The oral method of drug administration has received the most focus out of all the routes of drug administration. Administering oral dosage forms with ease allows for greater flexibility in their design compared to many other options and different pathways that have led to the success of administering drugs orally. In order to enhance the predictability and increase the availability of drugs, short gastric residence times and unpredictable gastric emptying must be considered.
Challenges posed by digestion, metabolism, and various bodily conditions must be addressed. This led to the development of prolonged gastric residence time in oral controlled drug delivery systems. This is especially crucial for medications that have an absorption window in the stomach and duodenum, as well as for medications with stability issues.¹  The gastro-retentive dosage form is one of the most preferable methods since one of the goals is to control the time spent in the stomach and thus achieve an extended and predictable drug delivery in the intestinal tract. These are mainly long acting; time released drug delivery systems which are also drug controlled. Therefore, employing this dosage form in the target area of the GI tract is beneficial especially for specializing the drug which targets the window of GI tract absorption.²

Basic GIT physiology³

The stomach is anatomically separated into three regions: the fundus, body, and antrum (pylorus). While the antrum is the primary location for mixing motions and serves as a pump for stomach emptying through pushing activities, the proximal portion, which is composed of the fundus and body, serves as a reservoir for undigested materials. Both when fasting and when eating, the stomach empties.

Phase 1 (Basic phase), which lasts 30 to 60 minutes and has occasional contractions.

Phase 2, also known as the pre-burst phase, lasts 20 to 40 minutes and is characterized by periodic contractions and action potentials.

Phase 3, the third phase, known as the burst phase, lasts 10 to 20 minutes and is characterized by brief, strong contractions.

Phase 4: Between phases 2 and 1 of two consecutive cycles, phase 4 lasts for 0–5 minutes.

       
           
       
 Figure.2.-Gastrointestinal motility pattern

Suitable Drug Candidates for Gastroretention⁴

Generally speaking, molecules with poor colonic absorption but superior absorption qualities at the higher regions of the GIT make good candidates for GRDDS.

• Drugs which are absorbed from the proximal part of gastro-intestinal tract(GIT)
• Drugs that are majorly absorbed from stomach and upper part of GIT
• Drugs which are less soluble or are degraded by alkaline pH.

Different approaches of the GRDDS⁵

Several strategies have been tried to improve oral dosage forms' stomach retention. While some are designed as multicomponent dosage forms, others are made as single components. GRDDS can be broadly divided into two types: floating and non-floating systems.

A. Non-floating system: These gastro-retentive drug delivery systems are retained in the stomach through a variety of mechanisms, but they do not float there. The non-floating system is further separated into:

1. High density (sinking) drug delivery system
2. Bioadhsive or mucoadhesive system

c. Magnetic system

d. Unfoldable system

B. Floating system: Unlike high density drug delivery systems, FDDSs have a density lower than the gastric contents, which allow them to stay buoyant in the stomach for an extended amount of time without affecting the gastric contents. Floating Drug Delivery Systems (FDDS) is a method devised to extend the gastric residence time of dosage forms. FDDS is beneficial for medications that work within the proximal gastrointestinal tract and has a lower bulk density compared to gastric fluids, allowing it to float in the stomach for an extended duration without impacting stomach emptying(5). Figure 1 illustrates the mechanism of floating of the floating drug delivery system (FDDS), also known as a low density system

1. 1. Effervescent system
   2. Non-effervescent system
      1. Hydrodynamically balanced system
      2. Microbaloons or hollow microspheres
      3. Alginate beads
      4. Microporous compartment

       
           
       
Figure 5. Different types of gastro-retentive drug delivery system.

Microballoons

Due to the center hollow region inside the microsphere, microballoons are regarded as one of the most advantageous buoyant systems, offering the special benefits of multiple unit systems together with improved floating capabilities. Simple solvent evaporation, emulsion-solvent diffusion, single and double emulsion techniques, phase separation coacervation techniques, polymerization techniques, spray drying and spray congealing techniques, and hot melt encapsulation techniques are some of the innovative methods used in their preparation. The kind of polymer, plasticizer, and solvents used in the preparation process primarily determine the gradual release of medications at the appropriate rate and improved floating qualities. Hollow microspheres are made from polymers such polylactic acid, Eudragit S, hydroxypropyl methylcellulose, and cellulose acetate and the polymer-plasticizer ratio and polymer concentration can be modified to control the drug's release.

Mechanism of Flotation of Microballoons⁷

Because of their low density and adequate buoyancy, Microballoons can float above gastric fluid and stay in the stomach for an extended amount of time. Increased gastric retention and less variation in plasma drug concentration are the results of the drug being released gradually at the desired rate while the system floats over the stomach fluid. A colloidal gel barrier that regulates the pace of fluid penetration into the device and, in turn, the release of drugs is created when microballoons come into contact with gastric fluid. The hydration of the nearby hydrocolloid layer keeps the gel layer intact as the dosage form's outer surface dissolves.  The air that the expanded polymer traps lowers the density compared to the stomach juice, giving the microspheres buoyancy. A small amount of stomach content is necessary, though, in order to achieve buoyancy.If the mucoadhesive qualities of the particles have not been altered by the stomach contents, specifically non-adherent mucus, adherence to the stomach wall will be achievable during the emptying process in both fed and fasted states. The most recent developments include Gelucire floating granules, acrylic resin hollow microspheres (microballoons), Eudragit, hypromellose, polyethylene oxide, cellulose acetate, polystyrene floatable shells, and polycarbonate floating balloons.

The following mechanisms can lead to drug release from microballoons:

Diffusion: Drug diffusion begins as gastrointestinal fluid is absorbed to the interior of the drug delivery system, which is followed by dissolution of the drug and slow release from the delivery system to the exterior by diffusion mechanism.

Erosion: The drug contained within the particle can be released when certain coatings are made to erode progressively over time,there by the drug action may be sustained.

Osmosis: osmotic pressure is built on uptake of water within the drug delivery system, by suitable means, which pushes the drug out of delivery system in a sustained manner.

 Advantages⁸

1. By reducing the frequency of doses, it enhances patient compliance,
2. Due to variations in drug plasma, bioavailability improves even with the first pass effect,
3. Avoiding concentration, continuous medication release maintains a desired plasma drug concentration,
4. Due to buoyancy, the gastric retention duration is prolonged,
5. More effective absorption of medications that dissolve solely in the stomach,
6. Controlled drug releases over an extended length of time,
7.  Site-specific drug delivery to stomach can be possible,
8.  Better than single unit floating dosage forms,microballoons distribute the medicine equally and eliminate the possibility of dose dumping,
9. Gastric irritation can be avoided due to the extended release action,
10. Better therapeutic effect can be achieved for drugs with short half-life.

Disadvantages⁸

1. FDDS is not an appropriate candidate for drugs that irritate the stomach mucosa.For instance, digoxin, theophylline, corticosteroids, iron (ferrous sulfate), oral contraceptives, tricyclic antidepressants, NSAIDs, and some antibiotics,
2. Drugs that undergo first-pass metabolism and are absorbed throughout the GIT, such as Nifedipine, may not be desirable.
3. They are also not favorable candidates for drugs that have stability or solubility issues in the stomach.For example Ranolazine  
4. The "all or none concept" that is connected to single unit floating capsules or tablets can be avoided by creating multiple unit systems, such as floating microballoons or microballoons.

Factors impacting gastric retention^9,10,11

Size of the dosage form

Gastric retention is significantly impacted by the dosage form's size. The GRT was longer for dosage forms with a diameter more than 7.5 mm than for those with a diameter of 9.9 mm.

Shape of the dosage form

One crucial element to take into account while creating a dosage form is its shape. With a 24-hour GRT of 90–100%, ring- and tetrahedron-shaped devices function better than other types in terms of stomach retention.

Density of a dosage form

When it comes to gastroretention, a dosage form's density matters. In gastric fluids, dose forms with a lower density than the contents of the stomach may float, allowing for gastroretention. Conversely, high-density systems have a propensity to sink to the bottom of the stomach. The drug or treatment is effectively separated from the pylorus by both dosage schedules.
Nature of food intake

The kind of food ingested has a significant impact on gastroretention. The calorie content, feeding frequency, meal viscosity, and meal volume all affect dosage form retention. In general, gastroretention is prolonged when food is present. For instance, a substantial breakfast rich in lipids and proteins might increase gastroretention by 4–10 hours. Fatty acid salts or indigestible polymers can alter the stomach's motility pattern to a fed condition, extending the duration of medication release and lowering the rate of stomach emptying. GRT can be increased
by four to 10 hours with a meal that is high in proteins and fats

Gender, posture, and age

Compared to men, women often have slower stomach emptying rates.GRT is not much different between upright, ambulatory, and supine positions. Gastric emptying slows down in the elderly.

Single or multiple unit formulation

Comparing multiple unit formulations to single unit dosage forms, the former allow co-administration of units with different release profiles or containing incompatible substances, allow a larger margin of safety against dosage form failure, and demonstrate a more predictable release profile with negligible performance impairment due to unit failure.

Fed or unfed state

GI motility during fasting is typified by bursts of vigorous motor activity or the migration of the myoelectric complex (MMC), which happens every 1.5 to 2 hours. If the timing of the formulation's administration aligns with that of the MMC, the unit's GRT should be extremely brief as the MMC removes undigested material from the stomach. However, MMC is delayed and GRT is significantly longer in the fed condition.

Feed frequency

Because of the low frequency of MMC, giving consecutive meals instead of a single meal can result in a GRT rise of more than 400 minutes.

Concomitant drug administration

Anticholinergics like Atropine and Propantheline, Opiates like Codeine and Prokinetic agents like Metoclopramideand Cisapride.

Biological factors – Diabetes and Crohn’s disease.

Materials for Preparation of Microballoons^12,13

Drugs
Drugs with narrow therapeutic window in GI tract, mainly absorbed from stomach and upper part of GIT, locally act in the stomach, degrade in the colon, disturb normal
colonic bacteria. E.g. Aspirin, Salicylic acid,Ethoxybenzamide, Indomethacin and Riboflavin, Para amino benzoic acid, Furosemide, Calcium supplements, Chlordiazepoxide, Scinnarazine, Riboflavin, Levodopa,Antacids, Misoprostol, Ranitidine HCl, Metronidazole and Amoxicillin trihydrate.

Polymers
Cellulose acetate, chitosan, eudragit, acrycoat, methocil, polyacrylates, polyvinyl acetate, carbopol, agar, polyethylene oxide, polycarbonates, acrylic resins and polyethylene
Solvents
It should have good volatile properties, so that it should easily come out from the emulsion leaving hollow microspheres eg ethanol, dichloromethane (DCM),acetonitrile,acetone, isopropyl alcohol(IPA),dimethylformamide (DMF).

Processing Medium

It is used to harden the drug polymer emulsified droplets when the drug polymer solution is poured into it, should not interact with the former; mainly used processing medium are liquid paraffin, polyvinyl alcohol and water.

Surfactant
They are stabilizers or emulsifiers, play the role of hardening the microspheres as well. E.g. tween 80, span 80 and SLS.

Cross linking agent

Chemical cross-linking of microspheres can be achieved using cross linking agents such as formaldehyde,glutaraldehyde or by using di acid chlorides such as terephthaloyl chloride. The method is limited to drugs that do not have any chemical interaction with the cross-linking agent.

Hardening agent

This helps to harden the microspheres formed in the processing medium eg n-hexane, petroleum ether (in case the processing medium is liquid paraffin)

Table 2: Components needed to prepare Micro balloons¹²

Development¹⁴

Floating microspheres are non-effervescent, gastro-retentive drug delivery methods. In the strictest sense, hollow microspheres are spherical, coreless particles. These microspheres, which are ideally smaller than 200 micrometers, are characterized as free-flowing powders made of proteins or synthetic polymers. The use of solid biodegradable microspheres with a drug dissolved or disseminated throughout the particle matrix may allow for controlled drug release. Microballoons are often made using straightforward solvent evaporation or solvent diffusion/evaporation procedures. Eudragit S, polycarbonate, cellulose acetate, Agar, low methoxylated pectin, and calcium alginate are frequently utilized as polymers. The amount of polymer, the plasticizer–polymer ratio, and the solvent utilized all affect buoyancy and drug release. The medication is either dissolved or dispersed in the polymer solution after the polymer is dissolved in an organic solvent. To create an oil in water emulsion, the drug-containing solution is subsequently emulsified into an aqueous phase that contains polyvinyl alcohol. The organic solvent is removed once a stable emulsion has formed, either by stirring constantly or by raising the temperature under pressure. Polymer precipitation results from the solvent removal at the o/w interface of droplets, creating a cavity and making them hollow to give them the ability to float.¹⁵

Method of preparation

Solvent Evaporation Method¹⁶

Among the polymers used in the development of these systems include ethyl cellulose, HPMC KM4, and Eudragit. To create a homogenous polymer solution, polymers are combined with drugs and then dissolved in ethanol, acetone, or dichloromethane, either alone or in combination. Pouring the resultant solution into 100 milliliters of liquid paraffin while it rotates at 1500 rpm. After three hours of heating to 35°C, the emulsion is created. The acetone or dichloromethane is totally evaporated once a stable emulsion has formed, and the resulting solidified microspheres are then filtered through Whattman filter paper. The floating and sustained properties are attributed to these hollow microspheres.

This technique involves adding a polymer and drug solution in ethanol, methylene chloride, to an agitated polyvinyl alcohol aqueous solution. The ethanol quickly separates into the external aqueous phase, and the polymer precipitates around the methylene chloride droplets. When trapped methylene chloride evaporates, internal cavitis are created inside the microparticles.

The primary steps in this procedure are as follows:

Step 1: A coating polymer solution is used to spread the core material.

Step 2: In the liquid manufacturing vehicle phase, the coating is achieved by carefully combining the coating solution and core material.

Step 3: Use the following techniques to solidify the coated polymer.

1. Thermal Change:

 At 80 ºC, the polymer is vigorously stirred to dissolve it in cyclohexane. The drug is then added to the aforementioned solution while being constantly stirred. The microsphere is produced by putting it in an ice bath to lower the temperature. After being twice cleaned with cyclohexane, the product is allowed to air dry.

2. Non-Solvent Addition:

First, the drug is distributed throughout a closed beaker filled with toluene and propyl isobutylene after the polymer has been dissolved in it for six hours at 500 rpm. With constant stirring, the resulting solution is added to benzene. The microcapsules are allowed to air dry for two hours after being cleaned with n-hexane.

3. Polymer addition

Methylene blue is used as a core material after the polymer (ethylcellulose) is dissolved in toluene to create microspheres. The addition of liquid polybutadiene achieves coacervation. Hexane is added as a nonsolvent to solidify the polymer covering. After that, the final product is cleaned and allowed to air dry.

4. Salt addition

Corn oil is used to dissolve the oil-soluble vitamin, which is then added to the    gelatin solution at 50ºC. Adding sodium sulphate causes coacervation, which gives the gelatin a consistent coating. After being gathered, the microspheres are cleaned, refrigerated, and dried.

The medication is introduced while the polymer solution is being homogenized at a high speed. When upward dispersion in a hot air stream is atomized, tiny droplets or fine mist are created. Rapid solvent evaporation creates microspheres that range in size from 1 to 100 ?m. It uses a cyclone separator to separate the microspheres from the heated air. The ability to operate in aseptic circumstances, which results in the quick and porous creation of microparticles that can be employed for poorly soluble medications, is a significant benefit of this process.

Spray drying: - The coating solidification can be done by rapid evaporating of solvent in which coating material is dissolved

Spray congealing: - The coating solidification can be done by thermally congealing a molten coating material. The removal of solvent is done by sorption, extraction or evaporation