Figure 1: Drug absorption in the case of (a) Conventional dosage forms (b) Gastroretentive drug delivery systems

The gastrointestinal tract is a long muscular tube, starting from the mouth and end at the anus, which capture the nutrients inside the body and eliminate waste by different physiological processes such as secretion, digestion, absorption and excretion. Figure 2 includes the basic Construction of gastrointestinal tract from stomach to large intestine.

Figure 2: Physiology of gastrointestinal tract

The stomach is a J-shaped organ which can be divided into four parts: cardia, fundus, body and antrum. The main function of the stomach is to store and mix food with gastric secretions. It consists of serosa, longitudinal muscle, intermuscular plane, circular muscle, submucosa, lamina propria and epithelium. The stomach has a third muscle layer called as the "oblique muscle layer", situated in the proximal stomach, branching over the fundus and higher regions of the gastric body [6].

2. Physiology of gastrointestinal tract

The stomach anatomy is mainly consists of 3 regions; fundus, body, and antrum pylorus. The proximal part is made up of fundus and body. It serves as a reservoir for the materials which remain undigested, whereas the antrum is the main site for mixing motions and acts as a pump for gastric emptying by propelling actions. Gastric emptying occurs during both fasting as well as fed states. The pattern of motility is distinguished in 2 states. During the fasting state an inter digestive series of electrical events takes place, which cycles through stomach and intestine every 2 to 3 hours [7].This is called the inter digestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington [8].

1. Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.

2. Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.

3. Phase III (burst phase) lasts for 4 to 6 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.

4. Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2consecutive cycles.

After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to less than 1 mm), which are propelled toward the pylorus in a suspension form. During the fed state onset of MMC is delayed resulting in slowdown of gastric emptying rate [9].

Need for gastroretentive drug delivery system

Various drugs have their greatest therapeutic effect when released in the stomach, particularly when the release is prolonged in a continuous, controlled manner. Drugs delivered in this manner have a lower level of side effects and provide their therapeutic effects without the need for repeated dosages or with a low dosage frequency. Sustained release in the stomach is also useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, which is where absorption occurs and contact time is limited. In general, appropriate candidates for controlled release gastroretentive dosage forms (CRGRDF) are molecules that have poor colonic absorption but are characterized by better absorption properties at the upper parts of the GIT [10].

· Drugs acting locally in the stomach

E.g. Antacids and drugs for H. Pylori viz., Misoprostol

· Drugs that are primarily absorbed in the stomach

E.g. Amoxicillin

· Drugs that are poorly soluble at alkaline pH

E.g. Furosemide, Diazepam, Verapamil etc.

· Drugs with a narrow window of absorption

E.g. Cyclosporine, Methotrexate, Levodopa etc.

· Drugs which are absorbed rapidly from the GI tract.

E.g. Metonidazole, tetracycline

· Drugs which degrade in the colon.

E.g. Ranitidine, Metformin HCl.

· Drugs that disturb normal colonic microbes

E.g. antibiotics against Helicobacter pylori.

Drugs those are unsuitable for gastroretentive drug delivery systems

1) Drugs that have very limited acid solubility e.g. phenytoin etc.

2) Drugs that suffer instability in the gastric environment e.g. erythromycin etc.

3) Drugs intended for selective release in the colon e.g. 5-amino salicylic acid and corticosteroids etc. [11].

Factors controlling gastric retention of dosage forms

The most important parameters controlling the gastric retention time (GRT) of oral dosage forms include: density, size and shape of the dosage form, food intake and its nature, caloric content and frequency of intake, posture, gender, age, sex, sleep, body mass index, physical activity and diseased states of the individual (e.g. chronic disease, diabetes etc.) and administration of drugs with impact on gastrointestinal transit time for example drugs acting as anticholinergic agents (e.g. atropine, propantheline), Opiates (e.g. codeine) and prokinetic agents (e.g. metclopramide, cisapride.) [12]. The molecular weight and lipophilicity of the drug depending on its ionization state are also important parameters [13].

1. Density of dosage form

Dosage forms having a density lower than that of gastric fluid experience floating behavior and hence gastric retention. A density of <1.0 gm/cm³ is required to exhibit floating property. However, the floating tendency of the dosage form usually decreases as a function of time, as the dosage form gets immersed into the fluid, as a result of the development of hydrodynamic equilibrium.

2. Size of dosage form

The size of the dosage form is another factor that influences gastric retention. The mean gastric residence times of non-floating dosage forms are highly variable and greatly dependent on their size, which may be small, medium, and large units. In fed conditions, the smaller units get emptied from the stomach during the digestive phase and the larger units during the housekeeping waves. In most cases, the larger the size of the dosage form, the greater will be the gastric retention time because the larger size would not allow the dosage form to quickly pass through the pyloric atrium into the intestine. Thus the size of the dosage form appears to be an important factor affecting gastric retention [14].

3. Food intake and its nature

Food intake, viscosity and volume of food, caloric value and frequency of feeding have profound effect on the gastric retention of dosage forms. The presence or absence of food in the gastrointestinal tract influences the gastric retention time of the dosage form. Usually the presence of food in the gastrointestinal tract improves the gastric retention time of the dosage form an thus, the drugs absorption increases by allowing its stay at the absorption site for a longer period. Again, increase in acidity and caloric value slows down gastric emptying time (GET), which can improve the gastric retention of dosage forms [15].

4. Effect of gender, posture and age

A study by Mojaverian et.al. found that females showed comparatively shorter mean gastroretentive time than males and the gastric emptying in women was slower than in men. In the upright position, the floating systems floated at the top of the gastric contents in upright position and stay for a long time in gastric fluid, showing prolonged gastric retention time. But the non-floating units settled to the lower part of the stomach and undergo faster emptying. However, in supine position, the floating units are emptied faster than non-floating units of similar size [16].

Formulation considerations for GRDDS

It must be effective retention in the stomach to suit for the clinical demand

1) It must have sufficient drug loading capacity

2) It must be control the drug release profile

3) It must have full degradation and evacuation of the system once the drug release is over

4) It should not have effect on gastric motility including emptying pattern

5) It should not have other local adverse effects [17].

Various approaches used to achieve gastric retention

Different systems have been developed to increase the gastric retention time of dosage forms by employing a variety of concepts. These systems have been classified as:

A) Bio/Mucoadhesive systems

B) Expandable/Swelling systems

C) High density systems

D) Floating drug delivery systems

E) Magnetic systems

A) Mucoadhesive (Bioadhesive) systems:

Several approaches have been immerged to prolong the residence time of the dosage forms at the absorption site and one of these is the development of oral controlled release bioadhesive system. In the early 1980’s, Professor Joseph R. Robinson at the University of Wisconsin pioneered the concept of bioadhesion as a new strategy to prolong the residence time of various drugs on the ocular surface. Various gastrointestinal mucoadhesive dosage forms, such as discs, microspheres, and tablets, have been prepared and reported by several research groups.

Adhesion: Adhesion can be defined as the bond produced by contact between a pressure sensitive adhesive and a surface.

The American Society of Testing and Materials has defined it as the state in which two surfaces are held together by interfacial forces which may consist of valence forces, interlocking action, or both.

A bioadhesive is defined as a substance that is capable of interacting with biological materials and being retained on them or holding them together for extended periods of time.

According to Good defined bioadhesion as the state in which two materials, at least one biological in nature, are held together for an extended period of time by interfacial forces. It is also defined as the ability of a material (synthetic or biological) to adhere to a biological tissue for an extended period of time.

In biological systems, four types of bioadhesion can be distinguished.

1. Adhesion of a normal cell on another normal cell

2. Adhesion of a cell with a foreign substance

3. Adhesion of a normal cell to a pathological cell

4. Adhesion of an adhesive to a biological substrate

Bioadhesive are classified into three types based on phenomenological observation, rather than on the mechanisms of bioadhesion[18]. The mechanisms responsible in the formation of bioadhesive bonds are not fully known, however most research has described bioadhesive bond formation as a three step process.

Step 1

The wetting and swelling step occurs when the polymer spreads over the surface of the biological substrate or mucosal membrane in order to develop an intimate contact with the substrate. Swelling of polymers occurs because the components within the polymers have an affinity for water.

Step 2

The surfaces of mucosal membranes are composed of high molecular weight polymers known as glycoproteins. In step 2 of the bioadhesive bond formation, the bioadhesive polymer chains and the mucosal polymer chains intermingle and entangle to form semi permeable adhesive bonds. In order to form strong adhesive bonds, one polymer group must be soluble in the other and both polymer types must be of similar chemical structure.

Step 3

This step involves the formation of weak chemical bonds between the entangled polymer chains. The types of bonding formed between the chains include primary bonds such as covalent- bonds and weaker secondary interactions such as Van-der Waals Interactions and hydrogen bonds [19].

The mucoadhesive/mucosa interaction:

1. Chemical bonds:

For adhesion to occur, molecules must bond across the interface. These bonds can arise in the following way

(1) Ionic bonds—where two oppositely charged ions attract each other via electrostatic interactions to form a strong bond (e.g. in a salt crystal).

(2) Covalent bonds—where electrons are shared, in pairs, between the bonded atoms in order to fill the orbital in both. These are also strong bonds.

(3) Hydrogen bonds—here a hydrogen atom, when covalently bonded to electronegative atoms such as oxygen, fluorine or nitrogen, carries a slight positively charge and is therefore attracted to other electronegative atoms. The hydrogen can therefore be thought of as being shared, and the bond formed is generally weaker than ionic or covalent bonds.

(4) Van-der-Waals bonds—these are some of the weakest forms of interaction that arise from dipole–dipole and dipole-induced dipole attractions in polar molecules, and dispersion forces with non-polar substances.

(5) Hydrophobic bonds—more accurately described as the hydrophobic effect, these are indirect bonds (such groups only appear to be attracted to each other) that occur when non-polar groups are present in an aqueous solution. Water molecules adjacent to nonpolar groups form hydrogen bonded structures, which lowers the system entropy. There is therefore an increase in the tendency of non-polar groups to associate with each other to minimize this effect [18].

Factors affecting mucoadhesion

The mucoadhesion of a drug carrier system to the mucous membrane depends on the following mentioned factors.

1. Polymer based factors such as molecular weight of the polymer, concentration of polymer used chains swelling factor, stereochemistry of polymer.

2. Physical factors such as pH at polymer substrate interface applied strength, contact time.

3. Physiological factors such as mucin turn over rate diseased state.

Advantages

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

· Due to an increased residence time it enhances absorption and hence the therapeutic efficacy of the drug.

· Excellent accessibility.

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

· Increase in drug bioavailability due to first pass metabolism avoidance.

· Drug is protected from degradation in the acidic environment in the GIT.

· Improved patient compliance.

· Ease of drug administration.

· Faster onset of action is achieved due to mucosal surface [20].

B) Expandable, unfoldable and swellable systems

Dosage forms in the stomach will with stand gastric transit if it is bigger than pyloric sphincter. However, the dosage form must be small enough to be swallowed, and must not cause gastric obstruction either singly or by accumulation. Thus, their configurations [21, 22] are required to develop an expandable system to prolong gastric retention time:

1) A small configuration for oral intake,

2) An expanded gastroretentive form, and

3) A final small form enabling evacuation following drug release from the device.

Thus, gastroretentivity is improved by the combination of substantial dimension with high rigidity of dosage form to withstand peristalsis and mechanical contractility of the stomach. Unfoldable and swellable systems have been investigated and recently tried to develop an effective gastroretentive drug delivery. Unfoldable systems are made of biodegradable polymers. They are available in different geometric forms like tetrahedron, ring or planner membrane (4 - label disc or 4 - limbed cross form) of bioerodible polymer compressed within a capsule which extends in the stomach [23, 24]. Swellable systems are also retained in the gastro intestinal tract due to their mechanical properties. The swelling is usually results from osmotic absorption of water and the dosage form is small enough to be swallowed by the gastric fluid (Figure 3). Expandable systems have some drawbacks like problematical storage of much easily hydrolysable, biodegradable polymers relatively short-lived mechanical shape memory for the unfolding system most difficult to industrialize and not cost effective [25]. Again, permanent retention of rigid, large single-unit expandable drug delivery dosage forms may cause brief obstruction, intestinal adhesion and gastropathy [26].

Figure 3: drug release from swellable system

c) High density systems

These systems with a density of about 3 g/cm³are retained in the antrum part of the stomach and are capable of withstanding its peristaltic movements. The only major drawbacks with such systems is that it is technically difficult to manufacture such formulations with high amount of drug (>50%) and to achieve a density of about 2.8 g/cm³. It is necessary to use diluents like barium sulfate, zinc oxide, titanium dioxide, iron powder etc. to manufacture such high density formulations [27, 28].

d) Floating drug delivery systems

Floating drug delivery system FDDS have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at the desired rate. After release of drug, the system is eliminated from the stomach. This results in an increased GRT and a better control of fluctuations in plasma drug concentrations.

The floating sustained release dosage forms exhibit most of the characteristics of hydrophilic matrices and are known as ‘hydrodynamically balanced systems’ (HBS) since they are able to maintain their low apparent density, while the polymer hydrates and builds a gel like barrier at the outer surface. The drug is released progressively from the swollen matrix, as in the case of conventional hydrophilic matrices. These forms are expected to remain buoyant (3–4 h) in the gastric contents without affecting the intrinsic rate of emptying because their bulk density is lower than that of the gastric contents. Many studies have demonstrated the validity of the concept of buoyancy in terms of prolonged GRT of the floating forms, improved bioavailability of drugs and improved effects in clinical situations. The results obtained have also demonstrated that the presence of gastric contents is needed to allow the proper achievement of the buoyancy retention effect.

Mechanism of floating systems

Various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention time. These attempts include introducing floating dosage forms (gas-generating systems (figure 4 C) and swelling or expanding systems), mucoadhesive systems, high-density systems, modified shape systems, gastric-emptying delaying devices and co-administration of gastric emptying delaying drugs. Among these, the floating dosage forms are the most commonly used. Floating drug delivery systems have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents (given in the Fig. 4A), the drug is released slowly at the desired rate from the system after release of drug, the residual system is eliminated from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention effect, a minimal level of floating force (F) is also required to maintain the buoyancy of the dosage form on the surface of the meal. To measure the floating force kinetics, a novel apparatus for determination of resultant weight has been reported in the literature. The apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain a submerged object. The object floats better if F is on the higher positive side (Fig. 4B). This apparatus helps in optimizing FDDS with respect to stability and sustainability of floating forces produced in order to prevent any unforeseeable variations in intragastric buoyancy.

F = Fbuoyancy – Fgravity = (Df – Ds) g v

Where, F = total vertical force, Df = fluid density, Ds = object density, v = volume and g = acceleration due to gravity [29].

Floating systems was first described by Davis in 1968. FDDS is an effective technology to prolong the gastric residence time in order to improve the bioavailability of the drug. FDDS are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. Floating systems can be classified as an effervescent and noneffervescent.

i) Effervescent systems

These buoyant delivery systems utilize matrices prepared with swellable polymers such as Methocel or polysaccharides, e.g., chitosan, and effervescent components, e.g., sodium bicarbonate and citric or tartaric acid or matrices containing chambers of liquid that gasify at body temperature. Flotation of a drug delivery system in the stomach can be achieved by incorporating a floating chamber filled with vacuum, air, or an inert gas. 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 as a result of an effervescent reaction between organic acids and carbonate–bicarbonate salts. The matrices are fabricated so that upon arrival in the stomach, carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the gellified hydrocolloid. This produces an upward motion of the dosage form and maintains its buoyancy. A decrease in specific gravity causes the dosage form to float. Recently a multiple-unit type of floating pill, which generates carbon dioxide gas, has been developed.

ii) Noneffervescent systems

Noneffervescent systems incorporate a high level (20– 75% w/w) of one or more gel-forming, highly swellable, cellulosic hydrocolloids (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose [HPMC], and sodium carboxymethylcellulose), polysaccharides, or matrix-forming polymers (e.g., polycarbophil, polyacrylates, and polystyrene) into tablets or capsules. Upon coming 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 [30].

Advantages of FDDS

An FDDS offers numerous advantages over conventional DDS:

· Sustained drug delivery

· Site-specific drug delivery

· Pharmacokinetic advantage

Limitations of FDDS

The main disadvantage of floating systems is that they require sufficiently high levels of fluid in the stomach for the FDDS to float therein and work efficiently. However, this can be overcome by administrating the dosage form with a glass full of water (200- 250 ml) with frequent meals or by coating the dosage form with bioadhesive polymers, thereby enabling them to adhere to the mucous lining of the stomach wall. The following consideration may help selecting the drug candidate for FDDS:

Drugs that are unstable and destroyed in the gastric environment are poor candidates for FDDS

· Drugs that are irritant to the gastric mucosa or induce gastric lesions are not good candidates for FDDS.

· Drugs that are absorbed throughout the GIT should be discarded for FDDS as prolonging the GRT of such drugs appears to offer no advantage in terms of BA .

· Poorly acid soluble drugs may show dissolution problem in gastric fluid and, consequently may not be released to a sufficient extent. It might, therefore, be advisable not to exploit FDDS with these drugs [31].

F) Magnetic Systems

This approach to enhance the gastric retention time is based on the simple principle that the dosage form contains a small internal magnet, and a magnet placed on the abdomen over the position of the stomach. Although magnetic system seems to work, the external magnet must be positioned with a degree of precision that might compromise patient compliance [11].

EVALUATION OF GASTRORETENTIVE DOSAGE FORM

A) In-vitro evaluation [32.33]

i) Floating systems

a) Buoyancy Lag Time

It is determined in order to assess the time taken by the dosage form to float on the top of the dissolution medium, after it is placed in the medium. These parameters can be measured as a part of the dissolution test [34]

b) Floating Time

Test for buoyancy is usually performed in Simulated Gastric Fluid (SGF) maintained at 37⁰C. The time for which the dosage form continuously floats on the dissolution media is termed as floating time [35].

c) Specific Gravity / Density

Density can be determined by the displacement method using Benzene as displacement medium.

d) Resultant Weight

Now we know that bulk density and floating time are the main parameters for describing buoyancy. But only single determination of density is not sufficient to describe the buoyancy because density changes with change in resultant weight as a function of time. For example a matrix tablet with bicarbonate and matrixing polymer floats initially by gas generation and entrapment but after some time, some drug is released and simultaneously some outer part of matrixing polymer may erode out leading to change in resultant weight of dosage form. The magnitude and direction of force/resultant weight (up or down) is corresponding to its buoyancy force (Fbuoy) and gravity force (Fgrav) acting on dosage form [36].

F = F_buoy – F_grav

F = D_f g V – D_sg V

F = (D_f – D_s) g V

F = (D_f – M/V) g V

Where,

F = resultant weight of object

D_f = density of fluid

D_s= density of solid object

g = gravitational force

M = mass of dosage form

V = volume of dosage form

ii) Swelling systems

a) Swelling Index

After immersion of swelling dosage form into SGF at 37⁰C, dosage form is removed out at regular interval and dimensional changes are measured in terms of increase in tablet thickness / diameter with time.

b) Water Uptake

It is an indirect measurement of swelling property of swellable matrix. Here dosage form is removed out at regular interval and weight changes are determined with respect to time. So it is also termed as Weight Gain.

Water uptake = WU = (Wt – Wo) * 100 / Wo

Where, Wt = weight of dosage form at time t

Wo = initial weight of dosage form

b) In-vitro dissolution tests [35, 37] (figure 5)

A. In vitro dissolution test is generally done by using USP apparatus with paddle and GRDDS is placed normally as for other conventional tablets. But sometimes as the vessel is large and paddles are at bottom, there is much lesser paddle force acts on floating dosage form which generally floats on surface. As floating dosage form not rotates may not give proper result and also not reproducible results. Similar problem occur with swellable dosage form, as they are hydrogel may stick to surface of vessel or paddle and gives irreproducible results. In order to prevent such problems, various types of modification in dissolution assembly made are as follows.

B. To prevent sticking at vessel or paddle and to improve movement of dosage form, method suggested is to keep paddle at surface and not too deep inside dissolution medium.

C. Floating unit can be made fully submerged, by attaching some small, loose, non- reacting material, such as few turns of wire helix, around dosage form. However this method can inhibit three dimensional swelling of some dosage form and also affects drug release.

D. Other modification is to make floating unit fully submerged under ring or mesh assembly and paddle is just over ring that gives better force for movement of unit.

E. Other method suggests placing dosage form between 2 ring/meshes.

F. In previous methods unit have very small area, which can inhibit 3D swelling of swellable units, another method suggest the change in dissolution vessel that is indented at some above place from bottom and mesh is place on indented protrusions, this gives more area for dosage form.

G. Inspite of the various modifications done to get the reproducible results, none of them showed co-relation with the in-vivo conditions. So a novel dissolution test apparatus with modification of Rossett-Rice test Apparatus was proposed.

c) In-vivo evaluation

a) Radiology

X-ray is widely used for examination of internal body systems. Barium Sulphate is widely used Radio Opaque Marker. So, BaSO4 is incorporated inside dosage form and X-ray images are taken at various intervals to view GR.

b) Scintigraphy

Similar to X-ray, emitting materials are incorporated into dosage form and then images are taken by scintigraphy. Widely used emitting material is 99Tc.

c) Gastroscopy

Gastroscopy is peroral endoscopy used with fiber optics or video systems. Gastroscopy is used to inspect visually the effect of prolongation in stomach. It can also give the detailed evaluation of GRDDS.

d) Magnetic Marker Monitoring

In this technique, dosage form is magnetically marked with incorporating iron powder inside, and images can be taken by very sensitive bio-magnetic measurement equipment. Advantage of this method is that it is radiation less and so not hazardous.

e) Ultrasonography

Used sometimes, not used generally because it is not traceable at intestine.

f) 13C Octanoic Acid Breath Test

13C Octanoic acid is incorporated into GRDDS. In stomach due to chemical reaction, octanoic acid liberates CO2 gas which comes out in breath. The important Carbon atom which will come in CO2 is replaced with 13C isotope. So time up to which 13CO2 gas is observed in breath can be considered as gastric retention time of dosage form. As the dosage form moves to intestine, there is no reaction and no CO2 release. So this method is cheaper than other.

Advantages of gastroretentive drug delivery systems

Enhanced bioavailability

The bioavailability of riboflavin CR-GRDF is significantly enhanced in comparison to the administration of non-GRDF CR polymeric formulations. There are several different processes, related to absorption and transit of the drug in the gastrointestinal tract, that act concomitantly to influence the magnitude of drug absorption [38].

Enhanced first-pass biotransformation

In a similar fashion to the increased efficacy of active transporters exhibiting capacity limited activity, the pre-systemic metabolism of the tested compound may be considerably increased when the drug is presented to the metabolic enzymes (cytochrome P450, in particular CYP3A4) in a sustained manner, rather than by a bolus input.

Sustained drug delivery/reduced frequency of dosing

For drugs with relatively short biological half-life, sustained and slow input from CR-GRDF may result in a flip-flop pharmacokinetics and enable reduced dosing frequency. This feature is associated with improved patient compliance, and thereby improves therapy.

Targeted therapy for local ailments in the upper GIT

The prolonged and sustained administration of the drug from GRDF to the stomach may be advantageous for local therapy in the stomach and small intestine. By this mode of administration, therapeutic drug concentrations may be attained locally while systemic concentrations, following drug absorption and distribution, are minimal.

Reduced fluctuations of drug concentration

Continuous input of the drug following CRGRDF administration produces blood drug concentrations within a narrower range compared to the immediate release dosage forms. Thus, fluctuations in drug effects are minimized and concentration dependent adverse effects that are associated with peak concentrations can be prevented. This feature is of special importance for drugs with a narrow therapeutic index [39].

Improved selectivity in receptor activation

Minimization of fluctuations in drug concentration also makes it possible to obtain certain selectivity in the elicited pharmacological effect of drugs that activate different types of receptors at different concentrations.

Reduced counter-activity of the body

In many cases, the pharmacological response which intervenes with the natural physiologic processes provokes a rebound activity of the body that minimizes drug activity. Slow input of the drug into the body was shown to minimize the counter activity leading to higher drug efficiency.

Extended time over critical (effective) concentration

For certain drugs that have non-concentration dependent pharmaco dynamics, such as beta lactam antibiotics, the clinical response is not associated with peak concentration, but rather with the duration of time over a critical therapeutic concentration. The sustained mode of administration enables extension of the time over a critical concentration and thus enhances the pharmacological effects and improves the clinical outcomes.

Minimized adverse activity at the colon

Retention of the drug in the GRDF at the stomach minimizes the amount of drug that reaches the colon. Thus, undesirable activities of the drug in colon may be prevented. This pharmacodynamic aspect provides the rationale for GRDF formulation for beta-lactam antibiotics that are absorbed only from the small intestine, and whose presence in the colon leads to the development of microorganism’s resistance.

Site specific drug delivery

A floating dosage form is a feasible approach especially for drugs which have limited absorption sites in upper small intestine [40]. The controlled, slow delivery of drug to the stomach provides sufficient local therapeutic levels and limits the systemic exposure to the drug. This reduces side effects that are caused by the drug in the blood circulation. In addition, the prolonged gastric availability from a site directed delivery system may also reduce the dosing frequency.

Limitations:

· Require a higher level of fluids in the stomach.

· Not suitable for Drugs that...have solubility problems in gastric fluid. E.g. phenytoincause G.I irritation. E.g.NSAIDS. are unstable in acidic environment.

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

· The floating systems in patients with achlorhydria can be questionable in case of swellable system.

· Retention of high density systems in the antrum part under the migrating waves of the stomach is questionable.

· The mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence.

· The mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence [41].

CONCLUSION:

Developing an efficient Gastroretentive dosage form is a real challenge and the drug delivery system must remain for a sufficient time in the stomach. Based on the literature surveyed, it may be concluded that gastroretentive drug delivery offers various potential advantages for drug with poor bioavailability due to their restricted absorption to the upper gastrointestinal tract and they can be delivered efficiently thereby minimizing their absorption and enhancing absolute bioavailability. The various gastroretentive drug delivery system have their own advantages and limitations. To design a successful gastroretentive drug delivery system, it is necessary to take in to consideration the physiochemical properties of the drug, physiological events in the gastrointestinal tract, formulation strategies and correct combination of drug and excipients.

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Received on 17.01.2012

Accepted on 10.04.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(3): May-June 2012, 143-152