Ethyl-Cellulose Nanosponges for Topical Delivery of Simvastatin with Preferential Skin Retention for Wound Healing in a Full-Thickness Wound Rat Model

Abstract

Novel topical nanosponges were implemented to improve the skin availability of simvastatin (SV) for treating full-thickness wounds while controlling the scarring process. SV exhibits great potential in treating various skin diseases owing to its antibacterial, antioxidant, anti-inflammatory, and immunomodulatory properties. However, its poor oral bioavailability and systemic side effects have hindered its clinical application in dermatology. For the first time, nanosponges were utilized to target injured skin, creating an SV reservoir within the wound bed to enhance therapeutic efficacy while minimizing adverse effects. Herein, SV-loaded ethyl-cellulose nanosponges (SV-NS) were prepared using the emulsion solvent evaporation technique, optimizing organic solvents, SV concentration, and stabilizer concentration. The selected SV-NS (20 mg SV) exhibited nanoporous particles (786.2 ± 50 nm), a specific surface area of 10.3 m²/g, and a total pore volume of 0.016 cm³/g, offering sustained release and enhanced skin retention capacity. In vivo studies on full-thickness rat wounds confirmed that topical SV-NS (5 mg SV, applied every 5 days) significantly accelerated wound closure (P < 0.0001), achieving 76.23 ± 3.20% closure by day 8, a 47% improvement over free SV. Consequently, SV-NS facilitated wound closure exceeding 90% by day 11, whereas free SV required 16 days to attain a comparable level, representing a 31.2% faster healing rate. Histological analysis further revealed that SV-NS promoted optimal epidermal layer formation and well-organized collagen deposition, with collagen expression significantly (P < 0.0001) reaching 59.85 ± 3.17% by day 16. Conclusively, SV-NS enhances SV’s dermal availability, improving wound healing and minimizing side effects, demonstrating a promising approach for wound restoration.

Introduction

The skin plays a vital role in controlling body temperature, avoiding infection, and acting as a barrier against the environment and loss of water and electrolytes [1, 2]. Healing large, full-thickness skin defects presents a significant clinical challenge, involving a complex sequence of events including inflammation, tissue formation, revascularization, and remodeling [3, 4]. In severe pathological conditions, disruptions in the healing cascade, often linked to oxidative stress and bacterial contamination, exacerbate tissue damage and necrosis [5, 6]. Therefore, it is imperative to identify better techniques to encourage wound healing.

SV, a common cholesterol-lowering drug that inhibits HMG-CoA reductase, has demonstrated numerous benefits beyond cholesterol reduction, including promoting wound healing and treating psoriasis, alopecia, and melanoma [7, 8]. Notably, SV possesses anti-inflammatory through reduced pro-inflammatory cytokine production (IL- 6, IL- 8) [9]. Furthermore, it demonstrates immunomodulatory activity and promotes microvascularization, angiogenesis, and lymphangiogenesis by upregulating vascular endothelial growth factor (VEGF) production [10, 11]. Additionally, SV facilitates wound healing through its inherent antioxidant [12] and antimicrobial properties [13, 14]. Topical SV application is considered a superior alternative to oral administration, mitigating issues such as low oral bioavailability and adverse reactions like myopathy, rhabdomyolysis, and hepatotoxicity [15]. The potential of SV in enhancing wound healing has been investigated, employing a range of nanocarriers such as lioposomal gel [16], nanostructured lipid carriers [17], nanoemulsion gel [18], cubosomes [19] and nanocrystals [20].

While targeted drug administration offers advantages, challenges remain, particularly the absence of the stratum corneum in injured skin and the need for sustained drug delivery to create a therapeutic reservoir [21,22,23]. To address these issues, various delivery systems have been developed to enhance skin retention and control drug release. Nanosponges, used for topical medication delivery, offer several benefits: high porosity, customizable drug release, a nanometric 3D network, encapsulation of both hydrophilic and lipophilic drugs, targeted delivery, improved patient compliance, reduced dosing frequency, and fewer adverse effects [24]. Nanosponges have emerged as an effective nanocarrier for promoting wound healing in various dematological conditions such as skin infections [25,26,27], diabetic ulcers [28] and in cosmeceutical applications [29, 30]. Ethyl-cellulose nanosponges (NS) are particularly suitable for injured or inflamed skin due to their non-toxic and non-irritating polymer composition [24, 31, 32]. Moreover, they exhibit good epidermal-targeting effects, controlled drug release and long drug residence time at application site [33,34,35]. Although many franchises of ethyl-cellulose nanosponges are reported, they did not investigate whether it would be possible to enhance the physiochemical characteristics of SV, skin retention and wound healing.

This study pioneered, for the first time, the development of SV-loaded ethyl-cellulose nanosponges (SV-NS) for enhanced SV dermal delivery, aiming to create a promising, side-effect-reduced therapy for skin diseases. SV-NS were fabricated, evaluated in vitro, and tested for ex vivo skin permeability using rat skin. In vivo wound healing potential was assessed in Wistar rats through histological and histomorphometric analysis.

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Materials

SV and ethyl-cellulose were purchased from Acros Organics, Belgium. Polyvinylalcohol (degree of polymerization 1700) was obtained from Hanaway, Japan. Hydroxypropylmethylcellulose 15000 c.p, (HPMC K15, Methocel), Colorcon, USA. Dichloromethane and Sodium lauryl sulphate and Formalin were obtained from El Gomhouria, Egypt. Acetonitrile was purchased from Merk, USA. Ketamine Alfasan 10% was from Woerden, Holland. Xylazine 2% was purchased from Adwia, Egypt. All other reagents were of analytical grade.

Aboelazayem, S., Nasra, M., Ebada, H. et al. Ethyl-Cellulose Nanosponges for Topical Delivery of Simvastatin with Preferential Skin Retention for Wound Healing in a Full-Thickness Wound Rat Model. AAPS PharmSciTech 26, 126 (2025). https://doi.org/10.1208/s12249-025-03114-7