Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control the emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms⁴. Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states. During the fasting state an interdigestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours. This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases-

Phase I– Period of no contraction (30-60 minutes)

Phase II– Period of intermittent contractions (20-40 minutes)

Phase III– Period of regular contractions at the maximal frequency also known as housekeeper

wave (10-20 minutes)

Phase IV– Period of transition between Phase III and Phase I (0-5 minutes)

Figure 1. Motility patterns of the GIT in the fasted state

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 Scintigraphic studies determining gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to basically 2 complications, that of short gastric residence time and unpredictable gastric emptying rate.

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 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 emptied from the stomach. This results in an increased GRT and a better control of fluctuations in plasma drug concentration. Floating drug Delivery systems are classified depending on the use of 2 formulation variables:

EFFERVESCENT AND NON-EFFERVESCENT SYSTEMS: -

A. Effervescent Floating Dosage Forms:-

1) Volatile liquid containing system: -

The GRT of a drug delivery system can be sustained by incorporating an inflatable chamber, which contains a liquid e.g. ether, cyclopentane, that gasifies at body temperature to cause the infatuation of the chamber in the stomach. The device may also consist of a bioerodible plug made up of PVA, Polyethylene, etc. that gradually dissolves causing the inflatable chamber to release gas and collapse after a predetermined time to permit the spontaneous ejection of the inflatable systems from the stomach. Developed floating capsules composed of a plurality of granules that have different residence times in the stomach and consist of an inner foamable layer of gas-generating agents. This layer was further divided into 2 sublayers, the outer containing sodium bicarbonate and the inner containing tartaric acid. This layer was surrounded by an expansive polymeric film (composed of poly vinyl acetate [PVA] and shellac), which allowed gastric juice to pass through, and was found to swell by foam produced by the action between the gastric juices and the gas-generating agents. It was shown that the Swellable membrane layer played an important role in maintaining the buoyancy of the pills for an extended period of time.

2) Gas-generating Systems:

These buoyant delivery systems utilize effervescent reactions between carbonate/bicarbonate salts and citric/tartaric acid to liberate CO2, which gets entrapped in the gellified hydrocolloid layer of the systems thus decreasing its specific gravity and making it to float over chyme.^{5, 6.}

B. Non-effervescent systems:

1. Colloidal gel barrier systems Hydrodymamically balance system (HBSTM) was first design by Sheth and Tossounian in 1975.Such systems contains drug with gel forming hydrocolloids meant to remain buoyant on stomach contents. This system incorporate a high level of one or more gel forming highly swellable cellulose type hydrocolloids.e.g.HEC, HPMC, NaCMC, Polysacchacarides and matrix forming polymer such as polycarbophil, polyacrylates and polystyrene, incorporated either in tablets or in capsule. On coming in contact with gastric fluid, the hydrocolloid in the system hydrates and forms a colloidal gel barrier around the gel surface. The air trapped by the swollen polymer maintains a density less than unity and confers buoyancy to this dosage forms. ⁷

2. Microporous Compartment System This technology is based on the encapsulation of drug reservoir inside a Microporous compartment with aperture along its top and bottom wall. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of the gastric mucosal surface with the undissolved drug. In stomach the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents. Gastric fluid enters throughthe apertures, dissolves the drug, and carries the dissolve drug for continuous transport across the intestine for absorption.

3. Alginate beads Multiple unit floating dosage forms have been developed from freeze-dried 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 fource over 12 hours.

4. Hollow Microspheres Hollow microspheres (microballons), loaded with ibuprofen in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method. The ehanol: dichloromethane solution of the drug and an enteric acrylic polymer was poured in to an agitated aqueous solution of PVA that was thermally controlled at 40°C.The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane formed in internal cavity in microspheres of the polymer with drug. The microballons floated continuously over the surface of acidic dissolution media containing surfactant for greater than 12 hours in vitro.

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 (given in the Fig. 2A), 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. 2B). 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^8.

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 gravity⁹.

Factors Affecting the Floating and Floating Time -

1. Density: - Floating is a function of dosage form buoyancy that is dependent on the density.

2. Shape of dosage form: - Tetrahedron and ring shaped devices with flexural modules of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better floating, 90% to 100% retention at 24 hours compared with other shapes¹⁰.

3. Concomitant drug administration: - Anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride; can affect floating time.

4. Fed or unfed state: - Under fasting conditions, the GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (MMC) that occurs every 1.5 to 2 hours¹¹

5. Nature of meal: - Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release¹².

6. Caloric content and feeding frequency: - Floating can be increased by four to 10 hours with a meal that is high in proteins and fats. The floating can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC.

7. Age: - Elderly people, especially those over 70, have a significantly longer; floating¹³. Disease condition such as diabetes and crohn’s disease etc also affect drug delivery.

8. Posture: - Floating can vary between supine and upright ambulatory states of the patient^14.

ADVANTAGES OF FLOATING DRUG DELIVERY SYSTEM

1. The Gastroretentive systems are advantageous for drugs absorbed through the stomach. E.g. Ferrous salts, antacids.

2. Acidic substances like aspirin cause irritation on the stomach wall when come in contact with it. Hence HBS formulation may be useful for the administration of aspirin and other similar drugs.

3. Administration of prolongs release floating dosage forms, tablet or capsules, will result in dissolution of the drug in the gastric fluid. They dissolve in the gastric fluid would be available for absorption in the small intestine after emptying of the stomach contents. It is therefore expected that a drug will be fully absorbed from floating dosage forms if it remains in the solution form even at the alkaline pH of the intestine. ^15,16

4. The gastro retentive systems are advantageous for drugs meant for local action in the Stomach. E.g. antacids.

5. When there is a vigorous intestinal movement and a short transit time as might occur in certain type of diarrhea, poor absorption is expected. Under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.

6. The gastroretentive systems are advantageous for drugs absorbed through the stomach, e.g. ferrous salts, antacids.

7. Acidic substances like aspirin cause irritation on the stomach wall when come in contact with it. Hence, HBS formulation may be useful for the administration of aspirin and other similar drugs.

8. Administration of prolongs release floating dosage forms, tablet or capsules, will result in dissolution of the drug in the gastric fluid. They dissolve in the gastric fluid would be available for absorption in the small intestine after empty-ing of the stomach contents. It is therefore expected that a drug will be fully absorbed from floating dosage forms if it remains in the solution form even at the alkaline pH of the intes-tine.

9. The gastro retentive systems are advantageous for drugs meant for local action in the stomach. E.g. antacids.

10. FDDS improves patient compliance by decreas-ing dosing frequency.

11. Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration are avoided; a desirable plasma drug concentration is maintained by continuous drug release.

12. Better therapeutic effect of short half-life drugs can be achieved.

13. Gastric retention time is increased because of buoyancy.

14. Enhanced absorption of drugs which solubilize only in stomach.

15. Avoidance of gastric irritation, because of sustained release effect, floatability and uniform release of drug through multi particulate sys-tem.¹⁶

DISADVANTAGES OF FLOATING DRUG DELIVERY SYSTEM

1. Floating system is not feasible for those drugs that have solubility or stability problem in G.I. tract.

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

3. The drugs that are significantly absorbed through out gastrointestinal tract, which undergo significant first pass metabolism, are only desirable candidate.

4. Floating system is not feasible for those drugs that have solubility or stability problem in G.I. tract.

5. Some drugs present in the floating system causes irritation to gastric mucosa

APPLICATION OF FLOATING DRUG DELIVERY SYSTEMS

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 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 <1 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. Eg. 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).¹⁷

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, eg, riboflavin and furosemide. Eg. 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 tablets.¹⁸

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. Eg. 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%).¹⁹

Evaluation of Floating Drug Delivery Systems

Various parameters that need to be evaluated in gastroretentive formulations include floating duration, dissolution profiles, specific gravity, content uniformity, hardness, and friability in case of solid dosage forms²⁰. In the case of multiparticulate drug delivery systems, differential scanning calorimetry (DSC), particle size analysis, flow properties, surface morphology, and mechanical properties are also performed.

A. In Vitro Methods

1) Floating lag time and floating time: The test for floating time measurement is usually performed in stimulated gastric fluid or 0.1 N HCl maintained at 37 °C. It is determined by using USP dissolution apparatus containing 900 ml of 0.1 N HCl as dissolution medium at 37 0C. The time taken by the dosage form to float is termed as floating lag time and the time for which the dosage form floats is termed as the floating or flotation time. The system to check continuous floating behavior contains a stainless steel basket connected to a metal string and suspended from a Sartorius electronic balance²¹.A lotus- spread sheet could automatically pick up the reading on the balances. Test medium used in floating kinetics measurements was 900 ml simulated gastric fluid (pH 1.2) maintained at 37°C, data was collected at 30 sec interval; baseline was recorded and subtracted from each measurement. Dissolution basket had a holder at the bottom to measure the downward force.

2) Dissolution study Gohel et al proposed a more relevant in vitro dissolution method to evaluate a floating drug delivery system (for tablet dosage form). A 100-mL glass beaker was modified by adding a side arm at the bottom of the beaker so that the beaker can hold 70 ml of 0.1 mole.lit-1 HCl dissolution medium and allow collection of samples. A burette was mounted above the beaker to deliver the dissolution medium at a flow rate of 2 ml/min to mimic gastric acid secretion rate. The performance of the modified dissolution apparatus was compared with USP dissolution Apparatus 2 (Paddle). The problem of adherence of the tablet to the shaft of the paddle was observed with the USP dissolution apparatus²². The tablet did not stick to the agitating device in the proposed dissolution method. The drug release followed zero-order kinetics in the proposed method. The proposed test may show good in vitroin vivo correlation since an attempt is made to mimic the in vivo conditions such as gastric volume, gastric emptying, and gastric acid secretion rate²³.

3) Swelling index An in vitro measuring apparatus has been conceived to determine the real floating capabilities of buoyant dosage forms as a function of time. It operates by measuring the force equivalent to the force F required to keep the object totally submerged in the fluid²⁴.This force determines the resultant weight of the object when immersed and may be used to quantify its floating or no floating capabilities²⁵. The magnitude and direction of the force and the resultant weight corresponds to the vectorial sum of buoyancy (F bouy) and gravity (F grav) forces acting on the object as shown in thee quation

F = F buoy – F grav

F = d f gV – d s gV = (d f - d s) gV

F = (df – M / V) gV

in which F is the total vertical force (resultant weight of the object), g is acceleration due to

Gravity, d f is the fluid density, d s is the object density, M is the object mass, and V is the volume of the object. By convention, a positive resultant weight signifies that the force F is exerted upward and that the object is able to float, whereas a negative resultant weight means that the force F acts downward and that the object sinks ^26,27.

B. In vivo method

1) X-Ray method - X-Ray is a very popular evaluation parameter for floating dosage form now a day.²⁹ It helps to locate dosage form in the g.i.t. and by which one can predict and correlate the gastric emptying time and the passage of dosage form in the GIT. Here the inclusion of a radio-opaque material into a solid dosage form enables it to be visualized by Xrays²⁶.

2) gamma-Scintigraphy - Gamma -Emitting radioisotopes compounded into CR-DFs has become the state-of-art for evaluation of gastroretentive formulation in healthy volunteers. A small amount of a stable isotope e.g. Sm, is compounded into DF during its preparation. The main drawbacks of gamma - scintigraphy are the associated ionizing radiation for the patient, the limited topographic information, low resolution inherent to the technique and the complicated and expensive preparation of radiopharmaceuticals²⁷.

3) Gastroscopy - It comprises of peroral endoscopy, used with a fibereoptic and video systems. It is suggested that gastroscopy may be used to inspect visually the effect of prolonged stay in stomach milieu on the FDDS. Alternatively, FDDS may be drawn out of the stomach for more detailed evaluation^{28, 29}.

4) Ultrasonography - Ultrasonic waves reflected substantially different acoustic impedances across interface enable the imaging of some abdominal organs. Most DFs do not have sharp acoustic mismatches across their interface with the physiological milieu. Therefore, Ultrasonography is not routinely used for the evaluation of FDDS. The characterization included assessment of intragastric location of the hydrogels, solvent penetration into the gel and interactions between gastric wall and FDDS during peristalsis³⁰.

CONCLUSION:

Recently many drugs have been formulated as floating drug delivery systems with an objective of sustained release and restricting the region of drug release to stomach. The principle of buoyant Preparation offers a simple and practical approach to achieve increased gastric residence time for the dosage form and sustained drug release. The currently available polymer‐mediated non effervescent and effervescent FDDS, designed on the basis of delayed gastric emptying and buoyancy principles, appear to be a very much effective approach to the modulation of controlled oral drug delivery. The most important criteria which has to be looked into for the productions of a floating drug delivery system is that the density of the dosage form should be less than that of gastric fluid. And hence, it can be concluded that these dosage forms serve the best in the treatment of diseases related to the GIT and for extracting a prolonged action from a drug with a short half life.

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Received on 06.08.2013

Modified on 30.08.2013

Accepted on 02.09.2013

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(6): November-December, 2013, 371-377