophobic drugs, often requiring incorporation of drugs to nanoparticles and use of mucoadhesive systems. This paper aimed to develop an antifungal chitosan (CHI)-based film loading itraconazole (ITZ) nanocrystals (NCs) with precisely controlled surface charge for enhanced mucoadhesion. Cationic and anionic ITZ NCs are prepared using wet media milling with mean particle sizes and zeta potentials of 226.9 ± 1.4 nm and 234.0 ± 2.90 nm, and +15.4 ± 2.8 mV and −16.2 ± 1.3 mV, for the cationic and anionic NCs, respectively. Cationic ITZ-NCs exhibits a higher affinity to mucin particles. NCs-loaded films showed stronger mechanical properties and adhesiveness compared with ITZ powder-loaded films. Physicochemical analysis reveals that crystalline properties of the ITZ are preserved, with no drug-excipients interaction. A significantly higher amount of ITZ mucosal deposition is obtained from films containing NCs (1360.23 ± 718.73 µg cm⁻²) compared with that from films containing ITZ powder (58.83 ± 37.45 µg cm⁻²). This work demonstrates the feasibility of tailoring the NCs surface, with the resultant systems showing potential for the management of fungal infections in mucosal tissues.

Introduction

Since the early 1980s, mucoadhesive drug delivery has gained extensive attraction due to its unique physicochemical properties. This drug delivery system enables prolonging the residence time of the dosage form at the site of application or absorption.[1] The binding ability between the polymer and mucosa facilitates the intimate contact of the active pharmaceutical ingredient with the absorption surface, thus enhancing the therapeutic performance of the drug.[1] Currently, numerous mucoadhesive drug delivery systems have been developed for oral, buccal nasal and vaginal administration for both local and systemic application.

Buccal polymeric films consist of active compounds embedded in polymeric matrix that can be applied to buccal mucosa as drug releasing platform. Biocompatible and biodegradable mucoadhesive films and patches are preferred dosage forms for buccal administration because of flexibility, comfort, lightness, acceptability, capacity to withstand mechanical stress, and customized size.[2] In addition, the application of films to oral cavity could protect wound surface, thus reducing pain and treating the disease more effectively.[1] The primary challenges in buccal formulations include salivary renovation cycle and mechanical stress caused by mastication when drinking or eating.[3] This could result in the displacement of the films from the application site, reducing contact time and potentially affecting drug absorption. To circumvent this issue, it is necessary to enhance the interaction between drug and membrane barrier of buccal tissue. Therefore, buccal film formulations should be designed to improve the drug permeation across the mucosa to systemic circulation or into submucosal epithelial layers unaffected by the impact of salivary flow, pH, electrolytes, and mucosal enzymes.[4] One of the most frequently utilised polymers, chitosan (CHI), has been extensively investigated for formulating mucoadhesive buccal films due to its unique physicochemical properties. This biocompatible and biodegradable polymer is positively charged in nature, and it is capable of interacting with the negatively charged O-linked oligosaccharide chains of mucin.[5] Another important bioactivity of CHI is that it enhances the paracellular transport of active molecules, which contributes to increasing the permeability of the payload of interest across the epithelial barrier.[6-9] In addition, CHI has antimicrobial activity and the ability to promote wound healing.[5]

Itraconazole (ITZ) is a potent triazole antifungal agent for the treatment of superficial fungal infections, such as oral and vagina mucosa.[10] However, the poor solubility of ITZ makes it difficult to formulate in bioadhesive drug delivery system, which results in insufficient bioavailability and reduced therapeutic efficacy. Decreasing particle size is an efficient way to improve the dissolution rate of poorly soluble compounds.[11, 12] Recent developments in nanotechnology have promoted the incorporation of nanocrystals (NCs) in dosage forms for buccal drug delivery.[13] This aims at reducing the drug particle size to sub-micron range, enhancing dissolution rate of poorly soluble drugs through increased surface to volume ratio.[13, 14] Wet media milling is a technique using top-down mechanism to produce nanosuspensions of crystalline drug particles. Using this technique, the drug powder, dispersed in aqueous stabilizers, is ground by shear forces and collisions, resulting in particles with a mean diameter in the nanometer range (100–1000 nm).[15] Furthermore, NCs possess a high drug loading (>90%), improving drug absorption on the application site when compared to conventional lipid and polymer nanoparticles.[13, 16] Currently, one of the most noticeable strategies used to enhance the drug permeability via buccal delivery is the application of nanoparticle-based drug formulations.[13] Both particle size and surface charges of nanoparticles play crucial roles in drug permeability. Roblegg et al. revealed that an increased particle size was attributed to the generation of protein-corona and agglomeration phenomena occurring during the interaction with buccal mucus.[17] The threshold particle size which facilitated drug permeation across the mucosa was ≈200 nm.[17] Importantly, particles with positive charges exhibited a favorable drug permeation across the porcine buccal mucosa in comparison to those with negative charges, resulting in an improvement in drug penetration and entrapment efficiency.[17] In addition, the electrostatic interactions between cationic particles and mucus layer could promote the drug release by the replacement of mucin on the particle surface.[18] Moreover, it has been found that the functional groups on the surface of the nanoparticles can interact with buccal mucosa to form hydrogen bonds, thereby, enhancing the mucoadhesive properties of the formulation.[19, 20] The challenge associated with fabricating NCs-based films is to achieve both homogeneous and mechanically performant films.[21] The potential of large aggregations and inhomogeneous drug distributions could affect mechanical and mucoadhesive properties of the films. Therefore, reducing particle size to nanoscale could effectively circumvent those limitations.[22, 23] In this study, the poorly soluble drug ITZ was formulated in NCs with a positive surface charge using a wet media milling technique. The mucoadhesive polymer CHI was used as polymeric matrix to formulate oral thin films containing cationic NCs for potential treatment of C. albicans via buccal delivery.

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Materials

Poly(vinyl alcohol) (PVA) with a molecular weight of 9–10 kDa and poly(vinylpyrrolidone) (PVP) with a molecular weight of 58 kDa were purchased from Sigma Aldrich, Steinheim, Poloxamer 407 (P407) was purchased from BASF SE, Ludwigshafen, Germany. CHI with a molecular weight of 10 kDa was purchased from VWR International Ltd, Leicestershire, UK. D-ɑ-tocopheryl polyethylene glycol succinate (TPGS) was purchased from Sigma- Aldrich, Dorset, UK. Sodium dodecyl sulfate (SDS) was purchased from Sigma–Aldrich, Dorset, UK. Polydimethylsiloxane (PDMS) was purchased from Dow Corning Wiesbaden, Germany. Porcine stomach mucin was purchased from Sigma- Aldrich, Dorset, UK. Bidistilled glycerol was purchased from VWR International, Leicestershire, UK. ITZ (purity, ≥98%) was purchased from Tokyo Chemical Industry, Tokyo, Japan. Zirconia beads partially stabilized with Yttria (type YTZP) with a diameter of 0.1–0.2 mm were obtained from Chemco, Guanfu, China. All reagents used in this work were of analytical grade.

Chunyang Zhang, Lucia Lopez-Vidal, Jiawen Wang, Achmad Himawan, Ryan F. Donnelly and Alejandro J. Paredes, Mucoadhesive Itraconazole Nanocrystals With Precise Control of Surface Charge Incorporated to Chitosan Films for Buccal Drug Delivery, 2024 The Author(s), Advanced Therapeutics published by Wiley-VCH GmbH, DOI: 10.1002/adtp.202400209

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