Turmeric oil-fortified nutraceutical-SNEDDS: An approach to boost therapeutic effectiveness of dapagliflozin during treatment of diabetic patients

1 Introduction

Diabetes mellitus is a widely spread chronic metabolic disorder that increases measured blood glucose levels [1,2]. This is ascribed to either insufficient or a lack of insulin production, resistance to insulin’s pharmacological action, or a combination of both [3]. Long-term exposure of body cells to dysregulation in glucose level results in various complications to body organs, including the heart (cardiovascular diseases), nerves (neuropathy), kidneys (nephropathy), and eyes (retinopathy) [4,5].

Dapagliflozin (DG) belongs to the sodium–glucose cotransporter-2 (SGLT2) inhibitors. It reduces blood glucose levels by inhibiting glucose reabsorption from proximal tubules in the kidney [6]. DG has been utilized extensively owing to its insulin-independent mechanism of action [7,8]. This ensures antidiabetic activity in patients with insulin resistance or impaired pancreatic function [9]. Furthermore, it contributed to weight loss due to increased glucose excretion [10]. In addition, DG exerts a mild diuretic effect following the inhibition of the sodium–glucose cotransporter system, which provides a cardioprotective effect [11].

The reported low solubility of DG negatively influences drug bioavailability and therapeutic outcomes [12]. Therefore, an innovative therapeutic approach, such as nutraceutical-self-nanoemulsifying drug delivery system (nutraceutical-SNEDDS), was implemented not only to boost therapeutic efficacy but also to improve patient outcomes. Nutraceutical-SNEDDS shares similar components of traditional SNEDDS (oil, surfactant, and cosurfactant), whereas the used oil derived from plants contains bioactive compounds with intended biological activity [13,14].

Turmeric oil is usually obtained from Curcuma longa rhizomes and has gained noteworthy attention owing to its reported multifaceted pharmacological activities. These are ascribed to the presence of a mixture of bioactive compounds, including curcuminoids and turmerones [15]. Among them, bioactive curcumin is responsible for beneficial biological activity during diabetes treatment [16,17]. Various studies revealed that curcumin enhances insulin sensitivity and alleviates damage caused to the β-cell of the pancreas [18,19]. This is attributed to the reported antioxidant activity of curcumin, which acts against oxidative and apoptotic factors [20,21].

The leakage of SNEDDS from soft gelatin capsules is considered a major limitation of its pharmaceutical application [22,23]. To overcome the reported limitation of liquid SNEDDS, the optimized turmeric oil-fortified nutraceutical-SNEDDS was converted into a solid dosage form. The adsorption approach has been utilized extensively during the preparation of solid SNEDDS owing to the reported advantages. The absence of organic solvents eliminates safety concerns about the prepared pharmaceutical dosage forms [24]. Moreover, the prepared powder has free-flowing properties, which could be filled within a hard gelatin capsule [25,26]. Furthermore, the manufacturing process of solid SNEDDS using adsorption technology is simple and cost-effective compared to other complex approaches [27].

Therefore, the present study was designed to prepare solid nutraceutical-SNEDDS fortified with turmeric oil to enhance DG dissolution and therapeutic activity. To achieve this, miscibility, emulsification, and DG solubility were studied to select the optimum formulation. After that, various solid SNEDDS formulations were prepared using Neusilin US2 and Neusilin UFL2 adsorbents. The optimized solid SNEDDS formulation was selected based on its physical appearance and in vitro dissolution study. Finally, the optimized solid SNEDDS was characterized using Zetasizer, scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and powder X-ray diffractometry (PXRD).

2 Materials and methods

3 Results

3.1 Cosurfactant selection

Turmeric oil was mixed with different types of cosurfactants, namely propylene glycol, polyethylene glycol 400, Tween-85, Span 80, Imwitor 308, lauroglycol, and peceol at a 2:1 weight ratio. The results revealed that propylene glycol, polyethylene glycol 400, and Tween-85 failed to produce homogeneous mixtures with turmeric oil. The white arrow shown in Figure 1a clearly indicates the distinct phase separation. In contrast, Span 80, Imwitor 308, lauroglycol, and peceol successfully formed homogeneous mixtures with turmeric oil, as shown in Figure 1b.

Figure 1

(a) Immiscible mixture of turmeric oil and cosurfactant. The white arrow shows the separation line between the components. (b) A miscible mixture of turmeric oil and cosurfactant.

3.2 Selection of optimized liquid nutraceutical-SNEDDS

The prepared nutraceutical-SNEDDS formulations were fully characterized to select the optimum formulation based on homogeneity, emulsification behavior, and solubility (Table 3).

Table 3

Characterization of nutraceutical-SNEDDS formulations

Formulation	Homogeneity	Dispersion	Physical appearance	Solubility (mg/g)	Overall assessment
L1	Pass	Fail	—	—	X
L2	Pass	Fail	—	—	X
L3	Pass	Fail	—	—	X
L4	Fail	Fail	—	—	X
L5	Pass	Fail	—	—	X
L6	Pass	Pass	Clear	150.0 ± 1.0	√
L7	Pass	Fail	—	—	X
L8	Pass	Pass	Bluish	82.3 ± 1.7	X
L9	Pass	Fail	—	—	X
L10	Pass	Fail	—	—	X
L11	Pass	Fail	—	—	X
L12	Pass	Fail	—	—	X

3.2.1 Homogeneity test

Various combinations of turmeric oil with selected cosurfactants (Span 80, Imwitor 308, lauroglycol, and peceol) and surfactants (Tween 20, Cremophor EL, and HCO-30) were evaluated to prepare a homogeneous SNEDDS formulation. Despite the initial miscibility between turmeric oil and Imwitor 308, phase separation was observed in the prepared L4 formulation. Consequently, L4 was excluded from the study, and the other formulations were subjected to further assessments.

3.2.2 Emulsification study

The current results showed that all formulations except L6 and L8 failed to produce a dispersed nanoemulsion. Figure 2a and b shows that the dispersed systems of L6 and L8 exhibited a clear and bluish appearance, respectively. Therefore, L6 and L8 were subjected to a solubility study to select the optimum liquid nutraceutical-SNEDDS formulation.

Figure 2

Physical appearance of (a) L6 and (b) L8 nutraceutical-SNEDDS formulations.

3.2.3 Solubility study

A solubility study was conducted to quantify the loading capacity of L6 and L8, which directly affects the total dosage of formulations. The L6 formulation exhibited an approximately two-fold increment in the measured solubility compared with the L8 formulation. Therefore, the L6 formulation was selected as an optimized nutraceutical-SNEDDS and subjected to solidification.

3.3 Selection of optimized solid nutraceutical-SNEDDS

The solid nutraceutical-SNEDDSs were prepared and subjected to different pharmaceutical assessments to select the optimized formulation.

3.3.1 Physical appearance

The images of Neusilin adsorbent and the prepared solid nutraceutical-SNEDDS formulations are presented in Figure 3. It is clear from the images that Neusilin US2 has a granular appearance with a fine particulate characteristic texture. In contrast, Neusilin UFL2 has a fluffy appearance and smooth texture. Moreover, the white color of both Neusilin adsorbents was converted to yellow following the adsorption of the liquid nutraceutical-SNEDDS formulation.

Figure 3

Visual comparison of solid SNEDDS formulations using Neusilin US2 and UFL2 adsorbents: (a) and (b) adsorbents alone, (c) and (d) 1:4, (e) and (f) 1:2, (g) and (h) 3:4, and (i) and (j) 1:1 adsorbent:liquid SNEDDS ratios.

Solid nutraceutical-SNEDDS formulations with an adsorbent: liquid SNEDDS ratio of 1:4 exhibited distinct physical characteristics. The Neusilin US2-based formulation exhibited a cake-like structure (Figure 3a), while the Neusilin UFL2-based formulation exhibited a gel-like appearance (Figure 3b). However, the remaining solid nutraceutical-SNEDDS formulations retain the powder nature of plain adsorbent.

3.3.2 In vitro dissolution

The in vitro dissolution study was conducted to investigate the impact of liquid nutraceutical-SNEDDS (L6) on the dissolution efficiency of DG. Figure 4a shows the in vitro dissolution profile of pure drug against optimum liquid nutraceutical-SNEDDS formulation (L6). It is clear from the results that L6 enhanced the dissolution profile compared with pure DG. Moreover, results showed that L6 significantly increased the dissolution efficiency of DG from 39.2 ± 7.62 to 91.6 ± 0.54 (Figure 4b).

Figure 4

(a) DG’s in vitro dissolution profiles from pure drug and optimum liquid nutraceutical-SNEDDS. (b) Bar graph comparing the dissolution efficiency.

Regarding Neusilin US2, the constructed dissolution profile showed that solid formulations enhanced the dissolution profile in the following order: S2 < S3 ≈ S4 (Figure 5a–c). Furthermore, dissolution efficiency results presented in Figure 5d revealed that S2 has a value of 81.1 ± 9.56% while S3 and S4 had approximately similar values of 89.8 ± 5.53 and 88.7 ± 0.33%, respectively. However, S4 showed a remarkably lower degree of variability in terms of dissolution profile and dissolution efficiency compared to other formulations (S2 and S3).

Figure 5

(a)–(c) In vitro dissolution profiles of DG from S2, S3, and S4 formulations, respectively. (d) Bar graph comparing the dissolution efficiency among the SNEDDS formulations.

Figure 6a–c shows the in vitro dissolution profile of solid formulations comprised Neusilin UFL2 in the following order: S6 < S7 ≈ S8. Dissolution efficiency results showed that S6 has a lower value of 65.6 ± 13.72%, while S7 and S8 had approximately similar values of 81.5 ± 3.46 and 79.0 ± 7.38%, respectively. Overall, solid formulations consisting of Neusilin US2 have a superior dissolution efficiency compared to others consisting of Neusilin UFL2 at the same level of adsorbent: liquid SNEDDS ratio.

Figure 6

(a)–(c) In vitro dissolution profiles of DG from S6, S7, and S8 formulations, respectively. (d) Bar graph comparing the dissolution efficiency among the SNEDDS formulations.

3.4 Characterization of optimized solid nutraceutical-SNEDDS

3.4.1 Particle size and zeta potential measurements

The selected optimum solid nutraceutical-SNEDDSs (S4) were measured using a Zetasizer. The results obtained show that the optimum solid nutraceutical-SNEDDS have particle sizes of 40.8 nm and a negative zeta potential value of −19.0 mV.

3.4.2 SEM

The SEM analysis presented in Figure 7 displays morphological characteristics at varying magnification levels of DG, Neusilin US2 carrier, and the optimized formulation S4. The captured images clearly show DG exhibiting an irregular crystalline appearance with a distinctive rod-like crystalline structure. Moreover, Neusilin US2 images confirm that the adsorbent has a granular appearance with characteristic spherical particles. The SEM analysis of the optimized formulation S4 demonstrated that after SNEDDS adsorption, the formulation maintained the general morphological features characteristic of pure Neusilin US2. However, when examined under higher magnification, it was observed that the SNEDDS adsorption process modified the Neusilin US2 surface, resulting in a smoother surface texture compared to the original carrier material.

Figure 7

SEM images of (a) and (b) pure DG, (c) and (d) Neusilin US2, and (e) and (f) optimized formulation S4 at low and high magnification power, respectively.

3.4.3 PXRD

Figure 8a–e shows the XRD spectra of DG, Neusilin US2, Neusilin US2 loaded with blank SNEDDS, physical mixture, and optimized formulation S4, respectively. The DG diffractogram shows multiple sharp and intense diffraction peaks, particularly prominent ones between 15 and 25° (2θ), indicating the crystalline nature of the pure drug. However, Neusilin US2 exhibits a largely flat diffractogram with minimal peaks, demonstrating its amorphous nature. Neusilin loaded with drug-free SNEDDS shows a similar amorphous pattern to pure Neusilin US2, confirming that loading with blank SNEDDS does not alter the carrier’s amorphous structure. The physical mixture shows some characteristic peaks of crystalline DG, though with reduced intensity compared to pure DG. This suggests that while some crystalline drug structure is maintained in the physical mixture, there may be partial amorphization or a dilution effect from Neusilin US2. The optimized formulation S4 shows a predominantly amorphous pattern similar to pure Neusilin US2, with the absence of characteristic DG peaks. This indicates successful conversion of crystalline DG to an amorphous form within the SNEDDS formulation, likely contributing to enhanced drug solubility and dissolution properties.

Figure 8

XRD spectra of (a) DG, (b) Neusilin US2, (c) Neusilin loaded with drug-free SNEDDS, (d) physical mixture, and (e) optimized formulation S4.

3.4.4 FTIR spectroscopy

The FTIR spectra presented in Figure 9 display the characteristic molecular vibrational patterns of several samples: pure DG, Neusilin US2 carrier material, Neusilin US2 loaded with blank SNEDDS (without drug), physical mixture, and the optimized solid SNEDDS formulation S4. These spectra help identify potential molecular interactions and compatibility between the formulation components. Figure 9a shows that DG has a broad band around 3,400 cm⁻¹ (O–H stretching), sharp peaks in the 2,900–2,800 cm⁻¹ region (C–H stretching), multiple distinctive peaks in the fingerprint region (1,800–400 cm⁻¹), notable peaks at around 1,730 cm⁻¹ (C═O stretching), and 1,620 cm⁻¹ (C═C stretching). In addition, the FTIR spectrum of Neusilin US2 shown in Figure 9b displays characteristic peaks at 1,060 cm⁻¹ (Si–O–Si asymmetric stretching). Furthermore, Figure 9c shows the FTIR spectrum of drug-free SNEDDS-loaded Neusilin US2 with new peaks at 2,924 and 2,854 cm⁻¹ (C–H stretching) and 1,726 cm⁻¹ (C═O stretching of ester). FTIR spectra of the physical mixture and optimum solid nutraceutical-SNEDDS (S4) are presented in Figure 9d and e, respectively. Both formations showed the presence of distinctive peaks of DG. Notably, a non-interfering peak at 1,512 cm⁻¹ of DG was present in both spectra compared to the drug-free SNEDDS-loaded Neusilin^® US2 spectrum.

Figure 9

FTIR spectra of (a) DG, (b) Neusilin US2, (c) Neusilin loaded with drug-free SNEDDS, (d) physical mixture, and (e) optimized formulation S4.

3.5 Comparative dissolution study with the marketed product

Figure 10a shows in vitro dissolution profiles of optimized formulation (S4) and marketed product (Forxiga^®). Both formulations attained complete drug release (>98%) at the end of the experiment, with S4 showing 98.5 ± 1.3% and Forxiga^® 98.0 ± 1.7% release. The calculated dissolution efficiency (Figure 10b) for S4 and Forxiga^® was 88.7 ± 0.33 and 90.8 ± 2.36%, respectively, with no statistically significant difference (p > 0.05).

Figure 10

(a) In vitro dissolution profiles of optimized solid nutraceutical-SNEDDS (S4) and marketed product (Forxiga^®). (b) Bar graph comparing the dissolution efficiency between S4 and Forxiga^® formulations.

4 Discussion

SNEDDS formulation comprises a homogenous mixture of surfactants, cosurfactants, and oils. Cosurfactants are usually incorporated to facilitate mixing between hydrophilic surfactants and lipophilic oils [28,29]. The solubility of turmeric oil was evaluated in various cosurfactants to determine their suitability and effectiveness as solubilizing agents in the formulation. Propylene glycol, polyethylene glycol 400, and Tween-85 were excluded from the study owing to their inability to produce a homogenous system with turmeric oil. On the other hand, Span 80, Imwitor 308, lauroglycol, and peceol were selected to prepare liquid nutraceutical-SNEDDS because they produced a homogenous system when mixed with turmeric oil.

The prepared formulations were subjected to a miscibility test to check the ability of SNEDDS to form a homogenous mixture during storage. The observed phase separation in the L4 formulation could be ascribed to the complex interaction within the ternary system of SNEDDS. It is hypothesized that Imwitor 308 could favor the formation of bonding with Tween 20 only rather than turmeric oil, resulting in the formation of two immiscible phases.

An emulsification study was performed to check the ability of nutraceutical-SNEDDS to form nanoemulsion droplets following dispersion in an aqueous system. This ensures the efficiency of combinations of surfactants and cosurfactants in encapsulating turmeric oil and producing stable nanoemulsions [30]. Most formulations failed to produce dispersed nanoemulsion systems, suggesting that combinations of surfactants and cosurfactants did not have favorable molecular interactions between the components when mixed with an aqueous system. In contrast, L6 and L8 formulations form successful nanoemulsions, as indicated by their physical appearance and the absence of floated oil on the surface.

A solubility study was conducted as a final step in selecting the optimum liquid nutraceutical-SNEDDS formulation. This ensures high drug-loading capacity and reduces the formulation’s total dosage [31]. Moreover, this is expected to facilitate drug integration within dispersed nanoemulsion droplets and prevent the precipitation of drugs in the GIT [32]. Consequently, L6 was chosen as the optimum formulation owing to its remarkable solubility compared to the L8 formulation.

DG was loaded in a liquid nutraceutical-SNEDDS formulation (L6) and subjected to an in vitro dissolution study. The observed enhancement in the dissolution of DG from L6 compared to the raw crystalline drug could have resulted from its solubilization within the SNEDDS formulation at a molecular level [33]. Therefore, the drug could be partitioned within nanoemulsion droplets and solubilized in dissolution media. This is expected to increase the bioavailability of loaded drugs owing to maintaining a higher concentration gradient between the GIT and systemic circulation [34].

The optimized liquid nutraceutical-SNEDDS formulation (L6) was solidified using two grades of Neusilin (US2 and UFL2) at various adsorbent: liquid SNEDDS ratios. The conversion of Neusilin’s color from white to yellow indicates the successful integration of liquid nutraceutical-SNEDDS within adsorbent pores, attributed to the turmeric oil color.

The observed physical appearance of the solid formulations varied significantly depending on the Neusilin grade and the adsorbent:liquid SNEDDS ratio. For S1 and S5 formulations (1:4 ratio), the observed gel-like appearance of the latter could result from its fine particulate characteristic of Neusilin UFL2 compared to the granular nature of the former. In harmony with current results, Park et al. found that solid SNEDDS prepared using Neusilin UFL2 were agglomerated compared to the discrete appearance of solid SNEDDS prepared using Neusilin US2 [35]. This could be attributed to the granular structure of Neusilin US2, which reduces the contact surface between particles, while the fine particulate characteristic nature of Neusilin UFL2 increases the contact surface between particles [36]. However, both formulations were excluded from the study due to their inapplicability during pharmaceutical production.

The observed superior performance of Neusilin US2 formulations in improving the dissolution profile corroborates the previously published data [37,38]. This could be ascribed to the reported study, which showed that drug release was decreased from the viscous SNEDDS formulation adsorbed onto Neusilin UFL2. This is aligned with the current study, where high drug loading (150 mg/g) in the liquid nutraceutical-SNEDDS formulation could increase its viscosity [38].

The observed low dissolution efficiency from the solid formulation with a low adsorbent:liquid SNEDDS ratio could be attributed to the overload adsorption of SNEDDS within the porous structure of the adsorbent. This resulted in the formation of gel-like material during dissolution, which delayed the formation of nanoemulsion droplets and retard drug dissolution [26]. Maximum dissolution efficiency was observed in medium and high adsorbent:liquid SNEDDS ratio formulations that could result from breaking the threshold point beyond which gel was not formed.

Even though S3 and S4 showed higher dissolution efficiency, S4 was selected as the optimum formulation due to its lower variability in the in vitro dissolution study. This reduced variability is expected to ensure a more consistent drug release pattern, which is essential for achieving uniform in vivo pharmacokinetic parameters. Particle size analysis revealed that the dispersed S4 formulation was in the nanosize range. This is expected to increase the bioavailability of the integrated drug within the prepared formulation [39]. Moreover, the measured negative zeta potential suggests the electrostatic stabilization of the nanoemulsion droplets following aqueous dispersion. In addition, the negative surface charge can promote migration and absorption of the nanoemulsion system via clathrin receptors [40]. This agrees with previous studies showing remarkable enhancement in drug bioavailability from dispersed nanoemulsion with a negative surface charge [41,42].

The selected optimum formulation (S4) was subjected to physicochemical analysis to examine the molecular state of DG within solidified nutraceutical-SNEDDS. The preservation of Neusilin US2’s spherical structure following the adsorption of SNEDDS suggests the successful integration of formulation within the porous structure of the adsorbent. Moreover, the absence of an irregular crystalline appearance of DG within SEM images of S4 confirms its integration within the adsorbent. However, XRD was performed to verify that the drug was present in an amorphous state within the prepared S4 formulation.

The XRD spectrum showed that DG has a distinctive crystalline structure, which agrees with the results of the previously published studies [12,43]. The present results revealed that the adsorption of SNEDDS did not influence the XRD spectrum of the adsorbent. However, the XRD spectrum of the physical mixture showed that DG crystalline peaks were retained. On the other hand, the incorporation of DG within the SNEDDS formulation resulted in its transformation to an amorphous state, indicated by the absence of drug crystalline peaks [44].

FTIR spectroscopy was performed to study any possible interaction between DG and excipients. The agreement between the FTIR spectra of DG [45,46] and Neusilin US2 [47] revealed the purity of the used ingredients. The observed new peaks in the FTIR spectrum of drug-free SNEDDS-loaded Neusilin US2 correspond to the adsorption of SNEDDS components, which agrees with previously published studies [31,48]. The presence of all characteristic DG peaks in the physical mixture and optimum solid nutraceutical-SNEDDS (S4) indicates the absence of a chemical interaction between the drug and excipients [49].

Innovator (Forxiga^®) was selected as the reference product for a comparative dissolution study. This will give a clear impression of the performance of the developed optimum formulation compared to the marketed product. The comparative dissolution study demonstrated that the optimized solid nutraceutical-SNEDDS formulation (S4) achieved a dissolution performance comparable to that of the marketed product Forxiga^®. Similar dissolution profiles and statistically insignificant differences in dissolution efficiency values (p > 0.05) suggest that incorporating DG into the SNEDDS system did not compromise its release characteristics. These findings suggest that the developed S4 formulation could provide similar in vivo performance to the marketed product while offering additional benefits of incorporating nutraceutical components.

5 Conclusions

The current study represents a multifaceted approach to treating diabetic patients on DG. This combined the benefits of enhancing the solubility of poorly water-soluble drugs and nutraceutical-SNEDDS. The prepared optimized formulation (S4) showed enhanced dissolution properties and a comparable drug release profile to the marketed product, with additional benefits in incorporating bioactive turmeric oil. SEM, FTIR, and PXRD analyses confirm the adsorption of liquid SNEDDS by Neusilin US2 and the conversion of the drug to an amorphous form with no potential chemical interaction. This research could lead to developing more effective therapeutic approaches for diabetes management. This could potentially offer patients enhanced blood glucose control and minimize disease-related complications. Further in vivo pharmacokinetic and pharmacodynamic studies are required to confirm the superior performance of the developed S4 formulation against the marketed tablet.