Lipid Nanoparticle Formulations for the Skin Delivery of Cannabidiol
Abstract
Background/Objectives: The aims of this work were to formulate cannabidiol in different lipid carriers for skin delivery after topical application and to study their stability, interaction with the skin, and antibacterial activity.
Methods: Solid lipid nanoparticles and nanostructured lipid carriers loaded with cannabidiol were prepared and characterized in terms of their physicochemical properties, colloidal stability, protection of the antioxidant capacity of cannabidiol, as well as their retention over time. Skin penetration was assessed using an in vitro model with human skin. The antibacterial activity was tested against Staphylococcus aureus and compared to free cannabidiol.
Results: Three nanoformulations exhibited the best size and reproducibility values and were selected for further studies. The formulations were stable, protected the active ingredient, succeeded in delivering it to deep skin layers, and demonstrated antibacterial activity.
Conclusions: These cannabidiol nanoformulations show potential for use in skin diseases and conditions, as they protect the active ingredient, enhance its delivery to the skin, and exhibit antibacterial effects.
Introduction
The human skin is the largest organ in the body, serving as a protective barrier against external factors such as heat, injuries, and infections. Its structure comprises three histological layers: the epidermis, dermis, and hypodermis, each performing vital functions in protection, regulation, and sensory communication [1]. In particular, the epidermis is responsible for impermeability and pigmentation but lacks vascularization, relying on diffusion for nutrient and waste exchange to maintain cellular viability [2,3]. Continuous regeneration occurs from the basal layer, where basal cells differentiate into various epidermal cell types, ultimately forming anucleate keratinocytes known as corneocytes. These corneocytes constitute the stratum corneum (SC), a dense layer of dead cells embedded in a lipid matrix. This outermost skin layer provides a robust barrier against external compounds and microorganisms, among other vital functions. Consequently, the SC is a critical barrier that must be overcome for effective skin drug delivery.
In recent years, cannabidiol (CBD), a non-psychoactive cannabinoid derived from Cannabis sativa L., has emerged as a potential therapeutic agent for various skin diseases and conditions [4]. Its reported benefits range from anti-inflammatory and antioxidant properties [5] to antitumor [6,7] and antibacterial effects [8], making it a candidate for addressing skin issues such as bacterial infections, dermatitis, psoriasis, acne, and even certain types of skin cancer. Despite the availability of CBD-based products on the market that target some of these conditions [9], achieving the effective delivery of CBD into deeper skin layers remains a challenge, largely due to the barrier posed by the SC, highlighting the need for further research to overcome this obstacle. The potential of CBD as a therapeutic agent remains largely untapped due to three main obstacles: its inherent instability—it is photosensitive, thermosensitive, prone to oxidation, and its stability is solvent-dependent—poor water solubility, and the need for efficient delivery across the SC to reach the viable layers of the epidermis [10]. Previous approaches, such as permeation enhancers, improve topical delivery but do not address the issues of solubility and stability. Consequently, encapsulation within nanoparticulate systems has emerged as a promising alternative to protect and enhance the efficacy of CBD formulations.
Nanomedicine offers innovative strategies for treating skin conditions and diseases. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are increasingly recognized as effective carriers that enhance drug bioavailability and skin penetration. These nanoparticle systems enable non-invasive administration and controlled drug release, minimizing adverse effects while targeting specific skin cell types for increased therapeutic efficacy [11,12,13]. Although recent studies have begun to explore CBD encapsulation within these nanoparticles [14,15], there remains a lack of formulations using pure CBD instead of extracts to enhance product reproducibility by eliminating the variability associated with extracts. Furthermore, the interaction of CBD-loaded nanoparticles with skin has been evaluated in only a few studies, often using artificial membranes or animal skin.
In this study, we propose and characterize novel SLN and NLC formulations, employing pure CBD powder, for the skin delivery of CBD into deep layers of the skin. We utilize the Saarbrücken Penetration Model, a method that closely simulates physiological conditions by recreating the transdermal hydration gradient and ensuring sample penetration exclusively through the SC [16]. Furthermore, while the efficacy of CBD against various bacteria has been documented in the literature [8,17], a gap remains in the research on the antimicrobial properties of CBD-loaded lipid nanoparticles (SLNs and NLCs). As far as we know, this study is the first to investigate and demonstrate the antibacterial potential of CBD-loaded lipid nanoparticles, with specific efficacy against Staphylococcus aureus, thereby introducing a novel application for treating skin infections. Currently, there is a strong demand for antimicrobial substances of natural origin and new antibiotics capable of overcoming bacterial resistance [18]. Notably, CBD shows effectiveness against highly resistant Gram-positive pathogens, and it has activity against biofilms and a low rate of resistance induction [8]. However, as mentioned above, CBD’s instability limits its application. Therefore, the development of formulations that protect the drug and allow proper delivery is crucial.
In summary, this study addresses critical challenges in CBD formulation and delivery by presenting SLN and NLC formulations designed to overcome the SC barrier and protect the unstable CBD molecule, using a physiologically relevant skin penetration model and human skin explants. Our work assesses the therapeutic potential of CBD-loaded SLNs and NLCs for treating skin infections, as well as other skin conditions requiring deep CBD delivery, laying the foundation for future applications in dermatology.
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Materials
The lipids Compritol® 888 ATO, consisting of mono-, di-, and triesters of behenic acid (C22), with the diester fraction being predominant, and Transcutol® HP, consisting of highly purified diethylene glycol monoethyl ether, were from Gattefossé s.a.s. (São Paulo, Brazil) and were generously donated by M.Cassab Argentina S.A. (Buenos Aires, Argentina). Witepsol® E 85 (Witepsol), which mainly comprises triglycerides with portions of a maximum of 15% diglycerides and a maximum of 1% monoglycerides of caprylic (C8) and stearic (C18) fatty acids, was from IOI Oleo GmbH (Hamburg, Germany). The Tween 80 (T80) and dimethyl sulfoxide (DMSO) used were from Biopack (Buenos Aires, Argentina), while Kolliphor® P 188 (P188), also known as Poloxamer 188, 1,1-diphenyl-2-picrylhydrazyl (DPPH), and butylated hydroxytoluene (BHT) were purchased from Sigma-Aldrich (Buenos Aires, Argentina). The CBD, presented as crystals with 99.9% purity, was from Kilab S.A. (Buenos Aires, Argentina). Mueller Hinton broth was obtained from Life Technologies™ (Thermo Fisher Scientific Inc., Waltham, MA, USA). All other reagents used were of analytical or HPLC grade. In all cases, the water used was Milli-Q grade.
Calienni, M.N.; Scavone, M.A.; Sanguinetti, A.P.; Corleto, M.; Di Meglio, M.R.; Raies, P.; Cristos, D.S.; Maffia, P.C.; Montanari, J. Lipid Nanoparticle Formulations for the Skin Delivery of Cannabidiol. Pharmaceutics 2024, 16, 1490. https://doi.org/10.3390/pharmaceutics16121490
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