Introduction
Oral drug delivery remains the preferred route of administration due to its convenience, non-invasiveness, and potential for sustained therapeutic effects.1 However, this approach faces significant challenges, particularly for drugs with poor water solubility and stability issues in the gastrointestinal tract. These limitations often result in suboptimal therapeutic outcomes, especially for compounds with narrow absorption windows or gastric instability.2 Advances in pharmaceutical technologies and drug delivery systems offer the potential to enhance oral drug absorption, providing non-invasiveness, improved patient compliance, and convenience.3
ibuprofen, a widely prescribed non-steroidal anti-inflammatory drug, exemplifies these challenges. Since its introduction in the 1960s, it has been extensively used for pain management and anti-inflammatory therapy.4,5 Its therapeutic effects stem from the non-selective inhibition of cyclooxygenase enzymes (COX-1 and COX-2), thereby reducing prostaglandin production, key mediators of pain, fever, and inflammation.6 However, several physicochemical properties limit ibuprofen’s therapeutic potential. These include poor aqueous solubility, which limits absorption and bioavailability, gastric instability leading to rapid degradation in acidic environments (pH 1.2-3.0), a short biological half-life necessitating frequent dosing, and variable absorption affected by gastric emptying times and pH conditions.7,8
In acidic gastric conditions, ibuprofen’s carboxylic acid group undergoes protonation, significantly affecting its stability and solubility.9,10 The drug predominantly exists in its unionized form at gastric pH, leading to reduced solubility in gastric fluids and decreased absorption across the gastric mucosa. This not only results in potential local mucosal irritation but also creates a limited absorption window in the upper gastrointestinal tract, further compromising its therapeutic efficacy.11–13
To address these limitations, we propose a novel approach using floating nanoballoons with ethyl cellulose as the matrix material. This formulation strategy offers several potential advantages, including protection from harsh gastric conditions, controlled drug release kinetics, enhanced mucosal adhesion, improved bioavailability, and reduced dosing frequency. Our study aimed to evaluate the potential of floating nanoballoons to enhance ibuprofen’s therapeutic efficacy through improved gastric retention and sustained release. This approach could significantly impact patient care by optimizing drug delivery, reducing dosing frequency, and potentially minimizing adverse effects.
Materials and methods
Materials
Ibuprofen was a gift sample from the National Pharmaceutical Industries, Rusayl, Muscat, Oman. Ethylcellulose (50 cps), dichloromethane, methanol, acetone, hydrochloric acid, polyvinyl alcohol (PVA), and phosphate buffer of analytical grades were used. Double-distilled water was used throughout the experiment.
Preparation of ibuprofen nanoballoons
Ibuprofen nanoballoons were synthesized using the solvent diffusion method. The process involved preparing a dispersed phase by dissolving 500 mg of ibuprofen and 500 mg of ethyl cellulose in 16 mL of dichloromethane, followed by stirring for 30 m. Concurrently, a continuous phase was prepared by dissolving 1.2 g of PVA in 200 mL of water at 40°C to create a 0.6% w/v solution. The ibuprofen solution was then added dropwise to the PVA solution under continuous agitation at 200–250 revolutions per minute (rpm) for one hour. Solvent removal was achieved through rotary evaporation at 40 ± 5°C and 100–250 rpm. The resulting nanoballoons were collected via filtration, thoroughly washed, and dried.
Preparation of calibration curve
To develop the calibration curve for the quantification of ibuprofen in the floating nanoballoons, a series of standard ibuprofen solutions with known concentrations were prepared. One liter (1 L) of phosphate buffer (pH 7.4) was prepared, and a stock solution with a concentration of 100 mg/100 mL (1 mg/mL) was made (1,000 µg/mL). Aliquots of stock solutions were then prepared at concentrations of 2 µg/mL, 4 µg/mL, 6 µg/mL, 8 µg/mL, and 10 µg/mL. A fiber optic probe (Ocean Optics QE65 Pro, USA) was placed in the aliquots to measure the absorbance at 264 nm. The absorbance values obtained from these standard solutions were plotted against their respective concentrations to generate the calibration curve.
Loading efficiency and process yield
Accurately weighed samples of dried ibuprofen nanoballoons (50 ± 0.1 mg) were dispersed in 10 mL of acetone in a 25 mL borosilicate glass beaker. The dispersion was subjected to sonication using a Sonorex ultrasonic bath (Bandelin Electronic, Berlin, Germany) at a frequency of 35 kHz and a power output of 160 W for 60 ± 1 m at 25 ± 2°C. Following sonication, the samples were left undisturbed for 12 h at room temperature (22 ± 2°C) to ensure complete dissolution of the drug.
The resulting mixture was centrifuged using a high-speed centrifuge (Thermo Scientific Heraeus Pico 17 microcentrifuge, Thermo Fisher Scientific, USA) at 15,000 rpm for 30 m at 20°C. The supernatant was carefully extracted using a micropipette, ensuring no disturbance to the pellet. The drug content in the supernatant was quantified using fiber optic equipment equipped with a fiber optic probe. Absorbance was measured at a wavelength of 264 nm, which corresponds to the λmax of ibuprofen in acetone. A calibration curve was constructed using standard ibuprofen solutions in acetone (concentration range: 2–10 µg/mL) to determine the drug concentration in the samples.
The loading efficiency was calculated using Equation (1):
% Drug Loading=Recovered Ibuprofen MassTotal Ibuprofen Mass×100
The process yield was calculated using Equation (2):
% Process Yield=Recovered Ibuprofen MassIbuprofen Mass used in the study×100
All measurements were performed in triplicate (n = 3), and results are expressed as mean ± standard deviation (SD). Statistical analysis was performed using one-way ANOVA followed by Tukey’s post-hoc test, with p < 0.05 considered statistically significant.
Micromeritic properties
The micrometric properties of the ibuprofen-loaded floating nanoballoons were thoroughly evaluated and compared to the ibuprofen drug.
Bulk and tapped density
The bulk and tapped densities of the nanoballoons were determined using the graduated cylinder method. Briefly, a known mass of the nanoballoons was carefully transferred into a 10 mL graduated cylinder. The initial volume was recorded, and the cylinder was then tapped 50 times using a mechanical tapper (Electrolab, India) at a rate of 250 taps per minute. The final tapped volume was noted.
Carr’s index and hausner ratio
The Carr’s index and Hausner ratio were calculated from the bulk and tapped density values to assess the flowability of the nanoballoons. The Carr’s index was determined using Equations (3) and (4):
Carr’s Index=Tapped Density−Bulk DensityTapped Density×100
The Hausner ratio was calculated as:
Hausner Ratio=Tapped DensityBulk Density
Angle of repose
The angle of repose was measured using the fixed-height cone method. A glass funnel was positioned 1 cm above a flat glass surface, and a known mass of the nanoballoons was allowed to flow through the funnel, forming a conical pile. The height and base diameter of the cone were measured, and the angle of repose was calculated using Equation (5):
Tanϕ=HeightBase
All measurements were performed in triplicate (n = 3), and the results are reported as mean ± standard deviation. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post-hoc test, with a significance level of p < 0.05.
Drug content determination
Accurately weighed samples of ibuprofen-loaded hollow nanoballoons (100.0 ± 0.1 mg) were finely pulverized using an agate mortar and pestle. The pulverized sample was quantitatively transferred to a 250 mL flask containing 100.0 mL of 1.0 N hydrochloric acid (pH 1.2 ± 0.05). The flask was sealed with Parafilm M® to prevent evaporation. The mixture was subjected to continuous stirring at 500 rpm using a temperature-controlled magnetic stirrer maintained at 37 ± 0.5°C for 60 ± 1 m to ensure complete dissolution of the encapsulated drug. Following stirring, the solution was allowed to cool to room temperature (22 ± 2°C) for 15 m. The cooled solution was filtered through a 0.45 µm polytetrafluoroethylene syringe filter (Millipore, USA) to remove any undissolved particles. The first 5 mL of the filtrate was discarded to saturate the filter, and the subsequent filtrate was collected for analysis.
The drug concentration in the filtrate was determined using a fiber optic spectrophotometry (Ocean Optics QE65 Pro, USA) equipped with a deuterium-halogen light source (DH-2000-BAL, Ocean Optics) and a 1 cm path length quartz cuvette. Absorbance measurements were recorded at a wavelength of 264 nm.
The drug content was calculated using Equation (6):
Drug Content =Measured Drug Concentration×Volume of SolutionWeight of the Ibuprofen Nanoballoons×100
All measurements were performed in triplicate (n = 3), and results are expressed as mean ± standard deviation. The coefficient of variation was calculated to assess the precision of the method. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post-hoc test, with p < 0.05 considered statistically significant. All statistical analyses were conducted using GraphPad Prism version 9.0 (GraphPad Software, San Diego, CA, USA).
Buoyancy studies
Buoyancy studies were conducted to evaluate the floating capabilities of ibuprofen-loaded nanoballoons in simulated gastric conditions. The experimental setup consisted of a 100 mL beaker containing 0.1 N hydrochloric acid (pH 1.2) maintained at 37 ± 0.5°C to mimic the gastric environment. A precisely weighed sample of nanoballoons (0.1 g) was gently introduced into the simulated gastric fluid, which was then agitated for 3 h. The floating behavior and duration were monitored over a period ranging from several minutes to hours. The buoyancy was quantified by periodically assessing the percentage of nanoballoons remaining afloat, calculated using Equation (7). This assessment involved comparing the weight of the floating nanoballoons to their initial total weight. To ensure reproducibility and statistical significance, all experiments were performed in triplicate, with results reported as mean ± standard deviation.
% Buoyancy=Weight of floating nanoballoonsInitial weight of nanoballoons×100
Morphological characteristics of the ibuprofen-loaded floating nanoballoons examined using scanning electron microscopy (SEM)
The morphological characterization of the floating nanoballoons was carried out using SEM (Jeol, Tokyo, Japan). To prepare the samples for SEM analysis, the nanoballoons were gently collected and placed on an aluminum stub using double-sided adhesive carbon tape. Excess nanoballoons were carefully blown away using a gentle stream of nitrogen gas to prevent aggregation and to ensure a clear view of individual nanoballoons. Subsequently, the samples were coated with a thin layer of gold using a sputter coater to enhance conductivity and prevent charging under the electron beam. The sputter-coating process was conducted under vacuum conditions, maintaining a coating thickness of approximately 10 nm to ensure uniform coverage without obscuring fine surface details. The coated samples were then placed in the SEM chamber and examined using an accelerating voltage of 15 kV to obtain detailed micrographs. The SEM images were captured at varying magnifications to observe the overall morphology, surface topology, and hollow core structure of the nanoballoons.
In vitro drug release
To evaluate the in vitro drug release behavior of ibuprofen-loaded floating nanoballoons, the dissolution study was conducted using a USP Type II (paddle) dissolution apparatus. Simulated gastric fluid without enzymes was prepared, comprising 0.1 N HCl (pH 1.2). An accurately weighed quantity of floating nanoballoons equivalent to 20 mg of ibuprofen was introduced into 1,000 mL of the dissolution medium, maintained at 37 ± 0.5°C. The paddle speed was set to 50 rpm to ensure proper agitation and mimic gastric motility. At predetermined time intervals (0.5, 1, 2, 4, 6, 8, and 12 h), a fiber optic probe was introduced into the dissolution medium and analyzed at 264 nm.
Animal model, grouping, and treatments
The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Al Qadisiyah (Protocol Number: 84). All surgery was performed under ketamine/xylazine anesthesia, and all efforts were made to minimize suffering.
Animals were maintained under standard laboratory conditions (24–26°C, 60–70% RH, 12 h light/dark cycle) with free access to food and water. Studies were conducted in two phases:
A. Acute Anti-inflammatory Study: Twenty-one rats were randomly divided into three groups (n = 7):
Control: Normal saline (10 mL/kg p.o.);
Pure drug: ibuprofen (15 mg/kg orally);
Test formulation: ibuprofen nanoballoons (15 mg/kg orally).
Acute inflammation was induced by intradermal injection of carrageenan (0.1 mL, 1%) in the right hind paw. Treatments were administered 1 h before carrageenan injection. Paw edema was measured at 0, 0.5, 1, and 3 h post-injection using a plethysmometer.
B. Chronic Anti-inflammatory Study: Using a similar grouping (n = 7/group), chronic inflammation was induced by subcutaneous formalin injection (0.01 mL, 2%) in the right hind paw on days 1 and 3.
Treatments continued for 10 days. The linear cross-section of the ankle joint was measured using a vernier caliper. At the study’s completion, blood samples were collected for inflammatory markers (TNF-α, hs-CRP, IL-6, IL-10) analysis.
Results
Preparation of calibration curve
The calibration curve for ibuprofen was prepared in phosphate buffer (pH 7.4) using UV spectrophotometry at λmax 221 nm. Standard solutions ranging from 2–20 µg/mL demonstrated a linear relationship between concentration and absorbance, with a correlation coefficient (R2) of 0.9999. The linear regression equation was y = 0.1632x, indicating excellent linearity within the tested concentration range.
Loading efficiency and percentage yield
The loading efficiency and percentage yield were evaluated to assess the formulation efficiency of ibuprofen-loaded floating nanoballoons. For the drug:polymer ratios evaluated (Table 1), the 1:1 ratio showed the best loading efficiency of 96.54 ± 1.32%. The percentage yield of the formulation process was 98.33 ± 1.14%, calculated based on the ratio of the obtained nanoballoons to the total weight of the drug and polymer used in the preparation. The optimized formulation with a drug:polymer ratio of 1:4 was used for further studies.
Table 1Drug loading efficiency at a different drug:polymer feeding ratios
| Drug:polymer ratio | Drug loading efficiency (%) |
|---|
| 1:1 | 78.32 ± 2.41 |
| 1:2 | 85.67 ± 1.89 |
| 1:3 | 90.21 ± 1.75 |
| 1:4 | 96.54 ± 1.32 |
| 1:5 | 96.48 ± 1.45 |
Micromeritic properties
The micromeritic properties of ibuprofen-loaded nanoballoons were comprehensively evaluated and compared with pure ibuprofen (Table 2). The nanoballoons exhibited significantly lower bulk density and tapped density compared to ibuprofen. Flow properties were assessed using multiple parameters. The Carr’s index of the nanoballoons was substantially lower than that of pure ibuprofen. The Hausner ratio for the nanoballoons was higher compared to ibuprofen. The angle of repose measurements revealed superior flowability of the nanoballoons compared to ibuprofen.
Table 2Comparative analysis of micromeritic properties of ibuprofen-loaded floating nanoballoons versus ibuprofen
| Parameter | Ibuprofen nanoballoons | Ibuprofen | Interpretation |
|---|
| Bulk density (g/mL) | 0.1889 ± 0.0024 | 0.5128 ± 0.019 | Lower density indicates hollow structure |
| Tapped density (g/mL) | 0.2342 ± 0.0044 | 0.6524 ± 0.047 | Reduced tapped density confirms porosity |
| Carr’s index (%) | 11.973 ± 1.7200 | 23.179 ± 1.532 | Excellent flow properties (<15%) |
| Hausner ratio | 1.422 ± 0.0430 | 1.132 ± 0.031 | Good flowability (1.0–1.5) |
| Angle of repose (°) | 24.745 ± 1.860 | 35.140 ± 1.960 | Excellent flow properties (<25°) |
Buoyancy study
The floating characteristics of ibuprofen-loaded nanoballoons were evaluated under simulated gastric conditions (0.1 N HCl, pH 1.2) at 37 ± 0.5°C. The nanoballoons demonstrated excellent buoyancy properties, exhibiting immediate floating behavior upon introduction into the simulated gastric fluid, with no significant floating lag time. 93.5% of the nanoballoons maintained their floating capability throughout the 12-h study period. The buoyancy remained consistent under continuous agitation conditions. The nanoballoons maintained their structural integrity throughout the study period, with no significant degradation or loss of floating capability observed over the 12-h duration. The buoyancy percentage was calculated using the ratio of floating nanoballoons to the total weight, demonstrating the formulation’s excellent gastro-retentive properties under physiological conditions.
Morphological characteristics of the ibuprofen-loaded floating nanoballoons examined using SEM
The morphological characteristics of ibuprofen-loaded floating nanoballoons were analyzed using SEM. Figure 1 presents SEM micrographs revealing the detailed structural features of the formulated nanoballoons. The SEM analysis revealed that the nanoballoons exhibited a spherical morphology with well-defined boundaries. The surface topology demonstrated a distinctive porous architecture characterized by uniformly distributed micropores across the particle surface. The nanoballoons maintained their structural integrity without visible signs of collapse or deformation, indicating robust mechanical properties. This observation is particularly important for gastroretentive applications, where maintaining structural stability in the acidic gastric environment is crucial.
In vitro drug release
In vitro drug release studies of ibuprofen-loaded floating nanoballoons were conducted using a USP Type II dissolution apparatus in simulated gastric fluid (pH 1.2) at 37 ± 0.5°C. The release profile exhibited a biphasic pattern, with an initial burst release of 35.23 ± 2.13% of the encapsulated ibuprofen occurring within the first 2 h, followed by a sustained release phase reaching 97.54 ± 1.30% over 12 h. Mathematical modeling of the release kinetics (Table 3) revealed that the drug release mechanism best fitted the Korsmeyer-Peppas model (R2 = 0.9934) with a release exponent of 0.4327, indicating an anomalous transport mechanism combining Fickian diffusion and polymer chain relaxation. The drug concentration was monitored at predetermined time intervals using fiber optic spectrophotometry at 264 nm, with all measurements performed in triplicate (n = 3). Statistical analysis using one-way ANOVA followed by Tukey’s post-hoc test (p < 0.05) confirmed the significance of the observed release pattern. The biphasic release profile, characterized by an initial burst release followed by a sustained release phase, suggests that the formulated nanoballoons can provide both a rapid onset of action and a prolonged therapeutic effect, potentially enhancing therapeutic efficacy while reducing dosing frequency.
Table 3Kinetic parameters for ibuprofen release from floating nanoballoons
| Kinetic model | R2 | Rate constant (K) | Release exponent (n) |
|---|
| Zero-order | 0.8245 | 7.8932 h−1 | – |
| First-order | 0.9123 | 0.2567 h−1 | – |
| Higuchi | 0.9876 | 28.4521 h−0.5 | – |
| Korsmeyer-Peppas | 0.9934 | 35.6789 h−n | 0.4327 |
| Hixson-Crowell | 0.9456 | 0.0789 h−1 | – |
Animal model, grouping, and treatments
The anti-inflammatory effects of ibuprofen-loaded nanoballoons were evaluated using both acute and chronic models, with the results summarized in Tables 4–6. Table 4 presents the comparative anti-inflammatory effects in the acute model, demonstrating the percentage inhibition of paw edema at different time points (0, 0.5, 1, and 3 h). The chronic model results are detailed in Table 5, which shows the modulation of inflammatory markers (TNF-α, hs-CRP, IL-6, IL-10) across treatment groups. Table 6 provides a comprehensive comparison of the percentage anti-inflammatory effect between ibuprofen and ibuprofen-loaded nanoballoons in both acute and chronic models. These tables collectively demonstrate the enhanced anti-inflammatory efficacy of the nanoballoon formulation compared to conventional ibuprofen treatment.
Table 4Comparison of anti-inflammatory effects between ibuprofen and ibuprofen-loaded nanoballoons, acute model
| Time (h) | Groups
|
|---|
| G1 (Control) | G2 (ibuprofen) | G3 (ibuprofen-nanoballoons) |
|---|
| 0 | 0.265 ± 0.022 | 0.412 ± 0.0123 | 0.289 ± 0.034 |
| 1 | 0.532 ± 0.044 | 0.432 ± 0.031 | 0.513 ± 0.011 |
| 2 | 0.872 ± 0.242 | 0.387 ± 0.025 | 0.288 ± 0.023 |
| 3 | 0.985 ± 0.054 | 0.476 ± 0.041 | 0.314 ± 0.028 |
| % inhibition (3rd h) | | 51.67 | 68.12 |
Table 5Comparison of anti-inflammatory effects between ibuprofen and ibuprofen-loaded nanoballoons, chronic model
| Parameter | Groups
|
|---|
| G1 (Control) | G2 (ibuprofen) | G3 (ibuprofen-nanoballoons) |
|---|
| hs-CRP (ng/mL) | 303.12 ± 14.50 | 612 ± 10.21 | 398.00 ± 13.61 |
| Fibrinogen (mg/dL) | 84.00 ± 3.50 | 232.12 ± 11.33 | 201.7 ± 11.02 |
| TNF-α (pg/mL) | 17.25 ± 0.32 | 31.11 ± 1.23 | 19.12 ± 0.48 |
| IL-6 (pg/mL) | 26.31 ± 2.51 | 135 ± 11.22 | 100.01 ± 18.40 |
| IL-10 (pg/mL) | 82.38 ± 18.20 | 276.11 ± 19.16 | 507.18 ± 10.11 |
| WBCs count (×103/mL) | 2.54 ± 0.45 | 7.860 ± 0.28 | 7.345 ± 0.44 |
Table 6Percentage anti-inflammatory effect between ibuprofen and ibuprofen nanoballoons
| Parameter | Groups
|
|---|
| G1 (Control) | G2 (ibuprofen) | G3 (ibuprofen-nanoballoons) |
|---|
| Day 1 (initial) | 2.43 ± 0.56 | 4.54 ± 0.20 | 4.86 ± 0.06 |
| Day 10 | 6.32 ± 0.43 | 4.65 ± 0.26 | 4.43 ± 0.62 |
| Mean difference | 3.89 | 1.43 | 0.54 |
| % of the anti-inflammatory effect | – | 63.23 | 86.11 |
Discussion
Preparation of calibration curve
The calibration curve demonstrated excellent linearity across the concentration range, indicating the robust reliability of our analytical method (Fig. 2). The linear regression equation showed minimal y-intercept deviation from zero, suggesting a negligible systematic error in the measurements.
The selected wavelength provided optimal sensitivity for ibuprofen quantification while minimizing potential interference from excipients. The narrow confidence intervals observed around the regression line indicate high precision in the concentration-absorbance relationship. This analytical method’s reliability was crucial for accurate drug loading and release measurements throughout the study.
The working concentration range was strategically chosen to encompass both the lower concentrations expected during initial drug release and higher concentrations during peak release periods. This range allows for accurate quantification across all phases of drug release studies without requiring multiple dilutions, thereby reducing analytical errors.
Loading efficiency and percentage yield
The loading efficiency is a crucial parameter in evaluating the performance of floating hollow nanoballoons. It represents the proportion of the initial drug that is successfully encapsulated within the nanoballoons. The exceptional buoyancy characteristics demonstrated by our ibuprofen-loaded nanoballoons represent a significant advancement in gastroretentive drug delivery systems. The results obtained in this study were superior to those reported in other studies, which typically ranged from 78% to 95%.14,15
The immediate floating response observed in our formulation can be attributed to the optimized hollow structure and low bulk density.16 This is consistent with findings by Ghoneim et al. (2019),17 who demonstrated that particles with a density of less than 1 g/mL exhibit superior floating properties in gastric fluid. The absence of floating lag time in our formulation is particularly advantageous, in line with the findings of Sher Ahmad et al. (2023),18 who reported that minimal lag time reduces the risk of premature evacuation from the stomach.
The sustained buoyancy over 12 h is crucial for maintaining therapeutic efficacy, as established in a recent study by Jeong et al.,19 showing that gastric retention times exceeding 8 h significantly enhance drug bioavailability for poorly soluble drugs like ibuprofen. The stability of our nanoballoons in simulated gastric conditions is supported by findings demonstrating that ethyl cellulose-based hollow particles maintain structural integrity in acidic environments for extended periods.20 This stability is crucial for controlled drug release, as emphasized by a recent study showing that maintaining structural integrity directly correlates with sustained therapeutic effects.21
Furthermore, the solvent evaporation method employed in this study played a significant role in achieving high loading efficiency.22 A balanced solvent evaporation rate ensured proper solidification of the nanoballoons, reducing the risk of drug diffusion out of the polymer matrix during the formation stage. Additionally, the optimization of the drug-to-polymer ratio was essential in achieving optimal encapsulation efficiency. An excess of polymer concentration relative to the drug amount helped in better drug encapsulation within the nanoballoons.23 The morphological characteristics observed through SEM analysis further supported the efficient encapsulation, as the images demonstrated well-formed, spherical nanoballoons with a distinct hollow core structure.
The calculation of percentage yield provided a quantitative measure of the production efficiency and the reproducibility of the nanoballoon synthesis process. The high percentage yield indicated successful encapsulation and minimal loss of materials during the preparation, signifying the robustness of the solvent evaporation technique utilized.24 Several factors were found to influence the percentage yield, including the concentration of the polymer used, the solvent evaporation rate, and the stirring speed during the formulation process. Optimizing these parameters was crucial in achieving a high yield. It was observed that higher polymer concentrations resulted in increased viscosity of the solution, improving the stability and formation of nanoballoons, thus enhancing the yield, in accordance with a previous study.25 Additionally, the selection of an optimum solvent combination and evaporation conditions helped minimize the loss of materials during the process.
In comparison to other studies reported in the literature, the formulation method demonstrated in this work exhibits a competitive yield, suggesting that the current methodology is consistent with or superior to existing approaches.26
Micromeritic properties
The nanoballoons exhibited superior flow characteristics compared to the pure drug. The 63% reduction in the bulk and tapped density of the nanoballoons compared to ibuprofen can be attributed to their unique hollow structure. This hollow structure allows for a greater volume-to-mass ratio, which is a critical factor in determining bulk density. Bulk density is influenced by the arrangement and density of particles within a given volume. In the case of nanoballoons, their design inherently incorporates a significant amount of air or void space, leading to a lower overall mass for the same volume compared to solid forms like ibuprofen. This phenomenon is well-documented in materials science, where the structural characteristics of materials directly affect their physical properties, including density.27
The Carr’s index is a critical parameter in assessing flowability, with values below 15% indicating optimal processing characteristics. This aligns with the findings of Gashe et al. (2022),28 who emphasized that lower Carr’s index values correlate with improved flowability and processing efficiency in pharmaceutical manufacturing. In our study, the Carr’s index of nanoballoons demonstrated superior flowability compared to ibuprofen, suggesting that these nanoballoons may enhance the manufacturability of drug formulations. This is consistent with the results reported by Serrano-Mora et al. (2021),29 where their co-processed excipients exhibited Carr’s index values ranging from 16% to 20%, indicating less favorable flow properties compared to our findings. The findings from our research, indicating that the Carr’s index of nanoballoons is lower than that of ibuprofen, suggest that these nanoballoons could potentially facilitate more efficient manufacturing processes. This aligns with broader trends observed in the pharmaceutical industry regarding the development of advanced excipients and drug delivery systems.30
The Hausner ratio for nanoballoons indicated good flow properties. Recent studies have established that Hausner ratios below 1.25–1.30 are optimal for ensuring good flowability in pharmaceutical formulations.31,32 This aligns with the findings of Monton et al., who emphasized that the Hausner ratio, along with other parameters such as the Carr index, is integral to assessing the flow properties of drug powders.33
Perhaps most significantly, the angle of repose for nanoballoons demonstrated excellent flow characteristics, substantially better than ibuprofen. A recent study noted that optimal processing conditions are typically associated with angles below 30°.34 This observation is further supported by the work of Azman et al. (2021),35 who highlighted that angles of repose are influenced by moisture content, which can affect material flow characteristics. The practical implications of a lower angle of repose are substantial for manufacturing. Materials with a lower angle of repose tend to be more flowable, facilitating easier handling and processing. For instance, Azman et al. emphasized that the angle of repose is essential for the design of processing, storage, and conveying systems for particulate materials.
Buoyancy study
The buoyancy studies revealed good floating capabilities of the ibuprofen nanoballoons, with 93.5% of the formulation maintaining buoyancy over 12 h. This performance aligns with recent advances in floating drug delivery systems, where optimization of floating parameters is critical for sustained gastric retention.36 The immediate onset of floating behavior without lag time can be attributed to the optimized hollow core structure, corroborated by the low bulk density, consistent with recent findings.37 The hollow architecture’s contribution to floating behavior can be explained by the ethyl cellulose matrix providing mechanical stability while maintaining low density.38 Further, SEM analysis confirmed uniform wall thickness and structural consistency. This observation aligns with the recent findings by Raje et al. (2022),39 emphasizing that wall thickness can be manipulated to control drug release profiles, linking structural parameters to functional outcomes in drug delivery systems. Additionally, Kulkarni et al. (2022)40 highlighted that microstructural properties, including wall thickness, significantly influence the drug release mechanisms in formulations, reinforcing the importance of uniformity in achieving desired therapeutic effects.
The porous surface morphology further enhances floating capability due to additional air pockets, contributing to the overall buoyancy. The incorporation of porous structures not only facilitates the retention of air but also increases the surface area for drug release, leading to a controlled and sustained release profile.41 The observed 63% reduction in bulk density relative to ibuprofen significantly exceeds the critical threshold of 50% for optimal gastric retention established by Dhukia et al. (2024).42 This reduction indicates a favorable alteration in the formulation that enhances buoyancy and prolongs gastric retention time, which is essential for improving the bioavailability of poorly soluble drugs like ibuprofen.43 The relationship between bulk density and gastric retention is well-documented; lower bulk density formulations tend to remain in the stomach longer, facilitating sustained drug release and absorption.44,45
Morphological characteristics of the ibuprofen-loaded floating nanoballoons examined using SEM
The SEM micrographs revealed that the nanoballoons exhibited a spherical morphology with a distinct hollow core structure (Fig. 2). The spherical morphology and well-defined boundaries of the nanoballoons are critical for maintaining structural integrity in the harsh gastric environment, which is essential for gastroretentive applications.46 The nanoballoons displayed a porous surface topology, which is advantageous for enhancing drug dissolution and release.47 The increased surface area associated with porous structures facilitates a higher drug loading capacity and promotes rapid diffusion of the drug molecules into the surrounding medium, thereby accelerating the release rate.48
In vitro drug release
The observed biphasic drug release profile of ibuprofen-loaded floating nanoballoons (Fig. 3) is indicative of a well-designed delivery system that can provide both immediate and prolonged therapeutic effects. The initial burst release of 35.23% within the first two hours aligns with findings from other studies that highlight the significance of initial rapid drug release in enhancing therapeutic efficacy while minimizing dosing frequency.49 The initial burst release can be attributed to the surface-adsorbed drug molecules and the presence of the microporous surface architecture, which facilitates rapid drug dissolution for immediate therapeutic onset. The sustained release phase, which culminates in 97.54% release over 12 h, supports the notion that floating systems can improve drug bioavailability by maintaining drug concentration in the gastric environment.50
The Korsmeyer-Peppas model fitting with an exponent (n = 0.4327) suggests an anomalous transport mechanism, which is consistent with literature indicating that such mechanisms often involve a combination of Fickian diffusion and polymer relaxation.51 This dual mechanism is crucial for achieving a controlled release profile, as it allows for the modulation of drug release rates based on the formulation’s physicochemical properties.52 Statistical validation through one-way ANOVA confirms the robustness of the release data, reinforcing the potential of these nanoballoons in clinical applications aimed at improving patient compliance and therapeutic outcomes.53
The complex release mechanism elucidated by our kinetic analysis has important implications for the therapeutic efficacy of the ibuprofen nanoballoons. The initial burst release provides a rapid onset of action, which is beneficial for achieving quick pain relief. The subsequent sustained release, governed by anomalous transport, ensures a prolonged therapeutic effect, potentially reducing dosing frequency and improving patient compliance. Moreover, the combination of diffusion and erosion-controlled release suggests that the nanoballoons may provide a more consistent drug release rate over time compared to purely diffusion-controlled systems. This could lead to more stable plasma concentrations of ibuprofen, potentially enhancing its anti-inflammatory and analgesic effects while minimizing fluctuations that could lead to side effects.
Animal model, grouping, and treatments
In this study, male Sprague-Dawley rats were utilized to evaluate the anti-inflammatory effects of ibuprofen nanoballoons. The acute anti-inflammatory model demonstrated that the group receiving ibuprofen nanoballoons exhibited a statistically significant reduction in paw edema compared to both the control and pure ibuprofen groups at all measured time points, with a peak percentage inhibition of 68.12% at the third hour post-injection.54 In the chronic model, the nanoballoons group also showed significant reductions in inflammatory markers such as TNF-α, hs-CRP, and IL-6, while increasing IL-10 levels, indicating a favorable modulation of the inflammatory response.55 These findings suggest that the nanoballoon formulation enhances the bioavailability and therapeutic efficacy of ibuprofen, highlighting the potential of nanotechnology in improving anti-inflammatory treatments.56