INTRODUCTION:

To achieve and maintain the desired drug concentration in the body any drug delivery system is designed with the goal of delivering the drug directly to the site of action. In recent years, there has been a lot of focus on the development of regulated and long-term medication delivery systems. The ability to extend and control the time it takes for dosage forms to empty in the stomach is a valuable asset.¹ Drugs those are poorly soluble or unstable in intestinal fluids which can be retained in the stomach which provides benefits from floating drug delivery systems. The system has bulk density lower than that of gastric fluids which allows them to float for longer periods of time in the stomach without affecting the gastric emptying rate while floating on the gastric contents, the gastric residence time is increased so the drug is slowly released at the desired rate from the system and plasma drug concentration fluctuations are better controlled.²This system is particularly useful for delivering drugs that are insoluble or only sparingly soluble in stomach. Gastrorententive dosage forms resulted in high drug concentrations at the gastric mucosa, which greatly improves GIT pharmacotherapy (eradicating Helicobacter pylori from the sub mucosal tissue of the stomach). Allowing nonsystemic controlled release antacid formulations to be used to treat gastric and duodenal ulcers, oseophagitis and other conditions while lowering the risk of gastric carcinoma. This technology has received a lot of attention in recent decades as a result of its potential application to improve oral delivery of some important drugs for which prolonged gestroretention can greatly improve their oral bioavailability.³

Drug absorption in: (A) conventional dosage form and (B) the gastrorententive drug delivery system.

Figure 1: Drug absorption in stomach

Floating Drug Delivery System Definition:

Floating systems are low-density systems with enough buoyancy to float over gastric content and remain buoyant in the stomach for an extended period of time without affecting gastric emptying rate. For some drug that are actively absorbed from the stomach region which results in increased gastric retention time and better control of fluctuations in plasma drug concentration

⁴

Anatomical and Physiological Aspects of the Stomach:

The gastrointestinal tract can be divided into three main regions. They are namely

1. Stomach

2. Small intestine— duodenum, jejunum and ileum

3. Large intestine

Figure 2: Physiology of stomach

The stomach is a j-shaped organ, with two openings. One just at the end of esophagus called the esophageal end and the rare end which opens in the intestine called duodenal end. The function is to take in nutrients and eliminate waste by such physiological processes such as secretion, motility, digestion, absorption and excretion. The total stomach can be divided into four regions- the cardia, fundus, body and pylorus. Each region performs different functions; the fundus collects digestive gases, the body act as reservoir and secretes pepsinogen and hydrochloric acid, and the pylorus is responsible for mucus, gastrin and pepsinogen secretion. Due to its small surface area very little absorption takes place from the stomach. Gastric emptying occurs in two states one when fasting and another when fed, but with different motility pattern. During the fasting state an interdigestive series of electrical events occur called as myoelectric or migrating motor cycle (MMC)⁵

Myoelectric Motor Cycle (MMC)⁶

Figure 3-Myoelectric motor cycle

Floating Drug Delivery Systems and its Mechanism:

Low-density systems that float above gastric fluid and stay in the stomach for longer periods of time are known as floating systems. The medicine is delivered slowly and at the desired rate while the system floats over the gastric contents, resulting in increased gastro-retention time and less variation. A minimum level of floating force (F) is required to keep the dosage form stably buoyant on the meal's surface, in addition to a minimum gastric content required for proper achievement of the buoyancy retention principle. The equipment measures the force required to keep the submerged object submerged in real time (as a function of time). The object floats more easily when F is positive. This equipment helps to optimize FDDS in terms of the stability and longevity of the floating forces produced, avoiding the disadvantages of unpredicted intra-gastric fluctuations.⁷

Factors Controlling Fdds of Dosage Forms:

Density:

Dosage forms with a lower density in the gastric content can float to the top of the stomach, while those with a higher density sink to the bottom. A density of less than 1.0gm/ cm3 is required for floating properties.

Size and shape:

The diameter should be greater than 7.5mm. It has been reported that those with a diameter of more than 7.5mm have a higher gastric retention time.

Single or multiple unit formulation:

There are a variety of unit formulations with highly anticipated release profiles and minor drawbacks Due to the predictable release profile, multiple units are preferred. This allows for the co-administration of units with different release profiles or containing incompatible substances. Furthermore, when compared to single-unit dosage forms, it provides a greater margin of safety against dosage from failure.

Fed or Unfed State:

Due to a rise in gastric motility during fasting, gastric retention time is reduced. GI motility is characterized by periods of strong motor activity or migrating myoelectric complexes (MMC) that occur every 1.5 to 2 hours. The MMC removes undigested material from the stomach, so if the formulation is given at the same time as the MMC, the unit's GRT should be very short. MMC is delayed in the fed state, and GRT is significantly longer.

Nature of Meal:

Due to variations in gastric motility, a high amount of fatty acid and other indigestible polymers slow down gastric retention time. Slowing gastric emptying and prolonging drug release by feeding indigestible polymers of fatty acid salts to the stomach can change the motility pattern to a fed state.

Frequency of Feed:

Low frequency of migrating myoelectric complex (MMC), which is dependent on food intake frequency, contributes up to 400 times to gastric retention time (GRT).

Caloric Content:

GRT can be increased by 4 to 10 hours by eating a high-protein, high-fat diet.⁸

Gender:

GRT is higher in males than in females. Males have a lower mean ambulatory GRT (3.40.6 hours) than their age and race-matched female counterparts (4.61.2 hours).

Age:

In geriatric patients, gastric retention time (GRT) is higher, while in neonates and children, it is lower. gastric retention time (GRT) is longer in people over the age of 70 (>70). Regardless of body size, height, or surface. The gastric retention time of the elderly particularly those over the age of 70, is significantly longer.

Posture:

gastric retention time can differ between with the patient's supine and upright ambulatory states.

Disease State:

Diabetes, chron's disease, hypothyroidism, hyperthyroidism, duodenal ulcers, and other gastric diseases cause the gastric retention time (GRT) to fluctuate.

Concomitant Intake of Drug:

Some drugs, in combination with gastric motility enhancers or depressants, have an effect on gastric motility.⁹

Classification of Floating Drug Delivery Systems (FDDS):

(A) Effervescent System FDDS:

Swellable polymers such as methocel polysaccharides, methylcellulose, (e.g., chitosan) and effervescent components are used in these buoyant systems (e.g., sodium bicarbonate, citric acid or tartaric acid). When it reaches to the stomach carbon dioxide is released, causing the formulation to float. (Gas-Producing Systems) .The formation of gas bubbles aids in the attainment of floatability. Assist in the creation of matrix-type systems. When they come into contact with gastric contents, CO2 is released and trapped in swollen hydrocolloids, making the dosage forms buoyant.

a) Gas generating system:

Swellable polymers such as methocel, polysaccharides (e.g., chitosan), and effervescent components are used in these floating systems (e.g., sodium bicarbonate, citric acid or tartaric acid) so in this system came in contact with acidic medium carbon dioxide is released when the formulation reaches the stomach, causing it to float, as well as floating systems based on ion exchange resin technology, have all been reported, among other approaches and materials.

b) Volatile Liquid Containing System:

An impermeable, pressure-responsive, and movable bladder in this all techniques they have two chambers .The first chamber contains drugs, while the second contains a volatile liquid. To keep a drug delivery system's GRT up, an inflatable chamber with a liquid, such as ether or cyclopentane must be incorporated into body. At body temperature liquid converts to a gaseous state, inflating the stomach chamber. It could include a biodegradable plug made of polyvinyl alcohol, polyethylene, or other biodegradable material. This plug gradually dissolves, allowing the chamber to release gas and collapse after a set period of time, allowing the inflatable systems to be released spontaneously from the stomach. As the device inflates, the drug continues to release¹¹

(B) NON-Effervescent FDDS:

Swellable cellulose hydrocolloids, polysaccharides, and matrix-forming polymers such as polycarbonate, polyacrylate, polymeth-acrylate, and polystyrene are used in non-effervescent floating dosage forms. It was created in a simple manner, with the drug being mixed with the gel forming polymer, then swelling as a result of coming into contact with gastric fluid after oral administration, and thus maintaining relative shape, integrity and a bulk density less than one. The air trapped in the swollen matrix gives the dosage form its buoyancy. The drug is stored in this swollen matrix, which is then released over time via gelatinous mass. Hydroxypropyl methyl cellulose (HPMC), polyacrylate, polyvinyl acetate, carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide, and polycarbonates are most widely used exicipients⁸

a) Colloidal Gel Barrier System:

A drug with gel-forming hydrocolloids is used in this system to keep the drug buoyant in the stomach contents. This system contains a high concentration of one or more gel-forming, highly soluble cellulose type hydrocolloids, such as hydroxypropyl cellulose, hydoxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), polysaccharides, and matrix-forming polymers like polycarbophil, polyacrylate, and polystyrene .The hydrocolloid in the system hydrates and forms a colloid gel barrier around its surface when it comes into contact with gastric fluid.

b) Micro-porous Compartment System:

Encapsulation of a drug in reservoir done within a micro porous compartment with pores. Due to the entrapment of air into floatation chamber, so the delivery system floats over the gastric content in the stomach. Gastric fluid enters the aperture, dissolves the drug, and transmits the dissolved drug across the intestine for absorption in a continuous flow.

c) Alginate Beads:

Dried calcium alginate complex has been used to create multi-unit floating dosage forms. Dropping sodium alginate solution into an aqueous solution of calcium chloride causes calcium alginate to precipitate, resulting in spherical beads with a diameter of about 2.5mm. After that, the beads are then separated and frozen in liquid nitrogen before being freeze-dried at -40^oC for 24 hours, resulting in a porous system with a floating force of more than 12 hours.

d) Hollow microspheres/ Microballons:

Hollow microspheres are thought to be one of the most promising buoyant systems available. Because of the central hollow space inside them, they have the unique advantages of multiple unit systems as well as better floating properties. Solvent evaporation, solvent diffusion is commonly used to prepare them. Hollow microsphere can prepare by using a novel emulsion solvent diffusion method. The drug was poured into an agitated solution of Poly Vinyl Alcohol (PVA) that was thermally controlled at 40oC, along with an enteric acrylic polymer in an ethanol/dichloromethane solution. The evaporation of dichloromethane formed in the internal cavity of the polymer microsphere with drug produces the gas phase in the dispersed polymer droplet. ¹²

(C) Raft forming system:

The raft forming system is one of the floating drug delivery systems. Drugs that are poorly soluble or unstable in intestinal fluids can benefit from a floating drug delivery system that is retained in the stomach. Because FDDS have a lower bulk density than gastric fluids, they can float in the stomach for longer periods of time without affecting the gastric emptying rate. The drug is slowly released from the system while floating on the gastric contents at the desired rate. The stomach's residual system is emptied after the drug has been released. As a result, the gastric residence time is increased, and drug concentration fluctuations in plasma are better controlled.¹³

Applications of Floating Drug Delivery Systems

Sustained Drug Delivery:

Hydro-dynamically balanced system can stay in the stomach for a long time, allowing the drug to be released over a longer period of time. These systems can thus overcome the problem of a short gastric residence time that can occur with an oral control release formulation

Site-Specific Drug Delivery:

These systems are especially useful for drugs that must be absorbed through the stomach or the proximal part of the small intestine. e.g., riboflavin and furosemide. The stomach absorbs the most furosemide, followed by the duodenum.

Absorption Enhancement:

Drugs that have poor bioavailability because of site-specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, there by maximizing their absorption.

Adverse Activity at the Colon Has Been Reduced:

When the drug is retained in the Hydro-dynamically balance systems, amount of drug that reaches the colon is reduced at the stomach. As a result, the drug's undesirable effects in the colon may be avoided. For beta lactam antibiotics that are only absorbed in the small intestine and whose presence in the colon leads to microorganism resistance, this pharmacodynamics aspect justifies GRDF formulation.

Reduced Fluctuations of Drug Concentration:

Continuous input of the drug following CR-GRDF administration produces blood drug concentrations and undesirable activities of the drug in colon may be prevented. This pharmacodynamics aspect justifies GRDF formulation for beta lactam antibiotics that are only absorbed from the small intestine and whose presence in the colon leads to the development of resistances¹⁴

Evaluation Parameters¹⁵:

*In-vivo* test	In-vitro test
X-ray Method	Floating Lag time
Gamma Scintigraphy	Floating Time
Gastroscopy	Dissolution Study
Magnetic Resonance imaging	Swelling index

CONCLUSION:

For drugs that are absorbed primarily in the upper GI tract, the FDDS becomes an additional benefit. Drug delivery using various drug candidates have benefited from gastrorententive technological approaches to improve bioavailability and controlled delivery. The increasing sophistication of these technologies will ensure the development of a variety of gastrorententive drug delivery systems to optimize the delivery of drugs with a narrow absorption window, low bioavailability, and extensive first pass metabolism. Number of commercial product and patents issued in this field are the evidence of it.

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Received on 12.01.2022 Modified on 07.06.2022

Res. J. Pharma. Dosage Forms and Tech.2022; 14(4):331-335.

DOI: 10.52711/0975-4377.2022.00054