An Experimental Design Approach for Producing Curcumin-Loaded Solid Lipid Nanoparticles

Abstract

Background/Objectives: Curcumin has well-established efficacy in a variety of disorders due to its prominent antioxidant, antiaging, anti-inflammatory, chemosensitizing, and anticancer activities. Despite its numerous benefits, curcumin exhibits low bioavailability mainly due to its poor solubility, poor absorption, rapid metabolism, and quick excretion, consequently limiting its clinical applications. In this study, we investigated the most convenient ingredients in SLNs to enhance curcumin’s solubility by examining the effects of multiple independent variables simultaneously using an experimental design.

Methods: After curcumin’s saturation solubility was investigated, SLN formulations were produced. The optimum formulation was determined with the help of experimental design. The SLNs were characterized in terms of the particle size and distribution, zeta potential, shape, entrapment efficiency, drug loading capacity, and drug release. The cell viability and cell internalization were also evaluated.

Results: An impressive synergistic effect was achieved with the combination of Brij and Gelucire 48/16, which increased curcumin’s solubility in water by 452.5 times. Curcumin-loaded SLNs were successfully produced with a spherical shape and particle size of 389.3 ± 9.95 nm. The encapsulation efficiency was directly proportionate to the amount of curcumin and the stirring speed. Curcumin in the SLNs entered the cancer cells more easily than curcumin alone.

Conclusions: Our results demonstrate that the quantity of surfactant is a significant factor influencing the efficiency of drug loading. Finally, the 3:1 (Brij–Gelucire48/16) ratio markedly enhanced the loading efficiency. The cellular internalization and, consequently, the anticancer efficacy against adenocarcinomic human alveolar basal epithelial cells were improved with SLNs. This could be a promising approach for lipid-based colloidal drug delivery systems.

Introduction

Curcumin is used in a wide range of pharmaceutical applications, including antioxidant, anti-inflammatory, antimicrobial, and anticancer drugs. In particular, the use of curcumin for cancer treatment inhibits carcinogenesis, angiogenesis, and tumor growth, while it reduces chemotherapy and radiotherapy side effects [1]. It is a versatile drug that can be used for treating many conditions such as cough/inflammation, respiratory diseases, flu, sinusitis, liver disorders, rheumatism, abdominal pain, burn wounds, neurological disorders, and tissue regeneration [2,3]. In addition to its potential usage, its effect on H. pylori treatment was also demonstrated recently [4]. However, this chemical generally shows limited serum levels after oral administration, due to its high susceptibility to metabolic degradation prior to absorption within the intestine and liver. Moreover, it is insoluble in water and unstable under light and oxygen. Because it is a light-sensitive substance, it can undergo photodegradation [5,6]. In the process of finding a solution to optimize curcumin administration, the use of nanotechnology has become a very promising and significant approach, especially since conventional methods for enhancing the water solubility of drugs typically lead to poor pharmacokinetics and low bioavailability [7].

With the help of nanotechnology, drug carriers serve as drug depot systems that enable the delivery of poorly water-soluble drugs, bypassing the liver, preventing first-pass metabolism, and, thus, increasing bioavailability while minimizing side effects. To overcome the aforementioned limitations related to curcumin, several attempts focusing on nanotechnology have been made such as polymeric micelles, nanoparticles, liposomes, cyclodextrins, biodegradable hydrogels, and microemulsions [8]. Solid lipid nanoparticles (SLNs), a type of colloidal carrier based on nanotechnology, consist of a solid lipid content (trimyristin, tristearin, trilaurin, stearic acid, glyceryl caprate, theobroma oil, triglyceride coconut oil, 1-octadecanol, glycerol behenate, glycerol palmitostearate, cetylpalmitate wax, etc.); a surfactant (tween, polysorbates, lecithins, etc.); and an incorporated drug. The SLN structures are stabilized by suitable surfactant(s) [9] and offer distinct advantages such as biocompatibility, biodegradability, nontoxicity, high drug payload capacity, a longer shelf life, ease of scalability, modifiable release patterns, and coalescence resistance. Furthermore, they are efficient carriers that improve solubility, increase bioavailability, and bypass first-pass metabolism [10]. Researchers have made significant efforts to enhance the bioavailability of curcumin by developing various novel drug delivery systems, including solid lipid nanoparticles. However, curcumin has not yet been licensed as a drug. Hassanzadeh et al. reviewed the obstacles against the commercialization of curcumin as a drug [11]. Bypassing these abovementioned limitations of curcumin still requires more applicative research despite a significant number of curcumin-based formulations.

Considering all this information, we proposed that combining traditional solubility enhancement methods with nanotechnology could be an effective solution to the challenges associated with curcumin. Therefore, the aim of the present study was to systematically evaluate the effect of cosolvency, complexation, and micellar solubilization approaches on curcumin solubility as well as to incorporate this approach into nanotechnology-based drug carrier systems, like SLNs. After the selection of the most convenient excipients, curcumin-loaded SLNs were produced and characterized in accordance with formulation optimization studies.

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Materials

Curcumin, stearic acid, Brij 35 (polyoxyethylene (23) lauryl ether), TritonX100 (polyoxyethylene octyl phenyl ether), triethanol amine (TEA), tween 80 (polyethylene glycol sorbitan monooleate), span 80 (sorbitane monooleate), benzalkonium chloride (Benz. Ch.), Sodium taurocholate (Na-Tau), and sodium lauryl sulfate (SLS) were provided from Sigma-Aldrich (Schnelldorf, Germany). β cyclodextrine sulfobutyl ethers (βCDSE) were kindly provided by Captisol. Gelucire 48/16 (polyoxyl-32 stearate) was kindly provided by Gattefossé (Mumbai, India). Propylene glycol (PG), polyethylene glycol 400, polyethylene glycol 4000, octyldodecanol (OD), poloxamer 188 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)), macrogol cetostrearyl ether 12 (MCE12), and macrogol (es könnte etwas von KLK Kolb passen) setotrearil ether 20 (MCE20) were kindly gifted by BASF. A549 cell line (ATCC-CCL-185) was kindly gifted from Dr. Rengin Reis (Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Acibadem Mehmet Ali Aydinlar University). All organic solvents and other chemicals were analytical-grade and obtained from Merck (Darmstadt, Germany.

Saka, O.M.; Aygüler, C.İ.; Özdemir, N.S.; Sürücü, B.; Çakırlı, E.; Nemutlu, E.; Demirbolat, G.M. An Experimental Design Approach for Producing Curcumin-Loaded Solid Lipid Nanoparticles. Pharmaceuticals 2025, 18, 470. https://doi.org/10.3390/ph18040470