INTRODUCTION:

The goal of any delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve on time and then maintain a preferred drug concentration. Oral drug delivery system is the oldest and most acceptable route of drug delivery due to the patient compliance, ease of administration, and flexibility in formulation¹.

Many orally administered drugs display poor bioavailability when administered as a conventional dosage form, i.e. the rate and extent to which the drugs are absorbed is less than desirable to compensate for this effect, a very large dose is often administered so that absorption of therapeutically required quantity of drug can occur. This technique may prove costly with expensive drugs; and the absorbed drug may also have undesirable side effects within the gastrointestinal tract. This problem may be overcome by a modified release drug delivery system with prolonged residence time in the stomach²Gastro retentive drug delivery system (GRDDS) is thus beneficial for such drugs by improving their bioavailability, therapeutic efficacy and by possible reduction of dose. Drug absorption in the gastrointestinal tract is depends upon the factors such as site of absorption of drugs, drug release from the dosage, gastric emptying process and gastrointestinal transit time of dosage forms^3,4 Drugs that are easily absorbed from the gastrointestinal tract (GIT) and have short half-lives are eliminated quickly from the systemic circulation. To achieve suitable therapeutic activity frequent dosing of these drugs is required. Also, the drugs which have a narrow absorption window (NAW) in the upper part of GIT are not suitable for oral sustained release drug delivery system due to the brief gastric emptying time as tablets have 2.7±1.5 hours (h) stomach transit and 3.1± 0.4 h intestinal transit time⁵ thus the bioavailability of such drugs in stomach is generally limited.

To prolong gastric residence time Gastro retentive drug delivery is one of the best approaches, thereby targeting site specific drug release in the stomach for local or systemic effects. These dosage forms can stay behind in the gastric region for extended periods and hence considerably prolong the gastric retention time of the drugs. It will release the drug in stomach in a controlled manner, so that the drug could be supplied constantly to absorption site in GIT i.e. stomach⁶

Need for GRDDS:

· Conventional oral delivery is widely used in the pharmaceutical field to treat diseases. However, conventional delivery had many drawbacks and major draw-back is non-site specificity.

· Some drugs are absorbed at specific sites only. They require release at a specific site or a release such that the greatest amount of drug reaches to the specific site.

· Pharmaceutical field is now targeting towards such drugs which require site specificity

· Gastro-retentive delivery is one of the best site specific delivery for the delivery of drugs either at stomach or at intestine. It is obtained by retaining dosage form into stomach and drug is being released at controlled manner to specific sites either in stomach, duodenum and intestine.^7,8

Merits:

· It delivers the drugs with a narrow absorption window in the small intestine region.

· Longer residence time in the stomach might be advantageous for local action in the upper part of the small intestine, for example treatment of peptic ulcer disease.

· Improved bioavailability is expected for drugs that are absorbed readily upon release in the GI tract such as cyclosporine, ciprofloxacin, ranitidine, amoxicillin, captopril etc.

· Patient compliance by making a once a day therapy.

· Improved therapeutic efficacy.

· Reduces frequency of dosing.

· Targeted therapy for local ailments in the upper GI tract.

· The bioavailability of therapeutic agents can be significantly enhanced especially for those which get metabolized in the upper GIT by this gastro retentive drug delivery approach in comparison to the administration of non gastro retentive drug delivery.

· Gastro retentive drug delivery can produce prolonged and sustained release of drugs from dosage forms which avail local therapy in the stomach and small intestine. Hence they are useful in the treatment of disorders related to the stomach and small intestine.

· Gastro retentive drug delivery can minimize the counter activity of the body leading to higher drug efficiency.

· Prolongs the residence time of the dosage form at the site of absorption.

· To avoid the first pass metabolism.

· Excellent accessibility.

· Rapid absorption because of enormous blood supply and good blood flow rates.

· Increase in drug bioavailability due to first pass metabolism.

· Site-specific drug delivery.

· Minimizing mucosal irritation by drugs, by drug releasing slowly at a controlled rate.

· Minimizing mucosal irritation by drugs, by drug releasing slowly at a controlled rate.^9,10

Demerits:

· Floating systems have limitations, that they require a high level of fluids in the stomach for floating and working efficiently. So more water intake is prescribed with such a dosage form.

· In supine posture (like sleeping), floating dosage form may be swept away (if not of larger size) by contractile waves. So patients should not take floating dosage form just before going to bed.¹¹

Ideal drug candidates for Gastro retentive Drug Delivery Systems

· Drugs that are locally active in the stomach e.g misoprostol, antacids etc.

· Drugs that have narrow absorption windows in gastrointestinal tract (GIT) e.g. L-DOPA, para aminobenzoic acid, furosemide, riboflavin etc.

· Drugs those are unstable in the intestinal or colonic environment e.g. captopril, ranitidine HCl,

· Drugs that disturb normal colonic microbes eg.antibiotics against Helicobacter pylori.

· Drugs that exhibit low solubility at high pH values e.g. diazepam, chlordiazepoxide, verapamil HCl.¹²

Unsuitable Drugs candidate for Gastro retentive Drug Delivery Systems:

· Drugs that have very limited acid solubility e.g. phenytoin.

· Drugs that suffer instability in the gastric environment e.g. erythromycin.

· Drugs intended for selective release in the colon. eg. 5- amino salicylic acid and corticosteroids etc.

· solubility in acidic environment and drugs causing irritation to gastric mucosa cannot be incorporated into GRDDS¹³

Factors affecting on gastric retention:

1. Volume of meal: The larger the bulk of meal, the longer will be the gastric emptying time.

2. Composition of meal: Fats promote the secretion of bile, which has an inhibitory effect on gastric emptying time.

3. Physical state of food and dosage form: Viscous material empty slowly than less viscous materials.

4. Exercise: Retards gastric emptying time.

5. Emotion: Stress and anxiety promotes gastric motility whereas depression retards it.

6. Circadian rhythms: Cardiac rhythms are increased in day time and less during night also affect the gastric retention time.

7. Size of the dosage form: Greater the energy content of meal (carbohydrate and high fat content), longer the duration of emptying.

8. Density of oral dosage form: The density of gastric fluid is reported to be 1.2g/cm. The density of the dosage form should be less than this for buoyancy so that it is retained in the stomach for a longer period of time.

9. Diseased state: state of the stomach also affects the environment for the dosage form as in case of ulcers, flatulence and spasms.

10. Drug therapy: It also plays an important role in gastric emptying e.g. prokinetic drugs like cisapride and mosapride increase gastric emptying time whereas imipramine and atropine retards it.

11. Age: Increase in age decreases gastric motility there by increasing the gastric emptying time.

12. Posture: Gastric emptying is favored while standing and by lying on right side since normal curvature of the stomach provides a downhill path whereas lying on the left side or in supine position retards it.^14,15

Approaches used in GRDDS:

Floating systems:

Floating systems are low density systems that have sufficient buoyancy property to float over the gastric contents and remain in the stomach for a extended period, While the floating system floats over the gastric contents in GIT & the drug started to release slowly at the desired rate .Which results in increased GRT and reduces fluctuation in plasma drug concentration. gel forming hydrophilic polymers are used in floating system such as Hydroxy propyl methyl cellulose (HPMC), hydroxyethylcellulose (HEC), hydroxyl propyl cellulose (HPC), sodium carboxymethyl cellulose etc.^16,17 Ershad S.et al.(2013) prepared Floating microspheres of Ritonavir by ionic gelation method with an aim of increasing the gastric residence time and for controlled release. Sodium alginate, polymeric mixture of Sodium alginate and Guar Gum were used as polymers. Sodium bicarbonate was used as the gas-forming gent.^18,19

Effervescent systems:

In this system gas can be introduced into the floating chamber by the volatilization of an organic solvent (e.g., ether or cyclopentane) or by the CO2 produced due to this an effervescent reaction occurs between organic acids and carbonate–bicarbonate salts. These devices contain a deformable hollow unit that converts collapsed from to an expanded position and returns to the collapsed position after a programmed amount of time to permit the spontaneous ejection of the inflatable system from the stomach. after the mixing of Drug and excipients independently,s the gas generating unit can be incorporated into any of the layers. Further refinements involve coating the matrix with a polymer which is permeable to water, but not to CO2²⁰.

Fig No.1Floating effervescent system

Non Effervescent systems:

Non Effervescent systems containgelforming, highly swellable, cellulosic hydrocolloids like HEC, HPC, HPMC, and NaCMC etc., polysaccharides, or matrix forming polymers like polycarbophil, polyacrylates, and polystyrene etc.into tablets or capsules. When it comes into contact with gastric fluid, these gel formers, polysaccharides, and polymers hydrate and form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer lowers the density of and confers buoyancy to the dosage form.²¹

Bio/mucoadhesive systems:

Bio/mucoadhesive systems bind to the gastric epithelial cell surface, or mucin, and extend the GRT by increasing the closeness and duration of contact between the dosage form and the biological membrane. The epithelial adhesive properties of mucin are well known and have been applied to the development of GRDFS through the use of bio/mucoadhesive polymers. The adherence of the delivery system to the gastric wall increases residence time at a particular site, thereby improving bioavailability.²²Different theories are invoked to explain these mechanisms. Firstly, the electronic theory proposes attractive electrostatic forces between the glycoprotein mucin network and the bioadhesive material. Secondly, the adsorption theory suggests that bioadhesion is due to secondary forces such as Vander Waals forces and hydrogen bonding. Third the wetting theory is based on the ability of bioadhesive polymers to spread and develop intimate contact with the mucus layers, and finally, the diffusion theory proposes physical entanglement of mucin strands and the flexible polymer chains, or an interpenetration of mucin strands into the porous structure of the polymer substrate. Materials commonly used for bioadhesion are poly (acrylic acid) (Carbopol\, polycarbophil), chitosan, cholestyramine, tragacanth, sodium alginate, HPMC, sephadex, sucralfate, polyethylene glycol, dextran, poly (alkyl cyanoacrylate) and polylactic acid. Navneetha K.et al. (2016) Formulate bioadhesive microsphere containing Methylprednisolone using Sodium alginate along with Methocel, Carbopol l971, and pectin as copolymers.²³

Fig No.2: Mucoadhesive system

Swelling systems:

These polymeric matrices remain in the gastric cavity for several hours even in the fed state.²⁴ The swollen system eventually will lose its integrity because of a loss of mechanical strength caused These systems are sometimes referred to as plug type systems because they tend to remain lodged at the pyloric sphincter. After being swallowed, these dosage forms swell to a size that prevents their passage through the pylorus. As a result, the dosage form is retained in the stomach for a long period of time by abrasion or erosion or will burst into small fragments when the membrane ruptures because of continuous expansion. These systems also may erode in the presence of gastric juices so that after a predetermined time the device no longer can attain or retain the expanded configuration

High-density systems:

These systems, which have a density of ~3g/cm, are retained in the rogue of the stomach and are capable of withstanding its peristaltic movements. Above a threshold density of 2.4–2.8g/cm³, such systems can be retained in the lower part of the stomach. If this phenomenon is confirmed by clinical studies, these heavy pellet formulations may appear on the market in the near future. The only main drawbacks with such systems is that it is technically difficult to manufacture them with a large amount of drug (>50%) and to achieve the required density of 2.4–2.8g/cm³. Diluents such as barium sulphate (density=4.9), zinc oxide, titanium dioxide, and iron powder must be used to manufacture such high density formulations²⁵

Fig No.3: high density system

Hydrodynamically Balanced systems:

It is single-unit dosage forms, containing one or more gel-forming hydrophilic polymers. Mechanism involves Continuous erosion of the surface allows water penetration to the inner layers, maintaining surface hydration and buoyancy.²⁶

Magnetic System:

In this system a small magnet is contained in the center of the magnetic tablet. After administration, an external magnet outside the body can be used to keep the tablet in stomach if it is placed in the correct position.²⁷

Fig No. 4: Magnetic system

Raft-forming systems:

The mechanism concerned within the raft formation is that this raft floats on viscous fluids owing to low bulk density created by the formation of carbon dioxide. This system contains carbonates to blame for the formation of carbon dioxide that build the system less dense and float on the viscous fluids. A raft forming formulation requires sodium carbonate, potassium bicarbonate and Calcium carbonate can be used as an alkalizing agent and raft strengthening agent. Alginic acid, alginates, pectin are the most widely used raft forming agents. Various polymers have been used such as carrageenan, isabgol, Xanthan gum, locust bean gum, guar gum etc. Poorve Bhatt et. al. formulate gastro retentive chewable tablet by raft approach using Gallic acid which is used as Antioxidant.^28-31

Fig no.5: Raft forming system

List of Drugs Explored for Various Floating Dosage Forms³²

1. Microspheres Tablets/Pills: Chlorpheniramine maleate, Aspirin, Griseofulvin, Terfenadine, Acetaminophen, p nitroaniline, Acetylsalicylic acid, Ibuprofen, Amoxycillintrihydrate, Ampicillin, Tranilast, Atenolol, Theophylline, Captopril, Isosorbide Dinitrate, Sotalol, Isosorbide Mononitrate

2. Films: P-Aminobenzoic acid, Cinnarizine, Prednisolone, Quinidine, gluconate.

3. Granules: Cinnarizine, Diclofenac sodium, Diltiazem, Indomethacin, Fluorouracil, Prednisolone, Isosorbide Mononitrate, Isosorbide Dinitrate.

4. Powders: Riboflavin phosphate, Sotalol, Theophylline

5. Capsules: Verapamil HCl, ChlordiazepoxideHCl, Diazepam, Furosemide, L-dopa and benserazide, Misoprostol, Propranolol HCl, Ursodeoxycholic acid, Nicardipine

Table no.1: Polymer and other material used in the formulation of GRDDS:³³

Category	Material
Polymers	HPMC K4M, HPMC K100, calcium alginate, CMC, Eudragit RL, Eudragit S100, Eudragit RS, polyethylene glycol, B cyclodextrin.
Inert fatty material (5-75%)	Edible inert materials having a specific gravity less than 1 can be used to decrease hydrophilic property of formulation and hence increase buoyancy e.g. beeswax, fatty acid.
Effervescent	Sodium bi carbonate, citric acid, tartaric acid
Release rate accelerants (5-65%)	Lactose, mannitol
Release rate retard (5-60%)	Talc, magnesium stearate, di calcium phosphate
Low density material	Propylene foam powder
Buoyancy increasing agent (up to 80%)	Ethyl cellulose

Table no.2: Marketed product of GRDDS:

Brand name	Drug	Dosage form	Dose	Use	Company
Cifran O.D	Ciprofloxacin	Tablet	500mg, 1 gm	Systemic treatment of infections	Ranbaxy, India
Liquid Gavison	Al hydroxide andMg carbonate	Liquid	95mg and 358 mg respectively	Antacid	GlaxoSmithKline, India
Madopar	Levodopa and Benserazide	Capsule	100mg and 25 mg respectively	Parkinson’s disease	Roche Products, USA
Glumetza	Metformin Hydrochloride	Tablet	500mg and 1000mg	Type 2 diabetes	Depomed, Canada
Cytotec	Misoprostol	Bilayer capsule	100 mcg/200 mcg	Used with nonsteroidal anti-inflammatory drugs to prevent gastric ulcers.	Pharmacia, USA

Table no.3: Patent for GRDDS³⁵

US Patent/App. No.	Patent title	Issue/ Publication Date	Patent owner
2013/0078,290	Gastroretentive Dosage Forms of GABA Analogs	Mar 28, 2013	Rubicon Research Private Limited
2013/0022,654	Controlled Release Pharmaceutical Compositions of Tapentadols	Jan 24, 2013	Lupin Limited
2013/0004,434	Gastroretentive, Extended Release Composition of Therapeutic Agent	Jan 3, 2013	Council of Scientific And Industrial Research
2012/0321,706	Novel Gastroretentive Dosage Forms of Poorly Soluble Drugs	Dec 20, 2012	Intec Pharma Ltd.
2012/0269,866	Gastroretentive Composition on the Basis of a Water-Soluble Reaction Product from a Vinyl Group-Containing Precursor	Oct 25, 2012	Basf Corporation
2012/0021,051	ZaleplonGastroretentive Drug Delivery System	Jan 26, 2012	Intec Pharma Ltd.
2011/0268,666	Novel Gastroretentive Delivery System	Nov 3, 2011	Intec Pharma Ltd., Yissum Research Development Company of the Hebrew University of Jerusalem,

Table no.4: Work done on Gastro Retentive Drug Delivery System:

Drug	Formulation and	Systems	Evaluation parameter	Outcomes
Gallic acid	Chewable tablet	Raft forming system	Determination of raft strength, acid neutralization capacity, in vitro drug release	Optimum raft strength found i.e.4.5gm, acid neutralizing capacity-6.80m Eq, %CDR-85.21%.³⁴
Berberine Hydrochloride and Aloe Vera Gel Powder	Bilayer Tablets	Floating Drug Delivery System	Floating capacity.in vitro drug release, stability study	Shows optimum Floating capacity -8hr total floating time and floating lag time was 32 sec,99 % drug release in 8 hrs. found stable during stability study³⁵
ranitidine hydrochloride	Microspheres	floating-mucoadhesive drug delivery system	Swelling ratio, buoyant capacity, encapsulation efficiency	Itshows optimum Swelling ratio,buoyant capacity,encapsulation efficiency³⁶
Antacid	alginate Beads	floating-mucoadhesive drug delivery system	Floating time, lag time, mucoadhesive capacity.	The antiulcer activity of beads is stronger than conventional tablets which containing the same amount of antacids.³⁷
Gabapentin (GBP), an antiepileptic and anti-neuropathic agent	raft forming systems	raft forming systems	Raft strength, in-vitro drug release,	Significant increase was observed for C_max, AUC_(0-t), and AUC_(0-∞). The increase in relative bioavailability of GBP³⁸
Rosiglitazone Maleate (Antidiabetic)	Micro Sphere	floating- drug delivery system	Floating lag time. particle size, drug entrapment capacity, drug release	Control release and improved bioavailability.³⁹
Amoxycillin trihydrate (Anti-bacterial)	Matrix tablet	floating- drug delivery system	Floating lag time., drug release profile, in vitro buoyancy study	Sustained release over 12hr⁴⁰
Trimetazidine Dihydro chloride(Antianginal agent)	Micro Spheres	Raft forming dds	Floating time, raft strength.in vitro drug release, drug intraptment capacity.	Prolonged drug release (12 h) and remained buoyant for > 11 hours⁴¹
Perindopril erbumine (Antihypertensive)	Microspheres	floating- drug delivery system	Floating time, raft strength.in vitro drug release, drug intraptment capacity.	Polymer ratio affected the size, entrapment efficiency, % buoyancy & drug release⁴²

CONCLUSION:

The literature searched during the review of the topic revealed that gastro retentive approach is the best alternative for the formulation of a drug with a narrow therapeutic window to increase the bioavailability. In the outgoing research work in the field of gastro retentive drug delivery various novel approaches & techniques have been successfully tried by various researchers. At present many formulations based on these approaches have found their way to the market & used by the physician for the treatment of patients.

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Received on 29.01.2021 Modified on 22.07.2021

Research J. Pharm. and Tech. 2022; 15(7):3324-3330.

DOI: 10.52711/0974-360X.2022.00556