Topical amlodipine-loaded solid lipid nanoparticles for enhanced burn wound healing: A repurposed approach

Injury is physical harm that happens when an individual is unexpectedly exposed to energy levels higher than his physiologic tolerance threshold. In the world, injuries are ranked fourth in terms of fatalities, accounting for 11 % of all fatalities, after neoplastic, infectious, and cardiovascular disorders. According to the International Society of Burn Injuries, burns are a significant mechanism of injury to the skin or other organic tissues, usually brought by thermal or other acute traumas. A burn happens when hot solids (contact burns), hot liquids (scalds), or flames partially or completely damage the cells of the skin or other tissues (Leon-Villapalos, 2019). According to their severity, burns are divided into; first-degree burns (superficial wounds), second-degree burns (superficial/deep partial thickness wounds), and third-degree burns (full-thickness wounds) (Abazari et al., 2022).

Burn healing is a natural body defense response to injuries. It is a complicated and dynamic process for rapidly restoring injured tissues and their normal function. This process comprises four considerably interrelated and overlapping stages: hemostasis, inflammation, proliferation, and remodeling (Abazari et al., 2022).

Diverse mediators, extracellular matrix (ECM) components, growth factors and proteinases are involved in the process of wound healing (W. Wang et al., 2019). Nitric oxide (NO) is one of the main endothelial-regulated factors that retain vascular homeostasis (Hirapara et al., 2016). It mediates blood clot formation and white blood cells’ movement toward the wound area. On the other hand, excessive free radical production during the inflammatory phase delays wound healing (Farmoudeh et al., 2022). NO is a free radical generated by nitric oxide synthase from L-arginine. It is produced by a variety of cells in the wound bed and contributes to multiple pathological and physiological responses during wound healing. It is a remarkable messenger that regulates the expression of several growth factors and cytokines, including vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and interleukins. A relevant study proved that topical nitric oxide can promote re-epithelialization, inflammatory cell accumulation, myeloperoxidase (MPO) expression, angiogenesis, and collagen synthesis in a full-thickness burn model in rats. Another study found that NO enhances re-epithelialization, follicular stem cell recruitment, angiogenesis, and procollagen-expressing fibroblasts in mice (Singer et al., 2018).

The main goal of wound management is to keep patients safe from serious infections, speed up wound healing, and reduce scars and pain. Currently, a variety of wound control therapies are available including debridement, autografts, and the application of therapeutic agents. The use of topical drugs, which primarily aim to promote healing and prevent infection, is still essential in the treatment of all types of wounds. As a result, there is still a high demand for novel therapeutic agents for topical wound therapy (W. Wang et al., 2019). Studies have demonstrated that multiple natural and synthetic products have the ability to promote wound healing by affecting one or more phases of the healing process. Because the infection is a leading risk factor for death and significantly slows wound healing, antimicrobial agents are commonly employed topically and systemically, such as silver sulfadiazine, mafenide acetate, mupirocin and zinc oxide. In addition, natural products such as aloe vera, honey, berberine, ginger and propolis were recently employed for burn healing. (Ait Abderrahim et al., 2019, Khan et al., 2020, Krupp et al., 2019, Mabvuure et al., 2020, Shedoeva et al., 2019, Wang et al., 2019)

Amlodipine besylate (ADB), a third-generation dihydropyridine calcium channel blocker, which is widely used in a variety of cardiovascular circumstances, may also play a role in non-cardiac conditions. According to some in-vitro studies, amlodipine was shown to be capable of promoting the healing process by regulation of collagen production, extracellular matrix, re-epithelialization and wound healing through its vasodilation and angiogenic activity (Hemmati et al., 2014, Mojiri-Forushani, 2018). Moreover, amlodipine was found to improve endothelial NO bioavailability by enhancing NO production and extending NO half-life via its antioxidant properties (Hirapara et al., 2016).

It was found that, upon using conventional topical formulations such as ointments, creams and gels, the skin functions as a barrier, limiting drug permeation. As a result, conventional topical therapies require a higher dose for optimal drug concentration delivery into the skin layers, which may probably cause skin irritation. Nanocarrier-based drug delivery systems have piqued the interest to overcome the limitations of traditional formulations. Topical drug delivery using nanocarriers may improve drug permeation and drug release in skin layers while protecting the drug from degradation as well as enhancing patient compliance (Anwer et al., 2019, Elhalmoushy et al., 2022). The literature suggested that nanocarriers could be a promising drug delivery system for overcoming the permeation and efficacy issues associated with conventional topical formulations. However, very few lipid nanocarriers have been investigated for topical delivery of ADB in burn conditions. When compared to other colloidal carriers, solid lipid nanocarriers (SLN) have a considerable drug-loading capacity and controlled release. The solid lipids used in the preparation of SLN are less expensive compared to phospholipids used in liposomes. Moreover, the nanosized SLN forms a thin film over the injured skin, preventing water evaporation, lowering trans-epidermal water loss, raising moisture levels, and hydrating the skin. Hydration creates gaps in the corneocytes and thus promotes the embedding of SLN in the skin. The nanoparticles embedded in skin layers boost skin retention, slow drug release, and provide extended action with little or no systemic absorption. As far as we are aware, no studies have been published for topical delivery of ADB-loaded SLN for the treatment of burn wounds. In the current work, the appraisal and in-vitro/in-vivo evaluation of topical ADB-loaded SLN with desirable particle size for improved penetration and prolonged drug release at intended skin layers was carried out for the treatment of burn wounds.

Materials

Amlodipine besylate (ADB) was kindly gifted by Sigma Pharmaceutical Industries, Precirol® ATO 5 (P ATO 5), Compritol® ATO 888 (C ATO 888), Gelucire 50/13 (G 50/13) and Gelucire 44/14 (G 44/14), were acquired by Gattefossé; Saint-Priest, France. Poloxamer 188 (P188), Poloxamer 407 (P407) and Solutol HS (SHS) were gifted gratefully by BASF Cesano Moderna, Italy. Hydroxypropylmethyl cellulose 4000 cp (HPMC); was provided by Pharco Pharmaceutical Co., Alexandria, Egypt.

Read more

Nada Magdy, Heba M. Elbedaiwy, Maged W. Helmy, Noha S. El-Salamouni, Topical amlodipine-loaded solid lipid nanoparticles for enhanced burn wound healing: A repurposed approach, International Journal of Pharmaceutics, 2024, 124484, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124484.

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