3. Phase III (burst phase) lasts for 10 to 20 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 2 consecutive cycles⁴. (Figure 1)

Fig. 1: Motility pattern in GIT

Gastroretentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Slowed motility of the gastrointestinal tract by concomitant administration of drugs or pharmaceutical excipients also increase gastric retention of drug⁵.

These efforts resulted in GRDFs that were designed, in large part, based on the following approaches. (Figure 2)

· Low density form of the DF that causes buoyancy in gastric fluid^{6, 7}

· High density DF that is retained in the bottom of the stomach^{8, 9}

· Bioadhesion to stomach mucosa¹⁰

· Expansion by swelling or unfolding to a large size which limits passage of dosage form through the pyloric sphincter¹¹

Fig. 2: Different approaches of gastric retention

Novel oral controlled dosage form that is retained in the stomach for prolonged and predictable period is of major interest among academic and industrial research groups. One of the most feasible approaches for achieving prolonged and predictable drug delivery profile in the GI tract is to control gastric residence time (GRT). Dosage form with prolonged GRT or gastro-retentive dosage form (GRDF) provides an important therapeutic option¹². Various approaches for preparation of gastroretentive drug delivery system include floating systems, swellable and expandable systems, high density systems, bioadhesive systems, altered shape systems, gel forming solution or suspension system and sachet systems. Among these, the floating dosage form has been used most commonly^{13, 14}.

FACTORS AFFECTING GASTRIC RESIDENCE TIME OF FDDS

a) Formulation factors

Size of tablets

Retention of floating dosage forms in stomach depends on the size of tablets. Small tablets are emptied from the stomach during the digestive phase, but large ones are expelled during the house keeping waves⁴.

Floating and nonfloating capsules of 3 different sizes having a diameter of 4.8 mm (small units), 7.5 mm (medium units), and 9.9 mm (large units), were formulated and analyzed for their different properties. It was found that floating dosage units remained buoyant regardless of their sizes on the gastric contents throughout their residence in the gastrointestinal tract, while the nonfloating dosage units sank and remained in the lower part of the stomach. Floating units away from the gastro‐duodenal junction were protected from the peristaltic waves during digestive phase while the nonfloating forms stayed close to the pylorus and were subjected to propelling and retropelling waves of the digestive phase¹⁵.

Density of tablets

Density is the main factor affecting the gastric residence time of dosage form. A buoyant dosage form having a density less than that of the gastric fluids floats, since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period. A density of less than 1.0g/ml i.e. less than that of gastric contents has been reported. However, the floating force kinetics of such dosage form has shown that the bulk density of a dosage form is not the most appropriate parameter for describing its buoyancy capabilities¹⁶.

Shape of tablets

The shape of dosage form is one of the factors that affect its gastric residence time. Six shapes (ring tetrahedron, cloverleaf, string, pellet, and disk) were screened in vivo for their gastric retention potential. The tetrahedron (each leg 2cm long) rings (3.6 cm in diameter) exhibited nearly 100% retention at 24 hr¹⁷.

Viscosity grade of polymer

Drug release and floating properties of FDDS are greatly affected by viscosity of polymers and their interaction. Low viscosity polymers (e.g., HPMC K100 LV) were found to be more beneficial than high viscosity polymers (e.g., HPMC K4M) in improving floating properties. In addition, a decrease in the release rate was observed with an increase in polymer viscosity¹⁸.

b) Idiosyncratic factors

Gender

Women have slower gastric emptying time than do men. Mean ambulatory GRT in meals (3.4±0.4 hours) is less compared with their age and race‐matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface¹⁹.

Age

Low gastric emptying time is observed in elderly than do in younger subjects. Intrasubject and intersubject variations also are observed in gastric and intestinal transit time. Elderly people, especially those over 70 years have a significantly longer GRT²⁰.

Posture

i) Upright position

An upright position protects floating forms against postprandial emptying because the floating form remains above the gastric contents irrespective of its size²⁰. Floating dosage forms show prolonged and more reproducible GRTs while the conventional dosage form sink to the lower part of the distal stomach from where they are expelled through the pylorus by antral peristaltic movements²¹.

ii) Supine position

This position offers no reliable protection against early and erratic emptying. In supine subjects large dosage forms (both conventional and floating) experience prolonged retention. The gastric retention of floating forms appear to remain buoyant anywhere between the lesser and greater curvature of the stomach. On moving distally, these units may be swept away by the peristaltic movements that propel the gastric contents towards the pylorus, leading to significant reduction in GRT compared with upright subjects²².

Concomitant intake of drugs

Drugs such as prokinetic agents (e.g., metoclopramide and cisapride), anti Cholinergics (e.g., atropine or propantheline), opiates (e.g., codeine) may affect the performance of FDDS. The coadministration of GI‐motility decreasing drugs can increase gastric emptying time²².

Feeding regimen

Gastric residence time increases in the presence of food, leading to increased drug dissolution of the dosage form at the most favorable site of absorption. A GRT of 4‐10 h has been reported after a meal of fats and proteins²³.

FLOATING DRUG DELIVERY SYSTEM:

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 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 (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 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. 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 buoyancy¹²(figure 3).

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 gravity²⁴.

CLASSIFICATION:

Floating Oral Drug Delivery System (FDDS) are retained in the stomach and are useful for drugs that are poorly soluble or unstable in intestinal fluids. 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 time¹³. While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system (Figure 4). After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of fluctuations in plasma drug concentration.

Fig. 9: (A) Multiple-unit oral floating drug delivery system

(B) Working principle of effervescent floating drug delivery system.

The duration during which the device could maintain its geometric obstruction (caused by a built-in triggering ballooning system) was dependent on the erosion rates of the incorporated polymers (the capsule in-hosed core matrix). After complete core matrix erosion, the ballooning system is automatically flattened off so that the device retains its normal capsule size to be eliminated by passing through the GIT³².

B. Multiple unit floating system

a) Non-effervescent Systems:

Alginate beads

Alginates have received much attention in the development of multiple unit systems. Alginates are nontoxic, biodegradable linear copolymers composed of L-glucuronic and L-mannuronic acid residues. Multiple unit floating dosage forms have been developed from

freezedried calcium alginate. Spherical beads of approximately 2.5 mm in diameter can be prepared by

dropping a sodium alginate solution in to aqueous solutions of calcium chloride, causing precipitation of calcium alginate. The beads are then separated snap and frozen in liquid nitrogen, and freeze dried at -40°C for 24 hours, leading to the formation of porous system, which can maintain a floating force over 12 hours^33,
34. A multiple unit system can be developed comprising of calcium alginate core and calcium alginate/PVA membrane, both separated by an air compartment. Air compartment provides bouncy to beads. In presence of water, the PVA leaches out and increases the membrane permeability, maintaining the integrity of the air compartment. Increase in molecular weight and concentration of PVA, resulted in enhancement of the floating properties of the system³⁵.

b) Effervescent systems:

Floating pills

Ichikawa et al developed a new multiple type of floating dosage system composed of effervescent layers and swellable membrane layers coated on sustained release pills. The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sublayers to avoid direct contact between the 2 agents. This is surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac. When this system was immersed in the buffer at 37ºC, produce swollen pills (like balloons) with a density less than 1.0 g/mL due to incorporation of co₂³⁶.(Figure 9)

C) Hollow Microspheres:

Hollow microspheres are considered as one of the most promising buoyant systems, as they possess the unique advantages of multiple unit systems as well as better floating properties, because of central hollow space inside the microsphere(Figure 10). The general techniques involved in their preparation include simple solvent evaporation, and solvent diffusion and evaporation. Polycarbonate, Eudragit S, cellulose acetate, calcium alginate, agar and low methoxylated pectin are commonly used as polymers in preparation of hollow microsphere. Buoyancy and drug release are dependent on quantity of polymer, the plasticizer–polymer ratio and the solvent used^{7, 37, 38}.

Fig. 10: Micro balloons

D. Raft forming system

Raft-forming systems

On contact with Gastric fluid A gel-forming solution (e.g. sodium alginate solution containing carbonates or bicarbonates) swells and forms a viscous cohesive gel containing entrapped CO₂ bubbles. This forms raft layer on top of gastric fluid which releases drug slowly in stomach. Such formulation typically contains antacids such as aluminium hydroxide or calcium carbonate to reduce gastric acidity. They are often used for gastro esophageal reflux treatment as with Liquid Gaviscon (GlaxoSmithKline) ³⁹. (Figure 11)

Fig. 11: Barrier formed by a raft-forming system

Drugs Used In the Formulations of Stomach Specific

Floating Dosage Forms

· Floating microspheres – Aspirin, Griseofulvin, pnitroaniline, Ibuprofen, Ketoprofen⁴⁰, Piroxicam, Verapamil HCl, Cholestyramine, Theophylline, Nifedipine, Nicardipine, Dipyridamol, Tranilast⁴¹ and Terfinadine⁴²

· Floating granules - Diclofenac sodium, Indomethacin and Prednisolone

· Films⁴³ – Cinnarizine, Albendazole

· Floating tablets and Pills - Isosorbide mononitrate³⁷, Diltiazem⁴⁴, Acetylsalicylic acid⁴⁵, Piretanide⁴⁶, Sotalol⁴⁷, carbamazepine, Furosamide⁴⁸, Pentoxyphylline⁴⁹, captopril⁵⁰, Nimodipine⁵¹, Acetaminophen⁵², Amoxicillin trihydrate⁵³, Diazepam⁵⁴

· Floating Capsules –Diazepam⁵⁵, Ursodeoxycholic acid⁴⁹, Verapamil HCl⁵⁶, Nicardipine⁵⁷, Furosemide⁵⁸, Misoprostal⁴

Commercial Gastroretentive Floating Formulations given in table 1.

Application:

Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability. These are summarized as follows.

1. Sustained Drug Delivery

HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of G1 as a result of which they can float on the gastric contents. These systems are relatively large in size and passing from the pyloric opening is prohibited. Recently sustained release floating capsules of nicardipine hydrochloride were developed and were evaluated in vivo. The formulation compared with commercially available MICARD capsules using rabbits. Plasma concentration time curves showed a longer duration for administration (16 hours) in the sustained release floating capsules as compared with conventional MICARD capsules (8 hours)⁵⁷. Similarly a comparative study between the Madopar HBS and Madopar standard formulation was done and it was shown that the drug was released up to 8 hours in vitro in the former case and the release was essentially complete in less than 30 minutes in the latter case⁵⁹.

2. Site-Specific Drug Delivery

These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine, e.g. riboflavin and furosemide. Furosemide is primarily absorbed from the stomach followed by the duodenum. It has been reported that a monolithic floating dosage form with prolonged gastric residence time was developed and the bioavailability was increased. AUC obtained with the floating tablets was approximately 1.8 times those of conventional furosemide tablets⁵⁸. A bilayer-floating capsule was developed for local delivery of misoprostol, which is a synthetic analog of prostaglandin E1 used as a protectant of gastric ulcers caused by administration of NSAIDs. By targeting slow delivery of misoprostol to the stomach, desired therapeutic levels could be achieved and drug waste could be reduced⁴.

3. Absorption Enhancement:

Drugs that have poor bioavailability because of sitespecific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption.

E.g. A significantly increase in the bioavailability of floating dosage forms(42.9%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric coated LASIX-long product (29.5%)⁵⁷.

EVALUATION OF GASTRORETENTIVE DOSAGEFORM

A) IN-VITRO EVALUATION⁶²,⁶³

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 test⁶⁴.

b) Floating Time

Test for buoyancy is usually performed in SGF-Simulated Gastric Fluid maintained at 37⁰C. The time for which the dosage form continuously floats on the dissolution media is termed as floating time⁶⁵.

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 (figure 11).

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

F = F_buoy - F_gravF = D_f g V – D_s g 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

So when Ds, density of dosage form is lower, F force is positive gives buoyancy and when it is Ds is higher, F will negative shows sinking²¹.

Fig. 12: Graph of resultant weight

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

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^{66, 67}(figure 13).

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:

1. Enhanced bioavailability the bioavailability of some drugs (e.g. riboflavin and levodopa) CR-GRDF is significantly enhanced in comparison to administration of non- GRDF CR polymeric formulations⁶⁸.

2. Enhanced first-pass biotransformation when the drug is presented to the metabolic enzymes (cytochrome P-450, in particular CYP-3A4) in a sustained manner, the presystemic metabolism of the tested compound may be considerably increased rather than by a bolus input⁶⁹.

3. Sustained drug delivery/reduced frequency of dosing the drugs having short biological half life, a sustained and slow input from FDDS may result in a flip-flop pharmacokinetics and it reduces the dose frequency. This feature is associated with improved patient compliance and thus improves the therapy⁶⁹.

4. Targeted therapy for local ailments in the upper GIT the prolonged and sustained administration of the drug from FDDS to the stomach may be useful for local therapy in the stomach.

5. Reduced fluctuations of drug concentration the fluctuations in plasma drug concentration 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 index⁷⁰.

6. Improved receptor activation selectivity FDDS reduces the drug concentration fluctuation that makes it possible to obtain certain selectivity in the elicited pharmacological effect of drugs that activate different types of receptors at different concentrations⁶⁹.

7. Reduced counter-activity of the body slow release of the drug into the body minimizes the counter activity leading to higher drug efficiency.

8. Extended time over critical (effective) 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.

9. Minimized adverse activity at the colon Retention of the drug in GRDF at stomach minimizes the amount of drugs that reaches the colon and hence prevents the degradation of drug that degraded in the colon.

10. Site specific drug delivery a floating dosage form is a widely accepted approach especially for drugs which have limited absorption sites in upper small intestine.

Limitations/Disadvantages^71,
72

These systems require a high level of fluid in the stomach for drug delivery tom float and work efficiently-coat, water.

· Not suitable for drugs that have solubility or stability problem in GIT.

· Drugs such as Nifedipine which is well absorbed along the entire GIT and which undergoes first pass metabolism, may not be desirable.

· Drugs which are irritant to Gastric mucosa are also not desirable or suitable.

· The drug substances that are unstable in the acidic environment of the stomach are not suitable candidates to be incorporated in the systems.

· The dosage form should be administered with a full glass of water (200-250 ml).

These systems do not offer significant advantages over the conventional dosage forms for drugs, which are absorbed throughout the gastrointestinal tract.

CONCLUSION:

Drug absorption in the gastrointestinal tract is a highly variable procedure and prolonging gastric retention of the dosage form extends the time for drug absorption. FDDS promises to be a potential approach for gastric retention. The FDDS proves advantageous for drugs that are absorbed primarily in the upper segments of GI tract, i.e., the stomach, duodenum, and jejunum when compared to the conventional dosage form. Due to the complexity of pharmacokinetic and pharmacodynamic parameters, in vivo studies are required to establish the optimal dosage form for a specific drug. For a certain drug, interplay of its pharmacokinetic and pharmacodynamic parameters will determine the effectiveness and benefits of the CRGRDF compared to the other dosage forms.

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Received on 13.01.2012

Modified on 20.01.2012

Accepted on 29.01.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(2): March-April 2012, 93-103