Gastroretentive Nanoformulations: The Role of Nanosponges in Enhanced Drug Delivery

Background

The field of drug delivery has continuously evolved to overcome limitations of conventional therapies, leading to the development of novel drug delivery systems aimed at optimizing therapeutic efficacy and patient outcomes [1,2]. Traditional oral drug administration, while convenient and widely preferred, faces significant physiological and physicochemical hurdles that can compromise therapeutic effectiveness [3]. Challenges include low bioavailability, limited drug loading capacity, and stability issues [4]. Conventional oral dosage forms are also associated with issues such as low site-specific accumulation, unfavorable body distribution, and adverse side effects [3]. Other obstacles include lack of acceptable bioavailability for certain molecules, first-pass metabolism, gastrointestinal disorders due to irritation, high dose frequency, low medication adherence, and swallowing difficulties [5]. The poor solubility and dissolution of drugs are also significant challenges in oral delivery, often requiring advanced formulation strategies to improve absorption [6,7]. These factors collectively highlight the persistent need for innovative delivery approaches that can control drug release, enhance drug stability, and improve drug targeting to specific sites within the body [8,9].

Need for Gastroretention

Gastroretentive drug delivery systems have emerged as a crucial strategy to overcome many challenges of conventional oral drug administration, particularly for drugs that benefit from prolonged gastric residence [10,11]. Gastroretention is especially important for drugs primarily absorbed in the stomach or upper small intestine, those acting locally in the stomach, or those exhibiting narrow absorption windows in the upper gastrointestinal tract [12,13]. By extending gastric residence time, GRDDS enhance drug bioavailability by providing more time for absorption—particularly for drugs poorly soluble at the higher intestinal pH [14,15]. This prolonged retention also improves therapeutic efficacy, reduces dosing frequency, and boosts patient compliance through consistent drug levels [12,16]. For example, drugs treating Helicobacter pylori infections or gastric ulcers benefit significantly from sustained local release in the stomach, maximizing therapeutic effects while minimizing systemic exposure and side effects [14]. Moreover, extended gastric retention reduces drug wastage, enhances solubility for drugs less stable in high-pH environments, and optimizes therapy for short half-life drugs [17]. Thus, developing effective gastroretentive strategies is essential for optimizing the therapeutic profiles of numerous oral medications [18,19]. The evolution of oral drug delivery systems has been transformative in the pharmaceutical sector, addressing challenges related to drug solubility, stability, and targeted therapeutic effects [20]. Among these systems, gastroretentive drug delivery systems have emerged as a promising approach, particularly for drugs that benefit from prolonged gastric retention or that require site-specific absorption in the gastrointestinal tract [21]. The fundamental premise behind GRDDS involves retaining the dosage form in the stomach for an extended period, thereby facilitating a gradual drug release at a predetermined rate, which is particularly advantageous for drugs with limited absorption windows, those that act locally in the stomach, or those susceptible to degradation in alkaline intestinal environments [22,23].

Introduction to Nanosponges

Nanosponges represent a cutting-edge class of nanoparticulate systems that have garnered significant attention for their unique properties and versatile applications in drug delivery [24]. These innovative carriers are characterized by their distinctive three-dimensional (3D) scaffold structure, often appearing as tiny, mesh-like or spongy spheres with nanometric cavities and numerous interconnected empty spaces or voids [25,26]. This highly porous nature allows nanosponges to effectively encapsulate a wide variety of active pharmaceutical ingredients, including both hydrophilic and hydrophobic drugs [27–29].

The design of nanosponges, typically involving the cross-linking of polymers such as cyclodextrins with carbonyl or dicarboxylate compounds, results in a stable, solid, and porous structure [30,31]. These cross-linkers are crucial for forming the internal cavities and influencing the porosity and surface charge density of the nanosponges, which in turn dictate their capacity to hold drug molecules and modulate drug release.[32]

A primary advantage of nanosponges is their remarkable capacity to bind poorly soluble medications, thereby significantly enhancing drug solubility and dissolution rates[33]. By improving the aqueous solubility of such drugs, nanosponges can augment their bioavailability, leading to more predictable and effective absorption [24,29,34]. Furthermore, nanosponges are adept at ensuring regulated and sustained drug release, which is critical for maintaining optimal drug levels over extended periods, reducing dosing frequency, and improving patient adherence [26,30]. This controlled release pattern also contributes to minimizing drug toxicity and preventing premature degradation of sensitive drug molecules [29]. Nanosponges offer a promising solution to several biopharmaceutical challenges, making them effective pharmaceutical transporters that address issues like toxicity and poor bioavailability [25].

Scope of the Review

This comprehensive review aims to thoroughly explore the advancements in nanosponge-based gastroretentive drug delivery systems. We will begin by detailing the fundamental aspects of nanosponges, including their precise definition, diverse structural characteristics, and the various methods employed for their synthesis. Subsequent sections will delve into the critical characterization techniques used to evaluate their physicochemical properties and in-vitro performance, such as particle size, morphology, drug loading capacity, and release kinetics. A significant portion of this review will focus on the specific mechanisms by which nanosponges contribute to gastroretention and how they enhance drug solubility, bioavailability, and provide sustained release[35]. Furthermore, we will highlight key therapeutic applications, presenting case studies and examples of drugs successfully formulated into nanosponge-based gastroretentive systems. Finally, the review will address the existing challenges in the field, including aspects related to scale-up, regulatory considerations, and biocompatibility, while also discussing future perspectives and emerging trends in nanosponge research and development. This will provide a holistic understanding of nanosponges as a revolutionary targeted drug delivery nanocarrier [24,30]. Their unique architecture enables precise drug delivery to specific physiological sites, thus maximizing therapeutic efficacy and minimizing systemic exposure [36].

Overview of Gastroretentive Drug Delivery Systems

These systems are engineered to reside in the stomach for an extended period, allowing for a sustained and localized drug release that optimizes therapeutic outcomes for specific conditions [37]. This extended retention time offers significant advantages, especially for drugs with narrow absorption windows, those acting locally within the stomach, or those susceptible to degradation in the lower gastrointestinal tract. By prolonging the gastric residence time, GRDDS can enhance drug solubility, improve bioavailability, and reduce dosing frequency, thereby improving patient compliance and therapeutic efficacy [20].

Various gastroretentive strategies have been explored, including floating systems, mucoadhesive systems, expandable systems, and high-density systems, each designed to overcome physiological barriers and maximize gastric retention [20,38].  Moreover, their ultra-small size and porous structure allow for efficient encapsulation and controlled release of drugs, making them ideal candidates for enhancing oral drug delivery systems [32].

Mechanisms of Gastric Retention: Floating Systems

Floating drug delivery systems (FDDS) represent one of the most extensively investigated gastroretentive approaches, designed to maintain buoyancy on gastric contents through density reduction below that of gastric fluid (approximately 1.004-1.01 g/cm³)[39]. These systems work by having a bulk density lower than the gastric contents, allowing them to remain buoyant in the stomach for prolonged periods without affecting the gastric emptying rate. The floating mechanism is achieved through various approaches, including gas-generating agents such as sodium bicarbonate and the use of low-density matrices[40]. Floating systems are categorized into two types: effervescent and non-effervescent. Effervescent systems maintain buoyancy through gas generation using agents such as sodium bicarbonate, while non-effervescent systems utilize low-density matrices or air-entrapping polymers[41].

Mucoadhesive Systems

Mucoadhesive systems exploit polymer-mucin interactions to adhere to the stomach's mucous membrane, thereby improving retention and bioavailability. The Bioadhesive Drug Delivery System stands out by ensuring prolonged gastric retention through strong adhesive properties with the gastric mucosa. These systems utilize mucoadhesive polymers such as Carbopol, chitosan, and hydroxypropyl methylcellulose (HPMC) [42].

High-Density Systems

High-density (sinking) systems are designed with a density greater than gastric fluids, causing them to sink and settle at the bottom of the stomach, thereby resisting gastric emptying. These systems typically have densities exceeding 1.5 g/cm³ and remain in the stomach through gravitational forces[43] as descripted in figure 1.

Expandable and Swelling Systems

Expandable systems utilize controlled swelling to prevent pyloric passage. These formulations incorporate swellable polymers that hydrate and expand to 2-3 folds in gastric fluid, achieving dimensions that prevent passage through the pyloric sphincter. Super porous hydrogels represent an innovative variation, capable of rapid swelling to significantly larger sizes[44].

Figure 1: Approaches of gastroretentive drug delivery system

Advantages of GRDDS

• Enhanced bioavailability for drugs with narrow absorption windows in the upper GIT  
• Reduced dosing frequency through sustained drug release, improving patient compliance  
• Improved drug stability in an acidic gastric environment for pH-sensitive drugs [45]
• Targeted local delivery to the stomach for treating peptic ulcers and H. pylori infections
• Consistent plasma drug levels minimize concentration fluctuations
• Bypasses first-pass metabolism for certain formulations [46]

Limitations of Traditional GRDDS

• Variable gastric retention due to inter- and intra-subject differences in gastric emptying
• Complex formulation with manufacturing scalability challenges  
• Potential local irritation from prolonged gastric contact
• Limited drug loading capacity and stability issues[47]

Addressing Limitations with Nanosponges

With great promise to overcome the drawbacks of conventional GRDDS, nanosponges have emerged as an ultramodern drug delivery technology. These biocompatible, porous, nanoscale carriers provide longer release profiles, better stability, increased solubility and bioavailability, and formulation flexibility[48]. Their unique sponge-like structure can encapsulate both hydrophobic and hydrophilic drugs. However, challenges such as large-scale production, stability issues, and regulatory hurdles must be addressed for widespread clinical translation[49]. Further research is imperative to optimize manufacturing processes for economic viability and to fully evaluate long-term safety profiles, ensuring these innovative systems can achieve their full therapeutic potential.

Indeed, the integration of nanosponges with established GRDDS platforms could represent a synergistic approach, leveraging the benefits of prolonged gastric retention with the enhanced drug encapsulation and controlled release characteristics of nanosponges [20]. This synergistic approach facilitates advanced pharmacokinetic profiles, leading to more consistent therapeutic drug levels and improved patient outcomes, particularly for drugs requiring site-specific absorption or extended gastric residence [38]. This allows for a reduction in dosing frequency and an improvement in therapeutic efficacy by ensuring that optimal drug concentrations are maintained over extended periods, thereby enhancing patient compliance [50].

Nanosponges: Structure, Properties, and Synthesis

Nanosponges are innovative, hyper-cross-linked polymeric colloidal structures characterized by their porous, sponge-like architecture and numerous cavities capable of encapsulating various payloads, ranging from 5 to 300 µm[51]. These structures, typically consisting of solid, crosslinked polymeric networks, are defined by their hydrophilic, water-insoluble nature and supramolecular three-dimensional organization, making them suitable for targeted and sustained drug delivery and cancer therapy[31]. This unique architecture enables both hydrophilic and hydrophobic drug absorption and transportation, proving effective in overcoming drug resistance and minimizing systemic toxicity while enhancing cytotoxic effects[52]. Their ability to form inclusion and non-inclusion complexes with a wide array of molecules further contributes to their utility in enhancing the solubility and bioavailability of poorly water-soluble compounds[53]. The drug loading capacity of nanosponges is notably influenced by their degree of crosslinking, as this directly dictates the available void space within the nanostructure for drug encapsulation as shown in figure 2 [26].

Figure 2: Figure: Schematic illustration of fine-pored sponges due to increased surface area.

Their porous structure also facilitates sustained drug release and targeted delivery, making them highly versatile for various biomedical applications, including theranostics and the encapsulation of natural bioactive compounds[26]. Different types of nanosponges, including metallic, β-cyclodextrin, silicon-based, ethylcellulose, and DNAzymes, have been developed with β-cyclodextrin nanosponges being particularly well-studied due to their selectivity, specificity, and low toxicity[54].

The exceptional physicochemical properties of nanosponges—including their high porosity, tunable particle size, favorable surface charge, superior drug loading capacity, and remarkable stability are directly attributed to the synthesis methodology employed. The selection of an appropriate synthesis method is crucial as it determines the structural architecture, cavity dimensions, cross-linking density, and ultimately the functional performance of the resulting nanosponges [55]. Various synthesis techniques have been developed to fabricate nanosponges with tailored characteristics suitable for specific pharmaceutical applications, particularly gastroretentive drug delivery systems.[56,57]

Figure 3: Comparison of Nanosponge Synthesis Methods

The emulsion solvent diffusion method represents one of the most widely employed techniques for nanosponge synthesis. This method involves dissolving cyclodextrin and cross-linking agent in a polar aprotic solvent (e.g., dimethylformamide or dimethyl sulfoxide), which is then dispersed into an aqueous continuous phase containing a surfactant under continuous stirring,  as mentioned in Figure 3 [58]. The ultrasonication method employs high-frequency sound waves (20-50 kHz) to induce cavitation and promote cross-linking reactions. Cyclodextrin and cross-linker are mixed in an appropriate solvent and subjected to ultrasonic irradiation, which generates localized high temperatures and pressures, accelerating the cross-linking process [59]. The solvent evaporation technique involves dissolving cyclodextrin and cross-linker in a volatile organic solvent, followed by gradual evaporation under controlled conditions. The mixture is typically stirred at elevated temperatures (50-70°C) or under reduced pressure to accelerate solvent removal, resulting in nanosponge formation[60]. Melting Method: A solvent-free approach where cyclodextrin and cross-linker are heated above their melting points and mixed, offering environmental advantages but limited to thermally stable components [61]. Microwave-Assisted Synthesis: Utilizes microwave irradiation to accelerate cross-linking reactions, significantly reducing synthesis time to minutes while maintaining product quality [62].

Supercritical Fluid Technology: Employs supercritical CO? as a green solvent for nanosponge synthesis and drug loading, eliminating organic solvent residues and enabling precise control over particle properties [63].

Characterization of Nanosponges

The thorough characterization of nanosponges is crucial for understanding their physicochemical properties, ensuring quality control, and predicting their in-vivo performance. A combination of physical and in-vitro evaluation techniques is employed for this purpose [64].

Physical Characterization

Physical characterization techniques provide insights into the structural and surface properties of nanosponges:

• Particle Size and Polydispersity Index: The size of nanosponge particles is typically determined using Dynamic Light Scattering. This technique provides the mean diameter of the particles and the PDI, which indicates the uniformity of the particle size distribution [65,66]. Nanosponges generally fall within the nanometer range, often between 50 and 1000 nm, which is critical for their biological interactions and ability to cross physiological barriers [67].
• Surface Morphology: The external shape and surface texture of nanosponges are visualized using electron microscopy techniques such as Scanning Electron Microscopy and Transmission Electron Microscopy. These analyses reveal the spherical or irregular shape and confirm the porous, sponge-like nature, often showing clear cavities on the surface [52,67–70].
• Pore Size and Surface Area: The extent of nanochannels and nanocavities, as well as the surface area, are vital characteristics. Porosity can be assessed by measuring the density of nanosponges, often using techniques like helium pycnometry, which determines the true volume of the material [28,71]. Standard porosimetry methods can also be applied to investigate pore size distribution in nanomaterials [72].
• Drug Loading and Encapsulation Efficiency: These parameters quantify the amount of drug successfully incorporated into the nanosponges. Drug loading efficiency is determined by estimating the drug content using analytical methods such as UV spectrophotometry or High-Performance Liquid Chromatography after separating the un-entrapped drug [28,66,73].
• Zeta Potential: Zeta potential measures the electrical charge at the surface of the nanosponge particles, which is indicative of their colloidal stability and potential interaction with biological membranes. It is typically measured using a zetasizer [28,30,65].
• Thermal Analysis: Techniques like Differential Scanning Calorimetry and Thermogravimetric Analysis are employed to study the thermal behavior of nanosponges and their drug complexes. These methods can reveal changes in melting points, evaporation, oxidation, decomposition, or polymeric transitions, indicating complex formation between the drug and nanosponges[71]
• X-ray Diffraction: Powder X-ray diffraction is used to examine the crystalline state of the drug before and after encapsulation within nanosponges. Changes in diffraction patterns can indicate complex formation or changes in the drug's physical form upon encapsulation [68,74]

In-vitro Evaluation

In-vitro studies are crucial for assessing the functional performance of nanosponges:

• Drug Release Kinetics: In-vitro drug release studies are performed to determine the rate and mechanism of drug release from nanosponges, often under simulated physiological conditions (e.g., pH-dependent release) [30,75]. The dissolution profile is typically examined using dissolution apparatus with modified baskets [76,77]. The release data can then be fitted to various kinetic models, such as Zero-order, First-order, Higuchi, or Korsmeyer–Peppas models, to understand the release mechanism [73,77]. It's important to note that standardized protocols for in-vitro release testing of colloidal drug carriers are still under development [78–80].
• Swelling Ratio: For swellable nanosponge polymers, the swelling ratio or water uptake is a significant parameter. It is determined by soaking the nanosponges in an aqueous solvent and measuring the increase in volume or mass [76,77]. These studies are essential to ensure the safety of the nanosponge formulations before in-vivo applications.

NANOSPONGES IN GASTRORETENTIVE DRUG DELIVERY

Nanosponges contribute to gastroretention through multiple synergistic mechanisms. Their inherent physicochemical properties enable prolonged gastric residence, enhancing drug bioavailability for locally acting agents and drugs with narrow absorption windows [81]

Size-Based Retention: Following oral administration, nanosponges can aggregate in the gastric environment to form structures exceeding the pyloric sphincter opening diameter (approximately 1-2 mm in fasted state).This size-dependent retention mechanism prevents rapid gastric emptying, particularly in fed state when the pylorus remains partially constricted[58]

Modulation: Nanosponges can be engineered with densities lower than gastric fluid (1.004-1.010 g/cm³) by incorporating gas-entrapping excipients or creating highly porous structures. These low-density systems float on gastric contents, remaining buoyant for extended periods[55]

Swelling Mechanism: pH-responsive swelling in acidic gastric environment increases nanosponge dimensions, contributing to size-based retention. Swelling ratios of 200-400% have been reported, significantly increasing effective particle size while maintaining structural integrity[83]

Figure 4: The buoyant and mucoadhesive mechanism of nanosponges in GRDDS

INTEGRATION WITH OTHER GRDDS

Nanosponges can be incorporated into various gastroretentive platforms to create multifunctional delivery systems: They can be integrated into floating systems, mucoadhesive patches, or even pulsatile release formulations to achieve more refined control over drug release profiles and gastric residence times.

Figure 5: Diagramatic represtation of nanosponges integrated in other GRDDS

This synergistic approach allows for optimization of drug delivery, leveraging the unique advantages of nanosponges in a broader gastroretentive context as shown in figure 4. These versatile carriers, characterized by their biodegradable, non-toxic, and biocompatible nature, offer predictable and extended drug release profiles, thereby enhancing stability and reducing side effects [84]. Targeted gastric delivery through gastroretentive nanosponges reduces systemic exposure for locally acting drugs, minimizing off-target effects [62].

Table 1: Key Properties of Nanosponges Contributing to Gastroretention and Enhanced Drug Delivery [85].

Therapeutic Applications of Nanosponge-Based Gastroretentive Drug Delivery Systems

The unique combination of nanosponge properties-including high drug loading capacity, controlled release kinetics, mucoadhesive potential, and biocompatibility-with gastroretentive mechanisms has enabled significant therapeutic advances across multiple disease conditions. This section comprehensively discusses the therapeutic applications of nanosponge-based GRDDS, supported by recent clinical and preclinical evidence. This approach facilitates improved patient adherence, reduced dosing frequency, and optimized therapeutic outcomes for various drug classes, ranging from antimicrobials to anti-diabetic agents [20]

Figure 6: Schematic representation of different mechanisms by which nanosponges achieve gastroretention, including size-based retention, modulation, mucoadhesion, and swelling mechanisms.

These mechanisms collectively contribute to extended gastric residence time, which is critical for drugs absorbed primarily in the upper gastrointestinal tract or those requiring prolonged local action[53,86] The release of encapsulated substances can be controlled by adjusting the crosslinking density, polymer type, and environmental factors such as pH and temperature. This allows for sustained and targeted delivery of drugs and other active agents  as shown in figure 7.[51]

Figure 7: A graph showing sustained release over time for a nanosponge formulation compared to a burst release from a conventional formulation.

This enhanced release profile, characterized by sustained drug levels, leads to improved therapeutic efficacy and reduced dosing frequency, ultimately contributing to better patient compliance and clinical outcomes [20]. Furthermore, the versatility of nanosponges extends to various drug types and administration routes, allowing for the precise targeting of specific tissues or cells and optimizing drug bioavailability [51].

CHALLENGES AND CONSIDERATIONS

Despite the significant potential of nanosponges in gastroretentive drug delivery, several challenges must be addressed for their successful translation from laboratory research to widespread clinical application [49].

Scale-up and Industrial Production

Translating laboratory-scale nanosponge synthesis to industrial-scale production presents considerable hurdles. Current synthesis methods, such as emulsion solvent diffusion or ultrasonication, often involve complex processes that can be difficult to control precisely at larger scales, potentially leading to inconsistencies in particle size, porosity, and drug loading efficiency [47]. Furthermore, the purification and isolation of nanosponges from reaction mixtures on a large scale can be cost-intensive and technically demanding [49].

Regulatory Aspects

The regulatory landscape for nanomedicines, including nanosponge-based drug products, is still evolving and complex. Regulatory bodies require extensive data on the safety, efficacy, and quality of these novel formulations. This includes comprehensive characterization of their physical and chemical properties, biodistribution, pharmacokinetics, and pharmacodynamics, as well as long-term stability data. Demonstrating the absence of genotoxicity, carcinogenicity, and immunogenicity for nanosponge materials and their degradation products is crucial for regulatory acceptance [49].

Toxicity and Biocompatibility

While many nanosponge materials, particularly those based on cyclodextrins, are generally considered biocompatible and low in toxicity, rigorous and extensive testing is still required. This involves both in vitro and in vivo studies to evaluate potential cytotoxicity, genotoxicity, systemic toxicity, and immunogenicity of the nanosponges themselves and their degradation products [52]. Long-term toxicity studies are essential to ensure safety, especially given the potential for prolonged gastric retention. The interaction of nanosponges with biological systems, including proteins and cells, must be thoroughly investigated to rule out any unforeseen adverse effects.

Cost-Effectiveness

The manufacturing processes for nanosponges can be expensive, involving specialized equipment, high-purity materials, and intricate production steps. This can drive up the final cost of nanosponge-based drug products, potentially limiting their accessibility and affordability compared to conventional drug formulations [49].  The long-term cost benefits, such as reduced dosing frequency and improved patient outcomes, need to outweigh the initial higher production costs.

Drug-Excipient Interactions

The formulation of nanosponge drug delivery systems requires careful selection of excipients to ensure stability, optimize drug release, and maintain the integrity of the nanosponge structure. Potential drug-excipient interactions can lead to drug degradation, reduced encapsulation efficiency, altered release profiles, or compromised nanosponge stability [47]. These studies help identify suitable excipients that do not interfere with the drug's therapeutic activity or the nanosponge's structural and functional properties, ensuring the overall quality and performance of the final product. Furthermore, rigorous analytical methods are necessary to characterize these interactions comprehensively and to predict their influence on long-term stability and bioavailability.

Based on my search, here are some recent patents related to nanosponges and gastroretentive systems: These patents highlight innovative approaches to overcoming challenges in drug delivery, particularly by leveraging the unique properties of cyclodextrin-based nanosponges [87]. Specifically, several patents focus on enhancing the solubility and bioavailability of poorly soluble drugs through the formation of inclusion complexes with cyclodextrins within nanosponge architectures [88].

TABLE 2: LIST OF PATENTS ON NANOSPONGES