Gastroretentive Drug Delivery System: A Systematic Review

 

Sarjavalagi Vishal Gopal*¹, Prabhat Kumar Chaurasia², Harshitha Arun Pardhe³,

Singh Suryansh Santosh², Narayan Sah Sonar³

¹M. Pharm, Dept. of Pharmaceutics, Oxbridge College of Pharmacy, Bengaluru, Karnataka.

²M. Pharm, Dept. of Pharmaceutics, Mallige College of Pharmacy, Bengaluru, Karnataka.

³M. Pharm, Dept. of Pharmacology, Mallige College of Pharmacy, Bengaluru, Karnataka.

 

ABSTRACT:

Gastroretentive drug delivery system is a novel drug delivery system that has an upper hand due to its ability to maintain prolonged stomach retention and thereby increase the stomach residence time of drugs and also enhance the bioavailability of drugs. Oral sustained drug delivery system is complicated by reduced stomach residence time (GRTs) and erratic stomach emptying time etc. In order to overcome these limitations, various approaches have been proposed to increase the gastric residence of drug delivery systems in the upper part of the gastrointestinal tract peptic ulcer, stomach ulcer, or gastric ulcer, also known as peptic ulcer disease, is a very common chronic stomach disorder that is mainly caused by stomach lining damage. Various factors such as pepsin, gastric acid, H. Pylori, NSAIDs, prostaglandins, mucus, bicarbonate, and mucosal blood flow play an important role in the development of peptic ulcers and so on. In this review article we concentrate on some important mechanisms for the delivery of gastro-retentive drugs (GRDDS) (floating, bioadhesive, high density, swellable, raft forming, and magnetic systems) which will be useful in the treatment of peptic ulcer in different dosage types. This manuscript highlights various developmental approaches, Comparison between Conventional drug delivery systems and Gastro retentive Drug delivery systems, characterization aspects, potential drug candidates, unsuitable drug candidates, List of commercialized gastro-retentive drug delivery system, advantages and applications of gastroretentive systems.

 

 

 

1.    INTRODUCTION:

Oral administration is the most comfortable and favored method of drug delivery to systemic circulation. Recently, oral controlled release of drugs has been of increasing interest in the pharmaceutical field in order to achieved enhanced therapeutic benefits, such as ease of dosing. Patients compliance and formulative versatility.

 

Drugs which are easily absorbed from the gastrointestinal tract (GIT) and drugs with short half life are quickly eliminated from the systemic circulation.^1,2

 

Gastroretentive dosage forms are a variable process and it is a valuable asset for controlling and prolonging the emptying time of the stomach content then that of conventional dosage forms. Gastro-retensive systems will remain in the gastric area for several hours and thus significantly extend the gastric residence time of the drug. Prolonged gastric retention improves bioavailability, decreases drug disposal and increases solubility for medications that are less soluble in a high environmental.^3,4

 

In case of several medications that are released in the stomach have the greatest therapeutic effect because their release is constantly delayed and controlled. This type of drug delivery will have comparatively less side effect and reduce the need for repeated dosages due to steady therapeutic levels of drugs example, furosemide and ofloxacin.^5,6

 

Gastro-retentive dosage formulation are also useful for both local and continuous delivery of drug under certain conditions, such as H. pylori Infection which causes peptic ulcers. The reduction in fluctuation in therapeutic levels minimizes the risk of resistance especially in case of β-lactam antibiotics (penicillins and cephalosporins) retentive drug delivery system, such as hydrodynamically balanced system (HBS)/floating drug delivery system, low density systems, raft systems incorporating alginate gels, bioadhesive or mucoadhesive systems, high density system, superporous hydrogels and magnetic systems.^{7, 8}

 

Table 1: Comparison between Conventional drug delivery systems and GRDDS.^9,10

PARAMETERS	CONVENTION DRUG DELIVERY SYSTEM	GRDDS
Patient compliance	Poor	Better
Dose Dumping	Risk of dose dumping is higher	No Risk.
Drug having low absorption in small intestine	Not appropriate	Appropriate
Drug acting locally in stomach   Toxicity	Not very much useful     Greater susceptibility toward toxicity	Much useful     Low susceptibility
Drug with poor solubility at higher pH	Not much beneficial	Much beneficial
Drug that undergo degradation in colon   Drug that have fast GIT Absorption	Not much beneficial     Not much beneficial	Much beneficial   Much beneficial

 

2.     Approaches for Gastric Retention^{1, 11}:

Different methods have been developed to enhance the retention of an oral dosage type in the stomach, e.g. floating systems, swelling and expanding systems, bioadhesive systems, altered density systems and other delayed gastric emptying devices. Floating Drug Delivery Systems (FDDS) or Hydro-dynamically Balanced Systems (HBS) have lower bulk density than gastric fluids, and thus remain floating in the stomach for an extended period of time5. The drug is slowly released from the floating system at the desired rate without any plasma concentration fluctuations resulting in an increased gastric residence time (GRT). The residual shall be removed from the stomach after the complete release of the delivery system. Bioadhesive systems are typically designed to localize delivery devices within a body cavity. Bioadhesion is achieved in these systems through the use of bioadhesive polymers which bind to epithelial surface of gastrointestional tract. Hydrogen formation and electrostatic bonding at the polymer mucous interface contributes to bioadhesion. Swellable systems are a type of gastro-retentive dosage forms that swell in the stomach to a degree that prevents its escape through the pyloric sphincter leading to prolonged retention of the swellable system in the stomach. Altered density gastroretentive dosage forms include systems that have either greater or lower density than the contents of the stomach leading to an increase in GRT and hence the release of drugs for an extended period of time.

 

Table 2: Potential Drug Candidates for GRDDS^{12, 13}

Suitable Drug candidates	Example
Drugs acting locally in the stomach	Antacids, Anti-ulcer drugs, drugs against H. Pylori, Misoprostol, Clarithromycin, Amoxicillin
Drugs with narrow absorption window in Gastrointestinal tract (GIT	Cyclosporine, Methotrexate, Levodopa, Repaglindine, Riboflavin, Furosemide, Para-aminobenzoic Acid, Atenolol, Theophyllin
Drugs having unstable properties in the intestinal or colonic environment	Captopril, Ranitidine HCl, Metronidazole, Metformin HCl
Drugs caused imbalance of normal colonic microbes	Antibiotics against H. Pylori, Amoxicillin Trihydrate
Drugs having low solubility at high pH values	Diazepam, Chlordiazepoxide, Furosemide, Verapamil HCl

 

Table 3: Unsuitable Drug Candidates for GRDDS

Unsuitable Drug Candidates	Example
Drugs having very limited acid solubility	Phenytoin
Drugs that exhibits instability in the gastric environment.	Erythromycin
Drugs that are used for selective release in the colon.	5aminosalicylicacid and corticosteroids

 

3.     Classification: ^{14, 15}:

 

4.     Floating drug delivery system (FDDS):

The drugs which have an absorption window in the stomach or the upper small intestine required FDDS.^14,15 The bulk density of FDDS is less than gastric fluids so it tends to float (buoyant) in the stomach for a prolonged period of time without affecting the gastric emptying process, while the system floats in the gastric contents, the drug is slowly released from the system at the desired rate. The residual system is drained from the stomach after release of drug. The results in an increased Gastro Retension Time and better control of the plasma drug concentration fluctuation.

4.1 Advantages of FDDS:

·       Improves patient compliance by reducing the frequency of dosing.

·       Improved therapeutic effect can be obtained with the drugs having shorter half-life.

·       Due to buoyancy the gastric retention time is increased.

·       The drug is released for prolonged period in a controlled manner

·       It is possible to achieve site-specific release of drugs to the stomach.

·       Increased absorption of medications that are only soluble in the stomach.

·       As single unit floating dosage such as microspheres it releases drugs uniformly and there is no risk of dose dumping.

 

4.2 Limitations of FDDS:

·       High levels of stomach fluids are necessary to maintain buoyancy.

·       Not possible for medications that have gastric fluid solubility issues or stability problems.

·       Drugs such as nifedipine, which is well absorbed throughout the GIT and undergoes significant first-pass metabolism, may not be suitable for FDDS as slow gastric emptying may lead to a reduction in systemic bioavailability.

·       FDDS is not applicable for the drugs which causes irritation to the stomach mucosa.

 

4.3 Formulation requirements for FDDS:

The system must meet the following criteria:

·       It must Posses sufficient strength to form a cohesive gel barrier.

·       The total specific gravity should be lower than that of the gastric contents (1.004-1.010).

·       It should gradually dissolve to act as a drug reservoir.¹⁶

 

A.   Non floating High Density:

If high-density pellets are given to patients, they may sink to the bottom of the stomach wall. For a high density system sedimentation has been used as a retention mechanism. A density-3g / cm3 is sufficient for substantial prolongation of stomach residence.¹⁷ This method requires the formulation of dosage forms whose density must be greater than the density of normal stomach contents (1.004g / ml). Such formulations are prepared by coating drug or blended with heavy inert material such as iron powder, titanium dioxide, zinc oxide, barium sulphate.¹⁸

 

Figure 1: GRDDS base on high density excipient.

 

B.    Bio-adhesive Systems:

These systems are basically based on bio-adhesive polymers which bind to both mucus and non mucous membranes ie., mucin and epithelial surface. When bio-adhesion is confined to the surface of the mucosa it is called muco-adhesion. Lecithin is the most widely used ligand for precise bio-adherence. The non-specific bio-adhesion depends on the quality of the polymer used in the system. Some of the polymers which are reported bio-adhesive in nature are poly (acrylates), chitosan poly (lactic acid), alginates, polystyrene and sodium hyaluronate.¹

 

Figure 2: (a) GRDDS base on Bioadhesive Systes.¹⁹ (b) GRDDS base on Contact stage and consolidation stage.²⁰

 

C.   Magnetic system:

This method is based on the simple concept that there is a small internal magnet in the dosage form, and a magnet mounted on the abdomen over the position of the stomach area. The gastric residence time of the dosage form may be increased for an extended period of time using an extracorporeal magnet.^{18, 21}

 

Figure 3: GRDDS base on Magnetic system.²²

 

D.   Swelling and expanding systems:

These are the dosage forms that swell to a certain degree after swallowing, and prevent their escape from the pylorus. Resulting the medication to remain for a longer time in the stomach. These systems may be referred to as "plugs type system," because they show a propensity to remain logged at the pyloric sphincter if in their extended state they reach a diameter of about 12-18mm. The formulation is optimized for stomach retention and controlled drug delivery to the gastric cavity the cross linking between the polymeric chain maintains the balance between the extent and duration of swelling.¹⁷

 

Figure 4: GRDDS base on Swelling and expanding systems.²³

 

E.    Raft forming system:

It is mainly used for the delivery of antacids and delivery of the drugs for gastrointestinal infections and disorders. The main principle involved in RFS of GRDDS is formation of viscous gel when it comes in contact with the gastric fluids, which then forms a continuous layer on top of gastric fluid known as RAFT it is caused due to the low bulk density induced by CO2 formation. Typically the components of this system include a gel forming agent (e.g. alginic acid) and alkaline bicarbonates or carbonates that are responsible for CO2 production making the system less denser and float on the gastric fluids. Usually the formulations contain antacids such as aluminum hydroxide or calcium carbonate to reduce gastric acidity. The raft formed floats on the gastric fluids and prevents the reflux of the gastric material into the esophagus by creating a barrier between the stomach and esophagus and is generally used for the treatment of gastro-oesophageal reflux. offers a schematic view of raft formation structures.²⁴ A gel forming solution (e.g. sodium alginate solution containing carbonates or bicarbonates) swells coming in contact with the gastric fluids and creates a viscous cohesive gel containing trapped CO₂ bubbles, which forms a raft layer on top of gastric fluid and gradually releases it into the stomach.¹⁷

 

Figure 5: GRDDS base on Raft forming system.²⁵

 

5.    Non-Effervescent FDDS:

The Non-effervescent FDDS is based on the mechanism of polymer swelling or bioadhesion in GI tract to mucosal layer. Hydrocolloids, hydrophilic gums, polysaccharides and matrix forming products such as polycarbonate, polyacrylate, polymethacrylate, polystyrene and as bioadhesive polymers such as chitosan are the most widely used excipients in non-effervescent FDDS.

 

a.     Single layer floating tablets:

They are formed by intimate mixing of drug product with gelforming hydrcolloid, which swells coming in contact with gastric fluid and holds a bulk density of less than unity. The swollen polymers traps the air bubbles and confers buoyancy.

 

b.    Bilayer floating tablets:

A bilayer tablet includes two layers firstly immediate release layer that release the initial dose from the system while the other layer is sustained release layer which absorb gastric fluid, and forms an impermeable colloidal gel barrier on its surface and retains a bulk density of less than unit and thus stays buoyant in the stomach.

 

c.     Alginate beads:

Multi-unit floating dosage forms were formed from freeze dried calcium alginate. Dropping sodium alginate solution into aqueous solution of calcium chloride, leads calcium precipitation of calcium alginate resulting in the formation of spherical beads of approximately 2-5 mm in diameter. The beads are then removed, snap-frozen in liquid nitrogen, and freeze-dried at -40oC for 24 hours, leading to the creation of a porous system that can sustain a floating force for more than 12 h. These floating beads gave more than 5.5 hours of extended residence time.

 

d.    Hollow microspheres (micro balloons):

A novel method of emulsion solvent diffusion was used to prepare hollow microspheres filled with drug in their outer polymer shelf. The drug's ethanol/dichloromethane solution and enteric acrylic polymer were poured into an agitated Poly Vinyl Alcohol (PVA) solution, which was thermally regulated at 40degree C. The gas phase is produced by the evaporation of dichloromethane formed in the dispersed polymer droplet and internal cavity in the microsphere of the polymers with drug. The micro balloon continuously floated over the surface of a surfactant-containing acid dissolution media for more than 12 hours.^26,27

 

6.     Effervescent floating dosage forms:

These are the matrix forms of systems that are formulated using swellable polymers such as methyl cellulose, HPMC and chitosan-based, as well as various effervescent compounds such as sodium carbonate, calcium carbonate, tartaric acid and citric acid. These are designed in such a way that the release of CO2 occurs when in contact with the acidic gastric contents and CO2 is trapped in the swollen hydrocolloids resulting in buoyancy of dosage form.¹

·       Volatile liquid containing systems

·       Gas generating systems

 

6.1 Gas generating systems:

These buoyant delivery systems use effervescent reaction between carbonate/bicarbonate salts and citric / tartaric acid to release CO2 that is trapped in the system's jellified hydrochloride layer, thus reducing its specific gravity and allowing it to float over chyme. Such tablets can either be single-layered in which the CO2-generating components are closely mixed within the tablet matrix, or they can be bilayer in which the gas-generating components are packed into one layer of hydrocolloid, and outer-layer medication for sustained release effect. Multiple unit types of floating pills which generate CO₂ is also being developed. Such types of systems float completely within 10 minutes and remain floating over extendend period of time (5-6 hours).¹²

 

Figure 6: GRDDS Base on Gas Generating Systems.²⁸

 

Table 4: List of Commercialized Gastro-Retentive Drug Delivery System (GRDDS).²⁸commerc

Product	Drug	Company	Technology
Liquid Gaviscon®	Alginic acid and sodium bicarbonate	Reckitt Benckiser Healthcare, UK	Effervescent floating
Cipro XR®	Ciprofloxacin HCl and betaine	Bayer, USA	Erodible matrix-based system
Prazopress XL®	Prazosin hydrochloride	Sun Pharma, Japan	Effervescent and swelling-based floating system
Conviron®	Ferrous sulfate	Ranbaxy, India	Colloidal gel forming floating system
Cefaclor LP®	Cefaclor	Galenix, France	Floating system
Tramadol LP®	Tramadol	Galenix, France	Floating system
Baclofen GRS®	Baclofen	Sun Pharma, India	Coated multi-layer floating and swelling system
Gabapentin GR®	Gabapentin	Depomed, Inc., USA	Polymer-based swelling technology
Proquin XR®	Ciprofloxacin	Depomed, Inc., USA	Polymer-based swelling technology
Glumetza®	Metformin HCl	Depomed, Inc., USA	Polymer-based swelling technology
Madopar®	Levodopa and benserazide	Roche, UK	Floating capsule
Valrelease® Topalkan® Xifaxan® Coreg CR® Inon Ace® Cytotec® Cifran OD® Oflin OD®	Diazepam Aluminum and magnesium Rifaximin Carvedilol Simethicone Misoprostol Ciprofloxacin HCl Ofloxacin	Roche, UK Pierre Fabre Medicament, France Lupin, India GlaxoSmithKline Sato Pharma, Japan Pharmacia/Pfizer Inc., USA Ranbaxy, India Ranbaxy, India	Floating capsule Floating liquid alginate Bioadhesive tablets Gastro-retention with osmotic system Foam-based floating system Bilayer floating capsules Floating tablets Gas generating floating tablets

 

7.    CONCLUSION:

Drug absorption is a highly variable process in the gastrointestinal tract, and prolonging the gastric retention of the medication type increases the duration for drug absorption. FDDS aims is to act as a possible gastric retention solution. While there are a number of challenges to be worked out in order to achieve prolonged gastric retention, for market this strategy, a significant number of Company are working on it. Such devices not only have managed drug release but also deliver the drug in an absorbable form in optimal absorption regions. Both these methods of delivering medicines have their own benefits and disadvantages.

 

8. ACKNOWLEDGEMENT:

I extend my heartfelt thanks to my family members, friends for their constant support and guidance.

 

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Received on 21.05.2020            Revised on 08.06.2020             

Accepted on 18.06.2020      ©Asian Pharma Press All Right Reserved