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Pharma Utility Volume 7, Issue 1, 2013

http://www.pharmautility.com

Review Article

Floating Drug Delivery Systems: A critical analysis

Author: Sudhir Pandya

NuLife Pharmaceuticals, Pimpri, Pune, MS, India. Pin- 411018

Email: [email protected]

ABSTRACT

Oral controlled drug delivery systems should be designed in order to achieve more predictable

and increased bioavailability of drugs. Sophisticated oral dosage forms such as controlled drug

delivery systems are playing major role. Such systems release drug at predetermined rate, as

determined by drug pharmacokinetics and desired therapeutic concentration. While optimizing

the delivery systems physiological challenges, such as short gastric residency, varying gastric

emptying and other factors are always the point of focus. Approaches that are currently utilized

in the prolongation of the gastro residency include floating drug delivery systems (FDDS),

swelling and expanding systems, polymeric bioadhesive systems, high-density systems,

modified-shape systems and other delayed gastric emptying devices. It is evident from the recent

scientific and patent literature that an increased interest in novel dosage forms that are retained in

the stomach for a prolonged and predictable period of time exists today in academic and

industrial research groups. One of the most feasible approaches for achieving a prolonged and

predictable drug delivery profile in the GI tract is to control the gastric residence time (GRT).

Dosage forms with a prolonged GRT, i.e. gastro-retentive dosage forms (GRDFs), provide new

and important therapeutic options.

Keywords: floating drug delivery, oral drug delivery, and gastric emptying time, drug retention

mailto:[email protected]

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INTRODUCTION

The design of an oral controlled drug delivery system should be primarily aimed at achieving

more predictable and increased bioavailability of drugs. Over the years, oral dosage forms have

become increasingly sophisticated with major role being played by controlled release drug

delivery systems. Such systems release drug at predetermined rate, as determined by drug

pharmacokinetics and desired therapeutic concentration.

The development of such systems is precluded by several physiological difficulties such as:

a. Inability to restrain and localise the drug delivery system within the desired range of

gastrointestinal tract and

b. Highly variable nature of gastric emptying process.

This variability may lead to unpredictable bioavailability and times to achieve peak plasma

levels, since the majority of drugs are preferentially absorbed in upper part of small intestine [1].

Gastric emptying time in humans is normally 2-3 hours through the major absorption zone

(stomach or upper part of the intestine), which may lead to incomplete drug release from the

dosage form resulting in diminished efficacy of administered dose. The intimate contact of the

drug delivery system (DDS) with the absorbing membrane has the potential to maximize drug

absorption and may also influence the rate of drug absorption [2, 3].

It is evident from the recent scientific and patent literature that an increased interest in novel

dosage forms that are retained in the stomach for a prolonged and predictable period of time

exists today in academic and industrial research groups. One of the most feasible approaches for

achieving a prolonged and predictable drug delivery profile in the GI tract is to control the

gastric residence time (GRT). Dosage forms with a prolonged GRT, i.e. gastro-retentive dosage

forms (GRDFs), provide new and important therapeutic options.

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ADVANTAGES OF GRDF’S

1. Sustained drug delivery:

Drug absorption from oral controlled release dosage forms is often limited by the short GRT

available for absorption. However, hydrodynamically balanced system (HBS) type forms

can remain in the stomach for several hours and, therefore, significantly prolong the GRT of

numerous drugs.

These special dosage forms are light, relatively large in size and do not easily pass through

the pylorus, which has an opening of approximately 0.9 – 1.9 cm [4]. It is worth noting here

that a prolonged GRT is not responsible for the slow absorption of a lipophilic drug such as

Isradipine that has been achieved with a ‘floating’ modified-release capsule [5]. This is

because the major portion of drug release from modified-release capsule took place in the

colon, rather than in the stomach. However, the assumed prolongation in the GRT is

postulated to cause the sustained drug-release behaviour [6].

2. Site-specific drug delivery:

For drugs such as Furosemide and Riboflavin, which have limited absorption sites in the

small intestine rather than in the stomach, floating dosage form is a feasible approach. In

fact, the absorption of Furosemide has been found to be site-specific, the stomach being the

major site of absorption, followed by the duodenum [7].

This property prompted the development of a monolithic floating dosage form for

Furosemide, which could prolong the GRT, and thus its bioavailability was increased [8].

Recently, a bilayer floating capsule has been used to achieve local delivery of Misoprostol, a

synthetic prostaglandin E analog which is approved and marketed in the United States (as

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Cytotec by Pharmacia United States of America) for prevention of gastric ulcers caused by

non-steroidal anti-inflammatory drugs [9].

Floating tablets containing 20–50 mg of 5-fluorouracil have been successfully evaluated in

four patients with stomach neoplasms in which tablets floated in the stomach for period of 2

hours after administration [10].

3. Pharmacokinetic advantages:

Drugs that have poor bioavailability owing to their absorption from the upper Gastro

Intestinal (GI) tract can be delivered efficiently, thereby maximizing their absorption and

improving their absolute bioavailability. For instance, a significant increase in the absolute

bioavailability of the floating dosage form of Furosemide has been obtained (42.9%),

compared to the commercial available tablet (Lasix; 33.4% Aventis Pharmaceuticals Inc.)

and enteric product (Lasix long; 29.5% Aventis Pharmaceuticals Inc). [11]

The reduced fluctuations in the plasma levels of drugs result from delayed gastric emptying.

After oral dosing the bioavailability of standard Madopar (Levodopa and Benserazide,

Roche USA) was found to be 60–70%; the difference in bioavailability of standard and HBS

formulations seems to be due to incomplete absorption rather than an altered disposition of

the drug [12].

Cook et al. demonstrated that a HBS capsule containing iron salts has an increased efficacy

and reduced side effects. Floating dosage forms with sustained release characteristic can also

be expected to reduce the variability in transit performance [13] and various

pharmacokinetic parameters [14]. It might be expected that developing HBS dosage form for

Tacrine might provide a better delivery system and reduce its GI side effects in Alzheimer’s

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patients. In addition, buoyant delivery systems might provide a beneficial strategy for the

treatment of gastric and duodenal cancers [1]. The concept of Floating Drug Delivery

System (FDDS) has also been utilized in the development of various anti-reflux

formulations. (Figure 1)

Figure 1 HBS Capsule

Another therapeutic area in which FDDS can be explored is in the formulations intended for the

eradication of Helicobacter pylori, which is now believed to be the causative bacterium for

chronic gastritis and peptic ulcers. Although the bacterium is highly sensitive to most antibiotics,

its eradication from patients requires high concentrations of drug to be maintained within the

gastric mucosa for a long duration [15]. Recently Katayama et al [16] developed a sustained

release liquid preparation of Ampicillin using Sodium Alginate that spreads out and adheres to

the gastric mucosal surface whereby the drug is continuously released. Thus, it can be expected

that topical delivery of a narrow spectrum antibiotic through a FDDS may result in complete

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removal of the organisms in the fundal area of the gastric mucosa due to bactericidal drug levels

being reached in this area, and might lead to better treatment of peptic ulcer disease.

LIMITATIONS

One of the disadvantages of floating systems is that they require sufficiently high level of fluids

in the stomach for the drug delivery to float therein and to work efficiently. However, this

limitation can be overcome by coating the dosage form with bio adhesive polymers, thereby

enabling them to adhere to the mucous lining of the stomach wall. Alternatively, the dosage form

may be administered with a glass full of water (200–250 ml). Floating systems are not feasible

for those drugs that have solubility or stability problems in gastric fluids. Drugs such as

Nifedipine, which is well absorbed along the entire GI tract and which undergoes significant

first-pass metabolism, may not be a desirable candidate for FDDS, since the slow gastric

emptying may lead to reduced systemic bioavailability [1]. Also there are limitations to the

applicability of FDDS for drugs that irritate gastric mucosa.

MECHANISTIC APPROACHES OF FDDS

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, modified shape

systems, gastric-emptying delaying devices and co-administration of gastric-emptying delaying

drugs. Among these, the floating dosage forms have been used most commonly. However, most

of these approaches are influenced by a number of factors that affect their efficacy as a

gastroretentive system: [18, 19] (Figure 2)

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Figure 2 Mechanism of floating systems

(GF- Gastric Fluid, RW- Resultant Weight)

It is very important that the floatation occurs as rapidly as possible in order to avoid the

pharmaceutical composition being expelled from the stomach. It is considered that if it does not

float within three minutes following absorption in a fasting subject the probability that it is

evacuated from the stomach becomes unacceptable. [20]

FACTORS AFFECTING PERFORMANCE OF FDDS [21]

A. Dosage form related factors:

1. Density – GRT is a function of dosage form buoyancy that is dependent on the density.

2. Size – Dosage form units with a diameter of more than 7.5mm are reported to have

increased GRT compared with those with a diameter of 9.9mm.

3. Shape of dosage form – Tetrahedron and ring shaped devices with a flexural modulus

of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT,

approximately 90% to 100% retention at 24 hours compared with other shapes;

4. Single or multiple unit formulation – multiple unit formulations show a more predictable

release profile and insignificant impairing of performance due to failure of units, allow

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co-administration of units with different release profiles or containing incompatible

substances and permit a larger margin of safety against dosage form failure compared

with single unit dosage forms.

B. Patient related factors:

Fed or unfed state – Under fasting conditions, the GI motility is characterized by

periods of strong motor activity or the MMC that occurs every 1.5 to 2 hours. The

MMC sweeps undigested material from the stomach and, if the timing of

administration of the formulation coincides with that of the MMC, the GRT of the

unit can be expected to be very short. However, in the fed state, MMC is delayed and

GRT is considerably longer.

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 release;

Caloric content – GRT can be increased by four to ten hours with a meal that is high in

proteins and fats.

Frequency of feed – The GRT can increase by over 400 minutes when successive

meals are given compared with a single meal due to the low frequency of MMC.

Gender – Mean ambulatory GRT in males (3.4±0.6hours) is less compared with their

age and race matched female counterparts (4.6±1.2 hours), regardless of the weight,

height and body surface.

Age – Elderly people, especially those over 70, have a significantly longer GRT.

Posture – GRT can vary between supine and upright ambulatory states of the patient.

Concomitant drug administration – Anticholinergics like Atropine and Propantheline,

opiates like codeine and prokinetic agents like Metoclopramide and Cisapride affect

GRT.

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Biological factors – Diabetes and Crohn’s disease alter GRT.

TECHNOLOGICAL DEVELOPMENTS

Floating systems, first described by Davis [22] in 1986 have bulk density lower than that of the

gastric fluid, and thus remains buoyant in stomach for a prolonged period. While the system is

floating on the gastric components, the drug is released slowly at the desired rate. This results in

increase in the GRT and a better control of fluctuations in the plasma drug concentrations.

Floating systems can be classified into two distinct categories, non-effervescent and effervescent

systems.

A. NON-EFFERVESCENT SYSTEMS

1. Colloidal gel barrier systems

Hydrodynamically balanced system (HBSTM

) contain drug with gel forming hydrocolloids

meant to remain buoyant on the stomach contents. This prolongs GI residence time,

maximizes drug reaching its absorption site in the solution form, and hence is ready for

absorption. These systems incorporate high level (20 to 75 % w/w) of one or more gel

forming highly swellable cellulose type hydrocolloids [for eg. Hydroxyethyl cellulose

(HEC), Hydroxypropyl Cellulose (HPC) Hydroxypropyl Methyl Cellulose (HPMC), Sodium

Carboxy Methyl Cellulose (NaCMC) [23], polysaccharides and matrix forming polymers

such as polycarbophill, polyacrylates and polystyrene, incorporated either in tablets or

capsules. On coming in contact with the gastric fluid, the hydrocolloid in the system

hydrates and forms a colloidal gel barrier around its surface. (Figure 3)

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Figure 3 Intragastric floating tablet

This gel barrier controls the rate of the fluid penetration into the device and consequent

release of drug. [23] As the exterior surface of the dosage form goes in to the solution, the

gel layer is maintained by the adjacent hydrocolloid layer becoming hydrated. The air

trapped in by the swollen polymer maintains density less than unity and confers buoyancy to

these dosage forms.

The HBS TM

must comply with three major criteria:

1. It must have sufficient structure to form cohesive gel barrier.

2. It must maintain an overall specific density lower than that of gastric contents.

3. It should dissolve slowly enough to serve as reservoir for the delivery system.

A bilayered tablet can also be prepared to contain one immediate release and other

sustained release layer (Figure 4)

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Figure 4 Bilayer intragastric floating tablet

Immediate release layer delivers the initial dose, whereas Sustained Release layer absorbs

gastric fluid and forms a colloidal gel barrier on its surface. This results in system with bulk

density lesser than that of gastric fluid and allows it to remain buoyant in the stomach for an

extended period of time [24].

A multi-layer, flexible, sheath-like device buoyant in gastric juice showing sustained release

characteristics has also been developed [25]. The device consisted of at least one self-

supporting carrier film made up of water insoluble polymer matrix having a drug

dispersed/dissolved therein, and a barrier film overlaying a carrier film. Both carrier and

barrier films were sealed together along their periphery and in such a way as to entrap a

plurality of small air pockets leading to buoyancy of laminated films.

2. Microporous compartment system.

This technology is based on encapsulation of a drug reservoir inside a microporous

compartment with aperture along its top and bottom walls. The peripheral walls of the drug

reservoir compartment are completely sealed to prevent any direct contact of gastric

mucosal surface with undissolved drug. In stomach, the floatation chamber containing

entrapped air causes the delivery system to float over the gastric contents. Gastric fluid

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enters through the aperture, dissolves the drug, and carries the dissolved drug for continuous

transport across the intestine for absorption. The microporous compartment system is shown

in (Figure 5) [26].

Figure 5 Microporous intragastric floating drug delivery device

Intragastric floating and sustained release granules of diclofenac sodium were developed

using HPC, Ethyl Cellulose and Calcium silicate as floating carriers, which had a

characteristically porous structure with numerous pores and a large individual pore volume

[26]. The coated granules acquire floating ability from the air trapped in the pores of

Calcium Silicate when they were coated with a polymer.

3. Alginate beads:

Multiunit floating dosage forms have been developed from freeze-dried Calcium alginate

[27]. Spherical beads of approximately 2.5mm in diameter can be prepared by dropping a

Sodium alginate solution in to aqueous solution of Calcium chloride, causing a precipitation

of Calcium alginate. The beads are then separated; snap frozen in liquid nitrogen, and

freeze-dried at - 40oC for 24 hours, leading to formation of porous system, which can

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maintain floating force for over 12 hrs. When compared with solid beads, which gave a short

residence time of 1 hour, these floating beads gave a prolonged residence time of more than

5.5 hours.

Floating systems comprising of Calcium alginate core separated by an air compartment from

a membrane of Calcium alginate or a Calcium alginate/Polyvinyl Alcohol (PVA) have also

been developed [28]. The porous structure generated by leaching of PVA (water soluble

additive in coating composition) was found to increase membrane permeability, preventing

the collapse of air compartment.

4. Hollow microspheres.

Hollow microspheres (micro balloons), loaded with Ibuprofen in their outer polymer shells

were prepared by novel emulsion solvent diffusion method. The ethanol: dichloromethane

solution of the drug and an enteric acrylic polymer was poured into an agitated aqueous

solution of PVA that was thermally controlled at 40oC. The gas phase generated in dispersed

polymer droplet by evaporation of dichloromethane formed an internal cavity in

microsphere of polymer with drug (Figure 6). The micro balloons floated continuously over

surface of acidic solution media containing surfactant for greater than 12 hours in vitro. The

drug release was high in pH 7.2 than in pH 6.8 [29].

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Figure 6 Mechanism of micro balloon formation by emulsion-solvent diffusion method.

5. Non Compressed Dosage form

This unique therapeutic dosage form comprises of therapeutically effective agent, gelling

agent in the concentration of 0.5 to 4 % along with 10 – 20% therapeutically acceptable inert

oil & water. The dosage form may also contain other conventional additives and excipients

such as thickening agents, surfactants, preservatives, bulking agents and antioxidants.[30]

These dosage forms, which are in the form of tablets, although not compressed, have

sufficient mechanical stability & hardness so that they will withstand the normal stress of

production, packaging and dispensing. They have a density which is less than one and

sufficiently low so that they will float on gastric fluid. Typically density is from about 0.6 to

0.95.

Except for agents which must be protected from in gastric fluid this novel dosage form is

applicable to therapeutic agents which include analgesics, anorexias, antacids, antibiotics,

antidiabetics, antihistamines, steroids, antispasmodics, cardiovascular preparations,

decongestants, muscle relaxants, diuretics, tranquilizers, & vitamins. [31]

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B. Effervescent Systems:

A drug delivery system can be made to float in the stomach by incorporating a floating chamber,

which may be filled with vacuum, air or inert gas. The gas in floating chamber can be introduced

either by volatilization of an organic solvent or by effervescent reaction between organic acids

and bicarbonate salts.

1. Volatile liquid containing systems:

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 inflation of the chamber in the stomach. These devices are osmotically controlled

floating systems containing a hollow deformable unit that can convert from a collapsed to an

expanded position, and returns to collapsed position after an extended period. A deformable

system consists of two chambers separated by an impermeable, pressure responsive,

movable bladder. The first chamber contains the drug and the second chamber contains

volatile liquid. The device inflates, and the drug is continuously released from the reservoir

into the gastric fluid. The device may also consist of 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

system from the stomach (Figure 7) [32].

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Figure 7 Intragastric osmotic controlled drug delivery system

Intragastric osmotically controlled drug delivery system consists of an osmotic pressure

controlled drug delivery device and an inflatable floating support in bioerodible capsule.

When the device reaches the stomach, bioerodible capsule quickly disintegrates to release

the drug delivery system. The floating support is made up of a deformable hollow polymeric

bag containing a liquid that gasifies at body temperature to inflate the bag. The osmotic

pressure controlled part consists of two compartments, a drug reservoir compartment, and an

osmotically active agent containing compartment. The drug reservoir compartment is

enclosed in a pressure responsive collapsible bag, which is impermeable to vapours and

liquid, and has a drug delivery orifice. The osmotic compartment contains an osmotically

active salt, and is enclosed within semipermeable housing. In stomach, water is absorbed

through the semipermeable membrane into the osmotic compartment to dissolve the salt. An

osmotic pressure is thus created, which acts on collapsible bag, and in turn forces the drug

reservoir compartment to reduce its volume and release the drug solution through the

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delivery orifice. The floating support also contains a bioerodible plug that erodes after a

predetermined time to deflate the support, which is then excreted from the stomach (Figure

8) [33].

2. Gas generating system:

These buoyant delivery systems utilize effervescent reaction between carbonate/ bicarbonate

salts and citric/ tartaric acid to liberate CO2, which gets entrapped in the gellified

hydrocolloid layer of the system, thus decreasing its specific gravity and making it float over

chyme. These tablets may be either single layered wherein the CO2 generating components

are intimately mixed within the tablet matrix, or they may be bilayered in which the gas

generating components are compressed in one hydrocolloid containing layer, and the drug in

outer layer for sustained release effect.

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Multi-unit types of floating pills (Figure 9), which generate CO2, have also been developed

[34]. The system consists of sustained release pill as a seed, surrounded by double layers.

The inner layer is an effervescent layer containing sodium bicarbonate and tartaric acid. The

outer layer is swellable membrane layer. These kinds of systems float completely within 10

minutes, and remain floating over extended period of 5-6 hours [35].

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Figure 9 Multiple unit oral floating dosage systems

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EVALUATION OF FDDS

Evaluation of a drug product is a tool to ensure

(1) performance characteristics, and

(2) control batch-to-batch quality,

(3) General appearance, hardness and friability, drug content, weight variation, uniformity of

content, drug release, etc, for gastro retentive performance.

1. Floating time:

The test for buoyancy is usually performed in simulated gastro intestinal fluids maintained at

37 0C. The floating time is determined by using the USP dissolution apparatus containing

900ml of 0.1N HCL as the testing medium maintained at 37 0C. The time for which the

dosage form floats is termed as the floating or floatation time.[36]

2. Specific gravity:

The specific gravity of floating systems can be determined by the displacement method

using benzene as a displacing medium [37].

3. Resultant weight:

Bulk density and floating duration have been the main parameters to describe the adequacy

of dosage form’s buoyancy. Resultant weight, corresponds to the vector sum of buoyancy

(Fbuoy) and gravity (Fgrav) forces acting on the object. [38]

F= Fbuoy - Fgrav

F= dfgV-dsgV= (df-ds) gV

F = (df-M/V) gV

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

gravity, df is the fluid density, ds is the object density, M is the object mass and V is the

volume of the object. By convention, a positive resultant weight signifies force F exerted

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vertically upwards and that the object is able to float, whereas a negative resultant weight

means that the force F acts vertically downwards and the object sinks (Figure 10). The

crossing of the zero base line by the resultant weight curve from positive towards negative

values indicate transition of the dosage form from floating to non-floating conditions.

Intersection of lines consequently corresponds, on time axis, to the floating time of the

dosage form.

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Figure 10 Forces acting during buoyancy and the floating time

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4. Gamma scintigraphic studies:

Gamma scintigraphy has been established as the method of choice for in vivo imaging studies of

formulations. In gamma scintigraphy, the formulation is visualised by gamma radiation emitted

from trace amounts of one or two radionuclides that have to be included in the dosage form. The

location of a single unit in the GI tract is determined from the position of the gamma camera

image. Since no image of the GI anatomy is obtainable, an external radioactive marker may be

positioned at a well defined anatomical position as a reference point in the determination of the

radio labelled formulation. [39]

CONCLUSION

The currently available polymer-mediated non-effervescent and effervescent FDDS, designed on

the basis of delayed gastric emptying and buoyancy principles, appear to be an effective and

rational approach to the modulation of controlled oral drug delivery. This is evident from the

number of commercial products and the myriad of patents issued in this field. The FDDS become

an additional advantage for drugs that are absorbed primarily in the upper segments of GI tract,

i.e., the stomach, duodenum and jejunum. Some of the unresolved, critical issues related to the

rational development of

FDDS include

1. The quantitative efficiency of FDDS in fasted and fed states.

2. Role of the buoyancy in enhancing GRT of the FDDS and

3. Correlation between prolonged GRT and Sustained Release /Pharmacokinetic

characteristics.

Finally, with an increasing understanding of polymer behaviour and the role of the biological

factors mentioned above, it is suggested that future research work in the FDDS should be aimed

at discovery means to accurately control the drug input rate into the GI tract for the optimisation

of pharmacokinetic and toxicological profiles of medicinal agents. The next two decades might

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result in the availability of new products with new therapeutic possibilities and substantial

benefits for patients. Soon, novel gastroretentive products with release and absorption phases of

approximately 24 hrs may replace the so-called ‘once-a-day’ formulations.

Drugs Dosage forms GRT (h) References

NFDS* FDDS

Diazepam Capsules 1-1.5 4-10 [23,38,40]

(Moricizine HCl) Tablets 1-1.5 >6 [41]

Gentamycin sulfate Tablets 1-2 >4 [42]

Isradipine Capsules 0.51-2.87 2.4-4.8 [5]

Metoprolol tartrate Tablets 1-1.5 5-6 [43]

Miocamycin Tablets 3-4 >7 [44]

Pepstatin Minicapsules NR 3-5 [45]

Salbutamol sulfate Capsules NR 8-9 [46]

Tranilast Microcapsules NR >3 [4]

*Non floating drug system

Table: 1 Comparison of GRTs of floating and nonfloating solid dosage form

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How to cite this article

Pandya S. Floating drug delivery systems: A critical analysis. Pharma Utility. 2013; 7(1)

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