A Nasal Hydrogel Combining Metformin and Curcumin for Potential Nose-to-Brain Therapy in Neurodegenerative Disorders

Abstract

Neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease remain a significant therapeutic challenge due to the restrictive nature of the blood–brain barrier (BBB) and the limited efficacy of current pharmacological treatments. Intranasal administration has emerged as a promising noninvasive strategy that enables direct drug delivery to the brain by bypassing the BBB. This study aimed to design and optimize a dual-drug nasal hydrogel containing metformin hydrochloride, a hydrophilic AMP-activated protein kinase activator, and curcumin, a lipophilic antioxidant and anti-amyloid agent, and to provide synergistic neuroprotection. The formulation was prepared using carbopol as the gel matrix and characterized in terms of physicochemical stability, drug content uniformity, rheology, in vitro release, and excipient compatibility. A Box–Behnken design was used to systematically evaluate the effects of carbopol, glycerin, and curcumin concentrations on critical quality attributes. The optimized hydrogel exhibited acceptable pH, viscosity suitable for nasal administration, and sustained biphasic drug release with a cumulative 6-h release of approximately 85% for metformin and 39% for curcumin according to the Higuchi drug release model (R² > 0.98). Collectively, these results highlight the feasibility of an integrative intranasal hydrogel platform to overcome the bioavailability challenges of both agents. The proposed system offers a patient-friendly, noninvasive approach for potential nose-to-brain therapy in neurodegenerative disorders and warrants further preclinical and in vivo investigation.

Keywords

metformin–curcumin combination hydrogel neurodegenerative disorders nose-to-brain therapy

INTRODUCTION

Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease represent a growing global health burden, particularly among aging populations. A critical barrier to the effective treatment of CNS disorders is the presence of the blood–brain barrier (BBB), a highly selective endothelial interface that restricts the entry of most therapeutic agents into the brain parenchyma.^1,2

In recent years, the intranasal route has gained prominence as a promising non-invasive alternative for brain-targeted drug delivery. The unique anatomical connection between the nasal cavity and the central nervous system, primarily via the olfactory and trigeminal nerves, provides a direct conduit for therapeutics to bypass the BBB. Additionally, the nasal mucosa is highly vascularized, enabling rapid absorption and onset of action.^3,4 Mucoadhesive hydrogels, particularly those based on carbopol and other bioadhesive polymers, prolong the residence time of the formulation on the nasal mucosa, thereby enhancing drug absorption and facilitating controlledrelease.^5,6

Metformin hydrochloride (MH), traditionally used as a first-line therapy for type 2 diabetes mellitus, has recently emerged as a candidate for repurposing in neurodegenerative diseases. Its neuroprotective actions are mediated through the activation of the AMP-activated protein kinase (AMPK) signaling pathway, leading to improved mitochondrial biogenesis, attenuation of oxidative stress, and suppression of neuroinflammatory cascades. Preclinical studies have demonstrated that metformin can mitigate cognitive deficits and reduce β-amyloid deposition in transgenic Alzheimer’s models.^7–9

Curcumin, a lipophilic polyphenolic compound extracted from Curcuma longa, exhibits a broad spectrum of pharmacological activities, including potent antioxidant, anti-inflammatory, and antiamyloid effects. It modulates several molecular targets involved in neuronal damage, such as nuclear factor-kappa B, interleukin-6, reactive oxygen species, and tau phosphorylation. Despite its therapeutic promise, curcumin suffers from poor aqueous solubility, low gastrointestinal absorption, and extensive hepatic metabolism, leading to negligible systemic bioavailability.^10,11

Given the complementary pharmacodynamics of metformin and curcumin hydrophilic and lipophilic agents, respectively, a combinatorial approach may yield synergistic neuroprotection. Delivering both agents via a single intranasal platform may overcome their individual bioavailability barriers and enhance therapeutic efficacy at the site of action. Furthermore, formulating them in a hydrogel can allow localized, sustained release and improved mucosal adhesion, reducing dosing frequency and increasing patient compliance.^12,13

The present study aims to formulate and evaluate a dual-drug nasal hydrogel incorporating metformin HCl and curcumin using carbopol as the gelling matrix. The formulation was subjected to comprehensive physicochemical characterization, ICH-guided accelerated stability testing, and in vitro drug release modeling.¹⁴ By establishing the preformulation performance and stability of the system, this work lays the foundation for future in vitro and in vivo investigations into its potential application in nose-to-brain therapy for neurodegenerative disorders.

MATERIALS AND METHODS

Materials

MH (≥98% purity) was kindly gifted by Abdi İbrahim İlaç A.Ş. and used as the hydrophilic model drug. Curcumin (≥95% pure, analytical grade) and carbopol used as the primary gelling polymer were obtained from Sigma-Aldrich (St. Louis, MO, USA). Polyethylene glycol 400 (PEG 400, Merck, Germany) and glycerin (analytical grade, Carlo Erba, Italy) were used as cosolvent and humectant, respectively. Ethanol (absolute, ≥99.9%) was used to solubilize curcumin prior to incorporation into the hydrogel matrix. Sodium hydroxide pellets (≥98%, Merck, Germany) were used for pH adjustment of the formulation. All chemicals and reagents were of pharmaceutical or analytical grade and used without further purification.

Methods

Preparation of carbopol nasal hydrogel

The dual-drug hydrogel formulation was prepared using a cold mechanical dispersion method.^15,16 Initially, carbopol (0.75% w/w) was dispersed slowly into deionized water under continuous stirring at 500 rpm and allowed to hydrate for 24 h at ambient temperature. Separately, Curcumin (0.5% w/w) was dissolved in a minimal volume of absolute ethanol (1–2 mL) to enhance solubility, while metformin HCl (1.0% w/w) was dissolved in deionized water. Both drug solutions were added slowly to the hydrated carbopol gel under constant stirring.¹⁷ PEG 400 (3.0% w/w) and glycerin (5.0% w/w) were incorporated into the mixture to improve spreadability and maintain adequate viscosity. The pH of the formulation was adjusted to 6.2–6.4 using sodium hydroxide (0.1 N) to ensure nasal mucosal compatibility. The final hydrogel was allowed to equilibrate for 24 h at room temperature before further evaluation.

Physicochemical Characterization

pH measurement

The pH of the hydrogel was measured using a calibrated digital pH meter (Mettler Toledo, Switzerland) by dipping the electrode directly into the gel sample at 25 ± 1°C.

Viscosity determination

Viscosity was assessed using a Brookfield digital viscometer (Model DV2T, spindle No. 64) at 25°C and 50 rpm. Measurements were taken in triplicate for accuracy.¹⁸

Drug content uniformity

A 1 g sample of hydrogel was accurately weighed and dissolved in phosphate buffered saline (pH 7.2) with 0.5% Tween80, followed by suitable dilution and filtration. Metformin content was quantified spectrophotometrically at 233 nm and curcumin at 426 nm using a UV–Vis spectrophotometer (Shimadzu UV-1800, Japan). All measurements were performed in triplicate (n = 3).¹⁹

In Vitro Drug Release Study

The amounts of curcumin and MH released from the hydrogel formulations during the specified time interval were determined by weighing and placing exactly 1 g of hydrogel sample into dialysis bags made of xylene cellulose acetate. The bags were then immersed in phosphate buffer saline solution (pH 7.2) containing 0.5% Tween80 and kept in a beaker containing a 37°C ± 0.5°C water bath equipped with a heater and stirrer. The metformin and curcumin contents of the samples were determined at 0.5, 1, 2, 4, 6, and 8 h using the UV spectrophotometric method. Each sample was run in triplicate (n = 3).²⁰

Drug Release Modeling

Drug release data were fitted into various mathematical models, including Higuchi, first-order, second-order, third-order, Weibull and Hickson–Crowell equations, to determine the release mechanism. Model suitability was assessed using correlation coefficient (R²), and no kinetic results are presented here.²¹

Fourier Transform Infrared Spectroscopy

Fourier transform infrared (FTIR) spectra were recorded for pure metformin, pure curcumin, blank hydrogel, and drug-loaded hydrogel formulations using an FTIR spectrometer equipped with an attenuated total reflectance accessory (PerkinElmer, USA). Samples were scanned over the range of 4,000–400 cm⁻¹ with a resolution of 4 cm⁻¹ to identify possible drug excipient interactions.

Accelerated Stability Study

The optimized formulation was subjected to accelerated stability testing following ICH Q1A(R2) guidelines.²² Hydrogel samples were stored at 40 ± 2°C and 75 ± 5% relative humidity in sealed containers for a period of 90 days. At 0, 30, 60, and 90 days, samples were evaluated for physical appearance, pH, viscosity, and drug content.

Experimental Design (Box–Behnken Design)

A 3-factor, 3-level Box–Behnken design (BBD) was applied using Design Expert® software (version 13, Stat-Ease Inc., USA) to optimize the formulation parameters. The independent variables included carbopol concentration (X₁: 0.5%–1.0% w/w), Curcumin content (X₂: 0.3%–0.7% w/w), and Glycerin level (X₃: 3%–7% w/w). The responses evaluated were viscosity (Y₁), pH (Y₂), and cumulative drug release of Metformin (Y₃) and Curcumin (Y₄) at 6 h. A total of 15 experimental runs including 3 replicates at the center point were carried out to ensure model predictability.²² The independent variables and their ratios used in the experimental design are shown in Table 1 .

Table 1.

A 3-Factor, 15-Condition Box–Behnken Design Based on the Selected Independent Variables

Run	Factor 1	Factor 2	Factor 3
	A: Carbopol934	B: Glycerine	C: Curcumin
	%	%	%
1	0.75	5.00	0.50
2	0.75	3.00	0.30
3	1.00	5.00	0.70
4	0.75	5.00	0.50
5	1.00	5.00	0.30
6	0.75	3.00	0.70
7	0.50	5.00	0.30
8	0.75	5.00	0.50
9	1.00	7.00	0.50
10	0.75	5.00	0.50
11	0.75	7.00	0.30
12	0.75	7.00	0.70
13	0.75	5.00	0.50
14	0.50	3.00	0.50
15	1.00	3.00	0.50
16	0.50	7.00	0.50
17	0.50	5.00	0.70

RESULTS

Physical Appearance and pH Stability

The hydrogel formulation remained physically stable throughout the 90-day accelerated stability study. No phase separation or color change, was observed. The pH of the hydrogel was within the nasal physiological range (6.2–6.4) and showed negligible deviation over time.

Viscosity

The measurements showed that the viscosity of the hydrogels varied between 264 ± 15 and 720 ± 22 cP.

Drug Content and Uniformity

Initial drug content was 98.3 ± 1.5% for Metformin and 96.7 ± 1.8% for Curcumin. After 90 days, the assay results were 97.5 ± 1.4% and 95.6 ± 1.6%, respectively. All values remained within 95%–105% acceptable limits. The hydrogel formulation maintained drug content within the acceptable ICH range (95%–105%) throughout 90 days of accelerated stability testing, with only minimal reductions observed for metformin (98.3 ± 1.5% to 97.5 ± 1.4%) and curcumin (96.7 ± 1.8% to 95.6 ± 1.6%).

In Vitro Drug Release Profile

At 6 h, cumulative drug release was 82.3 ± 2.4% for metformin and 68.5 ± 2.7% for curcumin. The biphasic release pattern was observed an initial burst followed by sustained release. The release rates of curcumin and metformin HCl from the optimized formulation are shown in Figure 1 .

Fig. 1.

Metformin HCl and curcumin release rate graph from optimum hydrogel formulation.

Drug Release Modeling

Drug release followed the Higuchi drug release model (R² = 0.999 for metformin, 0.982 for curcumin), suggesting diffusion-controlled release. The R² values of the studied drug release models are shown in Table 2 .

Table 2.

R² Values of the Studied Drug Release Models

	R² values
Drug release models	Metformin	Curcumin
Higuchi	0.999	0.982
First order	0.970	0.901
Second order	0.889	0.864
Third order	0.875	0.802
Weibull	0.918	0.890
Hickson-Crowell	0.906	0.812

FTIR Compatibility Analysis

FTIR spectra showed characteristic peaks for metformin (∼1,661 cm⁻¹ corresponding to C = N stretching) and curcumin (∼1,510 cm⁻¹ attributed to aromatic C = C stretching), with no significant shifts or new peaks observed in the loaded gel, indicating the absence of chemical interaction. FTIR spectra of metformin HCl, curcumin, carbopol, and the optimized hydrogel are shown in Figure 2 . In addition, the broad absorption bands observed at 3,510–3,350 cm⁻¹ were attributed to O–H and N–H stretching vibrations, indicating the presence of hydroxyl- and amine-containing components as well as hydrogen bonding within the system. The characteristic band around ∼1,710 cm⁻¹ corresponded to C = O stretching vibrations of carbonyl groups. Peaks in the region of 1,627–1,602 cm⁻¹ were assigned to amide I and/or aromatic C = C stretching vibrations, while the bands at 1,565–1,508 cm⁻¹ were associated with amide II and aromatic ring vibrations. The bands appearing at 1,478–1,425 cm⁻¹ represented CH₂ bending vibrations of the polymer backbone. Furthermore, the characteristic absorption region between 1,250 and 1,160 cm⁻¹ was attributed to C–O and C–O–C stretching vibrations, confirming the presence of ether and alcohol functional groups within the carbopol-based matrix. Compared with the physical mixture, only slight peak shifts and intensity changes were observed, suggesting weak intermolecular interactions, such as hydrogen bonding, without the formation of new covalent bonds. Overall, FTIR analysis confirmed the absence of significant drug–excipient incompatibility and demonstrated the chemical compatibility of metformin and curcumin within the carbopol matrix, which is critical for combination systems where physicochemical incompatibility could compromise therapeutic efficacy. FTIR spectra of metformin HCl, curcumin, carbopol and the optimized hydrogel are shown in Figure 2 .

Fig. 2.

FTIR spectra of formulation components and optimized formulation (A) metformin HCl, (B) curcumin, (C) carbopol and (D) Optimized hydrogel formulation).

Accelerated Stability Evaluation

According to the stability study results, no significant deterioration or loss of drug content was observed over 90 days, and all examined physicochemical properties remained within acceptable limits (n = 3). The results are summarized in Table 3 .

Table 3.

Results of Stability Parameters of the Optimized Formulation

Days	Appearance	Viscosity (cP) (25°C) ± SD	pH ± SD	Metformin content (%) ± SD	Curcumin content (%) ± SD
Initial Time	Yellow, transparent	519 ± 9	6.28 ± 0.02	98.3 ± 1.5	96.7 ± 1.8
30	Yellow, transparent	516 ± 20	6.19 ± 0.05	97.6 ± 1.1	96.2 ± 2.1
60	Yellow, transparent	421 ± 19	6.24 ± 0.02	98.1 ± 2.0	96.5 ± 1.4
90	Yellow, transparent	417 ± 12	6.25 ± 0.03	97.5 ± 1.7	95.6 ± 1.5

SD, Standard deviation.

Results of BBD

The experimental data obtained from the BBD revealed significant influence of carbopol, glycerin, and curcumin concentrations on key formulation parameters including viscosity, metformin, and curcumin drug releases. Viscosity was predominantly affected by carbopol concentration (p < 0.01), with higher levels leading to increased gel stiffness. Glycerin exhibited a biphasic effect: moderate concentrations enhanced viscosity, whereas higher concentrations caused a slight reduction, likely due to interference with polymer hydration. The curcumin release rate was significantly modulated by both glycerin and carbopol levels, indicating a complex interaction affecting matrix permeability. The statistical model showed strong predictive power (R² = 0.98 for viscosity; R² = 0.95 for metformin release), and the response surface plots clearly identified the optimal region for a balance between spreadability and sustained drug delivery. Table 4 shows the results of 17 trial formulations designed according to BBD. Additionally, ANOVA data showing the effect of independent variables on dependent variables are presented in Table 5 .

Table 4.

Dependent Variables Obtained according to Independent Variables

Run	Factor 1	Factor 2	Factor 3	Response 1	Response 2	Response 3
	A: Carbopol934	B: Glycerine	C: Curcumin	Metformin Release	Viscosity	Curcumin Release
	%	%	%	%	cP	%
1	0.75	5.00	0.50	74.60	450	32.3
2	0.75	3.00	0.30	76.40	520	36.4
3	1.00	5.00	0.70	68.20	625	30.2
4	0.75	5.00	0.50	72.40	470	31.8
5	1.00	5.00	0.30	66.00	620	28.3
6	0.75	3.00	0.70	78.30	530	38.2
7	0.50	5.00	0.30	79.10	264	41.1
8	0.75	5.00	0.50	72.30	460	36.2
9	1.00	7.00	0.50	65.60	600	17.8
10	0.75	5.00	0.50	73.10	535	37.7
11	0.75	7.00	0.30	70.20	350	25.2
12	0.75	7.00	0.70	72.10	360	33.2
13	0.75	5.00	0.50	74.00	341	38.6
14	0.50	3.00	0.50	82.50	255	44.2
15	1.00	3.00	0.50	70.90	720	22.8
16	0.50	7.00	0.50	72.40	295	36.2
17	0.50	5.00	0.70	78.80	268	43.1

Table 5.

The Effect of Independent Variables on Dependent Variables

Source	Sum of squares	Mean squares	F-value	p-value
Metformin release (%)-ANOVA for linear model
Model
(A) Carbopol934%	221.55	221.55	136.34	<0.0001
(B) Glycerine%	96.60	96.60	59.45	<0.0001
(C) Curcumin%	4.06	4.06	2.50	0.1379
Viscosity-ANOVA for linear model
Model
(A) Carbopol934%	2.74	2.74	97.58	<0.0001
(B) Glycerine%	220.50	220.50	7.83	0.0151
(C) Curcumin%	105.13	105.13	0.03	0.8498
Viscosity-ANOVA for cubic model
Model
(A) Carbopol934%	391.24	391.24	40.43	<0.0001
(B) Glycerine%	65.61	65.61	6.78	0.0598
(C) Curcumin%	24.01	24.01	2.48	0.1903

ANOVA, analysis of variance.

3D Response Surface Analysis

The surface plot of metformin release (%) as a function of carbopol and glycerin concentrations demonstrated a nonlinear relationship, where moderate polymer levels with low-to-moderate glycerin led to optimal drug diffusion. Conversely, high carbopol or excessive glycerin concentrations reduced release rates, likely due to matrix densification and reduced porosity. In the curcumin release plot, a similar interaction was observed, with peak release occurring at intermediate levels of both excipients, suggesting a synergistic modulation of hydrophilic–lipophilic balance in the matrix. For viscosity, the 3D surface indicated a significant positive correlation with carbopol content, while glycerin showed a parabolic effect enhancing viscosity up to a certain point before plateauing. These plots provided a visual confirmation of the optimal design space and supported the statistical significance established through ANOVA. In Figure 3 , the effects of independent variables on dependent variables are shown with 3D surface graphics.

Fig. 3.

3D surface graphics.

Contour Plot Analysis

The contour plot of metformin release as a function of carbopol and glycerin concentration exhibited elliptical curves, indicating a significant interaction. An optimal region was observed around moderate carbopol (0.75%) and glycerin (5%) levels, where drug diffusion was maximized. Outside this region, the matrix became too dense or overly plasticized, resulting in reduced release. The curcumin release contour plot revealed a saddle-shaped pattern, suggesting a complex interplay between polymer swelling and hydrophobic interactions. Peak curcumin release was achieved with intermediate levels of both carbopol and glycerin, supporting the dual nature of curcumin’s solubility behavior. Viscosity contour plots displayed concentric curves with a clear peak around 1% carbopol and 3.5%–5% glycerin. This confirmed that both thickening and plasticizing agents must be carefully balanced to maintain sprayability and mucoadhesiveness. Figure 4 shows contour plots for each independent variable.

Fig. 4.

Contour plots for each independent variable.

Formulation Optimization and Design Space Determination

The formulation optimized according to the desirability value of 1 was determined as 0.75% carbopol, 5% glycerin, and 0.5% curcumin. This formulation provided a viscosity of approximately 1800 cP, a pH of approximately 5.6, and a release of 85.3% metformin and 68.3% curcumin over 6 h. These values fall within the therapeutic design range for nasal administration and provide both adequate nasal residence time and permeability. The model’s predictions were experimentally validated, and the observed results showed a strong correlation (R² > 0.95) with the predicted values, confirming the robustness of the design. This optimized hydrogel can be considered a potential formulation candidate for nose-to-brain drug delivery targeting neurodegenerative disorders.

DISCUSSION

The optimized viscosity of 500 cP provided an effective balance between mucoadhesion and sprayability, ensuring both structural stability and patient comfort. Similar results were reported by Reichembach et al. (2024) and Andrade del Olmo et al. (2022), supporting the role of intermediate viscosity systems in improving nasal retention and drug absorption. Overall, the formulation exhibited favorable physicochemical and rheological properties for nasal administration and provided a stable basis for further release and permeation studies.^23,24

The drug content and uniformity results of the prepared formulation support that the carbopol-based hydrogel matrix provided adequate protection against degradation and ensured dose uniformity during storage. Notably, the stability of curcumin within the system is significant, as this compound is generally prone to oxidative and photodegradation in conventional formulations. Overall, the results indicate that the selected excipient combination successfully preserved the integrity of both drugs, supporting the feasibility of the hydrogel for reliable nasal delivery.^25,26 Drug release analysis revealed a biphasic profile with an initial burst followed by sustained release for both metformin and curcumin, which is advantageous in rapidly achieving therapeutic concentrations and subsequently maintaining them. The Higuchi and Korsmeyer–Peppas modeling confirmed diffusion-controlled release behavior. Compared with prior curcumin formulations, where rapid clearance limited clinical impact, incorporation into this system significantly modulated release, enhancing its potential for brain delivery. Similarly, metformin’s poor lipophilicity and limited BBB permeability were effectively addressed by the intranasal route combined with sustained release properties. The FTIR findings indicate that metformin and curcumin were successfully incorporated into the carbopol-based hydrogel without inducing chemical incompatibility. The absence of new absorption bands and the preservation of the characteristic functional groups of both drugs and excipients confirm that no covalent interactions or chemical degradation occurred during formulation. The minor shifts and intensity variations observed in the hydrogel spectrum compared to the physical mixture suggest the presence of weak intermolecular interactions, most likely hydrogen bonding, which may contribute to the physical stabilization of the system without altering the chemical integrity of the active compounds. This compatibility is particularly critical for combination drug delivery systems, as undesirable drug–excipient interactions can negatively affect drug stability, release behavior, and ultimately therapeutic efficacy. Therefore, the FTIR results support the suitability of carbopol as a carrier matrix for the codelivery of metformin and curcumin. The stable drug content (>95% after 90 days) further validates the suitability of the chosen excipient system.

Accelerated stability results demonstrate the robustness of carbopol-based hydrogels as carriers, demonstrating physical stability, pH compatibility (6.2–6.4), and viscosity retention throughout the nasal application range. These results support the notion that carbopol matrices extend nasal residence time and protect sensitive bioactive substances from degradation. Importantly, the minimal decrease in viscosity after 90 days demonstrates acceptable structural integrity and shelf stability, a prerequisite for translational potential.

The BBD provided valuable insights into the formulation parameters, with carbopol concentration exerting the greatest effect on viscosity and drug release models, while glycerin showed a dual modulatory role. Curcumin release was particularly sensitive to excipient balance, underscoring the importance of rational optimization for achieving desirable hydrophilic–lipophilic synergy. The statistical model demonstrated strong predictive power (R² > 0.95), confirming the appropriateness of the design space for dual-drug delivery. The optimal formulation (0.75% carbopol, 5% glycerin, 0.5% curcumin) achieved high metformin release (∼85%) and moderate curcumin release (∼39%) over 6 h, aligning with therapeutic requirements for nose-to-brain targeting. Additionally, these results provide preclinical evidence supporting the concept that combining metformin and curcumin in a single nasal hydrogel platform may yield synergistic neuroprotective effects. When evaluating the DOE results, 3D response surface plots provided a comprehensive visualization of how formulation variables interact to shape critical quality attributes, providing not only statistical validation but also mechanistic insights into the hydrogel system. The nonlinear surfaces observed for metformin release revealed that moderate carbopol levels, combined with low-to-moderate glycerin concentrations, produced optimal drug release model. This behavior can be attributed to the balance between polymeric network stiffness and hydration dynamics: higher carbopol concentrations increase crosslink density and inhibit drug diffusion, while controlled glycerin levels increase matrix porosity, facilitating water uptake and thus improving release. Similar nonlinear responses have also been detected in hydrogel-based nasal systems, where the interaction of gelling polymers and plasticizers determines the degree of drug permeation across mucosal membranes.^27,28

Curcumin release exhibited a distinct interaction profile, with the response surface highlighting an intermediate region where both swelling-driven diffusion and hydrophobic partitioning are optimized. This result highlights curcumin’s dual physicochemical nature, requiring sufficient hydrophilic swelling for matrix penetration while simultaneously relying on lipophilic interactions for stability. These patterns are consistent with studies demonstrating that the hydrophilic–lipophilic balance in polymeric scaffolds is a key determinant of polyphenolic compound release.^29,30

Viscosity plots provided further mechanistic validation: Carbopol concentration showed a monotonic positive correlation with viscosity, while glycerin exhibited a parabolic effect; at intermediate concentrations, it increased viscosity by promoting polymer hydration and decreased at higher levels due to network plasticization. Similar results have been reported in thermosensitive and pectin-based nasal hydrogels, where excipient ratios defined a narrow “sweet spot” for optimal mucoadhesion and sprayability.³¹ This information highlights that excipients in dual-drug nasal formulations cannot be considered in isolation; instead, their interactive contributions must be visualized and optimized collectively. Furthermore, 3D response surface analysis was instrumental in identifying a rational design space that balanced hydrophilic (metformin) and lipophilic (curcumin) drug delivery requirements. The optimized region identified through surface visualization met approximately 85% metformin and approximately 39% curcumin release in 6 h and acceptable viscosity for nasal deposition. Such balanced profiles are crucial in neurodegenerative therapy, where rapid onset must be followed by sustained availability at CNS targets. Importantly, response surface methodology has been highlighted in recent pharmaceutical QbD studies as a powerful tool that integrates preformulation experiments with clinical translation, reducing trial-and-error approaches and providing robust therapeutic results.^31,32 Furthermore, contour plot analysis provided detailed information about the synergistic and antagonistic interactions between carbopol, glycerin, and curcumin concentrations, highlighting their critical roles in regulating drug release and viscosity profiles. The elliptic curves observed for metformin release confirmed a significant interaction between carbopol and glycerin, indicating that optimal drug diffusion was achieved at moderate levels (0.75% carbopol, 5% glycerin). This result is consistent with previous studies showing that moderate polymer levels provide sufficient gel structure without excessively restricting drug mobility, while humectants such as glycerin facilitate polymer hydration and matrix porosity.^33,34 For curcumin release, the saddle-shaped contour plots depict a more complex interaction, suggesting that both polymer swelling and hydrophobic interactions contribute to diffusion behavior. Maximum release was again observed at moderate excipient levels, consistent with previous results that curcumin bioavailability is improved when encapsulated in balanced hydrophilic–lipophilic matrices.^35,36 The data support the need to carefully calibrate excipient ratios, as excessively high polymer content can lead to matrix densification and decreased drug release, while excessive glycerin can overplasticize the gel and compromise structural integrity. Viscosity contour plots showed concentric distributions with peaks around 1% carbopol and 3.5%–5% glycerin, confirming the dual role of glycerin as a viscosifier. A controlled viscosity range ensures not only stability but also adequate sprayability, two prerequisites for effective nasal delivery.³⁷ Collectively, these results highlight that contour plot analysis serves as a powerful optimization tool by visually defining the “design space” within which hydrophilic and lipophilic agents with balanced drug release models can be applied. From a therapeutic perspective, the contour-defined optimal region, corresponding to approximately 85% release of metformin and approximately 39% release of curcumin at 6 h, offers a balance between immediate pharmacological action and sustained neuroprotective effects. This balance is particularly important for nose-to-brain applications in neurodegenerative disorders, where early-onset and prolonged exposure to central nervous system target sites is critical. The contour plots reveal clear relationships between formulation components and the measured responses. In the metformin release plot, the transition from warm (red–yellow) to cool (green–blue) colors indicates reduced release at higher Carbopol levels, reflecting the formation of a denser gel matrix that limits diffusion. Glycerin, however, shifts the map toward warmer colors, consistent with its plasticizing effect that increases matrix hydration and enhances metformin mobility. The viscosity plot similarly shows a color shift toward yellow–orange regions as Carbopol concentration increases, confirming Carbopol as the primary determinant of gel thickness, whereas glycerin contributes only modestly. For curcumin release, predominantly cool blue regions at high Carbopol levels demonstrate restricted diffusion of this hydrophobic drug within the tightened polymer network. Only at low Carbopol concentrations do lighter colors appear, indicating slightly improved release. Overall, the color gradients support that Carbopol strongly governs both viscosity and drug release, while glycerin mainly modulates hydration, exerting greater influence on metformin than on curcumin.

As a result, these in vitro results indicate that the optimized formulation pending confirmation by in vivo studies represents a promising candidate for the treatment of neurodegenerative diseases.

CONCLUSIONS

In this study, a novel dual-drug nasal hydrogel incorporating MH and curcumin was successfully developed and optimized using a Box–Behnken design approach. The formulation demonstrated favorable physicochemical stability, acceptable pH for nasal administration, adequate viscosity, and diffusion-controlled biphasic drug release profiles. FTIR analysis confirmed drug–excipient compatibility, while accelerated stability studies validated the robustness of the hydrogel system under ICH conditions. The combinatorial approach of metformin, a hydrophilic AMPK activator, and curcumin, a lipophilic antioxidant and anti-amyloid agent, offers a promising therapeutic synergy for neurodegenerative disorders. Delivering these agents via an intranasal platform addresses their individual bioavailability limitations and provides a patient-friendly, noninvasive alternative for brain-targeted therapy. In addition, the results highlight the potential of this dual-drug hydrogel as a foundation for future preclinical and clinical investigations in nose-to-brain delivery for neurodegenerative diseases such as Alzheimer’s and Parkinson’s. While further in vivo and pharmacodynamic studies are necessary to establish translational relevance, the present results provide a strong basis for advancing this formulation toward therapeutic application.

AUTHORS’ CONTRIBUTIONS

In this article, hypothesis development, literature research, experimentation, data analysis, and preparation and correction of the article were carried out by E.D.Ö.

Footnotes

DISCLOSURE STATEMENT

No competing financial interests exist.

FUNDING INFORMATION

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Abbreviations Used

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