{"title":"Simvastatin and adenosine-co-loaded nanostructured lipid carriers for wound healing: Development, characterization and cell-based investigation","authors":"","doi":"10.1016/j.ejpb.2024.114533","DOIUrl":null,"url":null,"abstract":"<div><div>Chronic wounds represent a significant global health burden, characterized by delayed skin healing and associated comorbidities. The present study aimed to develop nanostructured lipid carriers (NLCs) as a topical delivery system for the co-administration of simvastatin and adenosine to address chronic wound management. The rationale behind the co-delivery approach was to mitigate the cytotoxicity associated with high-dose simvastatin, while preserving its therapeutic benefits through a potential synergistic or additive effect. A significant challenge in the development of these NLCs was the encapsulation of the highly hydrophilic adenosine within the hydrophobic lipid matrix. The NLCs were prepared using a hot homogenization-sonication method with a double emulsion technique and optimized through a series of formulation trials, employing various surfactants, solid and liquid lipids, to achieve efficient drug encapsulation, particularly for the hydrophilic adenosine. Optimized formulations F5- and F10-S/A 0.6 %/2 % (containing 0.6 % simvastatin and 2 % adenosine), exhibited promising physicochemical properties. The main difference was the liquid lipid used: F5 contained Miglyol 810 N, while F10 contained Capmul MCM C-8. Both formulations displayed a mean particle size below 230 nm, a polydispersity index (PDI) of approximately 0.2, and a zeta potential around –22 mV. While simvastatin association efficiency (AE) was nearly 100 %, adenosine AE was higher for F10 (24 %), compared to F5 (13.5 %). F5 demonstrated superior stability compared to F10, maintaining consistent particle size and PDI over a 60-day period. Formulation F5 also demonstrated superior cell-based <em>in vitro</em> performance compared to F10, with higher cell viability (MTT assay), greater cell proliferation induction (SRB assay), and enhanced cell proliferation and migration in the wound-scratch assay. While F10 displayed higher adenosine AE, F5 excelled in terms of stability and biological activity. The slight increase in intracellular reactive oxygen species levels observed with F5 may contribute to its enhanced proliferative effects. In-depth characterization revealed that F5 comprised spherical nanoparticles, and thermal analysis indicated no significant changes in the nanocarrier structure upon drug encapsulation. Additionally<em>, ex vivo</em> permeability study demonstrated superior skin retention of both simvastatin and adenosine for F5 compared to an emulsion control. Overall, the F5 nanocarrier demonstrated suitable physicochemical properties, cellular biocompatibility, induction of cell proliferation and migration events, and drug retention capacity in the skin layers, indicating its potential as a promising topical treatment for difficult-to-heal wounds.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Pharmaceutics and Biopharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S093964112400359X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Chronic wounds represent a significant global health burden, characterized by delayed skin healing and associated comorbidities. The present study aimed to develop nanostructured lipid carriers (NLCs) as a topical delivery system for the co-administration of simvastatin and adenosine to address chronic wound management. The rationale behind the co-delivery approach was to mitigate the cytotoxicity associated with high-dose simvastatin, while preserving its therapeutic benefits through a potential synergistic or additive effect. A significant challenge in the development of these NLCs was the encapsulation of the highly hydrophilic adenosine within the hydrophobic lipid matrix. The NLCs were prepared using a hot homogenization-sonication method with a double emulsion technique and optimized through a series of formulation trials, employing various surfactants, solid and liquid lipids, to achieve efficient drug encapsulation, particularly for the hydrophilic adenosine. Optimized formulations F5- and F10-S/A 0.6 %/2 % (containing 0.6 % simvastatin and 2 % adenosine), exhibited promising physicochemical properties. The main difference was the liquid lipid used: F5 contained Miglyol 810 N, while F10 contained Capmul MCM C-8. Both formulations displayed a mean particle size below 230 nm, a polydispersity index (PDI) of approximately 0.2, and a zeta potential around –22 mV. While simvastatin association efficiency (AE) was nearly 100 %, adenosine AE was higher for F10 (24 %), compared to F5 (13.5 %). F5 demonstrated superior stability compared to F10, maintaining consistent particle size and PDI over a 60-day period. Formulation F5 also demonstrated superior cell-based in vitro performance compared to F10, with higher cell viability (MTT assay), greater cell proliferation induction (SRB assay), and enhanced cell proliferation and migration in the wound-scratch assay. While F10 displayed higher adenosine AE, F5 excelled in terms of stability and biological activity. The slight increase in intracellular reactive oxygen species levels observed with F5 may contribute to its enhanced proliferative effects. In-depth characterization revealed that F5 comprised spherical nanoparticles, and thermal analysis indicated no significant changes in the nanocarrier structure upon drug encapsulation. Additionally, ex vivo permeability study demonstrated superior skin retention of both simvastatin and adenosine for F5 compared to an emulsion control. Overall, the F5 nanocarrier demonstrated suitable physicochemical properties, cellular biocompatibility, induction of cell proliferation and migration events, and drug retention capacity in the skin layers, indicating its potential as a promising topical treatment for difficult-to-heal wounds.
期刊介绍:
The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics.
Topics covered include for example:
Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids)
Aspects of manufacturing process design
Biomedical aspects of drug product design
Strategies and formulations for controlled drug transport across biological barriers
Physicochemical aspects of drug product development
Novel excipients for drug product design
Drug delivery and controlled release systems for systemic and local applications
Nanomaterials for therapeutic and diagnostic purposes
Advanced therapy medicinal products
Medical devices supporting a distinct pharmacological effect.