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Article

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

by
Panida Teerapipattanapong
1,
Pimrada Jaikon
1,
Nichapa Ningsanonda
1,
Etsuo Yonemochi
2,3,
Takayuki Furuishi
2,4,
Namon Hirun
1,5 and
Pakorn Kraisit
1,5,*
1
Faculty of Pharmacy, Thammasat University, Pathumthani 12120, Thailand
2
Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku 142-8501, Tokyo, Japan
3
School of Pharmacy at Narita, International University of Health and Welfare, 4-3 Kozunomori, Narita 286-8686, Chiba, Japan
4
Juntendo University Faculty of Pharmacy, 6-8-1 Hinode, Urayasu 279-0013, Chiba, Japan
5
Thammasat University Research Unit in Smart Materials and Innovative Technology for Pharmaceutical Applications (SMIT-Pharm), Faculty of Pharmacy, Thammasat University, Pathumthani 12120, Thailand
*
Author to whom correspondence should be addressed.
Sci 2024, 6(4), 69; https://doi.org/10.3390/sci6040069
Submission received: 27 September 2024 / Revised: 24 October 2024 / Accepted: 28 October 2024 / Published: 1 November 2024
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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.

1. 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.

2. Materials and Methods

2.1. 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).

2.2. Solubility Test

The solubility of curcumin in various oils and surfactants was determined by adding an excess amount of curcumin to 1 mL of each oil and surfactant in test tubes, followed by mixing with a magnetic stirrer at 650 rpm at room temperature for 24 h. The resulting suspension was centrifuged at 10,000 rpm for 15 min (Model 6000, KUBOTA, Tokyo, Japan). The supernatant was filtered through a 0.22 μm filter and analyzed by HPLC after diluting with methanol. The oil and surfactant that exhibited the highest solubility for curcumin were selected for the microemulsion preparation.

2.3. Construction of Ternary Phase Diagram of Microemulsion

Ternary phase diagrams were constructed using water titration [24]. The oil phase and surfactant were blended together in various weight ratios ranging from 1:19 to 19:1 (w/w). Distilled water was added dropwise to each mixture under gentle stirring with a magnetic stirrer. After each aliquot of water was added, the mixtures were observed for any change from a transparent to a turbid state. The transparent mixtures were identified as the microemulsion region, which was analyzed using ProSim software V1.0.3.

2.4. Preparation of S-SNEDDSs

Based on the microemulsion region of the ternary phase diagrams, the unloaded microemulsion ratio that exhibited optimal properties was selected. Jasmine oil and Cremophor® RH40 were selected for the microemulsion preparation due to their high solubility for curcumin. The optimal ratio of jasmine oil to Cremophor® RH40, as determined from the ternary phase diagrams, was 1:3, respectively. The unloaded microemulsion was stirred without water using a magnetic stirrer for 15 min. Subsequently, an accurate amount of curcumin was added to the microemulsion with continuous stirring for 24 h until the curcumin was fully dissolved, forming the liquid SNEDDS (L-SNEDDS) formulation. Using a physical adsorption method, solid carriers such as Tablettose® 80, FlowLac® 100, and GranuLac® 200 were employed to convert the L-SNEDDS into a S-SNEDDS. The L-SNEDDS was added dropwise to the solid carriers in a porcelain mortar to form a solid powder. The prepared S-SNEDDSs were stored in a desiccator at room temperature for further characterization. Figure 1A shows the preparation of S-SNEDDSs, and Figure 1B shows the formation of nanoemulsions.

2.5. Flow Property Study

The flow properties of the S-SNEDDS formulations were evaluated using the angle of repose method. Five grams of the formulation were passed through a funnel to form a conical pile. The mean radius (r) and height (h) of the powder base were measured. The angle of repose (α) was calculated using the following equation [25]:
Tan (α) = h/r

2.6. Particle Size, PDI, and Zeta Potential Analysis

Particle size, PDI, and zeta potential were evaluated by using a zeta potential and particle size analyzer (ELSZ-2000, Otsuka Electronics, Otsuka, Japan). All measurements were performed in triplicate.

2.7. Curcumin Content

L-SNEDDS and S-SNEDDS formulations, equivalent to 18 mg of curcumin, were accurately weighed and extracted by dissolving in 5 mL of methanol and stirring for 2 h using a magnetic stirrer. The resulting extract was transferred into a microcentrifuge tube and centrifuged at 15,000 rpm for 15 min at room temperature. The supernatant was then diluted with methanol and analyzed using the HPLC method. The curcumin remaining (%) was calculated by the following formula:
Curcumin   remaining % = Amount   of   curcumin   in   supernatant × 100 Amount   of   curcumin   added

2.8. High-Performance Liquid Chromatography (HPLC)

The amount of curcumin was quantified using HPLC [26] (Jasco AS-2055 Plus system, Jasco, Tokyo, Japan). The mobile phase was an isocratic mixture of 2% acetic acid in distilled water and acetonitrile (50:50, v/v). The flow rate was set to 1.2 mL/min. An Inertsil ODS3 C18 column (4.6 × 150 mm, 5 μm) was used for the analysis. The total run time was 10 min, and the curcumin detector wavelength was 425 nm. The injection volume was 10 μL.

2.9. Dissolution Studies

In vitro release tests for the S-SNEDDS and curcumin powder were performed using a USP Apparatus II set at 37 ± 0.5 °C and 100 rpm. The dissolution medium consisted of 750 mL of simulated gastric fluid (0.1N HCl, pH 1.2, without enzyme). Samples of 1.5 mL were withdrawn at 5, 15, 30, and 60 min, with an equal volume of fresh dissolution medium added after each sampling. The amount of curcumin released was then quantified using HPLC.

2.10. Fourier-Transform Infrared Spectroscopy (FT-IR)

Samples were analyzed using Fourier-transform infrared spectroscopy (FT/IR—4200, Jasco, Tokyo, Japan). Samples were placed at the center of the plate, and spectra were recorded over the wavenumber range of 500–4000 cm−1.

2.11. Differential Scanning Calorimetry (DSC)

Samples were analyzed using differential scanning calorimetry (DSC) (Rigaku, Tokyo, Japan). Approximately 3–8 mg of the sample was weighed and placed in an aluminum pan, with an empty pan being used as a reference. The samples were heated from 30 °C to 250 °C at a heating rate of 10 °C/min under a nitrogen atmosphere.

2.12. Powder X-Ray Diffraction (PXRD)

Samples were analyzed using an Ultima IV diffractometer (Rigaku, Japan). The samples were scanned over a 2θ range of 5°–40° at a defined scan speed.

2.13. Stability Study

The stability of the S-SNEDDS was evaluated under accelerated conditions. The samples were placed in amber glass bottles and stored at 40 ± 2 °C with a relative humidity (RH) of 75 ± 5% in a stability chamber for four weeks. The samples’ appearance, droplet size, PDI, zeta potential, percentage of curcumin remaining, and dissolution were evaluated.

2.14. Statistical Analysis

All data were statistically analyzed using IBM SPSS Statistics 23. One-way ANOVA was performed to determine the significant differences between more than two groups, followed by Tukey’s Multiple Comparison Test, which assessed the differences between the groups. A p-value of <0.05 was considered statistically significant.

3. Results and Discussion

3.1. Solubility Test

Curcumin was selected as a hydrophobic drug model for this study because its non-polar structure results in very low water solubility [27,28]. Therefore, it is essential to determine its solubility in oils and surfactants, which are key components in the SNEDDS system, in order to optimize both the quantity and efficacy of the drug delivery system. The solubility of curcumin in various oils and surfactants is shown in Table 1. In this study, natural oils were utilized to investigate the solubility of curcumin. Natural oils contain several key components, and previous research has shown that many natural oils can enhance the solubility of curcumin more effectively than ethanol, a commonly used solvent. Therefore, natural oils present an attractive alternative for dissolving curcumin and are also considered alternative green solvents [29,30]. The study revealed that curcumin had the highest solubility in jasmine oil (7.28 ± 0.615 mg/mL). The least solubility was observed in rose oil (0.20 ± 0.006 mg/mL). The partition coefficient of jasmine oil expressed in the logarithmic form (log P) is 3.10–3.32 [31]; the log p value of curcumin is 3.2 [2]. These compounds have high log p values (log p > 3), suggesting they have lipophilic characteristics. A vehicle and a substance with similar partition coefficient values may demonstrate good compatibility, leading to the preferred tendency of curcumin to solubilize in jasmine oil. Among the various surfactants, Cremophor® RH40 revealed the highest solubility of curcumin (27.12 ± 0.45 mg/mL). The least curcumin solubility (1.47 ± 0.01 mg/mL) was observed in Span® 80. Cremophor® RH40, with a hydrophilic–lipophilic balance (HLB) value in the range of 14–16, is a hydrophilic surfactant [32]. The potential for spontaneous emulsion formation and the small droplet size of produced emulsions are significantly influenced by the HLB values of the surfactants. Surfactants with high HLB values have high hydrophilicity, making them suitable for small droplet formation and providing a large surface area that promotes the rapid spread of the formulation in the aqueous phase or the formation of oil-in-water-type emulsions [33]. Thus, in this study, we selected jasmine oil as an oil phase and Cremophor® RH40 as a surfactant to prepare SNEDDS formulation.

3.2. Ternary Phase Diagram of Microemulsion

Based on the solubility results, the phase diagram study was conducted using jasmine oil as the oil phase and Cremophor® RH40 as the surfactant. A ternary phase diagram was constructed to represent the corresponding phases formed at varying proportions of oil (jasmine oil), surfactant (Cremophor® RH40), and water. The colored regions, as shown in Figure 2, represent the microemulsion region. The system produced microemulsions with up to 90% (w/w) oil phase composition. It was observed that when the surfactant concentration was less than 10%, the appearance of the resulting microemulsions became turbid. From Figure 2, five points were selected from the shaded regions for further analysis.

3.3. Characterization of Microemulsion and L-SNEDDS

The droplet size, polydispersity index (PDI), and zeta potential for five ratios of Cremophor® RH40/jasmine oil/water without curcumin are presented in Table 2. The droplet sizes of the liquid SNEDDS ranged from 2.67 to 83.56 nm, with significant differences being observed across the various oil/surfactant/water ratios. The formulation with Cremophor® RH40/jasmine oil/water at a ratio of 3.5:0.5:1.0 (70/10/20, %w/w) exhibited the smallest droplet size, while the ratio of 4:0.5:0.5 (80/10/10, %w/w) resulted in the largest droplet size. The zeta potential values for all formulations ranged from −0.80 to 0.43 mV, showing no significant variation between ratios. The PDI values were relatively low, ranging from 0.05 to 0.18, indicating a high degree of uniformity in particle size distribution. When selecting the optimal formulation for further study, it is important to consider the small particle size, the narrow size distribution, and the amount of surfactant used. Typically, the goal is to use a minimal surfactant amount that can still produce nanoparticles. The formulation with Cremophor® RH40/jasmine oil/water at a ratio of 3:1:1 (60/20/20, %w/w) was chosen for the preparation of curcumin-loaded L-SNEDDSs, as it exhibited a size in the nanosize range, narrow PDI, and required the least amount of surfactant.
After determining the optimal ratio for preparing microemulsion, curcumin was incorporated into the formulation at the specified ratio. In this curcumin-loaded L-SNEDDS, water was excluded as a component to facilitate its subsequent mixing with an absorbent. The resulting formulation appeared as a red-brownish viscous liquid, as shown in Figure 3.
The droplet size and zeta potential values of unloaded L-SNEDDSs and curcumin-loaded L-SNEDDSs are presented in Table 3. The mean droplet size of the curcumin-loaded L-SNEDDS was 188.52 ± 26.21 nm, showing a significant increase in droplet size compared to the unloaded L-SNEDDS. This observation aligns with the findings of Thirapit Subongkot et al. [34], who reported that the particle size of drug-loaded microemulsions tends to be larger than blank microemulsions due to the incorporation of drug molecules into the internal phase of the microemulsion. This provides clear evidence that adding curcumin increased the droplet size in the microemulsion. In contrast, no significant changes were observed in the zeta potential and PDI values.

3.4. Characterization of Microemulsion and S-SNEDDS

In preparing S-SNEDDSs, the curcumin-loaded L-SNEDDS was mixed with three different adsorbents, namely Tablettose® 80, FlowLac® 100, and GranuLac® 200, until a dry powder was obtained. The optimal ratio of curcumin-loaded L-SNEDDSs to each adsorbent varied. For Tablettose® 80 and FlowLac® 100, the ratio of curcumin-loaded L-SNEDDSs to adsorbent was 1:4 to achieve a dry powder, while for GranuLac® 200, the ratio was 1:5. This indicates that GranuLac® 200 has a lower adsorption capacity compared to Tablettose® 80 and FlowLac® 100, which may be due to GranuLac® 200 having fewer pores and smaller particle size, resulting in less effective liquid adsorption compared to the other two adsorbents. The S-SNEDDS formulations were tested for flowability, and it was found that the formulation using GranuLac® 200 as the absorbent exhibited the best flow properties, as shown in Table 4. This result did not align with theoretical expectations [35]. FlowLac® 100 and Tablettose® 80, which have spherical particle shapes and smoother surfaces, were anticipated to flow better due to their granular characteristics. In contrast, GranuLac® 200 is a dry powder. However, the better flow properties of GranuLac® 200 may be attributed to the higher proportion of absorbent used in its formulation. Additionally, the poorer flowability of FlowLac® 100 and Tablettose® 80 may be due to their tendency to absorb moisture, which can reduce their granular properties.
The mean droplet size and zeta potential values of the S-SNEDDS formulations after redispersion in HCl (pH 1.2) are presented in Table 5. Among the formulations, GranuLac® 200 showed the smallest droplet size, while Tablettose® 80 exhibited the largest. There were no significant differences in the zeta potential and PDI values across the formulations, with PDI values for all formulations remaining below 0.21. These results suggest that the S-SNEDDS formed homogenous droplets and uniform microemulsions [36]. The mean zeta potential values of the formulations ranged from +0.31 to +1.25 mV. In this study, nonionic surfactants were used in each formulation. Nonionic surfactants will likely reside at the interface between the internal phase and the dispersing medium [37]. The relatively low zeta potential observed could be due to the adsorption of the nonionic surfactant. The adsorption of surfactants at the interface helps stabilize emulsions through either electrostatic or steric stabilization mechanisms [38]. Some colloidal systems remain stable despite a low zeta potential, which may be attributed to van der Waals attractive forces and steric effects [39].
Figure 4 shows that the S-SNEDDS formulations improve curcumin dissolution compared to the curcumin powder. The FlowLac® 100 formulation released 69.81% of loaded curcumin within 15 min, while the percentage of curcumin dissolution at 15 min for Tablettose® 80 and GranuLac® 200 formulations were 68.31% and 60.58%, respectively. Compared to the curcumin powder, it was shown that the dissolution of curcumin was significantly higher in the S-SNEDDS formulation. The initial rapid release of curcumin from the S-SNEDDS formulation under pH 1.2 conditions can be explained by various factors related to the design and composition of the formulation. The S-SNEDDS improves curcumin’s solubility and bioavailability, which typically exhibits low values for these parameters in aqueous environments. Key components of the formulation, such as surfactants, significantly contribute to promoting the quick release of curcumin. Surfactants such as Cremophor® RH40 are incorporated into SNEDDS formulations to lower interfacial tension, creating nano-sized droplets when exposed to the aqueous phase. This enhances the surface area available for drug release, facilitating the fast dissolution of curcumin [10,40]. Accordingly, the developed solid SNEDDS formulations improved the solubility and dissolution of curcumin at pH 1.2.
The DSC thermograms of curcumin powder, the plain solid carrier (FlowLac® 100), and the curcumin-loaded S-SNEDDS formulation are displayed in Figure 5. Curcumin powder exhibited a sharp endothermic melting peak at 179.4 °C, confirming its crystalline state [41]. The solid carrier, α-lactose monohydrate (FlowLac® 100), showed two distinct endothermic peaks at approximately 145 °C and 220 °C, corresponding to the loss of crystalline water [42] and the melting point of anhydrous α-lactose [43], respectively. The other solid carriers exhibited peaks similar to those of FlowLac® 100, with only minor differences in the positions of the observed peaks. Therefore, only the results for FlowLac® 100 are presented. In the S-SNEDDS formulation, the melting peak of curcumin completely disappeared. This absence of the melting peak may be attributed to the small quantity of curcumin present or the conversion of crystalline curcumin into an amorphous state within the formulation. This assumption was consistent with the preparation of the physical mixture shown in Figure 5C,D. It was observed that when the amount of FlowLac® 100 was reduced in Figure 5D, a peak corresponding to curcumin appeared in the same region as that of curcumin powder. Therefore, the absence of a curcumin peak in the S-SNEDDS formulation is likely in line with the assumption above.
The PXRD patterns are shown in Figure 6. Curcumin powder exhibited characteristic X-ray diffraction peaks, particularly in the 2θ range of 5° to 30°, consistent with the PXRD results reported by Abdulrahman Alshadidi et al. [44] and Zahra Sayyar et al. [45]. The solid carriers (FlowLac® 100) displayed diffraction peaks, especially in the 2θ range of 5° to 40°, in agreement with the PXRD findings of Rafael Fagnani et al. [46]. The physical mixture of curcumin and the solid carrier at a 1:2 ratio showed diffraction peaks corresponding to both curcumin and α-lactose monohydrate. In contrast, the S-SNEDDS formulation revealed only the X-ray diffraction peaks of α-lactose monohydrate, while the peaks corresponding to curcumin were absent. Thus, the PXRD results were consistent with the DSC findings, indicating that when a large amount of the solid carrier was present, it masked the curcumin peaks, causing them to not appear in the PXRD pattern of the S-SNEDDS.
The FTIR spectra of curcumin powder, FlowLac® 100, the physical mixture of curcumin with FlowLac® 100, and the curcumin-loaded S-SNEDDS formulation are shown in Figure 7. As depicted in Figure 7A, the FTIR spectrum of curcumin matches the spectrum reported by E.H. Ismail et al. [47]. Key peaks in the IR spectrum of curcumin include the stretching vibration of the phenolic O-H at 3509 cm−1, the peak at 1625 cm−1 attributed predominantly to the overlapping stretching vibrations of alkenes (C=C) and carbonyl (C=O), and the peak at 1599 cm−1 representing benzene ring stretching vibrations. Additional peaks include C-H bending vibrations at 1427 cm−1, aromatic C-O stretching at 1271 cm−1, and C-O-C stretching vibrations at 1150 cm−1. For pure FlowLac® 100, the α-lactose monohydrate exhibited characteristic bands at 2974 cm−1 (stretching vibration of the OH group), a weak band at 1381 cm−1 (bending vibration of the OH group), and bands between 1256 and 1120 cm−1 corresponding to the asymmetric stretching vibrations of C-O-C in glucose and galactose. A band specific to crystalline lactose was observed around 920 cm−1 [48].
For the physical mixture of curcumin and FlowLac® 100 at a ratio of 1:2 (Figure 7D), the vibrational peaks corresponding to the characteristic functional groups of both α-lactose monohydrate and curcumin were present in the IR spectra, with no significant changes in peak characteristics. In the IR spectrum of the curcumin-loaded S-SNEDDS formulation (Figure 7B), a key peak at 3509 cm−1 which corresponds to the stretching of the phenolic O-H group of curcumin, was observed, confirming the presence of curcumin in the formulation. However, the intensity of this peak was reduced. A decrease in the peak intensity of the drug in SNEDDS formulations has been suggested to indicate the miscibility of the drug with the formulation vehicles [49]. The FTIR peaks in the range of 1150–920 cm−1 for the SNEDDS formulations were similar to those observed in the physical mixture of curcumin and FlowLac® 100 at a 1:4 ratio. The high content of FlowLac® 100 had masked the curcumin peaks in this region. This observation was consistent with the results of DSC and PXRD studies, where a large amount of the solid carrier had obscured the curcumin peaks, making them less distinct in the SNEDDS formulations.

3.5. Stability Study

During storage, the three formulations of curcumin-loaded S-SNEDDSs retained their yellowish powder appearance, consistent with the baseline observed on day 0, as shown in Figure 8. There were no visible changes in the color or evidence of drug separation or aggregation, indicating that the curcumin-loaded S-SNEDDS exhibited good physical stability. The percentage of curcumin remaining at 40 °C and 75% relative humidity (RH), compared to the baseline, is presented in Figure 9. After four weeks, the average percentage of curcumin remaining in the Tablettose® 80 formulation was 70.11 ± 0.7% (a decrease of 18.39% from day 0), while the FlowLac® 100 formulation retained 73.84 ± 1.58% (a reduction of 11.56% from day 0). The GranuLac® 200 formulation retained 69.73 ± 1.19% (a decrease of 20.01% from day 0). This significant reduction in the percentage of curcumin remaining across all formulations indicates that curcumin was not stable under these conditions. A study by Mahesh Kharat et al. [50] reported that curcumin in solution degraded (remaining at >85%) at 37 °C after one month. Similarly, an accelerated stability test conducted by Ahmad Abdul-Wahhab Shahba et al. [16] at 40 °C and 75% RH over six months examined multi-layer self-nanoemulsifying pellets (ML-SNEPs) in comparison to single-layer self-nanoemulsifying pellets (SL-SNEPs) and liquid SNEDDSs. Their results showed that cinnarizine remained at 86% in ML-SNEP formulations, whereas it remained at 79% and 75% in SL-SNEP formulations and liquid SNEDDSs, respectively. This finding highlighted that solidifying cinnarizine in ML-SNEPs significantly improved its stability compared to SL-SNEPs and liquid SNEDDSs [16]. Therefore, to enhance the stability of curcumin-loaded S-SNEDDSs, transitioning from a powder form to multi-layer self-nanoemulsifying pellets (ML-SNEPs) might be a promising strategy.
Table 6 presents the average droplet size, and Table 7 shows the zeta potential values for the curcumin-loaded S-SNEDDSs at 0, 1, 2, 3, and 4 weeks of storage at 40 °C and 75% RH. A general trend of increasing average droplet size was observed for all three formulations during storage, although the sizes remained within the nano-range (44.97–185.77 nm). In the Tablettose® 80, FlowLac® 100, and GranuLac® 200 formulations, the droplet size showed a significant increase after two weeks. These results suggest that storage temperature and humidity influence droplet size. Bijoy Bera et al. [51] reported that increased temperature promotes coalescence events. Therefore, an extended, accelerated stability study, lasting up to 3 months, is recommended to monitor potential coalescence events. The PDI values for all formulations remained below 0.24, ranging from 0.095 ± 0.001 to 0.227 ± 0.02, indicating that the curcumin-loaded S-SNEDDSs maintained homogeneous droplet distribution and uniform microemulsions under the storage conditions. The zeta potential values for all formulations ranged from −0.85 ± 1.08 to 2.29 ± 2.23, and the average zeta potential at 1, 2, 3, and 4 weeks of nearly all formulations did not differ significantly from the baseline. Thus, storage temperature and humidity had no significant impact on zeta potential.
The dissolution profiles of the S-SNEDDS formulations after four weeks of storage at 40 °C and 75% RH are shown in Figure 10. The storage conditions affected the dissolution rate of each formulation. Specifically, the dissolution rate was slowed down for curcumin and all formulations, including Tablettose® 80, FlowLac® 100, and GranuLac® 200. Among the formulations, the highest dissolution rates after four weeks were observed for the FlowLac® 100 and GranuLac® 200 formulations, at 45.22% (a 24.59% decrease from baseline) and 45.28% (a 15.30% decrease from baseline), respectively. The Tablettose® 80 formulation exhibited the lowest dissolution rate compared to the other formulations, at 41.32% (a 26.99% decrease from baseline). The dissolution rate of curcumin itself also showed a marked decline, dropping from 11.62% to 1.58%. This reduction may be attributed to curcumin degradation at elevated temperatures during storage, which aligns with the curcumin content results in this study, showing a significant decrease in the percentage of curcumin after the 4-week period. Therefore, the observed decrease in the dissolution rate across all formulations is correlated with the reduction in the percentage of curcumin, as indicated by the curcumin content results.

4. Conclusions

The study successfully developed a solid self-nanoemulsifying drug delivery system (S-SNEDDS) incorporating curcumin, jasmine oil, and Cremophor® RH40, utilizing various lactose types as solid carriers. Upon redispersion in 0.1 M HCl, the particle sizes of all S-SNEDDS formulations ranged from 44.97 to 75.27 nm, with low PDI values, indicating the formation of homogeneous droplets and uniform microemulsions. The mean zeta potential values for the formulations varied between +0.31 and +1.25 mV, with the relatively low zeta potential likely resulting from the adsorption of nonionic surfactants. This adsorption aids in stabilizing the emulsions through electrostatic or steric mechanisms. Dissolution studies in simulated gastric fluid showed a marked improvement in curcumin solubility in the S-SNEDDS formulations compared to the curcumin powder. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses confirmed the presence of curcumin in the S-SNEDDS, while Fourier-transform infrared (FTIR) spectroscopy indicated compatibility between curcumin and the excipients. Furthermore, an accelerated stability study conducted over four weeks at 40 °C and 75% relative humidity revealed no significant changes in the physical appearance of the S-SNEDDS formulations. These results suggest that the S-SNEDDS effectively enhances curcumin solubility and may improve its bioavailability for oral delivery.

5. Patents

Portions of this content have been submitted for a petty patent application in Thailand under application number 2403000236.

Author Contributions

Conceptualization, P.T., P.J., N.N., E.Y., T.F., N.H. and P.K.; methodology, P.T., P.J., N.N., E.Y., T.F. and P.K.; formal analysis, P.T., P.J., N.N. and P.K.; investigation, P.T., P.J., N.N. and P.K.; resources, E.Y., T.F., N.H. and P.K.; writing—original draft preparation, P.T., P.J. and N.N.; writing—review and editing, N.H. and P.K.; visualization, P.T., P.J., N.N. and P.K.; supervision, E.Y., T.F., N.H. and P.K.; project administration, P.K.; funding acquisition, P.K. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Thammasat University Research Unit in Smart Materials and Innovative Technology for Pharmaceutical Applications (SMIT-Pharm) [Project ID 6305016].

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.

Acknowledgments

This work was supported by the Thammasat University Research Unit in Smart Materials and Innovative Technology for Pharmaceutical Applications (SMIT-Pharm) [Project ID 6305016]. The authors would like to express their sincere gratitude to Thirapit Subongkot for suggesting the development of the ternary phase diagram. We also deeply appreciate the laboratory assistance provided by Premjit Limpamanoch. Furthermore, we extend our thanks to MEGGLE GmbH & Co. KG for their generous provision of Tablettose® 80, FlowLac® 100, and GranuLac® 200 samples. Additionally, we are grateful to the School of Pharmacy and Pharmaceutical Sciences at Hoshi University and the Faculty of Pharmacy at Thammasat University for their support in providing facilities and equipment essential to this work.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Liu, Z.; Smart, J.D.; Pannala, A.S. Recent developments in formulation design for improving oral bioavailability of curcumin: A review. J. Drug Deliv. Sci. Technol. 2020, 60, 102082. [Google Scholar] [CrossRef]
  2. Sabet, S.; Rashidinejad, A.; Melton, L.D.; McGillivray, D.J. Recent advances to improve curcumin oral bioavailability. Trends Food Sci. Technol. 2021, 110, 253–266. [Google Scholar] [CrossRef]
  3. Kim, M.-K.; Choi, G.-J.; Lee, H.-S. Fungicidal Property of Curcuma longa L. Rhizome-Derived Curcumin against Phytopathogenic Fungi in a Greenhouse. J. Agric. Food Chem. 2003, 51, 1578–1581. [Google Scholar] [CrossRef] [PubMed]
  4. Reddy, R.C.; Vatsala, P.G.; Keshamouni, V.G.; Padmanaban, G.; Rangarajan, P.N. Curcumin for malaria therapy. Biochem. Biophys. Res. Commun. 2005, 326, 472–474. [Google Scholar] [CrossRef]
  5. Senft, C.; Polacin, M.; Priester, M.; Seifert, V.; Kögel, D.; Weissenberger, J. The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas. BMC Cancer 2010, 10, 491. [Google Scholar] [CrossRef]
  6. Schneider, C.; Gordon, O.N.; Edwards, R.L.; Luis, P.B. Degradation of Curcumin: From Mechanism to Biological Implications. J. Agric. Food Chem. 2015, 63, 7606–7614. [Google Scholar] [CrossRef]
  7. Paolino, D.; Vero, A.; Cosco, D.; Pecora, T.M.; Cianciolo, S.; Fresta, M.; Pignatello, R. Improvement of Oral Bioavailability of Curcumin upon Microencapsulation with Methacrylic Copolymers. Front. Pharmacol. 2016, 7, 485. [Google Scholar] [CrossRef]
  8. Hafez Ghoran, S.; Calcaterra, A.; Abbasi, M.; Taktaz, F.; Nieselt, K.; Babaei, E. Curcumin-Based Nanoformulations: A Promising Adjuvant towards Cancer Treatment. Molecules 2022, 27, 5236. [Google Scholar] [CrossRef]
  9. Marques, M.S.; Cordeiro, M.F.; Marinho, M.A.G.; Vian, C.O.; Vaz, G.R.; Alves, B.S.; Jardim, R.D.; Hort, M.A.; Dora, C.L.; Horn, A.P. Curcumin-loaded nanoemulsion improves haemorrhagic stroke recovery in wistar rats. Brain Res. 2020, 1746, 147007. [Google Scholar] [CrossRef]
  10. Ahmad, S.; Hafeez, A. Formulation and Development of Curcumin-Piperine-Loaded S-SNEDDS for the Treatment of Alzheimer’s Disease. Mol. Neurobiol. 2023, 60, 1067–1082. [Google Scholar] [CrossRef]
  11. Kazi, M.; Shahba, A.A.; Alrashoud, S.; Alwadei, M.; Sherif, A.Y.; Alanazi, F.K. Bioactive Self-Nanoemulsifying Drug Delivery Systems (Bio-SNEDDS) for Combined Oral Delivery of Curcumin and Piperine. Molecules 2020, 25, 1703. [Google Scholar] [CrossRef] [PubMed]
  12. Venkata Ramana Rao, S.; Shao, J. Self-nanoemulsifying drug delivery systems (SNEDDS) for oral delivery of protein drugs: I. Formulation development. Int. J. Pharm. 2008, 362, 2–9. [Google Scholar] [CrossRef] [PubMed]
  13. Buya, A.B.; Beloqui, A.; Memvanga, P.B.; Préat, V. Self-Nano-Emulsifying Drug-Delivery Systems: From the Development to the Current Applications and Challenges in Oral Drug Delivery. Pharmaceutics 2020, 12, 1194. [Google Scholar] [CrossRef] [PubMed]
  14. Nazari-Vanani, R.; Moezi, L.; Heli, H. In vivo evaluation of a self-nanoemulsifying drug delivery system for curcumin. Biomed. Pharmacother. 2017, 88, 715–720. [Google Scholar] [CrossRef]
  15. Khursheed, R.; Singh, S.K.; Kumar, B.; Wadhwa, S.; Gulati, M.; Anupriya, A.; Awasthi, A.; Vishwas, S.; Kaur, J.; Corrie, L.; et al. Self-nanoemulsifying composition containing curcumin, quercetin, Ganoderma lucidum extract powder and probiotics for effective treatment of type 2 diabetes mellitus in streptozotocin induced rats. Int. J. Pharm. 2022, 612, 121306. [Google Scholar] [CrossRef]
  16. Shahba, A.A.-W.; Alanazi, F.K.; Abdel-Rahman, S.I. Stabilization benefits of single and multi-layer self-nanoemulsifying pellets: A poorly-water soluble model drug with hydrolytic susceptibility. PLoS ONE 2018, 13, e0198469. [Google Scholar] [CrossRef]
  17. Yi, T.; Wan, J.; Xu, H.; Yang, X. A new solid self-microemulsifying formulation prepared by spray-drying to improve the oral bioavailability of poorly water soluble drugs. Eur. J. Pharm. Biopharm. 2008, 70, 439–444. [Google Scholar] [CrossRef]
  18. Abdalla, A.; Mäder, K. ESR studies on the influence of physiological dissolution and digestion media on the lipid phase characteristics of SEDDS and SEDDS pellets. Int. J. Pharm. 2009, 367, 29–36. [Google Scholar] [CrossRef]
  19. Kim, J.S.; Din, F.u.; Cho, H.J.; Choi, Y.J.; Woo, M.R.; Cheon, S.; Ji, S.H.; Park, S.; Youn, Y.S.; Oh, K.T.; et al. Impact of carrier hydrophilicity on solid self nano-emulsifying drug delivery system and self nano-emulsifying granule system. Int. J. Pharm. 2023, 648, 123578. [Google Scholar] [CrossRef]
  20. Beg, S.; Swain, S.; Singh, H.P.; Patra Ch, N.; Rao, M.E. Development, optimization, and characterization of solid self-nanoemulsifying drug delivery systems of valsartan using porous carriers. AAPS PharmSciTech 2012, 13, 1416–1427. [Google Scholar] [CrossRef]
  21. Christensen, K.L.; Pedersen, G.P.; Kristensen, H.G. Physical stability of redispersible dry emulsions containing amorphous sucrose. Eur. J. Pharm. Biopharm. 2002, 53, 147–153. [Google Scholar] [CrossRef] [PubMed]
  22. Chen, Y.; Chen, C.; Zheng, J.; Chen, Z.; Shi, Q.; Liu, H. Development of a Solid Supersaturatable Self-Emulsifying Drug Delivery System of Docetaxel with Improved Dissolution and Bioavailability. Biol. Pharm. Bull. 2011, 34, 278–286. [Google Scholar] [CrossRef] [PubMed]
  23. Kim, D.W.; Kang, J.H.; Oh, D.H.; Yong, C.S.; Choi, H.G. Development of novel flurbiprofen-loaded solid self-microemulsifying drug delivery system using gelatin as solid carrier. J. Microencapsul. 2012, 29, 323–330. [Google Scholar] [CrossRef] [PubMed]
  24. Subongkot, T.; Sirirak, T. Development and skin penetration pathway evaluation of microemulsions for enhancing the dermal delivery of celecoxib. Colloids Surf. B Biointerfaces 2020, 193, 111103. [Google Scholar] [CrossRef]
  25. Shah, D.S.; Moravkar, K.K.; Jha, D.K.; Lonkar, V.; Amin, P.D.; Chalikwar, S.S. A concise summary of powder processing methodologies for flow enhancement. Heliyon 2023, 9, e16498. [Google Scholar] [CrossRef]
  26. Fonseca-Santos, B.; Gremião, M.P.D.; Chorilli, M. A simple reversed phase high-performance liquid chromatography (HPLC) method for determination of in situ gelling curcumin-loaded liquid crystals in in vitro performance tests. Arab. J. Chem. 2017, 10, 1029–1037. [Google Scholar] [CrossRef]
  27. Nonsuwan, P.; Phiboonchaiyanan, P.P.; Hirun, N.; Kraisit, P. Curcumin-loaded methacrylate pullulan with grafted carboxymethyl-β-cyclodextrin to form hydrogels for wound healing: In vitro evaluation. Carbohydr. Polym. 2023, 321, 121294. [Google Scholar] [CrossRef]
  28. Tønnesen, H.H. Solubility, chemical and photochemical stability of curcumin in surfactant solutions. Studies of curcumin and curcuminoids, XXVIII. Pharmazie 2002, 57, 820–824. [Google Scholar]
  29. Schmidt, M.; Huber, V.; Touraud, D.; Kunz, W. Aromas: Lovely to Smell and Nice Solvents for Polyphenols? Curcumin Solubilisation Power of Fragrances and Flavours. Molecules 2024, 29, 294. [Google Scholar] [CrossRef]
  30. Huber, V.; Schmidt, M.; Touraud, D.; Kunz, W. Towards a sustainable and green extraction of curcuminoids using the essential oil of Cinnamomum cassia. Sustain. Food Technol. 2023, 1, 319–327. [Google Scholar] [CrossRef]
  31. Engelberg, S.; Lin, Y.; Assaraf, Y.G.; Livney, Y.D. Targeted Nanoparticles Harboring Jasmine-Oil-Entrapped Paclitaxel for Elimination of Lung Cancer Cells. Int. J. Mol. Sci. 2021, 22, 1019. [Google Scholar] [CrossRef] [PubMed]
  32. Weerapol, Y.; Limmatvapirat, S.; Nunthanid, J.; Sriamornsak, P. Self-nanoemulsifying drug delivery system of nifedipine: Impact of hydrophilic-lipophilic balance and molecular structure of mixed surfactants. AAPS PharmSciTech 2014, 15, 456–464. [Google Scholar] [CrossRef] [PubMed]
  33. Singh, I.R.; Pulikkal, A.K. Preparation, stability and biological activity of essential oil-based nano emulsions: A comprehensive review. OpenNano 2022, 8, 100066. [Google Scholar] [CrossRef]
  34. Subongkot, T.; Ngawhirunpat, T. Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid. Int. J. Nanomed. 2017, 12, 5585–5599. [Google Scholar] [CrossRef]
  35. Bettie van der Walt, E. Evaluation and Comparison of the Physical Properties and Drug Release Characteristics of Directly Compressible Lactose-Based Filler/Binders; North-West University, Potchefstroom Campus: Potchefstroom, South Africa, 2010; Available online: https://dspace.nwu.ac.za/bitstream/handle/10394/4922/vanderwalt_erasmus_b.pdf?sequence=2 (accessed on 20 October 2024).
  36. Nasr, A.; Gardouh, A.; Ghorab, M. Novel Solid Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) for Oral Delivery of Olmesartan Medoxomil: Design, Formulation, Pharmacokinetic and Bioavailability Evaluation. Pharmaceutics 2016, 8, 20. [Google Scholar] [CrossRef]
  37. Sargam, Y.; Wang, K.; Tsyrenova, A.; Liu, F.; Jiang, S. Effects of anionic and nonionic surfactants on the dispersion and stability of nanoSiO2 in aqueous and cement pore solutions. Cem. Concr. Res. 2021, 144, 106417. [Google Scholar] [CrossRef]
  38. McClements, D.J.; Jafari, S.M. Improving emulsion formation, stability and performance using mixed emulsifiers: A review. Adv. Colloid Interface Sci. 2018, 251, 55–79. [Google Scholar] [CrossRef]
  39. Agmo Hernández, V. An overview of surface forces and the DLVO theory. ChemTexts 2023, 9, 10. [Google Scholar] [CrossRef]
  40. Józsa, L.; Vasvári, G.; Sinka, D.; Nemes, D.; Ujhelyi, Z.; Vecsernyés, M.; Váradi, J.; Fenyvesi, F.; Lekli, I.; Gyöngyösi, A.; et al. Enhanced Antioxidant and Anti-Inflammatory Effects of Self-Nano and Microemulsifying Drug Delivery Systems Containing Curcumin. Molecules 2022, 27, 6652. [Google Scholar] [CrossRef]
  41. Opustilová, K.; Lapčíková, B.; Lapčík, L.; Gautam, S.; Valenta, T.; Li, P. Physico-Chemical Study of Curcumin and Its Application in O/W/O Multiple Emulsion. Foods 2023, 12, 1394. [Google Scholar] [CrossRef]
  42. GombÁs, Á.; Szabó-Révész, P.; Kata, M.; Regdon, G.; Erős, I. Quantitative Determination of Crystallinity of α-Lactose Monohydrate by DSC. J. Therm. Anal. Calorim. 2002, 68, 503–510. [Google Scholar] [CrossRef]
  43. Larhrib, H.; Martin, G.P.; Prime, D.; Marriott, C. Characterisation and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolised salbutamol sulfate from dry powder inhalers. Eur. J. Pharm. Sci. 2003, 19, 211–221. [Google Scholar] [CrossRef] [PubMed]
  44. Alshadidi, A.; Shahba, A.A.; Sales, I.; Rashid, M.A.; Kazi, M. Combined Curcumin and Lansoprazole-Loaded Bioactive Solid Self-Nanoemulsifying Drug Delivery Systems (Bio-SSNEDDS). Pharmaceutics 2021, 14, 2. [Google Scholar] [CrossRef] [PubMed]
  45. Sayyar, Z.; Jafarizadeh, H. Photocatalytic and antibacterial activities study of prepared self-cleaning nanostructure surfaces using synthesized and coated ZnO nanoparticles with Curcumin nanodispersion. Z. Fur Krist. Mater. 2018, 234, 307–328. [Google Scholar] [CrossRef]
  46. Fagnani, R.; Battaglini, A.; Beloti, V.; Urbano, A.; Bronzol, J. Alcohol Stability of Milk from the Perspective of X-Ray Diffractometry. Food Biophys. 2016, 11, 198–205. [Google Scholar] [CrossRef]
  47. Ismail, E.; Sabry, D.; Mahdi, H.; Khalil, M. Synthesis and Characterization of some Ternary Metal Complexes of Curcumin with 1,10-phenanthroline and their Anticancer Applications. J. Sci. Res. 2014, 6, 509–519. [Google Scholar] [CrossRef]
  48. Balieiro, A.L.; Santos, R.A.; Pereira, M.M.; Figueiredo, R.T.; Freitas, L.S.; Alsina, O.L.S.d.; Lima, A.S.; Soares, C.M.F. Adsorption process of molecularly imprinted silica for extraction of lactose from milk. Braz. J. Chem. Eng. 2016, 33, 361–372. [Google Scholar] [CrossRef]
  49. Rajesh, S.Y.; Singh, S.K.; Pandey, N.K.; Sharma, P.; Bawa, P.; Kumar, B.; Gulati, M.; Jain, S.K.; Gowthamarajan, K.; Singh, S. Impact of various solid carriers and spray drying on pre/post compression properties of solid SNEDDS loaded with glimepiride: In vitro-ex vivo evaluation and cytotoxicity assessment. Drug Dev. Ind. Pharm. 2018, 44, 1056–1069. [Google Scholar] [CrossRef]
  50. Kharat, M.; Du, Z.; Zhang, G.; McClements, D.J. Physical and Chemical Stability of Curcumin in Aqueous Solutions and Emulsions: Impact of pH, Temperature, and Molecular Environment. J. Agric. Food Chem. 2017, 65, 1525–1532. [Google Scholar] [CrossRef]
  51. Bera, B.; Khazal, R.; Schroën, K. Coalescence dynamics in oil-in-water emulsions at elevated temperatures. Sci. Rep. 2021, 11, 10990. [Google Scholar] [CrossRef]
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Figure 1. The preparation of S-SNEDDSs (A) and the formation of nanoemulsions (B).
Figure 1. The preparation of S-SNEDDSs (A) and the formation of nanoemulsions (B).
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Figure 2. Ternary phase diagram with jasmine oil as the oil phase, water as the aqueous phase, and Cremophor® RH40 as the surfactant. The yellow-shaded area represents the microemulsion region. The description of the proportions of each ingredient, indicated by numbers 1 to 5, is provided in Table 2.
Figure 2. Ternary phase diagram with jasmine oil as the oil phase, water as the aqueous phase, and Cremophor® RH40 as the surfactant. The yellow-shaded area represents the microemulsion region. The description of the proportions of each ingredient, indicated by numbers 1 to 5, is provided in Table 2.
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Figure 3. Appearance of curcumin-loaded L-SNEDDS.
Figure 3. Appearance of curcumin-loaded L-SNEDDS.
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Figure 4. In vitro dissolution profiles of S-SNEDDS formulations and curcumin powder in simulated gastric fluid pH 1.2. Data are expressed as mean ± SD (n = 6). * (at 5 min), ** (at 60 min) p < 0.05 compared with the curcumin.
Figure 4. In vitro dissolution profiles of S-SNEDDS formulations and curcumin powder in simulated gastric fluid pH 1.2. Data are expressed as mean ± SD (n = 6). * (at 5 min), ** (at 60 min) p < 0.05 compared with the curcumin.
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Figure 5. DSC thermograms of (A) curcumin powder, (B) curcumin-loaded S-SNEDDS formulations that used FlowLac® 100 as the solid carrier, (C) physical mixtures of curcumin with FlowLac® 100 in ratio 1:4, (D) physical mixtures of curcumin with FlowLac® 100 in ratio 1:2, and (E) pure FlowLac® 100.
Figure 5. DSC thermograms of (A) curcumin powder, (B) curcumin-loaded S-SNEDDS formulations that used FlowLac® 100 as the solid carrier, (C) physical mixtures of curcumin with FlowLac® 100 in ratio 1:4, (D) physical mixtures of curcumin with FlowLac® 100 in ratio 1:2, and (E) pure FlowLac® 100.
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Figure 6. X-ray powder diffraction of (A) curcumin powder, (B) curcumin-loaded S-SNEDDS formulations that used FlowLac® 100 as the solid carrier, (C) physical mixtures of curcumin with FlowLac® 100 in ratio 1:4, (D) physical mixtures of curcumin with FlowLac® 100 in ratio 1:2, and (E) pure FlowLac® 100.
Figure 6. X-ray powder diffraction of (A) curcumin powder, (B) curcumin-loaded S-SNEDDS formulations that used FlowLac® 100 as the solid carrier, (C) physical mixtures of curcumin with FlowLac® 100 in ratio 1:4, (D) physical mixtures of curcumin with FlowLac® 100 in ratio 1:2, and (E) pure FlowLac® 100.
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Figure 7. FTIR spectra of (A) curcumin powder, (B) curcumin-loaded S-SNEDDS formulations that used FlowLac® 100 as the solid carrier, (C) physical mixtures of curcumin with FlowLac® 100 in ratio 1:4, (D) physical mixtures of curcumin with FlowLac® 100 in ratio 1:2, and (E) pure FlowLac® 100.
Figure 7. FTIR spectra of (A) curcumin powder, (B) curcumin-loaded S-SNEDDS formulations that used FlowLac® 100 as the solid carrier, (C) physical mixtures of curcumin with FlowLac® 100 in ratio 1:4, (D) physical mixtures of curcumin with FlowLac® 100 in ratio 1:2, and (E) pure FlowLac® 100.
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Figure 8. The physical appearance of the three S-SNEDDS formulations (Tablettose® 80 formulation; T, FlowLac® 100 formulation; F, GranuLac® 200 formulation; G) during the accelerated stability test at various time points: (A) 1 week, (B) 2 weeks, (C) 3 weeks, and (D) 4 weeks.
Figure 8. The physical appearance of the three S-SNEDDS formulations (Tablettose® 80 formulation; T, FlowLac® 100 formulation; F, GranuLac® 200 formulation; G) during the accelerated stability test at various time points: (A) 1 week, (B) 2 weeks, (C) 3 weeks, and (D) 4 weeks.
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Figure 9. The percentage of curcumin remaining in the S-SNEDDS formulations after storage for 0 and 4 weeks at 40 °C and 75% RH. Each value represents the mean ± standard deviation (n = 3). * p < 0.05 compared with the 0 week.
Figure 9. The percentage of curcumin remaining in the S-SNEDDS formulations after storage for 0 and 4 weeks at 40 °C and 75% RH. Each value represents the mean ± standard deviation (n = 3). * p < 0.05 compared with the 0 week.
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Figure 10. In vitro dissolution profiles of S-SNEDDS formulations and curcumin powder after four weeks of storage at 40 °C and 75% RH. Data are expressed as mean ± SD (n = 6). * (at 5 min), ** (at 60 min) p < 0.05 compared with the curcumin.
Figure 10. In vitro dissolution profiles of S-SNEDDS formulations and curcumin powder after four weeks of storage at 40 °C and 75% RH. Data are expressed as mean ± SD (n = 6). * (at 5 min), ** (at 60 min) p < 0.05 compared with the curcumin.
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Table 1. The solubility of curcumin in various oils and surfactants.
Table 1. The solubility of curcumin in various oils and surfactants.
OilsSolubility (mg/mL)SurfactantsSolubility (mg/mL)
Chamomile0.31 ± 0.006Tween® 2014.86 ± 0.07
Clove2.14 ± 0.043Tween® 8015.63 ± 0.03
Rose0.2 ± 0.006Span® 203.08 ± 0.03
Eucalyptus1.56 ± 0.026Span® 801.47 ± 0.01
Jasmine7.28 ± 0.615Cremophor® EL15.08 ± 0.06
Lavender2.41 ± 0.037Cremophor® RH4027.12 ± 0.45
Lemon0.3 ± 0.001
Sunflower0.26 ± 0.011
Each value represents the mean ± SD (n = 3).
Table 2. Droplet size and zeta potential of five selected ratios from the microemulsion region.
Table 2. Droplet size and zeta potential of five selected ratios from the microemulsion region.
OrderCremophor® RH40 (g)Jasmine Oil (g)Water (g)Size (nm)PDIZeta Potential (mV)
13.01.001.003.75 ± 0.52 *0.05 ± 0.01 **−0.68 ± 1.44
23.51.000.505.44 ± 0.90 *0.09 ± 0.04 **−0.80 ± 1.63
33.50.750.753.67 ± 0.51 *0.10 ± 0.06 **0.35 ± 1.83
43.50.501.002.67 ± 1.16 *0.17 ± 0.080.43 ± 1.28
54.00.500.5083.56 ± 61.770.18 ± 0.06−0.59 ± 2.92
Each value represents the mean ± SD (n = 3). * (size), ** (PDI); p < 0.05 compared with the order No. 5.
Table 3. Droplet size, PDI, and zeta potential of unloaded L-SNEDDSs and curcumin-loaded L-SNEDDSs (n = 3).
Table 3. Droplet size, PDI, and zeta potential of unloaded L-SNEDDSs and curcumin-loaded L-SNEDDSs (n = 3).
Cremophor® RH40 (g)Jasmine Oil (g)Water (g)Curcumin (mg)Size (nm)PDIZeta Potential (mV)
311-3.75 ± 0.520.05 ± 0.01−0.68 ± 1.44
31-100 mg188.52 ± 26.210.06 ± 0.030.42 ± 1.07
p-values <0.001<0.1660.085
Table 4. Comparison of flow properties for each S-SNEDDS formulation (n = 3).
Table 4. Comparison of flow properties for each S-SNEDDS formulation (n = 3).
Formulations
(Type of Solid Carriers)		Angle of Repose
(Degrees)		Results
GranuLac® 20025.95 ± 0.27Excellent
Tablettose® 8038.77 ± 0.53Fair
FlowLac® 10042.08 ± 0.97Passable
Table 5. Mean droplet size and zeta potential of the S-SNEDDS formulations.
Table 5. Mean droplet size and zeta potential of the S-SNEDDS formulations.
FormulationsMean Droplet Size (nm)PDIZeta Potential (mV)
Tablettose® 8075.27 ± 2.400.157 ± 0.02+0.31 ± 0.71
FlowLac® 10049.53 ± 6.79 *0.203 ± 0.04+1.25 ± 0.60
GranuLac® 20044.97 ± 4.80 *0.193 ± 0.06+1.20 ± 1.00
Each value represents the mean ± SD (n = 3). * p < 0.05 compared with the Tablettose® 80.
Table 6. The mean particle size of curcumin-loaded S-SNEDDSs at baseline and after 1, 2, 3, and 4 weeks of storage at 40 °C and 75% RH.
Table 6. The mean particle size of curcumin-loaded S-SNEDDSs at baseline and after 1, 2, 3, and 4 weeks of storage at 40 °C and 75% RH.
BaselineOne WeekTwo WeeksThree WeeksFour Weeks
Tablettose® 80
formulation		Size (nm)75.27 ± 2.4092.57 ± 3.78129.6 ± 4.77 *147.4 ± 4.54 *185.77 ± 21.91 *
PDI0.157 ± 0.020.153 ± 0.010.104 ± 0.01 a0.115 ± 0.01 a0.137 ± 0.01
FlowLac® 100 formulationSize (nm)49.53 ± 6.7968.03 ± 4.4785.30 ± 3.03 **92.70 ± 8.56 **117.23 ± 14.14 **
PDI0.203 ± 0.040.166 ± 0.010.111 ± 0.01 b0.120 ± 0.01 b0.095 ± 0.01 b
GranuLac® 200 formulationSize (nm)44.97 ± 4.8059.00 ± 0.6267.77 ± 7.67 ***65.50 ± 3.92 ***68.93 ± 8.95 ***
PDI0.193 ± 0.060.227 ± 0.020.141 ± 0.020.200 ± 0.030.159 ± 0.04
Each value represents the mean ± standard deviation (n = 3). * (size of Tablettose® 80 formulation), ** (size of FlowLac® 100 formulation, *** (size of GranuLac® 200 formulation), a (PDI of Tablettose® 80 formulation), b (PDI of FlowLac® 100 formulation; p < 0.05 compared with the baseline.
Table 7. Zeta potential of curcumin-loaded S-SNEDDSs at baseline and after 1, 2, 3, and 4 weeks of storage at 40 °C and 75% RH.
Table 7. Zeta potential of curcumin-loaded S-SNEDDSs at baseline and after 1, 2, 3, and 4 weeks of storage at 40 °C and 75% RH.
Zeta Potential (mV)
BaselineOne WeekTwo WeeksThree WeeksFour Weeks
Tablettose® 80
formulation		0.31 ± 0.71−0.78 ± 0.24−0.74 ± 0.18−0.59 ± 0.442.29 ± 2.33 *
FlowLac® 100
formulation		1.25 ± 0.601.02 ± 0.661.13 ± 0.63−0.66 ± 2.16−0.50 ± 0.59
GranuLac® 200
formulation		1.20 ± 1.001.64 ± 0.441.41 ± 0.41−0.85 ± 1.081.06 ± 3.02
Each value represents the mean ± standard deviation (n = 3). * (Tablettose® 80 formulation) p < 0.05 compared with the baseline.
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MDPI and ACS Style

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

AMA Style

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(4):69. https://doi.org/10.3390/sci6040069

Chicago/Turabian Style

Teerapipattanapong, Panida, Pimrada Jaikon, Nichapa Ningsanonda, Etsuo Yonemochi, Takayuki Furuishi, Namon Hirun, and Pakorn Kraisit. 2024. "Evaluating Various Lactose Types as Solid Carriers for Improving Curcumin Solubility in Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDSs) for Oral Administration" Sci 6, no. 4: 69. https://doi.org/10.3390/sci6040069

APA Style

Teerapipattanapong, P., Jaikon, P., Ningsanonda, N., Yonemochi, E., Furuishi, T., Hirun, N., & Kraisit, P. (2024). Evaluating Various Lactose Types as Solid Carriers for Improving Curcumin Solubility in Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDSs) for Oral Administration. Sci, 6(4), 69. https://doi.org/10.3390/sci6040069

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