Electrospun Nanofiber-Scaffold-Loaded Levocetirizine Dihydrochloride Cerosomes for Combined Management of Atopic Dermatitis and Methicillin-Resistant Staphylococcus Aureus (MRSA) Skin Infection: In Vitro and In Vivo Studies
Abstract
Objectives: In this study, we aimed to incorporate levocetirizine dihydrochloride (LVC) into electrospun nanovesicle-in-nanofiber (NF) scaffolds for combined management of atopic dermatitis and methicillin-resistant Staphylococcus Aureus skin infection, to sustain LVC release for continuous skin improvement.
Methods: Firstly, LVC was encapsulated in cerosomes (CERs) by employing a thin-film hydration approach using a 21.31 factorial design. CERs were assessed by calculating entrapment efficiency (EE%), particle size (PS) and polydispersity index (PDI). In addition, the optimized CERs were further subjected to stability evaluation. After that, the optimized CERs were incorporated into polyurethane nanofibers (NFs) using a coaxial electrospinning technique. An in vitro release assay was used to calculate the amount of LVC released from the LVC-NFs and the optimized CERs-NFs. For morphological assessment of NFs, LVC-NFs and CERs-NFs were subjected to transmission electron microscopy, scanning electron microscopy, and confocal laser scanning microscopy. Atomic force microscopy was utilized to evaluate the roughness of CERs and both NFs. The optimum formulation was further subjected to in vivo study.
Results: The optimum CERs exhibited an EE% of 65.03 ± 1.07%, a PS of 680.00 ± 39.50 nm, and a PDI of 0.51 ± 0.04. LVC was released in a sustained manner from CERs NFs. Further, a dermatokinetic study confirmed that CERs-NFs sustained the infiltration of LVC, compared with the other groups. Finally, a safety assessment showed that all formulations were safe when topically applied to rat skin.
Conclusions: In conclusion, AD and MRSA skin infections may be cured by employing electrospun nanofiber-scaffold-loaded LVC CERs, which can thus be regarded as a promising system.
Introduction
Atopic dermatitis (AD) is a pruritic, inflammatory condition that can range from mild to severe. Patients usually go through periods of remission interrupted by flares, which are acute inflammatory relapses. A family history of allergic illnesses has been shown to be a good predictor of the onset of AD, which is the most common reason for such atopic disease [1]. The prevalence of AD differs with age, sex, and region, with children demonstrating higher rates compared to adults. Globally, females are slightly more affected than males. Moreover, AD patients are frequently colonized by Staphylococcus Aureus, including methicillin-resistant Staphylococcus Aureus (MRSA), which exacerbates disease severity and poses significant treatment challenges [1]. Studies show that MRSA colonization rates in AD patients are significantly higher than in healthy populations, ranging from 4% to 18%, depending on geographical and demographic factors. Pediatric AD patients particularly exhibit elevated MRSA colonization rates, predisposing them to invasive infections and systemic complications [2]. Moreover, MRSA produces virulence elements that increase skin barrier dysfunction, which is one way that MRSA contributes to AD [2]. It has previously been established that a lack of typical ceramides in the stratum corneum (SC) is a key etiologic reason for the dry, barrier-damaged skin seen in AD patients [3].
Further, it has been shown that sphingoid, a fundamental constituent of ceramides, may have a defensive effect against Gram-positive bacteria like Staphylococcus Aureus, preventing them from colonizing and infecting the skin [4]. Ceramides are the least polar and most hydrophobic lipids in the SC, giving it its barrier qualities [5]. Cerosomes (CERs) are ceramide-containing nanovesicles that have previously been reported as a successful drug-delivery nanosystem for the curing of psoriasis, topical fungal infections, alopecia, MRSA skin infection, and hirsutism [6,7,8,9,10,11].
Levocetirizine dihydrochloride (LVC) is an antihistaminic medication that is commonly used to manage allergic rhinitis, hay fever, and idiopathic urticaria. It has a higher attraction for H1 receptors than its enantiomer cetirizine. In vitro studies of LVC reveal that it modifies the inflammatory mediators produced by eosinophils [12]. In a previous study, LVC was fabricated into vesicles for its action against AD, to decrease LVC side effects such as dry mouth, drowsiness, and tiredness [12]. The topical route also provides an effective strategy to overcome LVC’s intolerably bitter taste [13]. It is worth noting that therapy for AD disease necessitates the production of a topical drug delivery system that maintains skin improvement over time [14]. Further, recent publications by the authors have highlighted the activity of LVC against MRSA skin infection when used topically [15].
Electrospun nanofibers (NFs) are gaining popularity due to their unique features. Natural and synthetic polymers, as well as their combinations, can be used to make NFs. NFs exhibit a high surface area, which allows hydrophilic or lipophilic drugs to be delivered efficiently. Various characteristics such as polymer concentration, polymer type, morphology, fiber diameter, surface roughness, and porosity can be changed to alter drug release profiles. The selection of polymer(s) is a critical factor in achieving the required drug release qualities [16]. Several researchers have successfully demonstrated the desired sustained effect of NFs for the treatment of topical candidiasis using sertaconazole, application of the wound-healing property of phenytoin, and the effective eradication of Staphylococcus Aureus by moxifloxacin hydrochloride [17,18,19].
Polyurethane (PU) has been widely employed in the manufacture of NF scaffolds. PU’s extremely variable chemistry enables the creation of materials with precisely regulated mechanical, physicochemical, and biodegradation qualities, which can be achieved by electing the right monomers and using hard and soft components. For instance, adding urea linkages or aromatic groups to chain extenders increases hard-segment contacts by forming bidentate hydrogen bonds between adjacent chains or stacking p-bonds between adjacent aromatic rings. The mutual aspect of all interaction within the hard segment domains establishes the thermal, mechanical, and hydrolytic behavior [20].
To develop drug delivery techniques based on electrospinning, a drug should be mixed with the polymer in the electrospinning mixture. Because of the large surface area of electrospun mats, solvent evaporation is quick and effective; this gives the integrated drug little time to recrystallize, favoring the development of amorphous dispersions. The drug is then diffused into the dissolving liquid by the mat. The drug is consistently dispersed through the polymer matrix in a matrix diffusion-control system. The infiltration of the drug via the matrix is controlled by the distribution of the dissolution media throughout the matrix phase. Further, the system parameters and the thickness of the membranes might additionally have an impact on the rate of drug release [21].
Coaxial electrospinning is a modification of the conventional electrospinning process [22]. It is a new type of electrospinning that employs two concentrically supported capillaries to ensure the creation of core-shell fibers. The primary rationale for using coaxial-electrospinning in controlled release is to avoid the drawbacks of single-nozzle electrospinning in encapsulating weak, water-soluble bioactive compounds that are important in regenerative medicine. Other benefits of coaxial electrospinning include a more sustained effect of the encapsulated medications as well as one-step co-encapsulation of several pharmaceuticals with differing solubility aspects [23].
As far as we know, the effect of coaxially produced electrospun nanovesicle-in-NF-scaffold-loaded LVC upon its combined management of AD and MRSA skin infection has yet to be discussed in any scientific paper. Consequently, LVC, which is a hydrophilic drug, was fabricated into nanovesicles (CERs) and then incorporated into hydrophobic PU electrospun NFs to sustain its effect. CERs were optimized using factorial design 21.31, in which the categoric factor ceramide type (X1) with two levels (IIIB and IV) and the numeric factor phospholipid (PC) amount (X2) with three levels (50, 75 and 100 mg) were selected as independent variables, and EE% (Y1), PS (Y2) and PDI (Y3) were chosen as dependent variables. The optimized CERs were examined in further investigations and then incorporated into NFs. The fabricated NFs were studied in terms of fiber size and surface morphology. The NF-loaded CERs were further evaluated via an in vitro release study and an in vivo study. A histopathological assessment was accomplished to assess the safety of NF-loaded CERs.
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Materials
Levocetrizine dihydrochloride (LVC) was provided by Global-Napi Pharmaceutical Co. (Cairo, Egypt). Fluorescein diacetate (FDA), phospholipid (PC), and polyurethane (PU) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Pluronic F127) was gifted from BASF Co. (New Jersy, NY, USA). Ceramide IIIB and VI were provided by Evonik Co. (GmbH, Germany). Acetone, dimethylformamide (DMF), chloroform, and methanol were obtained from Merck (Darmstadt, Germany). Hydroxypropyl methylcellulose HPMC K4M was purchased from Colorcon (Kent, UK).
Albash, R.; Ali, S.K.; Abdelmonem, R.; Agiba, A.M.; Aldhahri, R.; Saleh, A.; Kassem, A.B.; Abdellatif, M.M. Electrospun Nanofiber-Scaffold-Loaded Levocetirizine Dihydrochloride Cerosomes for Combined Management of Atopic Dermatitis and Methicillin-Resistant Staphylococcus Aureus (MRSA) Skin Infection: In Vitro and In Vivo Studies. Pharmaceuticals 2025, 18, 633. https://doi.org/10.3390/ph18050633
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