R. G Sapkal College of Pharmacy, Sapkal Knowledge Hub, Kalyani Hills, Anjaneri, Trimbakeshwar Rd, Nashik, 422213, Maharashtra, India.
Gastroprotective drug delivery systems (GRDDS) represent an innovative approach to overcome limitations of conventional oral drug delivery by prolonging gastric residence time and enabling controlled drug release in the upper gastrointestinal tract. This review examines various GRDDS approaches including floating systems, bio adhesive matrices, swelling systems, and combination strategies. GRDDS demonstrate significant advantages for drugs with narrow absorption windows, acid-labile compounds, and therapeutics requiring local gastric action. Floating systems utilizing natural polymers (HPMC, chitosan, sodium alginate) and synthetic polymers (Carbopol, ethyl cellulose) have shown commercial success with products like Metformin GR™ and Gabapentin GR. Clinical applications span neurological disorders, cardiovascular conditions, metabolic diseases, and gastrointestinal therapeutics. Despite challenges including physiological variability and formulation complexity, GRDDS represent a mature technology with proven clinical efficacy for enhancing oral bioavailability and therapeutic outcomes. Future research should focus on patient-specific formulations and expanding applications to emerging therapeutic areas.
1.1 Overview of Oral Drug Delivery Systems:
The oral route is the most preferred and widely used method for drug administration due to its convenience, safety, and patient compliance. It enables self-administration without medical supervision and is cost-effective since it avoids sterile manufacturing and specialized administration needs. Additionally, it provides formulation flexibility through various dosage forms such as tablets, capsules, and modified-release systems, supporting systemic therapeutic effects with predictable pharmacokinetics1.
However, conventional oral drug delivery faces major challenges like poor bioavailability—especially for BCS class II and IV drugs—owing to low aqueous solubility and unpredictable absorption. First-pass hepatic metabolism further reduces systemic availability, while variations in gastrointestinal conditions affect drug absorption. Traditional tablets and capsules also suffer from short gastric residence times (about 2–3 hours when fed, and less than 1 hour when fasted), limiting absorption efficiency for many drugs2.(americanpharmaceuticalreview+1)
Limitations of Traditional Dosage Forms in GI Transit:
Traditional oral dosage forms suffer from inherent limitations related to their rapid transit through the upper GI tract, where many drugs exhibit optimal absorption characteristics. Conventional tablets and capsules typically have a gastric residence time of only 2-3 hours in fed conditions and as little as 30 minutes in fasted states2.
1.2 Concept of Gastroretentive Drug Delivery Systems (GRDDS):
Gastroretentive Drug Delivery Systems (GRDDS) represent an innovative pharmaceutical approach designed to prolong the gastric residence time of oral dosage forms, thereby enhancing drug bioavailability and therapeutic efficacy. GRDDS are specifically engineered drug delivery platforms that remain in the gastric cavity for extended periods while releasing their active pharmaceutical ingredients in a controlled manner.(ijrpr+3)
The fundamental principle underlying GRDDS involves overcoming the natural propensity for rapid gastric emptying by employing various retention mechanisms that enable dosage forms to resist the physiological forces that typically propel materials from the stomach into the small intestine. These systems are designed to maintain prolonged contact between the drug and the gastric mucosa, facilitating enhanced absorption of drugs with site-specific absorption requirements3. GRDDS function by targeting drug release to specific areas in the upper GI tract for both local and systemic therapeutic effects. The controlled drug release from these systems ensures continuous drug availability at the absorption site, leading to improved bioavailability compared to conventional dosage forms4.
Historical Perspective and Evolution:
The concept of gastroretentive drug delivery emerged from the recognition that conventional oral dosage forms were inadequate for drugs requiring prolonged gastric contact for optimal absorption. Early research in the 1980s focused on understanding the physiological barriers to gastric retention and developing strategies to overcome rapid gastric emptying5.
The field has evolved significantly with advances in polymer science and pharmaceutical technology, leading to the development of sophisticated retention mechanisms including floating systems, expandable matrices, mucoadhesive formulations, and high-density systems. Modern GRDDS incorporate smart polymers and stimuli-responsive materials that can adapt to changing gastric conditions6.
1.3 Physiological Considerations:
Anatomy and Physiology of the Stomach:
The stomach serves as a crucial organ in both digestion and drug delivery, functioning as a flexible reservoir capable of accommodating large volumes while performing complex mechanical and chemical processing of ingested materials. Anatomically, the stomach can be divided into distinct functional regions: the fundus and proximal corpus serve as a flexible reservoir and pressure pump, while the distal corpus and proximal antrum constitute the peristaltic pump that primarily functions as a mixer. The terminal antrum and pyloric sphincter form the functional grinder and filter that regulates the passage of materials into the duodenum7.
The stomach's muscular architecture consists of three distinct smooth muscle layers: the oblique layer (unique to the stomach), circular muscle layer, and longitudinal layer. These layers work in coordination to produce the forceful churning motions necessary for mechanical breakdown of food bolus into chyme. The gastric mucosa secretes hydrochloric acid, pepsinogen, mucus, and intrinsic factor, creating a highly acidic environment (pH 1-2) that facilitates protein digestion and affects drug stability and solubility8.
pH Variations and Gastric Motility Patterns:
Gastric pH variations represent a fundamental consideration in GRDDS design, as these changes significantly affect drug stability, solubility, and release characteristics. The fasted stomach typically maintains a pH of 1.5-2.0, while fed conditions can raise gastric pH to 3.0-5.0 depending on meal composition and buffering capacity. These pH fluctuations create challenges for formulation scientists, as they must ensure consistent drug release and stability across varying acidic conditions.(dmpkservice.wuxiapptec+1)
Gastric acid secretion follows circadian rhythms and is influenced by neural, hormonal, and local factors. Vagal stimulation increases acid production, while somatostatin and prostaglandins have inhibitory effects. Disease states such as achlorhydria, gastritis, or peptic ulcer disease can significantly alter gastric pH patterns, affecting GRDDS performance9.
1.4 Advantages and Limitations of GRDDS:
Enhanced Bioavailability and Therapeutic Efficacy:
GRDDS offer substantial improvements in bioavailability for drugs that face absorption challenges with conventional formulations. By prolonging gastric residence time, these systems ensure optimal drug concentration at the primary absorption site, leading to enhanced and more predictable bioavailability. This is particularly beneficial for drugs with narrow absorption windows in the stomach or proximal small intestine, where conventional formulations may pass through too rapidly for complete absorption10.
The sustained drug release characteristics of GRDDS enable maintenance of therapeutic drug concentrations for extended periods, resulting in improved therapeutic efficacy compared to immediate-release formulations. Drugs with short biological half-lives particularly benefit from this approach, as gastroretentive formulations can provide prolonged therapeutic effects that would otherwise require frequent dosing with conventional systems11.
Site-specific drug delivery capabilities of GRDDS enable targeted therapy for gastric disorders, allowing high local drug concentrations to be maintained at the gastric mucosa while minimizing systemic exposure and associated side effects. This targeted approach is particularly valuable for treating peptic ulcers, gastritis, and Helicobacter pylori infections12.
Improved Patient Compliance and Reduced Dosing Frequency:
Enhanced patient convenience results from the elimination of complex dosing schedules, reducing the likelihood of missed doses and improving overall treatment outcomes. Elderly patients and those with cognitive impairments particularly benefit from simplified dosing regimens that reduce confusion and improve adherence12.
The protective environment of the stomach can be utilized for acid-labile drugs that would otherwise be degraded in the alkaline conditions of the small intestine. This protective effect enables the oral delivery of proteins, peptides, and other sensitive compounds that would require parenteral administration with conventional formulations13.
Absorption window optimization allows drugs with specific absorption sites in the stomach or proximal small intestine to achieve maximum bioavailability through prolonged exposure to optimal absorption conditions. This targeted approach can rescue drug candidates that might otherwise fail due to poor absorption characteristics.(americanpharmaceuticalreview+)
Challenges and Potential Drawbacks:
Despite their advantages, GRDDS face several significant challenges and limitations that must be carefully considered during development. Physiological variability represents a major challenge, as individual differences in gastric emptying patterns, MMC cycles, pH variations, and motility can significantly affect system performance. Fed versus fasted state variations can dramatically alter retention characteristics, making consistent performance difficult to achieve.
Drug-related limitations restrict the applicability of GRDDS to certain therapeutic compounds. Drugs that cause gastric irritation or have erosive properties are unsuitable for gastroretentive formulations due to the risk of prolonged mucosal contact14.
Formulation complexity associated with GRDDS development presents substantial technical challenges. Manufacturing difficulties related to achieving consistent buoyancy, swelling behavior, or mucoadhesive properties can complicate scale-up and quality control. Stability issues may arise from prolonged exposure to gastric conditions, particularly for sensitive drug compounds15.
Patient-related factors including gastrointestinal disorders, gastric surgery history, or medication-induced motility changes can significantly impact GRDDS performance. Large dosage form size required for some retention mechanisms may cause swallowing difficulties or patient discomfort15.
2. Drug Candidates Suitable for GRDDS:
2.1 Classification of Suitable Drugs:
The selection of appropriate drug candidates is fundamental to the successful development of gastroretentive drug delivery systems. Not all therapeutic compounds are suitable for gastric retention, and careful evaluation of drug properties is essential to identify optimal candidates that can benefit from prolonged gastric residence time. The classification of suitable drugs for GRDDS is based on several critical characteristics that align with the physiological advantages offered by gastric retention mechanisms.
Drugs with Narrow Absorption Windows:
Drugs with narrow absorption windows represent one of the most important categories for GRDDS applications, as these compounds exhibit site-specific absorption primarily in the stomach or upper small intestine. These drugs face significant challenges with conventional oral formulations due to their limited absorption sites and rapid gastrointestinal transit, which can result in incomplete drug absorption and poor bioavailability16.
Riboflavin (Vitamin B2) serves as a classic example of a drug with a narrow absorption window, being primarily absorbed in the proximal small intestine through a saturable transport mechanism. Le vodopa, the cornerstone therapy for Parkinson's disease, exhibits preferential absorption in the duodenum and proximal jejunum through the large amino acid transporter (LAT1). The short elimination half-life of levodopa (approximately 1-3 hours) necessitates frequent dosing with conventional formulations, leading to motor fluctuations and wearing-off phenomena in Parkinson's patients17.
Pregabalin, used for neuropathic pain and epilepsy, demonstrates dose-dependent absorption with saturable uptake mechanisms in the upper small intestine. Cilostazol, an antiplatelet agent, exhibits narrow absorption characteristics that can benefit significantly from gastroretentive formulations to ensure consistent therapeutic levels. Furosemide, a loop diuretic, has limited absorption sites in the ascending limb of the loop of Henle, making gastric retention advantageous for sustained drug delivery18.
Acid-Labile Drugs Requiring Gastric Protection:
Acid-labile drugs that require protection from gastric acid degradation represent a unique category where GRDDS can provide dual benefits: protection from acid degradation while ensuring controlled release in the gastric environment. Paradoxically, some drugs that are typically considered acid-labile can benefit from gastric retention when appropriately formulated with protective excipients or enteric coating systems19.
Macrolide antibiotics such as erythromycin and clarithromycin are particularly susceptible to acid degradation but can be successfully incorporated into GRDDS using enteric-coated formulations that protect the drug while maintaining gastric retention. Omeprazole and other proton pump inhibitors require protection from gastric acid but benefit from local gastric action when formulated in appropriate gastroretentive systems20.
Protein and peptide drugs represent a growing class of acid-labile therapeutics that can benefit from GRDDS approaches. These biopharmaceuticals are particularly vulnerable to pepsin degradation in the gastric environment but can be protected through appropriate formulation strategies including enzyme inhibitors, pH-sensitive polymers, and encapsulation techniques. The development of gut-stable peptides through chemical modifications such as cyclization, methylation, and amino acid substitutions has opened new possibilities for gastroretentive peptide delivery21.
Drugs with Poor Solubility at Alkaline pH:
Drugs exhibiting pH-dependent solubility with poor dissolution characteristics at alkaline pH represent excellent candidates for GRDDS, as the acidic gastric environment provides optimal solubilization conditions. These compounds typically exhibit significantly reduced bioavailability when administered as conventional formulations due to precipitation and poor dissolution in the neutral to alkaline pH of the small intestine22.
Basic drugs with weak base characteristics demonstrate enhanced solubility in acidic conditions compared to neutral or alkaline environments. Cinnarizine, an antihistamine and calcium channel blocker, exhibits extremely poor solubility at alkaline pH (pH > 7) but demonstrates significantly enhanced dissolution in gastric acid conditions. This pH-dependent solubility makes cinnarizine an ideal candidate for gastroretentive formulations to maximize drug dissolution and enhance bioavailability23.
Ketoconazole, an antifungal agent, requires acidic conditions for optimal dissolution and absorption. Dipyridamole, used for stroke prevention, demonstrates pH-dependent solubility characteristics that favor gastric retention. Albendazole, an antiparasitic drug, exhibits poor water solubility that is enhanced under acidic conditions24.
Diazepam, a benzodiazepine anxiolytic, shows limited solubility at intestinal pH levels, making it suitable for gastroretentive formulations. Nifedipine and other calcium channel blockers demonstrate pH-sensitive dissolution profiles that can be optimized through gastric retention25.
Local Gastric Action Drugs:
Drugs intended for local therapeutic action within the gastric environment represent a specialized category where GRDDS can provide targeted delivery while minimizing systemic exposure. These formulations are particularly valuable for treating gastric and duodenal disorders where high local drug concentrations are required for therapeutic efficacy18.
Helicobacter pylori eradication therapy represents one of the most important applications of gastroretentive local delivery systems. Amoxicillin, clarithromycin, metronidazole, and levofloxacin formulated in gastroretentive systems can achieve higher local concentrations at the site of bacterial colonization while reducing systemic side effects. The mucus-penetrating properties and sustained release characteristics of GRDDS enable these antibiotics to reach deep gastric mucosa where H. pylori resides26.
Proton pump inhibitors including omeprazole, lansoprazole, and esomeprazole benefit from gastric retention for local acid suppression and gastric mucosal protection. H2 receptor antagonists such as ranitidine, famotidine, and nizatidine can provide sustained acid suppression through gastroretentive formulations27.
Antacids and gastric cytoprotective agents including sucralfate, bismuth compounds, and prostaglandin analogs are designed for local gastric action and can benefit significantly from prolonged gastric residence. Misoprostol, a synthetic prostaglandin E1 analog, has been successfully formulated in gastroretentive systems for gastric mucosal protection28.
2.2 Specific Drug Examples:
CNS Drugs (Parkinson's, Epilepsy, Alzheimer's)
Central nervous system drugs represent a significant therapeutic area where GRDDS can provide substantial clinical benefits through improved bioavailability, reduced dosing frequency, and enhanced patient compliance.ncbi.nlm.nih+1
Parkinson's Disease Medications constitute the most extensively studied CNS applications for GRDDS. Levodopa (L-DOPA), the gold standard treatment for Parkinson's disease, faces significant challenges with conventional formulations due to its narrow absorption window, short half-life (1-3 hours), and requirement for frequent dosing. Levodopa is preferentially absorbed in the duodenum and proximal jejunum through the large amino acid transporter (LAT1), making gastric retention highly beneficial29.
Carbidopa/levodopa combinations have been successfully developed in gastroretentive formulations, with products like Madopar HBS® and Prolopa HBS® demonstrating sustained therapeutic effects and reduced motor fluctuations. The Accordion Pill® represents an innovative expandable gastroretentive system for carbidopa/levodopa delivery. Recent research has focused on developing once-daily gastroretentive formulations to replace the current multiple daily dosing regimens30.
Mesdopetam, a dopamine D3-receptor antagonist under development, targets levodopa-induced dyskinesias affecting over 30% of Parkinson's patients. IRL1117, a dual D1/D2 receptor agonist, is being developed as a next-generation oral treatment with rapid onset and sustained efficacy exceeding 10 hours30.
Epilepsy Medications benefit from GRDDS through sustained therapeutic levels and reduced seizure breakthrough. Gabapentin, formulated using AcuForm™ polymer-based swelling technology, has achieved commercial success as Gabapentin GR with improved bioavailability and reduced dosing frequency. Pregabalin demonstrates dose-dependent absorption with saturable transport mechanisms, making gastric retention advantageous for consistent therapeutic levels31.
Vitamin B6 (Pyridoxine) deficiency associated with carbidopa/levodopa therapy can lead to refractory seizures in Parkinson's patients, highlighting the importance of nutritional monitoring and potential supplementation in gastroretentive formulations32.
Alzheimer's Disease Therapeutics represent an emerging area for GRDDS applications. Cholinesterase inhibitors and NMDA receptor antagonists could benefit from sustained gastric delivery to maintain consistent therapeutic levels and reduce dosing-related side effects33.
Anti-hypertensive and Anti-diabetic Agents:
Cardiovascular and metabolic drugs represent major therapeutic areas where GRDDS can provide significant clinical advantages through sustained therapeutic effects, improved patient compliance, and synergistic drug interactions34.
Anti-hypertensive Agents benefit from gastroretentive formulations through sustained blood pressure control and reduced dosing frequency. Verapamil, a non-dihydropyridine calcium channel blocker, has been extensively studied in gastroretentive formulations for hypertension management. Verapamil demonstrates pH-dependent stability and benefits from controlled gastric release to maintain consistent therapeutic levels30.
Captopril, an ACE inhibitor, exhibits instability at alkaline pH and benefits from gastroretentive formulations that protect the drug while providing sustained antihypertensive effects. Atenolol demonstrates poor absorption from the lower gastrointestinal tract, making gastric retention advantageous for improved bioavailability35.
Anti-diabetic Agents represent a rapidly growing area for GRDDS applications. Metformin, the first-line therapy for type 2 diabetes, has been successfully formulated in multiple gastroretentive systems including Glumetza®, Riomet OD®, and Metformin GR™. Metformin demonstrates saturable absorption primarily in the small intestine and benefits from sustained gastric release to maximize bioavailability and reduce gastrointestinal side effects35.
Verapamil-metformin combination therapy has emerged as an innovative approach for diabetic patients with hypertension. Verapamil demonstrates glucose-lowering effects through enhanced β-cell survival and improved insulin secretion, while OCT2-mediated pharmacokinetic interactions between verapamil and metformin can enhance metformin exposure. R-form verapamil at doses of 300-450 mg daily in combination with metformin has shown significant HbA1c reduction with favorable safety profiles36.
2.3 Selection Criteria for Drug Candidates:
The successful development of gastroretentive drug delivery systems requires systematic evaluation of drug candidates based on multiple interconnected criteria that determine both the feasibility and clinical benefit of gastric retention. The selection process must carefully balance drug-specific properties, formulation considerations, and therapeutic requirements to ensure optimal system performance37.
3. Approaches To Gastroretentive Drug Delivery Systems:
3.1 Floating Drug Delivery Systems (FDDS):
Floating drug delivery systems represent the most extensively studied gastroretentive approach, utilizing buoyancy mechanisms to maintain prolonged gastric residence. These systems have bulk density lower than gastric fluids (< 1.004 g/mL), enabling them to float on stomach contents for extended periods38. (Figure 1)
3.1.1 Effervescent Floating Systems:
Gas-generating mechanisms using CO2 form the basis of effervescent floating systems, utilizing chemical reactions between carbonates and organic acids to produce buoyancy39. Formulation components typically include sodium bicarbonate as the gas-generating agent and citric acid or
Figure 1: Floating System Mechanism (Buoyancy / Imbibition)
tartaric acid as the acid source. The optimal stoichiometric ratio of citric acid to sodium bicarbonate is 0.76:1 for maximum CO2 generation40. Design principles and buoyancy mechanisms involve CO2 entrapment within a gellified hydrocolloid matrix, reducing system density and enabling flotation. Systems include single-layer tablets (Hydrodynamically Balanced Systems) and bilayer tablets with immediate and sustained release layers38.
3.1.2 Non-Effervescent Floating Systems:
Low-density matrix systems utilize gel-forming hydrocolloids and swellable polymers without gas generation. These systems form colloidal gel barriers upon hydration that control fluid penetration and drug release41. Hollow microspheres and air-filled chambers represent sophisticated non-effervescent approaches using spherical empty particles with sizes ranging 1-1000 μm. These hollow microballoons maintain buoyancy through entrapped air and provide controlled drug release42. Oil entrapment and foam tablet technologies incorporate low-density oils or foam-forming agents to achieve buoyancy without effervescence. These systems offer predictable floating behavior and sustained drug release characteristics43.
3.2 Bioadhesive/Mucoadhesive Systems:
Mucoadhesion mechanisms and theories include five primary theories: Electronic Theory (electrostatic interactions), Adsorption Theory (physical adsorption), Wetting Theory (surface spreading), Diffusion Theory (polymer chain penetration), and Fracture Theory (micro-bond formation)44.
Polymer selection for bioadhesive properties involves natural polymers (chitosan, sodium alginate, gelatin), semi-synthetic polymers (HPMC, carbopol), and synthetic polymers (polyacrylic acid, polyethylene glycol). Thiolated polymers enhance bioadhesion through disulfide bond formation with mucin proteins45.
Factors affecting mucoadhesive strength include molecular weight, polymer concentration, pH, hydration degree, and cross-linking density. Adhesion mechanisms occur through hydration-mediated, bonding-mediated, or receptor-mediated interactions30.
3.3 Swelling and Expandable Systems:
Hydrogel-based swelling mechanisms involve rapid water uptake leading to dimensional expansion beyond the pyloric sphincter diameter (12-20 mm).ijrpas+1
Superporous hydrogel systems exhibit rapid swelling within minutes due to interconnected pore networks with fast capillary wetting. These systems demonstrate high swelling ratios and prolonged gastric retention through mechanical lodging46.
Unfolding and geometric transformation systems utilize shape-memory polymers or mechanical devices that expand from compact forms suitable for swallowing to large configurations for gastric retention.
3.4 High-Density Systems:
Sedimentation approach for gastroretention utilizes high-density formulations (2.5-3.0 g/mL) that sink to the stomach bottom and become trapped in gastric rugae47. Dense particle formulations incorporate barium sulfate, iron powder, titanium oxide, or zinc oxide to achieve required density. These systems can extend gastric retention time from 5.8 to 25 hours48. Antral retention mechanisms involve physical lodging in the stomach's dependent portions where dense pellets resist peristaltic waves49.
3.5 Magnetic Systems:
Magnetic retention using external magnets employs externally applied magnetic fields to retain magnetic drug delivery systems in the gastric region50. Magnetic particle incorporation utilizes ferrite materials embedded within dosage forms that respond to external magnetic positioning. Automated magnetic measurement systems enable real-time monitoring of system position18. Clinical feasibility and limitations include requirement for external magnetic devices, patient compliance challenges, and limited clinical applicability due to practical constraints51. (Figure 2)
3.6 Raft-Forming Systems:
Alginate-based raft formation utilizes sodium alginate as the primary gel-forming agent combined with alkaline carbonates for CO2 generation52. Mechanism of raft floating involves viscous gel formation upon contact with gastric acid, creating a cohesive floating layer with low bulk density due to entrapped CO2 bubbles53. Applications in gastric disorders include gastroesophageal reflux
Figure 2: Magnetic GRDDS with External Control
disease (GERD) treatment where rafts act as physical barriers preventing acid reflux into the esophagus54.
3.7 Ion-Exchange Systems:
Resin-based drug delivery employs ion-exchange resins that interact with gastric ions to control drug release and provide gastric retention54. Ion-exchange mechanisms in gastric pH involve electrostatic interactions between charged resin functional groups and ionic drug molecules, with release controlled by ionic strength and pH variations55.
3.8 Combination Approaches:
Dual-mechanism systems for enhanced retention combine multiple retention principles to achieve superior gastric residence compared to single-mechanism systems45. Floating-bioadhesive combinations integrate buoyancy mechanisms with mucoadhesive properties using hollow-bioadhesive microspheres or floating mucoadhesive tablets56. Swelling-floating hybrid systems combine rapid swelling with buoyancy mechanisms, utilizing gas-generating agents within swellable matrices for dual retention
4.Formulation Strategies and Materials:
4.1 Polymers in GRDDS:
4.1.1 Natural Polymers:
Hydroxypropyl methylcellulose (HPMC) is widely used in GRDDS for its rapid hydration and gel-forming properties, providing both buoyancy and controlled drug release. Upon contact with gastric fluid, HPMC swells to form a viscous gel barrier that entraps CO? in effervescent systems or supports low-density matrices in non-effervescent systems57. Sodium alginate and chitosan serve dual roles in raft-forming and mucoadhesive GRDDS. Sodium alginate gels in acidic pH through ionic crosslinking with gastric calcium ions, forming floating alginate rafts for reflux management. Chitosan, a cationic polymer, interacts electrostatically with anionic mucin to enhance gastric adhesion and swelling in mucoadhesive and expandable formulations53.
Guar gum and xanthan gum are high-viscosity natural gums that swell extensively upon hydration, reinforcing matrix integrity in floating and non-effervescent systems. Their high molecular weight and gel viscosity retard matrix erosion and enable sustained drug release over extended gastric residence times58.
4.1.2 Synthetic Polymers:
Ethyl cellulose and carbopol (polyacrylic acid) are key synthetic polymers in GRDDS. Ethyl cellulose, being water-insoluble, forms coatings and microsphere shells that resist rapid fluid ingress, supporting buoyancy in floating microspheres and providing controlled release via diffusion through the polymer shell. Carbopol exhibits high mucoadhesive strength and pH-responsive swelling, making it ideal for bioadhesive tablet and bead formulations that adhere tightly to the gastric mucosa58. Polyethylene oxide (PEO) and polyvinyl alcohol (PVA) are hydrophilic polymers that swell to form low-density matrices in non-effervescent floating systems. Their rapid water uptake and gel formation reduce bulk density below that of gastric fluid, enabling prolonged floatation without gas generation59. Eudragit grades and other polymethacrylates provide versatile, pH-sensitive release profiles. Eudragit RL/RS impart sustained release through water-insoluble matrices, while Eudragit L/S dissolve at specific pH thresholds. These polymers are employed in coatings and matrix tablets to tailor drug release kinetics and protect acid-labile drugs until gastric retention requirements are met60.
4.1.3 Biodegradable Polymers:
Polylactic acid (PLA) and polyglycolic acid (PGA) are biodegradable polyesters used primarily in microsphere and nanoparticle GRDDS. These polymers degrade by hydrolysis to lactic and glycolic acids, enabling controlled erosion and sustained release over days to weeks. In floating microspheres, PLA/PGA shells encapsulate drug payloads and gradually erode, maintaining buoyancy until complete drug release60. Applications in sustained release systems extend beyond simple erosion-controlled release; PLA/PGA-based implants and in situ gelling depots are under investigation for long-acting gastric therapies, combining biodegradability with extended gastric retention features60.
4.2 Excipients and Additives:
4.2.1 Buoyancy-Enhancing Agents:
Gas-generating agents such as sodium bicarbonate react with gastric acid to release CO?, which is entrapped by hydrophilic polymer matrices (e.g., HPMC) to impart buoyancy in effervescent floating systems. Low-density fillers—including talc, light magnesium oxide, and microcrystalline cellulose—introduce porosity and decrease bulk density in non-effervescent matrices. Oils and lipids such as castor oil and medium-chain triglycerides are incorporated to entrap air, reducing effective density and sustaining floatation in matrix tablets61.
Pore-forming agents (e.g., polyethylene glycol, pore-inducing salts) create interconnecting channels within polymer matrices, facilitating rapid fluid penetration for swelling and gas entrapment, thereby optimizing floating behavior and release kinetics62.
4.2.2 Matrix-Forming Agents:
Matrix-forming agents provide the structural backbone for controlled drug release within GRDDS. Hydrophilic matrices, composed of polymers such as high-viscosity HPMC, xanthan gum, and sodium alginate, swell upon contact with gastric fluid to form a gel layer that governs drug diffusion and system integrity. These systems enable both floating and non-floating formulations by modulating matrix viscosity and erosion rates. In contrast, hydrophobic matrices utilize water-insoluble materials—such as ethyl cellulose and various waxes—to slow water penetration and create diffusion barriers, extending drug release through controlled partitioning and erosion59. Wax-based systems employ low-melting-point waxes (e.g., glyceryl behenate, stearic acid, cetyl alcohol) that, upon tablet compression or coating, form a hydrophobic matrix resisting fluid uptake. Drug release occurs primarily via diffusion through microporous channels generated in the wax network, providing consistent sustained release profiles over extended gastric retention periods58.
Lipid matrices for controlled release leverage solid lipids—such as Compritol (glyceryl behenate) and Dynasan (hydrogenated triglycerides)—processed via melt granulation or hot-melt extrusion. The lipid phase encapsulates drug particles and, upon gastric contact, gradually erodes or allows drug diffusion, resulting in prolonged, zero-order release kinetics and reliable buoyancy when combined with floating excipients63.
4.2.3 Other Functional Excipients:
Plasticizers and surfactants adjust polymer flexibility and interfacial properties. Polyethylene glycol and propylene glycol, commonly used plasticizers, reduce brittleness in polymer coatings and matrices, improving mechanical integrity during gastric residence. Surfactants such as polysorbate 80 and poloxamers enhance polymer hydration and wetting, facilitating uniform matrix swelling and drug diffusion64.
Antioxidants and stabilizers including butylated hydroxytoluene, ascorbyl palmitate, and α-tocopherol are incorporated to protect acid-sensitive drugs from oxidative degradation under low gastric pH and elevated temperature. Chelating agents (e.g., EDTA) sequester trace metal ions that catalyze oxidative pathways, ensuring drug potency during extended gastric exposure65.
pH modifiers and buffering agents (e.g., sodium citrate, phosphate buffers) maintain a localized microenvironment within the dosage form, optimizing polymer swelling, drug solubility, and stability. In effervescent formulations, carbonate and citrate salts also coordinate CO? generation for buoyancy enhancement while stabilizing acid-sensitive actives66.
4.3 Dosage Form Design:
The design of GRDDS dosage forms must balance gastric retention mechanisms with manufacturability and patient acceptability. Tablet formulations typically employ direct compression or wet granulation techniques to produce monolithic floating or swelling matrices. Bilayer tablets can combine immediate and sustained release layers or integrate effervescent and non-effervescent components within a single dosage form67.
Capsule-based systems encapsulate floating granules, beads, or polymer discs within gelatin or HPMC shells. These can be engineered for delayed shell dissolution, releasing the floating units in the gastric environment, or for retaining the intact shell as a floating body59.
Multiparticulate systems including beads, pellets, and microspheres offer uniform gastric distribution, reduced dose dumping risk, and flexibility in combining multiple retention mechanisms. Floating microspheres leverage hollow cores for buoyancy, while bioadhesive pellets utilize mucoadhesive polymers for gastric lining attachment. Such systems can be filled into capsules or compressed into tablets, providing versatile platforms for tailored GRDDS performance63.
5. Manufacturing Technologies and Scale-Up Considerations:
The successful translation of gastroretentive drug delivery systems from laboratory prototypes to commercial products depends on robust manufacturing technologies and careful scale-up strategies. Traditional pharmaceutical processes have been adapted to produce GRDDS with minimal modifications to equipment and procedures, while emerging technologies offer new capabilities for customization and precision.
5.1 Conventional Manufacturing Methods:
Direct compression remains the most straightforward and widely used method for GRDDS tablet production, requiring only blending of drug, polymers, and excipients followed by compression into floating, mucoadhesive, or swelling matrices. Its simplicity minimizes solvent use and processing time, but demands fine-tuned powder flow, compressibility, and uniformity to maintain dosage form integrity and buoyancy. In wet granulation, drug and polymer are agglomerated into granules using a granulating fluid—often aqueous HPMC or PVA solution—then dried and compressed. This approach enhances content uniformity and granule strength, improving buoyancy and swelling consistency in systems such as superporous hydrogels. Controlled-release coatings are applied via pan or fluid?bed techniques, depositing polymeric films (e.g., Eudragit®, ethyl cellulose) onto cores or multiparticulates to modulate drug diffusion and protect acid-labile actives63.
5.2 Advanced Manufacturing Technologies:
Three-dimensional (3D) printing enables layer-by-layer fabrication of bespoke GRDDS geometries, integrating multiple retention mechanisms into a single dosage form. By varying infill density, polymer composition, and internal architecture, 3D printed tablets can be tailored for specific buoyancy profiles and release kinetics, supporting personalized medicine approaches. Hot melt extrusion (HME) processes melt polymers and drug together under controlled heat and shear, extruding homogeneous filaments or pellets that can be cut, spheronized, or printed into floating or swelling systems. HME eliminates solvents and offers continuous, scalable production of lipid-based or polymer matrix units. Spray drying and fluid bed granulation produce floating microspheres and bioadhesive beads by atomizing drug–polymer solutions or suspensions into hot air, rapidly forming hollow or porous particles with controlled size and density68.
5.3 Scale-up Challenges and Solutions:
Scaling GRDDS formulations from bench to commercial scale introduces challenges in maintaining critical process parameters. Process optimization and validation require systematic evaluation of mixing times, granulation endpoints, compression forces, and coating conditions to ensure consistent buoyancy, swelling behavior, and drug release. Equipment selection must consider heat and shear sensitivity of polymers choosing suitable extruder screws or spray dryer nozzle configurations—and technology transfer protocols must align laboratory methods with production-scale capabilities. Quality control focuses on batch-to-batch consistency in particle size distribution, matrix integrity, floatation lag time, and in vitro release profiles, necessitating robust analytical methods and process controls to detect deviations early68.
5.4 Quality by Design (QbD) Approach:
Implementation of Quality by Design principles strengthens GRDDS development by embedding risk assessment, design space exploration, and critical quality attribute (CQA) identification into the process. Early risk assessments map formulation and process parameters such as polymer viscosity, granulation moisture content, and coating weight to key performance attributes like buoyancy duration and release kinetics. Design of experiments (DoE) tools optimize multivariate interactions, defining design spaces where CQAs remain within acceptable limits. Identifying CQAs—including floating lag time, matrix swelling index, and mucoadhesive strength—enables targeted control strategies and continuous process verification, ensuring robust, reproducible GRDDS products throughout their lifecycle69.
6. Clinical Applications and Therapeutic Areas:
Gastroretentive drug delivery systems (GRDDS) have found significant applications across various therapeutic areas by enabling prolonged gastric residence, improving bioavailability, and offering site-specific drug release.
6.1 Gastrointestinal Disorders:
In the treatment of peptic ulcers, GRDDS provide sustained delivery of anti-ulcer agents directly to the gastric mucosa, facilitating enhanced local therapeutic effect and quicker mucosal healing. For Helicobacter pylori eradication, gastroretentive formulations maintain high concentrations of antibiotics such as amoxicillin and clarithromycin in the stomach, improving eradication rates by prolonged mucosal contact. In gastroesophageal reflux disease (GERD), raft-forming gastroretentive systems float on gastric contents to form a physical barrier, preventing acid reflux into the esophagus and providing symptomatic relief69.
6.2 Cardiovascular Applications:
Antihypertensive drugs such as verapamil and metoprolol benefit from gastroretentive delivery that sustains plasma levels over extended periods, improving blood pressure control and minimizing peak-trough fluctuations associated with conventional formulations. Sustained-release gastroretentive formulations of cardiac medications reduce dosing frequency and enhance patient compliance in chronic cardiovascular conditions such as hypertension and angina70.
6.3 Metabolic Disorders:
For type 2 diabetes management, gastroretentive formulations of metformin enhance its bioavailability and reduce gastrointestinal side effects by sustaining release in the upper gastrointestinal tract. Emerging sustained insulin delivery systems employing gastroretentive platforms aim to extend the insulin release profile, reduce injection frequency, and improve glycemic control through oral administration routes71.
6.4 Neurological Applications:
In Parkinson’s disease, gastroretentive formulations of levodopa/carbidopa prolong drug availability in the absorption window of the proximal small intestine, reducing motor fluctuations and improving clinical outcomes. Epilepsy management benefits from gastroretentive delivery of anticonvulsants like gabapentin, allowing sustained therapeutic plasma concentrations and decreased dosing frequency. Additionally, gastroretentive sustained release formulations are investigated for migraine prevention agents to enhance efficacy and compliance.
6.5 Infectious Diseases:
Gastroprotective systems for antibiotic delivery target gastric infections by maintaining high local drug concentrations, essential in treating Helicobacter pylori and other gastric pathogens. Floating and mucoadhesive formulations have been developed to enhance antibiotic retention in the stomach, improving eradication success rates and reducing systemic side effects72. These clinical applications underscore the versatility of GRDDS as effective oral platforms for drugs requiring prolonged gastric residence and site-specific delivery, with ongoing research expanding their therapeutic scope and formulation sophistication72.
CONCLUSION:
Gastroprotective drug delivery systems represent a mature and clinically validated pharmaceutical technology that successfully addresses limitations of conventional oral drug delivery. The comprehensive examination of floating systems, bio adhesive matrices, swelling systems, and combination approaches demonstrates significant therapeutic advantages for drugs with narrow absorption windows and those requiring sustained release profiles.
Commercial successes including Metformin GR™, Gabapentin GR, and levodopa/carbidopa formulations validate clinical efficacy across neurological, metabolic, and gastrointestinal disorders. Advanced polymer science utilizing natural materials like HPMC and chitosan, combined with sophisticated manufacturing techniques including 3D printing and hot melt extrusion, enables robust scalable production.
Despite proven benefits, challenges persist including physiological variability in gastric emptying, drug-related limitations for gastric irritants, and formulation complexity. Future research directions emphasize personalized medicine applications, smart responsive polymers, and expansion into protein/peptide delivery systems.
GRDDS have evolved from experimental concepts to commercially viable solutions with measurable clinical impact. Continued technological advancement and integration with precision medicine approaches position gastroretentive systems as essential tools for optimizing oral drug delivery, particularly for challenging therapeutic compounds requiring sustained gastric residence and controlled release.
REFERENCES
Mamata Wadkar*, Nidhi Kalamkar, Jotshna Adhagale, Pallavi Borse, Pratiksha Wagh, Gastroprotective Drug Delivery Systems: A Comprehensive Review of Mechanisms, Formulation Strategies, and Clinical Applications, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 10, 1382-1401 https://doi.org/10.5281/zenodo.17346897
10.5281/zenodo.17346897
