A Comprehensive Review On: Floating Microbeads for Gastroretentive Drug Delivery Systems

Abstract

Floating microbeads are an advanced gastro-retentive drug delivery system designed to prolong gastric residence time and enhance the bioavailability of drugs that are primarily absorbed in the upper gastrointestinal tract. Conventional oral drug delivery systems often require frequent dosing due to rapid drug elimination and short biological half-life, leading to fluctuations in plasma drug concentration. Floating drug delivery systems overcome these limitations by maintaining the dosage form in the stomach for an extended period through buoyancy, thereby allowing sustained and controlled drug release. Floating microbeads are hollow, spherical, free-flowing particles typically ranging from 1–1000 ?m in diameter and are prepared using various polymers such as sodium alginate, chitosan, gelatin, and other natural or synthetic materials. These systems employ different preparation techniques including ionotropic gelation, emulsion gelation, internal and external gelation, and polyelectrolyte complexation. Drug release from microbeads occurs mainly through diffusion, erosion, and osmotic mechanisms. Floating microbeads offer several advantages such as improved bioavailability, reduced dosing frequency, minimized side effects, and better patient compliance. This review highlights the concept of floating drug delivery systems, classification, mechanisms, preparation methods, polymers used, evaluation parameters, and pharmaceutical applications of floating microbeads in controlled drug delivery.

Keywords

Floating Microbeads, Gastroretentive Drug Delivery Systems, enhance the bioavailability, drug elimination and short biological half-life

Introduction

Oral administration is the most convenient and preferred means of any drug delivery to the systematic circulation. Oral controlled release drug delivery have recently been of  increasing interest  in  pharmaceutical  field  to  achieve improved therapeutic advantages, such as ease of dosing administration,   patient   compliance and  flexibility   in formulation.   Drugs   that   are easily   absorbed   from gastrointestinal tract (GIT) and  have  short  half-lives  are eliminated    quickly from    the    systemic    circulation. Frequent  dosing of  these  drugs  is  required  to  achieve suitable therapeutic activity. To avoid this limitation, the development    of    oral    sustained-controlled release formulations is an attempt to release the drug slowly into the gastrointestinal tract (GIT) and maintain an effective drug concentration in the systemic circulation for a long time ¹.  After oral  administration,  such  a  drug  delivery would be retained in the stomach and release the drug in a  controlled  manner,  so  that  the  drug  could  be supplied continuously to its absorption sites in the gastrointestinal tract  (GIT).  These  drug delivery  systems  suffer  from mainly  two adversities:  the  short  gastric  retention  time(GRT)  and  unpredictable  short  gastric  emptying time (GET), which can result in incomplete drug release from the  dosage  form  in  the  absorption zone  (stomach  or upper  part  of  small  intestine)leading  to  diminished efficacy   of   administered dose.   To   formulate   a   site-specific orally administered controlled release dosage form, itis desirable to achieve prolong gastric residence time by the drug delivery.  Prolonged gastric  retention improves  bioavailability, increases  the  duration  of  drug release,  reduces drug   waste,  and  improves  the  drug solubility that    are    less    soluble    in    a    high    pH environment ². Also  prolonged  gastric  retention  time (GRT)in  the  stomach  could  be  advantageous  for  local action  in  the   upper  part  of  the   small  intestine e.g. treatment  of  peptic  ulcer,  etc. Gastro retentive  drug delivery  is  an  approach  to prolong  gastric  residence time,  there by targeting  site-specific  drug  release  in  the upper gastrointestinal  tract  (GIT)  for  local  or systemic effects. Gastro retentive dosage forms can remain in the gastric region for long periods and hence significantly prolong the gastric retention time (GRT) of drugs. Over the last   few   decades,   several gastro retentive drug delivery   approaches   being   designed   and developed, including: high density (sinking)systems that is retained in  the  bottom  of  the stomach,  low  density  (floating) systems    that causes    buoyancy    in    gastric    fluids, mucoadhesive   systems   that   causes   bioadhesion to stomach  mucosa,  unfoldable,  extendible, or  swellable systems  which  limits  emptying  of the  dosage  forms through  the  pyloric  sphincter of  stomach, super  porous hydrogel  systems, magnetic  systems  etc.  The  current review  deals  with  various  gastro retentive approaches that  have  recently  become leading  methodologies  in  the field   of   site-specific   orally administered   controlled release drug delivery systems.

The oral route is the most common way to administer medication. Traditional medicine delivery systems maintain drug concentrations within the therapeutic range only when taken multiple times a day, depending on the prescribed dosage schedule. This results in significant fluctuations in medication levels. Efforts to address these fluctuations have led to the development of various Novel Drug Delivery Systems (NDDS).

The goal of all drug delivery systems is to ensure that a therapeutic amount of medication reaches a specific site in the body at effective concentrations. Floating drug delivery systems are designed to keep the drug in the stomach, making them ideal for drugs with low solubility and poor stability in intestinal fluids. These systems work by making the dosage form less dense than gastric fluids, allowing it to float without affecting the rate of gastric emptying. Drugs with short half-lives that are easily absorbed in the gastrointestinal tract are quickly eliminated from the bloodstream. To address these challenges, oral drug delivery systems have been developed to release medication in the gastrointestinal tract over extended periods, maintaining a consistent drug concentration in the bloodstream.

Gastro-retentive dosage forms can remain in the gastric region for several hours, significantly increasing gastric retention time (GRT) to enhance bioavailability, reduce drug waste, and improve the solubility of poorly soluble drugs. Floating microbeads are hollow spherical particles without a core, with free-flowing particles ranging in size from 1 to 1000μm. These solid and free-flowing particulate carriers, which contain dispersed drug particles in either solution or crystalline form, enable sustained or multiple release profiles of treatments with various active agents while minimizing significant side effects. Furthermore, these microbeads remain effective under physiological conditions and can incorporate drugs for localized delivery at high concentrations, ensuring therapeutic levels are achieved at the target site while minimizing side effects by maintaining low systemic concentrations. ^3,4

Microbeads have a diameter of 0.5-1000 μm and are almost spherical in shape. Treatment with different active agents can be carried out with numerous release profiles or a sustained release with minimal adverse effects thanks to the solid and free-flowing particulate carriers that contain dispersed drug particles in crystalline or solution form. Furthermore, under physiological settings, the microbeads remain effective. They can also be modified to include medications and deliver them locally at high concentrations, ensuring that therapeutic amounts are achieved at the target site and minimising negative effects by maintaining low systemic concentrations. A variety of polymers, including cationic polymers like chitosan, anionic polymers like sodium alginate, and binding components like gelatin, chondroitin sulphate, and avid in, are combined in a present ratio to create the microbeads ^5,6. A typical method for creating controlled release dosage forms is microencapsulation. A method for producing polymeric gel beads using a controlled release formulation of various medicinal ingredients. The medicine is coated or encapsulated in the centre of the beads, which are distinct spherical microcapsules that function as a solid substrate. Drugs can be distributed more uniformly throughout the gastrointestinal tract and have sustained-release qualities thanks to beads. Additionally, medications packaged in beads have improved in terms of bioavailability. Alginate beads have been the subject of numerous reported investigations regarding its usage as a controlled release carrier⁷.

FLOATING SYSTEM

The floating drug delivery method is characterized by a bulk density lower than that of gastrointestinal (GI) fluids, allowing it to remain buoyant in the stomach for an extended period without affecting the gastric emptying rate. In this process, the material floats, delaying the release of the drug from the system at a critical rate, which increases the risk of bacterial invasion and ensures effective control of bacterial drug concentrations.

Classification of Floating Drug Delivery Systems

• Effervescent System

This system utilizes the production of carbon dioxide bubbles to enable the medication to float. It involves the use of carbonate or bicarbonate, which reacts with the stomach's natural acid or tartaric acid, leading to carbon dioxide formation.

1. Volatile Liquid Containing Device : This method includes a deformable device that expands from a collapsed state and then returns to its original form, maximizing the drug's delivery time.

2. Gas Producing Device: In this system, a medium is added to bicarbonate material in an acidic environment,

resulting in carbon dioxide formation, which reduces bulk density and aids in floating over GI fluids.

• Non effervescent System

In this system, the drug reacts with gastric fluids upon ingestion, causing it to swell, reduce its bulk density, and float over gastric fluids.

1. Micro Porous Compartment System: Here, the medication is placed within a porous micro compartment with pores on its top and bottom walls. The floatation chamber traps air, allowing gastric fluids to float.

2. Micro Balloon Floating: These are made of lightweight concrete or synthetic materials and have a hollow glass nature.

3. Colloidal Gel Barrier Device: This system features a hydro colloidal gel form that keeps the medication floating on gastric material.

4. Alginate Beads: This involves the generation of calcium alginate precipitate by dropping sodium alginate into an aqueous calcium chloride solution, creating a porous system that floats over gastric fluid for more than 12 hours.

5. Raft Forming Method (in situ gel formation): A gel forming polysaccharide polymer solution swells and forms a viscous gel trapped with CO2 bubbles, creating a raftlaye r on top of gastric fluid, allowing for the slow release of medication in the stomach.

The Advantages of microbeads include

1. Minimizing fluctuations within the therapeutic range.

2. Reducing side effects.

3. Lowering the frequency of dosing.

4. Enhancing bioavailability.

5. Improving patient adherence ⁸

 

The potential candidates for delivering gastro retentive medications

1. Drugs with a short absorption window in the GI tract, like furosemide.

2. Medications that act locally in the stomach, such as antacids and ulcer resistant drugs.

3. Drugs primarily absorbed in the stomach and upper GI tract, like calcium supplements.

4. Medications that break down in the colon, such as ranitidine HCl and metronidazole.

5. Drug s that disrupt normal colonic bacteria, like trihydrate amoxicillin.

6. Substances with poor solubility at high pH levels, such as diazepam ^{9, 10}

Drugs which are not suitable for gastro retentive delivery

1. Drugs with very limited acid solubility, like phenytoin.

2. Medications that are unstable in the stomach, such as erythromycin.

3. Drugs recommended for selective colon release, like corticosteroids ¹¹

Criteria for drug release kinetics

In a sustained-release system aim to deliver a drug at a rate that maintains a constant blood level. This means the delivery rate should be independent of the remaining drug in the dosage form and remain constant over time, ideally following zero-order kinetics. Although zero-order release is theoretically ideal, non-zero-order release rates can be clinically equivalent to constant release in many cases. To quickly achieve and maintain therapeutic levels, the dosage form typically consists of two parts: a loading dose and a maintenance dose. The loading dose is released immediately upon administration, characterized by a first-order kinetic process, to quickly reach therapeutic plasma levels. The remaining dose is released slowly and in a controlled manner to maintain constant plasma drug concentration, following zero-order kinetics. Thus, the release rate is independent of the remaining dose fraction. The controlled oral dosage form releases the maintenance dose at a rate matching the drug's elimination rate. ^12,13

Mechanism of floating microbeads

Involves interaction with stomach acid after administration. The outer layer of these microbeads contains polysaccharides and polymers that hydrate to form a colloidal gel barrier, regulating the movement of the drug and gastric fluid in and out of the microbeads. This membrane traps air molecules, reducing bulk density and allowing the microbeads to float on the gastric fluid surface. A minimal amount of gastric fluid is needed for the floatation of the dosage form in most cases. ¹⁴

Drug release from microbeads occurs through

1. EROSION

Some coatings can be designed to erode gradually with time, thereby releasing the drug contained within the particle. The polymer erosion, i.e. loss of polymer, is accompanied by accumulation of the monomer in the release medium. The erosion of the polymer begins with the changes in the microstructure of the carrier as the water penetrates within it leading to the plasticization of the matrix.

2. DIFFUSION

Rate limiting step is diffusion of drug through inert water-insoluble membrane barrier. In the case of a polymer matrix, the diffusion of the active ingredient can be through the intact polymer network or through the pores filled with water. Water-soluble drugs may also dissolve in the aqueous pore networks. Water uptake causes polymer chains to swell, indicating the formation of new pores and/or osmotic pressure. During swelling, the volume increases, the effective diffusion coefficient of the drug is increased, and more pharmacon molecules enter the aqueous part. The rate of release also depends upon where the polymer degradation by homogeneous or heterogeneous mechanism. The drug release depends on the rate of drug dissolution in the dissolution fluid, rate of penetration of dissolution fluid to the microbeads, and rate at which the dissolved drug escapes from the microbeads.

3. OSMOSIS

The osmosis mechanism involves water entering a semipermeable membrane due to osmotic pressure, dissolving an osmogen and the drug inside, creating pressure that forces the dissolved drug out through pores formed by water-soluble pore-formers leached from the coating, resulting in controlled, pH-independent drug release. This creates a microporous "osmotic pump," driving a steady flow of drug solution out as water continually enters. ^{15, 16, 17}

Techniques of Microbeads

3.1. Ionotropic Gelation Method

To begin cross-linking, an ionic polymer interacting with an oppositely charged ion is all that is required. The electroneutrality principle cannot fully account for the interaction of polyanion with cations, in contrast to simple monomeric ions. The capacity of cations to conjugate with anionic functions or vice versa is influenced by the three-dimensional structure and the presence of other groups ¹⁸. The ionotropic gelation technique has two sub-methods for producing beads. The cross-linking ion source varies throughout the approaches. One of the techniques places the crosslinker ion outside, whereas the other technique incorporates it inactively into the polymer solution. Two categories of ionortopic gelation methods exist:

3.2. External Gelation Method

As a source of the cross-linking ion in the external gelation process, a metal ion solution is employed. A needle is used to gently stir the drug-containing polymer solution before it is extruded into the mixture. Self-sustaining bead formation is the result of instantaneous gelation that takes place as soon as the polymeric drop comes into contact with the metal ion solution. Before being taken out and dried, the beads are cured for a predetermined amount of time in the gelation medium. The cross-linker ions diffuse quickly into the partially gelled beads, causing the external gelation to happen ¹⁹.

3.3. Internal Gelation Method

In the internal gelation process, the cross-linker ion is created "in situ." Using an insoluble metal salt (such calcium or barium carbonate) as a source of crosslinking cation is the technique used in this procedure. By decreasing the pH of the solution, the cation is liberated in situ along with the metal ion and the metal salt.

3.4. Emulsion Gelation Method 

Emulsion gelation procedures are another way to prepare microbeads. By dispersing the weighed amount of sodium alginate in deionized water, the sodium alginate solution was created. To obtain a homogenous drug-polymeric mixture, a precisely weighed quantity of drug was introduced to a polymeric solution of sodium alginate and the drug was magnetically agitated with low heat. A certain amount of cross-linking agent was added to create a viscous dispersion, which was then extruded into oil containing span 80 and 0.2% glacial acetic acid using a syringe fitted with a flat-tipped needle of size no. 23 while being stirred magnetically at 1500 rpm. To create stiff, distinct particles, the microbeads are left in the oil for thirty minutes. They were collected by decantation and the products thus separated was washed with chloroform to remove the traces of oil the microbeads were dried at 400ºC for 12 h.

3.5. Polyelectrolyte Complexation Method ²⁰

An additional technique for creating microbeads is the complex coacervation of polyelectrolytes with opposing charges, polycation and polyanion materials, and alginate-chitosan microcapsules that are biocompatible and biodegradable. These microcapsules can be produced in mild or even physiological conditions, making them appropriate for use in biomedical fields. The use of alginate–chitosan microcapsules as drug-delivery vehicles for proteins and polypeptides has drawn more attention in recent years. Using this technique, the mixture will split into a dilute equilibrium phase and a dense coacertive phase that contains the microbeads, depending on the pH, ionic strength, and polyion concentration. By spraying the sodium alginate solution into the chitosan solution, for instance, complicated coacervation between alginic acid and chitosan was accomplished, resulting in robust microbeads that remained stable over a wide pH range. The optimal yield when using coacervative beads requires preparation conditions of pH 3.9, ionic strength of 1 mM, and total polyion content of 0.15% w/v.

POLYMERS USED FOR THE PREPARATION OF MICROBEADS ^20,21,22

Various biodegradable and non-biodegradable materials have been explored for creating microbeads. These include both natural and synthetic polymers, as well as modified natural substances. Examples of such polymers are Albumin, Gelatin, Sodium alginate, Chitosan, Starch, Dextran, Polylactide, Polyglycolide, Polyanhydride, and Polyphosphazene, among others. Sodium alginate microbeads are a type of multi-particulate drug delivery system designed to achieve prolonged or controlled drug release, enhance bioavailability or stability, and target specific sites for drug delivery. Multi-unit dosage forms like microspheres or beads have become popular as oral drug delivery systems due to their more uniform drug distribution in the gastrointestinal tract, consistent drug absorption, reduced local irritation, and prevention of unwanted intestinal retention of polymeric material compared to non-disintegrating single-unit dosage forms.

1. Alginates

Alginates are natural polysaccharide polymers derived from brown seaweed (Phaeophyceae). Alginic acid can be transformed into its salts, with sodium alginate being the most commonly used form. Alginates have various applications in drug delivery, such as in matrix-type alginate gel beads, liposomes, modulating gastrointestinal transit time, local applications, and delivering biomolecules in tissue engineering. The bioadhesive properties of alginates make them valuable in the pharmaceutical industry. Sodium alginate-based drug delivery systems have numerous applications and can be formulated as gels, matrices, membranes, nanospheres, microspheres, and microbeads, among others.

Alginate beads can be administered by encapsulating them in capsules or compressing them into tablets. A novel approach in the pharmaceutical field involves developing alginate polymer systems that can adjust drug release according to physiological needs (e.g., pH-responsive systems based on polymer swelling, magnetically triggered delivery systems). Alginate also has the physicochemical properties necessary to be a significant contributor to future research in this area.

2.Chitosan

Chitosan is a cationic natural polysaccharide derived from the chitin of crustaceans, with crab and shrimp shell waste as its primary source. Its properties, including the degree of deacetylation and average molecular weight, along with low toxicity and good bioavailability, make it a novel excipient in pharmaceutical formulations as a relatively new development. Chitosan is a biopolymer that can be used to prepare various polyelectrolyte complex products with natural polyanions like xanthan, alginate, and carrageenan. Many formulations have recently been developed and evaluated in different dosage forms, such as ophthalmic, nasal, sublingual, buccal, periodontal, gastrointestinal, colon-specific, vaginal, transdermal, and as gene carriers, based on the application of chitosan and its derivatives.

EVALUATION OF FLOATING MICROBEADS ^23-26

1. Particle Size: The size of the microbeads was assessed using an optical microscope. The average size was calculated by measuring 100 particles with a calibrated ocular micro-meter.

2. Bulk Density: Bulk density is calculated as the mass of the powder divided by the bulk volume, expressed in gm/cm3.The formula for Bulk Density is Sample Weight / Sample Volume.

3. Tapped Density: Tapped density can be measured using a tapping method. After 100 and 1000 taps with a tapped density apparatus, the volume of the weighed microbeads was recorded. Tapped Density is calculated as Sample

Weight/ Volume Tapped.

4. Hausner Ratio: The compressibility index and Hausner ratio were derived from the bulk and tapped density values.The Compressibility Index percentage is calculated as (Tapped density -Bulk density) / Tapped density.

The Hausner Ratio is Tapped Density / Bulk Density.

5. Angle of Repose: The angle of repose, which indicates the resistance to particle flow, was measured using the formula tan θ = h/r, where θ is the angle of repose, h is the height of the pile, and r is the radius of the pile.

6. Percentage Yield: The percentage yield of floating microbeads was calculated by dividing the actual weight of the product by the total weight of the components used in the preparation of the floating microbeads.

The formula is % yield = (Actual weight of product / Total weight of drug and excipients) × 100.

7. Surface Morphology: The SEM sample was prepared by coating a mixture of gold and palladium, with a thickness of 250-450 Å, under an argon atmosphere in a high vacuum evaporator at 20KV, 10mA, and low pressure. The powder was spread on an aluminium stub coated with the content for photomicrographs.

8. Drug Entrapment Efficiency (DEE):The drug entrapment efficiency was determined by repeatedly crushing the microbeads and extracting them with aliquots of 0.1NHCl. The extract was transferred to a 100 ml volumetric flask, and the volume was adjusted with 0.1N HCl. The solution was filtered, and its absorbance was measured against a blank using a spectrophotometer.

The Drug Entrapment percentage is calculated as (actual drug content / theoretical drug content) ~10 percent

9. Swelling index: The experiment involved immersing microspheres of a known weight in 0.1 N HCl at a temperature of 37 ± 0.5 °C for a designated period. The microbeads were allowed to expand and were extracted at different time intervals. Swelling Ratio = Weight of Wet Formulation / Weight of Formulation

10. Buoyancy Analysis: Microbeads were placed on the surface of a type II USP dissolution apparatus containing 900 ml of 0.1 N HCl with 0.02 percent between 80 and 20. The medium was stirred for 12 hours with a paddle rotating at 100 rpm. The floating and settled portions of the microbeads were collected separately. They were dried and weighed.

Percentage buoyancy = Wf/ (Wf+Ws) x 100

Where, Wf represents the Floating Weight, and Ws represents the Settled Microbeads, respectively.

11. In-vitro Drug Release Studies: This study utilized USP dissolution devices operating at a specific speed. Distilled water and dissolution fluid were maintained at 37±0.5°C. The dissolution test was performed using 900mL of 0.1N HCl dissolution medium at 100 rpm for the required duration. Samples were taken at regular intervals, and the same volume of fresh medium was added to maintain spectrophotometrically analyzed sink conditions.

APPLICATIONS OF FLOATING MICROBEADS ^27-30

FDDS is particularly useful for drugs with low bioavailability due to the limited absorption window in the upper part of the GIT.

1.Sustained Drug Delivery

These systems have a bulk density of less than 1, allowing them to float on gastric contents. Their larger size and shape prevent them from passing through the pyloric opening.

2.Site-Specific Drug Delivery

Floating microbeads can greatly improve abdominal pharmacotherapy by releasing drugs locally, resulting in high concentrations in the gastric mucosa. This helps eliminate Helicobacter pylori from the submucosal tissue and facilitates the treatment of gastritis, stomach, and duodenal ulcers.

3.Absorption Enhancement

They are effective in delivering drugs that are poorly soluble or insoluble. As drug solubility decreases, the time available for drug dissolution becomes limited, making transit time a crucial factor affecting drug absorption.

4.As Carriers

These agents, including antiviral, antifungal, and antibiotic substances, serve as carriers for drugs with specific absorption windows, which are absorbed only at certain locations in the GI mucosa.

5.Maintaining Consistent Blood Levels

This system offers a convenient method to maintain steady blood levels, simplifying administration and enhancing patient compliance.

CONCLUSION

Floating microbeads represent a promising and effective approach in gastro-retentive drug delivery systems for improving the therapeutic performance of orally administered drugs. By prolonging gastric retention time and enabling controlled drug release, these systems enhance drug absorption, improve bioavailability, and maintain consistent plasma drug concentrations. The use of biodegradable polymers such as alginate and chitosan further contributes to the safety and effectiveness of these delivery systems. Various preparation techniques and evaluation parameters ensure the production of microbeads with desirable characteristics such as adequate buoyancy, high drug entrapment efficiency, and sustained release behaviour. Due to their ability to provide site-specific delivery, reduced dosing frequency, and improved patient compliance, floating microbeads have gained considerable attention in pharmaceutical research. Continued advancements in polymer science and formulation techniques are expected to further expand the potential applications of floating microbeads in targeted and controlled drug delivery.

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