Evaluating Various Lactose Types as Solid Carriers for Improving Curcumin Solubility in Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDSs) for Oral Administration

Abstract

Curcumin, a bioactive compound derived from turmeric, possesses numerous pharmaceutical properties; however, its poor aqueous solubility and permeability result in low bioavailability. This study aims to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) using different lactose types as solid carriers for the oral administration of curcumin to enhance its solubility. The system comprised curcumin, an oil phase, and a surfactant. Jasmine oil, as the oil phase, and Cremophor^® RH40, as the surfactant, were selected due to their superior ability to solubilize curcumin. A microemulsion was then prepared using a ternary phase diagram. The liquid SNEDDSs were converted into S-SNEDDSs by employing three solid carriers: Tablettose® 80, FlowLac® 100, and GranuLac® 200. Dissolution studies conducted in simulated gastric fluid demonstrated a significant improvement in curcumin solubility in the S-SNEDDS formulations compared to curcumin powder. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses confirmed the appearance of curcumin in the S-SNEDDS, while Fourier-transform infrared (FTIR) spectroscopy indicated compatibility between the excipients and curcumin. Additionally, an accelerated stability study conducted over four weeks at 40 °C and 75% relative humidity showed no significant changes in the physical appearance of the S-SNEDDS formulations. These findings suggest that the S-SNEDDS formulation effectively enhances curcumin’s solubility, potentially improving its bioavailability for oral administration.

Introduction

Curcuma longa L., a member of the Zingiberaceae family and the Curcuma genus, contains curcuminoids as its primary constituents, comprising 77–90% curcumin, 6–17% desmethoxycurcumin, and 2–4% bisdemethoxycurcumin [1,2]. Curcumin exhibits various biological and pharmacological activities, including antitumor, antioxidant, anti-inflammatory, hepatoprotective, antihyperglycemic, and antiviral effects [1,3,4,5]. Curcumin, the main curcuminoid, is a polyphenol with a bis-α,β-unsaturated β-diketone structure [1]. It exists in at least two tautomeric forms: the keto, predominant in acidic and neutral conditions, and the stable enol form in alkaline solutions. Curcumin is practically insoluble in water at both acidic and neutral pH levels but is soluble in alkaline conditions. However, it is unstable in alkaline environments and under light exposure but stable in acidic conditions and high temperatures [6]. According to the Biopharmaceutics Classification System (BCS), curcumin falls under Class IV, characterized by low solubility and permeability [1]. This classification leads to poor absorption and low bioavailability. In recent years, nano-based drug delivery systems have been developed to enhance the oral bioavailability of curcumin, including microparticles [7], nanoparticles [8], liposomes, micelles [8], nanoemulsions [9], and self-nanoemulsifying drug delivery systems (SNEDDSs) [10,11].

Self-nanoemulsifying drug delivery systems (SNEDDSs) are an anhydrous form of nanoemulsions. These systems comprise isotropic mixtures of active pharmaceutical ingredients, oil, surfactants, and/or co-surfactants. Upon contact with an aqueous phase, such as gastric fluid under gastric motility, oil-in-water (O/W) nanoemulsions are rapidly and spontaneously formed [12]. The drug, dissolved in the oil phase, is encapsulated in droplets ranging in size from a few nanometers to around 200 nm, enhancing drug solubilization and absorption. The lipid carrier (oil phase) in SNEDDSs, often composed of medium-chain triglycerides and short-chain fatty acids, facilitates easy nanoemulsification [13]. Additionally, modified or hydrolyzed vegetable oils are commonly employed. The oil phase can promote the lymphatic uptake of highly lipophilic drugs, which helps reduce first-pass metabolism. Curcumin has been developed into a SNEDDS, which has been shown to significantly enhance the bioavailability of curcumin compared to its conventional forms [14].

Additionally, a study conducted in rats demonstrated that curcumin encapsulated in SNEDDSs significantly enhanced bioavailability compared to conventional curcumin formulations [15]. Based on the points mentioned above, this system is particularly suitable for drugs with poor water solubility and limited permeability, such as curcumin. However, SNEDDSs still face certain limitations in drug administration. After preparation, these systems typically exist in a liquid form, which requires encapsulation in soft gelatin capsules. This method incurs higher costs and may lead to leakage or instability due to moisture or oxygen exposure. To overcome these limitations, solid adsorbents are incorporated into the SNEDDS to facilitate manufacturing, improve stability, and simplify drug administration. This approach leads to the development of solid self-nanoemulsifying drug delivery systems (S-SNEDDSs), which offer enhanced practicality in production and administration while maintaining the benefits of the original SNEDDS. S-SNEDD formulations are anhydrous, and they provide improved chemical and physical stability.

This anhydrous form also enables the development of various dosage forms, such as capsules, tablets, or powders, potentially enhancing patient compliance [16]. The preparation of self-nanoemulsifying drug delivery systems (SNEDDSs) in solid form can be achieved through various methods, such as spray drying [17], melt granulation, melt extrusion/extrusion spheronization [18], and the use of solid carriers [19]. Solid carriers are a simple and widely adopted method that involves mixing SNEDDSs with an adsorbent. The adsorbent should possess high absorption efficiency and easily release the drug from the system when exposed to gastrointestinal fluids. Commonly used adsorbents include porous silica materials, such as fumed silica [20]; polysaccharides, such as mannitol, sorbitol, sucrose, lactose, and trehalose [21]; polymers, such as poloxamers, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose sodium (sodium CMC), and polyvinylpyrrolidone (PVP) [22]; and proteins, such as gelatin [23].

Lactose-based substances are interesting to use as adsorbents due to several key advantages. Lactose is an inert substance that rarely undergoes chemical reactions with other compounds, making it safe and biocompatible. Additionally, lactose is a readily available, cost-effective material. Importantly, its structure allows for the effective adsorption of oils or viscous liquids, facilitating the easy conversion of SNEDDSs into a powder form. Furthermore, lactose does not interfere with the process of nanoemulsion formation in SNEDDSs, ensuring that the particle structure within the drug delivery system maintains the desired size in the nanometer range, with minimal changes over time. The lactose types selected as adsorbents for SNEDDSs include Tablettose® 80, FlowLac® 100, and GranuLac® 200, each exhibiting distinct properties in terms of flowability, particle size, and liquid adsorption capacity. These differences make all three lactose types of intriguing candidates for use as adsorbents in SNEDDSs, facilitating the preparation of S-SNEDDSs.

Therefore, this study formulated curcumin into S-SNEDDSs to enhance its solubility for potential oral delivery. The process began by determining the solubility of curcumin in various oils and surfactants, followed by selecting the components from each group that exhibit the highest solubility for curcumin. These selected components were then used to prepare a microemulsion by plotting the ratios of the components on ternary phase diagrams. The ratio of oil to surfactant varied from 1:19 to 19:1 (w/w) and was titrated with water to identify the microemulsion region (nano size range). The ratio that results in the formation of a microemulsion was further evaluated for particle size, polydispersity index (PDI), and zeta potential. The optimal ratio was chosen to incorporate curcumin; the same measurements were performed on this curcumin-loaded microemulsion. Without water, this curcumin-loaded formulation was mixed with the adsorbents Tablettose® 80, FlowLac® 100, and GranuLac® 200 to produce a dry powder, resulting in S-SNEDDSs. The S-SNEDDS was dispersed in 0.1 N HCl to assess its ability to form nanoemulsions. The resulting S-SNEDDS was characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FT-IR). Additionally, the release of curcumin from S-SNEDDSs was studied under simulated gastric conditions. The stability of S-SNEDDSs was evaluated under accelerated conditions at 40 ± 2 °C with a relative humidity (RH) of 75 ± 5% for four weeks, with stability assessments performed weekly.

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Materials

Curcumin was purchased from TCI (Tokyo, Japan). Rose oil, sunflower oil, jasmine oil, clove oil, eucalyptus oil, lavender oil, chamomile oil, lemon oil, and Cremophore®RH40 were purchased from Chemipan Corporation Co., Ltd. (Bangkok, Thailand). Tween® 20, Tween® 80, Span® 20, Span® 80, and Cremophore®EL were purchased from PC Drug Co., Ltd. (Bangkok, Thailand). Tablettose® 80 (agglomerated lactose), FlowLac® 100 (spray-dried lactose), and GranuLac® 200 (milled lactose) were manufactured by MEGGLE GmbH & Co. KF. (Wasserburg, Germany).

Teerapipattanapong, P.; Jaikon, P.; Ningsanonda, N.; Yonemochi, E.; Furuishi, T.; Hirun, N.; Kraisit, P. Evaluating Various Lactose Types as Solid Carriers for Improving Curcumin Solubility in Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDSs) for Oral Administration. Sci 2024, 6, 69. https://doi.org/10.3390/sci6040069