A Review on Gastroretentive Floating Tablet: A Tool to Improve Bioavailibility in Gastric

Oral drug delivery remains the most preferred route of drug administration due to its convenience, patient compliance, and cost-effectiveness. However, one of the major challenges in oral drug delivery is achieving and maintaining adequate drug bioavailability, particularly for drugs with narrow absorption windows, poor solubility in intestinal fluids, or instability in the alkaline pH of the intestine. Gastroretentive drug delivery systems (GRDDS) have emerged as a promising approach to enhance the bioavailability of such drugs by prolonging gastric residence time (GRT) and ensuring site-specific drug release in the stomach. Among the different types of GRDDS, floating drug delivery systems (FDDS) have gained significant attention due to their ability to remain buoyant in gastric fluid for an extended period without being affected by gastric emptying. These floating tablets work by incorporating gas-generating agents or low-density polymers that enable them to float on gastric contents, thereby facilitating prolonged drug release at the desired site of absorption. This approach is particularly beneficial for drugs such as metformin, ciprofloxacin, and levodopa, which exhibit improved solubility and absorption in the acidic environment of the stomach. The effectiveness of gastroretentive floating tablets depends on several factors, including polymer selection, formulation techniques, and physiological conditions such as gastric motility and fed/fasting state. Advances in polymer science, including the use of hydrophilic polymers such as hydroxypropyl methylcellulose (HPMC) and polyethylene oxide (PEO), have further enhanced the floating properties and drug release characteristics of these formulations

Importance of GRDDs:

The importance of GRDDs can be highlighted as follows:

• Prolonged Gastric Retention: Ensures the drug stays in the stomach longer, allowing extended release and improved therapeutic outcomes.
• Enhanced Bioavailability: Increases drug absorption for drugs with a narrow absorption window in the stomach or upper GI tract.
• Improved Drug Stability: Protects drugs that are unstable in the alkaline environment of the intestines.
• Targeted Drug Release: Ideal for local treatment of gastric conditions (e.g., ulcers or infections like Helicobacter pylori).
• Reduced Dosing Frequency: By maintaining sustained release, GRDDs can reduce the need for frequent dosing, improving patient compliance.
• Minimized Drug Wastage: Prevents premature drug passage into the intestines, maximizing therapeutic efficacy.
• Controlled Drug Release: Provides a steady, controlled release of medication over time, reducing fluctuations in plasma drug concentration

GRDDs offer several merits and demerits in drug delivery. Merits include prolonged gastric retention, which ensures a sustained release of the drug in the stomach, improving BA, especially for drugs that are absorbed in the upper GIT.GRDDs are beneficial for drugs with narrow absorption windows and those that degrade in the alkaline pH of the intestine. They also reduce dosing frequency, which can improve patient compliance, especially in long-term therapies. Moreover, they can help in local drug action in the stomach, such as in the treatment of gastric ulcers. However, GRDDs also have demerits. Their success is highly dependent on individual gastric motility and emptying, which can vary due to factors like age, diet, and disease conditions. Additionally, these systems may not be suitable for drugs that are unstable in acidic conditions or drugs that cause gastric irritation. The size of the dosage form must be large enough to avoid premature gastric emptying but not so large that it causes discomfort. Formulation complexity and higher production costs also pose challenges for widespread use of GRDDS.

Significance of Extended Gastric Retention

Extended gastric retention is a crucial aspect of Gastroretentive Drug Delivery Systems (GRDDS), particularly for drugs with narrow absorption windows, poor solubility in intestinal fluids, or localized gastric activity. By increasing the residence time of the drug in the stomach, gastroretentive systems, including floating tablets, provide several therapeutic and pharmacokinetic benefits.

1. Enhanced Bioavailability

Many drugs, such as ciprofloxacin, levodopa, and riboflavin, exhibit site-specific absorption in the stomach or upper small intestine. Prolonging gastric retention ensures higher drug absorption, leading to improved bioavailability and therapeutic efficacy.

Example: A study by Singh & Kim (2000) demonstrated that gastroretentive dosage forms improved the bioavailability of furosemide, which has limited solubility in alkaline conditions.

2. Improved Drug Solubility

Weakly basic drugs like verapamil and diazepam show pH-dependent solubility and dissolve better in the acidic gastric environment. Extending gastric retention ensures optimal solubility and absorption before the drug reaches the less acidic small intestine.

Example: Research by Chawla et al. (2003) found that floating tablets enhanced the solubility of weakly basic drugs, improving their overall absorption.

3. Prolonged Drug Release and Reduced Dosing Frequency

Floating drug delivery systems provide sustained drug release, reducing fluctuations in plasma drug levels and minimizing frequent dosing requirements.

Example: Jaimini et al. (2008) reported that floating microspheres of metformin maintained therapeutic levels for an extended duration, reducing the need for multiple daily doses.

4. Better Therapeutic Efficacy for Gastric Disorders

For drugs treating gastric infections (e.g., Helicobacter pylori), gastroesophageal reflux disease (GERD), and peptic ulcers, extended gastric retention ensures localized drug action and prolonged therapeutic effect.

Example: Awasthi et al. (2015) demonstrated that floating formulations of amoxicillin and clarithromycin improved the eradication rate of H. pylori infections.

5. Minimization of Drug Wastage

Some drugs degrade or lose potency in the alkaline intestinal pH. Prolonged gastric retention prevents premature drug degradation, ensuring maximum drug utilization before transit to the intestines.

Example: Streubel et al. (2006) highlighted that drugs such as atenolol and captopril benefitted from extended gastric retention by reducing degradation in the intestine.

6. Better Patient Compliance

Since extended gastric retention allows controlled release and prolonged drug action, it reduces the need for multiple daily doses, improving patient adherence to therapy.

Example: Deshpande et al. (1997) developed floating drug delivery systems that reduced dosing frequency, enhancing patient compliance in long-term therapies.

Swellable And Floating Gastroretentivery Delivery System

A Swellable and Floating GRDDs is a drug delivery approach designed to prolong the gastric retention time of medications, allowing for extended release and improved BA, particularly for drugs that are absorbed in the stomach or the upper part of the small intestine . These systems work by swelling upon contact with gastric fluids, increasing in size to prevent their passage through the pylorus. Simultaneously, they are formulated to float on the gastric contents due to their low density, maintaining their position in the stomach . This dual mechanism enhances drug absorption by providing a longer window for drug release in the gastric environment, making it ideal for drugs with a narrow absorption window or those that are unstable or poorly soluble in the intestines.

Swellable Gastro Delivery System:

A Swellable SGDDs is designed to retain a drug in the stomach for an extended period by expanding in size upon contact with gastric fluids. The system contains polymers that absorb water and swell, increasing in volume to prevent the dosage form from passing through the pylorus into the intestines. This swelling ensures prolonged gastric retention, allowing for sustained or controlled release of the drug. SGDDs is particularly beneficial for drugs with narrow absorption windows or those primarily absorbed in the stomach or upper small intestine, enhancing their bioavailability and therapeutic efficacy. An ideal SGDDs should possess several key characteristics to ensure effective and prolonged gastric retention. Firstly, it must have excellent swelling capacity to significantly increase its size upon contact with gastric fluids, preventing premature passage through the pyloric sphincter. The system should demonstrate mechanical strength and integrity after swelling, maintaining its structure to allow for controlled drug release. Additionally, the polymers used should be biocompatible, non-toxic, and capable of rapid swelling while being resistant to degradation in the acidic gastric environment . The system should also release the drug at a controlled rate, providing sustained therapeutic levels without causing irritation to the stomach lining. Lastly, it should be easy to administer, patient-friendly, and stable under various storage conditions to ensure consistent performance.

Mechanism of Action of Swellable Systems: The mechanism of action of SGDDs is based on their ability to expand and retain in the stomach for an extended period. These systems typically contain hydrophilic polymers that absorb gastric fluids upon ingestion 58. Once in contact with these fluids, the polymers swell by taking in water, increasing the size of the dosage form. This expansion is critical as it prevents the system from passing through the pylorus into the small intestine. The swollen dosage form remains buoyant or large enough to stay in the stomach, allowing for prolonged residence time. During this period, the drug is gradually released through diffusion or erosion, providing a controlled or sustained drug release profile 57. As the system stays in the stomach, drugs with narrow absorption windows or those that benefit from extended gastric exposure can be more effectively absorbed, enhancing BA and therapeutic effects. Eventually, the system either degrades naturally or deflates and passes into the intestines once its function is complete.

Floating Gastro Delivery System: A Floating Gastroretentive Drug Delivery System (FGDDS) is designed to prolong the retention of drugs in the stomach by remaining buoyant on gastric fluids. This system incorporates low-density materials that enable the dosage form to float on the stomach's surface, preventing it from passing into the intestines prematurely. By maintaining a position in the upper part of the stomach, FGDDs allows for a sustained or controlled release of drugs, particularly those that are better absorbed in the stomach or upper small intestine. This approach improves drug BA, reduces dosing frequency, and enhances therapeutic outcomes, especially for drugs with short half-lives or narrow absorption windows. The FGDDs representation in the Fig. 1 as below following.

Figure 1: Representation of FGDDs and their details

• Effervescent Systems: These systems rely on gas generation to achieve buoyancy. They contain effervescent components like sodium bicarbonate, citric acid, or tartaric acid, which react with gastric fluids to produce carbon dioxide. The generated gas causes the system to float on the stomach's surface. Examples include floating tablets and capsules that release gas upon contact with stomach acid.
• Non-Effervescent Systems: These systems use swellable polymers or gel-forming agents, such as hydroxypropyl methylcellulose (HPMC), that expand and become less dense when they come into contact with gastric fluids. The swollen matrix remains buoyant due to its reduced density, allowing it to float and provide prolonged drug release

Both types ensure extended gastric retention, enhancing the bioavailability of drugs with narrow absorption windows in the upper GI tract.

Buoyancy Mechanism in Floating Systems: The buoyancy mechanism in floating drug delivery systems is based on the principle of reducing the system's overall density to remain afloat on gastric fluids. In effervescent floating systems, the dosage form contains gas generating agents, such as sodium bicarbonate and acids like citric or tartaric acid 63. Upon contact with gastric fluids, these agents react to release carbon dioxide (CO?) gas. The gas gets trapped in the polymer matrix or capsule, lowering the overall density of the dosage form, allowing it to float on the surface of gastric contents. The drug is gradually released while the system remains buoyant. In non-effervescent systems, hydrophilic polymers like hydroxypropyl methylcellulose (HPMC) or alginate are used. When these polymers contact gastric fluids, they swell and form a gel-like structure, increasing the volume and decreasing the density of the system 65. This swollen, low-density matrix stays afloat in the stomach, providing a controlled or sustained release of the drug over time. These systems ensure prolonged retention in the stomach, allowing for sustained drug release, which is particularly beneficial for drugs that degrade in the intestine or have limited solubility in higher pH environments. Swellable systems utilize polymers that expand upon contact with gastric fluids, while floating systems maintain buoyancy to prevent premature gastric emptying. Together, these technologies improve drug absorption, reduce dosing frequency, and enhance patient compliance. However, challenges such as patient variability in gastric motility and the need for precise formulation design still exist, requiring ongoing research to optimize their clinical application.

Methods Of Preparation

Methodology for single-layer floating tablets: Basically, single-layer floating tablets are prepared by compression methods. For this normally three basic compression methods are used. They are as follows: -

Direct compression: The practice of compressing tablets straight from powdered ingredients without changing the materials' physical composition is known as direct compression. This technique is applied to crystalline substances with good compressibility and flow characteristics, such as ammonium chloride, sodium chloride, methenamine, and potassium salts (chloride, chlorate, and bromide). Tablet computers are used to create compressed tablets using a single compression process. The tablet machine's upper and lower punches crush the material under high pressure when a certain amount of powdered tablet material flows into a die. is especially suitable for active ingredients that are sensitive to solvents, or labile to moisture and elevated temperatures.

Dry granulation method: It is defined as the formation of granules by slugging if the tablet ingredients are sensitive to moisture and/or unable to withstand elevated temperature during drying.

Wet granulation method: In wet granulation, the active ingredient, diluents, and disintegrants are mixed or blended well in a rapid mixer granulator (RMG). The RMG is a multi-purpose chopper that consists of an impeller and a chopper and is used for high-speed dispersion of dry powders and aqueous or solvent granulations. Moist materials from wet milling steps are placed on large trays and placed in drying chambers with a circulating air current and thermo-stable heat controller. Commonly used dryers are tray dryersand fluidized bed dryers. After drying, the granules are reduced in particle size by passing through the smaller mesh screen. After this, the lubricant or glidant is added as a fine powder to promote the flow of granules. These granules are then compressed to get a tablet. Dry granulation when compared with wet granulation has a shorter, more cost-effective manufacturing process. Because it does not entail heat or moisture, dry granulation is especially suitable for active ingredients that are sensitive to solvents, or labile to moisture and elevated temperatures.

Method Of Evaluation

Pre compression parameter

Drug-excipientinteractions: This is done using FTIR. Appearance of a new peak, and/or disappearance of the original drug or excipient peak indicate the DE interaction. Apart from the above-mentioned evaluation parameters, for the effect of aging with the help of Differential Scanning Calorimeter or Hot stage polarizing microscopy.

Bulk density: It is the ratio of total mass of powder to the bulk volume of powder. Accurately weighed batch (F1–F9) powder was placed in a 10 mL graduated measuring cylinder. The initial volume was observed. The Db was calculated in gm/mL using the following formulae,

Db =M/Vb

Where, Db =Bulk density, M=Mass of the powder, Vb =Bulk volume of powder

Tapped density: Accurately weighed batch (F1-F10) powder was placed in 10 mL graduated measuring cylinder. The cylinder was tapped initially 100 times from a distance of 14+2 mm. The tapped volume was measured to the nearest graduated unit. Again the tap volume was measured to the nearest graduated unit. The Dt was calculated in g/mL using the following formulae,

Dt =M/Vt

Where, Dt =Tapped density, Vt =Tapped volume of the powder, Dt =Tapped density, M=Mass of the powder

Angle of repose: Good flow properties are critical for the development of any pharmaceutical tablets, capsules, or powder formulations. The angle of repose is defined as the maximum angle possible between the surface of the pie of powder and the horizontal plane. It is performed to determine the flow property of powder done by the funnel method. The powder mass was allowed to flow through the funnel orifice, kept vertically to a plane paper kept on a horizontal surface, giving a heap angle of powder on a paper. The diameter of the powder cone was measured and the angle of repose was calculated using the following equation

Tan θ=h/r

Where, h and r are the height and radius of the powder cone, respectively.

Hasusner’s ratio: Hasusner’s ratio is carried out by tapped density divided by bulk density.

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Carr’s consolidation index: Carr developed an indirect method of measuring powder flow from bulk densities. The % compressibility of the powder was a direct measure of the potential powder arch or bridge strength and stability. Carr’s index of each formulation was calculated using the given formula.

Carr’s index (%)=[(Dt –Db) × 100]/Dt

Post compression parameter

Appearance: The tablets were checked for the presence of cracks, pinholes, etc. There should be uniformity in the color and the dimensions of the tablets.

Hardness: A tablet's hardness reveals its capacity to tolerate managing mechanical shocks. The hardness of the tablet was assessed using the Monsanto hardness tester. The unit of measurement is kg/cm2. Five tablets were chosen at random, and their hardness was assessed. Friability: Roche Friabilator was used to gauge tablet strength. 20 tablets were weighed, put into the friabilator, turned 100 times, then removed and dusted. Reweighing the tablets allowed for the calculation of the weight reduction percentage. The % friability was calculated by:

F= [(W_initial- W_final) ×100]/ W_initial)

Weight variation: From each batch, 20 tablets were chosen at random, and they were all weighed separately and collectively using an electronic balance. The typical weight was recorded.

PD= [(WH-WL) × 100]/ WH

Where, PD= percentage deviation

WH= highest weight (mg)

WL= lowest weight (mg)

Drug content: Ten tablets from each batch were weighed and powdered. Powder equivalent to the average weight of the tablet was accurately weighed in a 100 ml volumetric flask and dissolved in a suitable quantity of 0.1 N HCl. Then the volume was made up to 100ml with 0.1 N HCl and filtered. 2 ml of filtrate was transferred to a 100 ml volumetric flask and the volume was made with 0.1 N HCl. The absorbance of the resulting solution is measured by UV spectrophotometer at drug-specificnm range.

Floating Test: The tablets were placed in a 100 ml beaker containing 0.1 N HCl. The time between the introduction of the dosage form and its buoyancy on 0.1 N HCl, and the time during which the dosage form remains buoyant were measured. The time taken for the dosage form to emerge on the surface of the medium is called Floating Lag Time(FLT) or Buoyancy Lag Time (BLT) and the total duration of time during which the dosage form remains buoyant is called Total Floating Time (TFT).

Swelling Study: The swelling behavior of a dosage form is measured by studying its weight gain or water uptake (WU). The study was done by immersing the dosage form in 0.1 N HCl at 37oC and determining these factors at regular intervals up to a period of 12 hours. Water uptake was measured in terms of percent weight gain, as given by the equation.

WU = (Wt –Wo) x 100 / Wo

Wt = Weight of the dosage form at time t.

Wo = Initial weight of the dosage form.

In-vitro drug release study:

 The USP basket technique was used for the release testing. 900ml of 0.1N HCL was added to the jar, and the medium was allowed to acclimate to a temperature of 370C while rotating at 50 rpm. The tablet was placed inside the container and basket, and the machine ran for twelve hours at a speed of fifty rotations per minute. At regular intervals, 10 ml of the fluid was withdrawn, filtered, and then reintroduced. With the use of the dissolving solution, the samples were properly diluted

Stability Studies: The success of an effective formulation can be evaluated only through stability studies. The purpose of stability testing is to obtain a stable product that assures its safety and efficacy up to the end of shelf life at defined storage conditions and pack profile. The prepared floating tablets of glimepiride were placed in plastic tubes containing desiccant and stored at ambient humidity conditions, at room temperature, oven temperature (40±20c), and in the refrigerator (2-80c) for a period of one month after storing them at 400C±20C/75%RH±5%RH for 28 days.

Factors that Affect Gastric Retention

The retention of an orally administered drug in gastric fluid is dependent on several factors. Firstly, as explained in the above section, the size of the particles should fall below 1 mm and it surpass to the small intestine via the pyloric valve. Another aspect is the pH of the GIT. During fasting, it is 1.5 to 2.0 and in the fed state, it ranges from 2.0 to 6.0. However, the presence of a large amount of water in the form of oral doses increases the pH of the stomach from 6.0 to 9.0. When the fluid empties the stomach, the stomach has no time to make enough acid. The pH is towards the basic side so; basic drugs have more chances of getting dissolved in the fed state rather than a fasting state. Other than size and pH, the volume, viscosity and calorie content of the food affects how fast or slow the gastric emptying will take place. The nutrient concentration of the food helps to know the gastric emptying rate. As long as the calorie content is the same, it makes no distinction that the diet has high fat, carbohydrate or protein content. However, it is affected by caloric value; acidity status; and certain biological factors like body mass index (BMI), age (lowers in old age), sex (lower in females than males), disease status (depression reduces it) as well as the posture (standing increases retention time in floating type delivery system while supine position increases retention time in non-floating type delivery systems). The resting level of the stomach is 25–50 ml. The shape and size of the dosing unit affect the gastric residence. Devices with tetrahedrons and rings type shape have an improved gastric emptying rate when compared to other forms. The size of the dosage form is similarly very essential just like any formulation parameters. There is improved gastric delay reported with a dosage unit having > 7.5 mm diameter. Density is also a prime factor that affects gastric emptying. These factors can be chiefly divided into physiological factors, pharmaceutical factors, and patient-related factors.

Physiological Factors

 Numerous studies reports that various physiological factors such as posture, frequency of eating, performance, physical activity and sleep influence the GRT of gastric drugs. Throughout this age, motor activity knocks the digestible material out of the GIT. If the administration time of dosage is equal to the MMC, the residence of the dosage form is extremely low. On the other hand, in the existence of food in the belly, MMC disrup tion and lack of housekeeper wave can lead to increased GRT Similarly, the nature of calories and caloric density also affect the rate of gastric emptying. Calbet et al. in 1997 has reported that caloric density appreciably affects GRT, but the nature of theses the calories hardly affect GRT. The high viscosity of food increases GRT. In addition, posture affects GRT and its effect on floating and non-floating dosage forms is different. Standing increases retention time in floating type delivery system while supine position increases retention time in non-floating type delivery systems. In comparison, the non floating systems have a higher GRT in contrast to the floating system.

Pharmaceutical Factors

To design GRDDS properly it is essential to know the function of pharmaceutical factors like polymers and excipients used in different classes of GRDDs. For example, in mucoadhesive systems, the proper design of the mucoadhesive dosage forms may require high mucosal strength polymers like hydroxypropyl methylcellulose (HPMC) and Carbopol. Similarly, in expandable systems, higher swelling polymers are mostly required. Furthermore, the viscosity, physicochemical properties and molecular weight of the polymers too influence the dosage form. Furthermore, the size and shape of the dosing unit are equally important.It has been reported that both tetrahedron and ring-shaped dosage forms had higher GRT in comparison to other forms. In most cases, the GRT is proportional to the diameter of the dosage form, especially for non-disintegrating systems. Boost in the size of the dosage forms may avoid it from passing throughout the pyloric sphincter with mean diameter 12.8 ± 7 mm in humans, if the size of the dosage form is more than this. For high-density systems, the density of the dosage form is a significant feature to withstand the continuous in vivo peristaltic movement. The density of dosage forms must be less than gastric juices in low-density systems, i.e., 1.004 g/cm3 to float in the gastric environment. A rise in the floating ability improves the GRT of a low-density system. But this outcome is diminished in the existence of food. Further, the buoyancy of the dosage form reduces with time, which may be due to hydrodynamic equilibrium. Similarly, the density of dosage form must be more than gastric fluids so that they sink to the lower side of the stomach and prevent emptying of the stomach. Dosage forms having a greater density than 2.5 g/cm3 are reported to increase GRT as they will be retained more owing to their higher density than the gastric content

Patient-Related Factors

Factors for instance age, gender, disease and emotional status affect GRDDS. In a study by Wang et al., gender affected intraluminal pH and gastric emptying time. The authors found that women had a slower gastric emptying than men. Hormonal effects  may explain the reason for greater GRT in women than in men. A new study found that women had higher acid secretion than men. Similarly, patient age also affects GRT. GRT is higher in older patients rather than young patients. type of disease also affects the GRT of the dosage form. It is reported that a Parkinson’s patients have longer GRT and this leads to constipation. In diabetic patient, the gastric emptying is reduced by 30–50%. The psychological state of the patient also often affects GRDDS. The rate of gastric emptying is reported to be on the lower side in patients with depression, while increased rates were found in patients with anxiety. Let’s have a discussion on the disease situations in which such systems can be helpful. The GRDDS are useful in diseases like cardiovascular diseases, diabetes, Chron’s disease, peptic ulcers, etc. In diabetes mellitus, the body produces less amount insulin or do not respond to it, resulting in abnormally high blood sugar (glucose) levels. Crohn’s disease refers to inflammatory bowel disease (IBD) which leads to swelling of our GIT. Thus, it can direct to weight loss, abdominal ache, fatigue, malnutrition and severe diarrhea. Crohn’s disease affects several parts of the GIT in most individuals. The peptic ulcer is affected by the pH of gastric fluid and decreased mucous resistance. The bet terretention of the drug for a longer duration will help in eradicating the Helicobacter pylori (H. pylori) infections more effectively. The oral controlled release dosage form still has two main problems which are unpredictable gastric emptying and short residence time. The use of GRDDS can prevent peristaltic waves and gastric contractions and shows a sustained drug release in GIT. Therefore, those drugs that is stable in the stomach/ upper GIT acidic environment offer better bioavailability by an increase in their gastric delay. For some drugs like Metformin HCl and Baclofen, the key sites for absorption of the drug are in the small intestine or upper abdomen. Hence, the gastric delay is very beneficial for the long-term delivery of those drugs. The primary reason for controlled delivery is to manage the absorption of the drug in the target site, dropping the administration and modifying the pharmacodynamics and pharmacokinetics of the drug. Administration through oral route is done due to the noninvasive means of drug management, high patient compliance, cost-effectiveness, and ease of use. To lessen the drug absorption as peak-trough fluctuations which are typically observed in first order release kinetics and may offer the toxicity in the plasma, the geometry control of such drug systems can be an effective tool to manage the limitation of the conventional formulations and shifting the release pattern to follow zero order kinetics.

List Of Drugs Gastroretentive Floating Tablet