INDEX1. INTRODUCTION

a. Definition

b. Classification

c. Basic GIT physiology

d. Advantages & disadvantages

e. Floating Tablet

f. Literature review

g. Physiochemical characteristics

h. List of drugs

i. Marketed preparation

2. INGREDIENTS

3. MECHANISM OF FLOATING

4. APPROACH & METHODS

5. FACTORS AFFECTING

6. LIMITATIONS

7. PRODUCTION & DEVELOPMENT

8. EVALUATION

9. APPLICATION

10. CONCLUSION

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INTRODUCTION

The oral route is considered as the most promising route of drug delivery. Effective oral

drug delivery may depend upon the factors such as gastric emptying process,

gastrointestinal transit time of dosage form, drug release from the dosage form and site of

absorption of drugs. Most of the oral dosage forms possess several physiological

limitations such as variable gastrointestinal transit, because of variable gastric emptying 

leading to non-uniform absorption profiles, incomplete drug release and shorter residence

time of the dosage form in the stomach. This leads to incomplete absorption of drugs

having absorption window especially in the upper part of the small intestine, as once the

drug passes down the absorption site, the remaining quantity goes unabsorbed. The

gastric emptying of dosage forms in humans is affected by several factors because of

which wide inter- and intra-subject variations are observed. Since many drugs are well

absorbed in the upper part of the gastrointestinal tract, such high variability may lead to

non-uniform absorption and makes the bioavailability unpredictable. Hence a beneficial

delivery system would be one which possesses the ability to control and prolong the

gastric emptying time and can deliver drugs in higher concentrations to the absorption site

(i.e. upper part of the small intestine).

The identification of new diseases and the resistance shown towards the existing drugs

called for the introduction of new therapeutic molecules. In response, a large number of

chemical entities have been introduced, of which some have absorption all over the

gastrointestinal tract (GIT), some have absorption windows (i.e. absorption sites,

especially the upper part of the small intestine) and some drugs have poor solubility in

intestinal media. The drugs belonging to the second and third categories, and the drugs

which are required for local action in the stomach, require a specialized delivery system.

All the above requirements can be met and effective delivery of the drugs to the

absorption window, for local action and for the treatment of gastric disorders such as

gastro-esophageal reflux, can be achieved by floating drug delivery systems (FDDS).

To date, a number of FDDS involving various technologies, carrying their own

advantages and limitations were developed such as, single and multiple unit hydro

dynamically balanced systems (HBS), single and multiple unit gas generating systems,

hollow microspheres and raft forming systems.

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The hydrodynamic balanced system (HBS) also called Floating drug delivery system

(FDDS) is an oral dosage form (capsule or tablet) designed to prolong the residence time

of the dosage form within the GIT. It is a formulation of a drug with gel forming

hydrocolloids meant to remain buoyant in the stomach contents. Drug dissolution and

release from the dosage form retained in the stomach fluids occur at the pH of the

stomach under fairly controlled conditions. The retentive characteristics of the dosage

form are not significant for the drugs that:

ØAre insoluble in intestinal fluids

ØAct locally

ØExhibit site-specific absorption.

The formulation of the dosage form must comply with three major criteria for HBS.

ØIt must have sufficient structure to form a cohesive gel barrier.

ØIt must maintain an overall specific gravity less than that of gastric content.

ØIt should dissolve slowly enough to serve as a “Reservoir” for the delivery system.

Floating systems are one of the important categories of drug delivery systems with gastric

retentive behavior. Drugs that could take advantage of gastric retention include: 

furosemide, cyclosporine, allopurinol ciprofloxacin and metformin. Drugs whose

solubility is less in the higher pH of the small intestine than the stomach (e.g.

chlordiazepoxide and cinnarizine, the drugs prone for degradation in the intestinal pH

(e.g. captopril), and the drugs for local action in the stomach (e.g. misoprostol) can be

delivered in the form of dosage forms with gastric retention. Antibiotics, catecholamines,

sedative, analgesics, anticonvulsants, muscle relaxants, antihypertensive and vitamins can

be administered in HBS dosage form.

Drugs reported to be used in the formulation of floating dosage forms are:

Floating microspheres (aspirin, griseofulvin, p-nitroaniline, ibuprofen, terfinadine and

tranilast), floating granules (diclofenac sodium, indomethacin and prednisolone), films

(cinnarizine), floating capsules (chlordiazepoxide hydrogen chloride,diazepam,

furosemide, misoprostol, L-Dopa, benserazide, ursodeoxycholic acid and pepstatin)

andfloating tablets and pills  (acetaminophen, acetylsalicylic acid, ampicillin, amoxycillin

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trihydrate, atenolol, diltiazem, fluorouracil, isosorbide mononitrate, para aminobenzoic

acid, piretamide, theophylline and verapimil hydrochloride, etc.).

Excipients used most commonly in these systems include HPMC, polyacrylate polymers,

polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide

and polycarbonates.

Floating tablets are the low density systems; contain one or more Hydro-Colloids which

swell on contact with water to form a gel layer. This layer presents a low density system

that floats on the gastro intestinal contents, thereby prolonging gastric residence time. Or

Floating tablet is a solid controlled release, oral, buoyant unit dose pharmaceutical

composition, which comprises of one or more therapeutic agent/drug, a gel forming husk

powder one or more cross linking enhancer, one or more gas generating component and

pharmaceutically accepted excipients. Or Floating tablet is a therapeutic unit dosage form

as a non compressed tablet having network of multitudinous air holes and passage therein

and a density of less than one and capable of floating on gastric fluid in vivo and

providing sustained release of the therapeutic agent over an extended period of time.

DEFINITION

Tablets are solid dosage forms usually prepared with the aid of suitable pharmaceutical

excipients. They may vary in size, shape, and weight, hardness, thickness, and

disintegration and dissolution characteristic and in other aspects depending upon their

intended use and method of manufacturing. Tablet is an essentially tamperproof dosage

form.

TYPES OF TABLETS

A. Tablets Ingested Orally

(I) Compressed Tablets (C. T.) : - In addition to medicinal agent compressed tablets

usually contains a number of pharmaceuticals adjancts including

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(a) Diluents or fillers, which add the necessary bulk to formulation to prepare tablets of

the desired size.

(b) Binders or adhesives which promote the adhesion of the particles of the formulation,

enabling a granulation to be prepared and the maintenance of the integrity of the

final tablet.

(c) Disintegrates which promote the breakup of the tablets after administration to smaller

particles for more ready drug availability.

(d) Glidants lubricant

(e) Colorant & flavorants

(II)Multiple compressed tablets(M.C.T.) : - Multiple compressed tablets are prepared

by subjecting the fill material to more than a single compression. The result may be

a multiple layered tablet or a tablet-within-a-tablet, the inner tablet being the core

and the outer being the shell. Each layer may contain different medical agent,

separated from one another from for reasons of chemical or physical incompatibility

or for unique appearance of multiple layered tablets.

(III) Sugar coated tablets(S.C.T.) : - Compressed tablets may be         coated

with a colored or an uncolored sugar later . the coating          is water soluble and

is quickly dissolved after swallowing, it serves the purpose of protecting the

enclosed drug from the environment mask the objectionable tasting or smelling

drugs.

(IV) Film coated tablets : - Film coated tablets are compressed tablets coated with a thin

layer film over the tablet. The film is usually ( colored & more durable Jess bulky

& less time consuming to apply.

(V) Chewable tablets : - Chewable tablets have a smooth rapid

disintegration when chewed or allowed to dissolved in the mouth chewable tablets

are especially useful for administration of tablets of large size to children and

adults who have difficulty swallowing solid dosage forms.

(VI) Enteric Coated tablets (ECT) : - E C T have delayed relays features. They are

designed to pass unchanged through the stomach with transit to the intestines

where the tablets disintegrates and allow drug dissolution and absorption effect.

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(VII) Gelatin coated tablets : - The innovator product termed GELCAPS is capsule

shaped compressed tablet that allows the coated product to be about one third

smaller than a capsule filled with an equivalent amount of powder.

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B. Tablet Used In Oral Cavity

(I) Buccal and Sublingual Tablets: -Buccal Tablets are intended to be dissolve in the

buccal and sublingual tablets, beneath tongue for absorption through the oral

mucosa

(II) Troches and Eozenges: - These are used in the oral cavity when they are intended to

extent a local effect in the mouth or throat. These tablet forms are commonly used

to treat throat or to do control coughing in the common cold. They may contain

local anaesthetic and antibacterial agent's demulcents, astringents.

(iii) Dental cones: - dental cones are design to be placed in the empty socket remaining

following a tooth extraction. Their usual purpose is to present multiplication of

bacteria in the socket following suck extraction by employing a slow-releasing

antibacterial compound or to reduce bleeding by ( containing an astringent or

coagulant.

(C) Tablets Administerd By Other Routes

(I) Implementation Tablets: - Implantation or depot tablets are designed for subcutaneous

implantation in animals or man. There purpose is to provide prolonged drug effect

from one month to one a year. They are usually designed to provide as constant a

drug delivery release rate as possible.

(II) Vaginal Tablets:-Vaginal tablets are designed to undergo slave and delay releases in

the vaginal cavity tablets are ovoid or pear shape to facilitate retention in the

vaginal. Tablet used to release antibacterial; agents antiseptics are astringents to

treat vaginal infection are possible to release ( steroids for systematic absorption.

(D) Tablets Used To Prepare Solution (I) Effervescent Tablets

Effervescent tablets are prepared by compressing granular effervescent salts that releases

gas when in contact with water, These tablets generally content medicinal substances

which dissolve rapidly when added to water.

(II) Dispensing Tablets

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Materials that have been commonly incorporated in dispensing tablets include mild silver

proteinate, bichloride of mercury, quaternary ammonium compounds.The dispensing

tablets must typically comprised totally soluble components and the excipients

ingredients of the tablet must not produce deleterious effects in the intended application

of the solution or undesirable, physical or chemical interactions with the active agent.

(III) Hypodermic Tablets

Hypodermic tablets are composed of one or more drugs with other readily water-soluble

ingredients and are intended to be adding to sterile water for injection. Little used today.

(IV) Tablet Triturates

Tablet triturates are small usually cylindrical molded are compressed tablets containing

small amount of usually patient drugs. Since tablet triturate must be readily and

completely soluble in water only a minimal amount of pressure is applied during their

manufacture

There are few tablet triturates, which remain, are used sublingually as nitroglycerine

tablets.

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Sustained release dosage form are drug delivery system that are designed to achieve a

prolonged therapeutic effect by continuously releasing medication over an extended

period of time after administration of a single dose.

In recent years scientific and technological advancements have been made in the research

and development of rate-controlled oral drug delivery systems by overcoming

physiological adversities, such as short gastric residence times (GRT) and unpredictable

gastric emptying times (GET).

Several approaches are currently utilized in the prolongation of the GRT, including

floating drug delivery systems (FDDS), also known as hydrodynamically balanced

systems (HBS), swelling and expanding systems, polymeric bio-adhesive systems,

modified-shape systems, high-density systems, and other delayed gastric emptying

devices.

In this review, the current technological developments of FDDS including patented

delivery systems and marketed products, and their advantages and future potential for oral

controlled drug delivery are discussed.

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BASIC GASTROINTESTINAL TRACT

PHYSIOLOGYAnatomically the stomach is divided into three regions: Fundus: proximal part of

stomach. Body: it acts as a reservoir for undigested material. Antrum: main sight for

mixing motions and act as a pump for gastric emptying by propelling actions.

Gastric emptying occurs during fasting as well as fed states. The pattern of motility is

however distinct in the two states. During the fasting state an inter-digestive series of

electrical events take place ,which cycle both through stomach and intestine every two to

three hours. This is called the INTERDIGESTIVE MYLOELECTRIC CYCLE or

MIGRATING MYLOELECTRIC CYCLE (MMC), which is further divided into

following four phases as described by Wilson and Washington.

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

2) Phase 2 (pre-burst phase) lasts for 40 to 60 minutes intermittent action potential and

contractions. As the phase progresses the intensity and frequency also increases

gradually.

3) Phase 3 (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 4 lasts for 0 to 5 minutes and occurs between phase 3 and 1 of two

consecutive cycles.

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After the ingestion of 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 contraction as in phase 2 of fasted state. These contractions results in

reducing the size of food particles(to less than 1mm), which are propelled toward

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,l)short gastric residence time and 2)

unpredictable gastric emptying rate.

These above 2 problems are overcome by designing the floating tablets. On

comparison of floating and non-floating dosage units, it was concluded that regardless

of their size (the floating dosage units remained buoyant on the gastric contents

throughout their (. residence in the GIT, while the non floating 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 non floating forms stayed close to the pylorus and were subjected to

propelling and retropelling waves of the digestive phase.

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CLASSIFICATION OF FLOATING

DRUG DELIVERY SYSTEMSFloating drug delivery systems are classified depending on the use of 2 formulation

variables: effervescent and non-effervescent systems.

Effervescent Floating Dosage Form

These are matrix type of systems prepared with the help of swell able polymers

such as methylcellulose and chitosan and various effervescent compounds

e.g. sodium carbonate, tartaric acid, and citric acid. They are formulated in such a

way that when in contact with the acidic gastric contents, carbon dioxide is liberated

and gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage

forms.

There has been developed a new multiple type of floating dosage system

composed of effervescent layers and swell able 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 two

agents. These sublayers were surrounded by a swellable polymer membrane

containing polyvinyl acetate and purified shellac. When this system was immersed in

the buffer at 37 oC, it settled down and the solution permeated into the effervescent

layer through the outer swellable membrane. Carbon dioxide was generated by the

neutralization reaction between the effervescent agents, producing swollen pills (like

balloons) with a density lees than 1.0 g/ml. it was found that the system has good

floating ability independent of pH and viscosity and the drug released in a sustained

manner.

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It has also been developed a swellable asymmetric triple layer tablet with floating ability

to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole,

(and clarithromycin) in Helicobacter pylori-associated peptic ulcers using hydroxyl

propyl ( methyl cellulose (HPMC) and poly ethylene oxide (PEO) as the rate controlling

polymeric membrane excipients. Tetracycline and metronidazole were incorporated into

the core layer of the triple layer on matrix for controlled delivery, while bismuth salt was

included in one layer of the outer layers for instant release. The floatation was

accomplished by incorporating a gas generating layer consisting of sodium bicarbonate:

calcium carbonate (1:2) ratios along with the polymers. The in vitro results revealed that

the sustained release of tetracycline and metronidazole over 6 to8 hours could be

( achieved while the tablet remained afloat. The floating feature aided in prolonging the)

C gastric residence time of this system to maintain high localized concentration of

tetracycline and metronidazole.

There has been developed a floating system using ion exchange resin that was

loaded with bicarbonate by mixing the beads with 1 M sodium bicarbonate solution. The

loaded beads were then surrounded by a semi-permeable membrane to avoid sudden loss

of carbon dioxide . Upon coming in contact with gastric contents an exchange of chloride

and bicarbonate ions took place that resulted in carbon dioxide generation thereby

carrying beads towards the top of gastric contents and producing a floating layer of resin

beads.

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Non Effervescent Floating Dosage Forms

Non effervescent floating dosage forms use a gel forming or swellable

cellulose type of hydrocolloids, polysaccharides, and matrix forming polymers like

polycarbonate, polyacrylate, polymethacrylate and polystyrene. The formulation

method includes a simple approach of thoroughly mixing the drug and the gel forming

hydrocolloid. After oral administration this dosage form swells in contact with gastric

fluids and attains a bulk density of <1. the air entrapped within the swollen matrix

imparts buoyancy to the dosage form. The so formed swollen gel like structure acts as

a reservoir and allows sustained release of drug through the gelatinous mass.

It has been developed an HBS system containing a homogeneous mixture of drug and

the hydrocolloid in a capsule, which upon contact with gastric fluid acquired and

maintained a bulk density of <1 thereby being buoyant on the gastric contents of

stomach until all the drug was released.

It has also been developed hydrodynamically balanced sustained release tablets

containing drug and hydrophilic hydrocolloid, which on contact with gastric fluids at

body temperature form a soft gelatinous mass on the surface of the tablet and provided

a water impermeable colloid gel barrier on the surface of the tablets. The drug slowly

released from the surface of the gelatinous mass that remained buoyant on gastric

fluids.

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ADVANTAGES & DISADVANTAGES

Advantages

1. convenient to patients.

2. less loss of drug.

3. toxicity can be reduced.

4. steady state of drug is obtained.

5. reduction in dosing frequency.

6. improve the tolerability

7.higher minimum plasma concentration increases the efficacy.

Disadvantages

1. Administration of sustained release medication dose not permit termination of

therapy.

2. Physicians has less flexibility in adjusting dosage regimens.

3. It is designed for the normal population.

4. More costly when compared to normal formulations.

5. The drug is not effectively absorbed in the lower intestine; sustained release

can not be formulated when —

*drugs have short half life e.g.-furosemide.

*drugs have long biologically half life e.g.-diazepam.

* large dose is required e.g.-sulphonamides.

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FLOATING TABLET

Floating tablet is related to an effervescent pharmaceutical preparation comprising

effervescent excipients and a plurality of individual units comprising a

pharmaceutically active compound and optional excipients wherein the units (1) are

provided with a floating generating system. The floating generating systems

comprises at least two coating layers, one of which is a gas generating layer (2) and

the other layer is a barrier layer (3) enclosing the generated gas. Furthermore the

invention is related to a process for the manufacture of the dosage forms, and their use

in medicine.

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LITERATURE REVIEW

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. These sublayers were

surrounded by a swellable polymer membrane containing polyvinyl acetate and purified

shellac. When this system was immersed in the buffer at 37ºC, it settled down and the

solution permeated into the effervescent layer through the outer swellable membrane. CO2

was generated by the neutralization reaction between the 2 effervescent agents, producing

swollen pills (like balloons) with a density less than 1.0 g/mL. It was found that the system

had good floating ability independent of pH and viscosity and the drug (para-amino benzoic

acid) released in a sustained manner(Ichikawa et al) (Figure 1, A and B).

Figure 1.  (A) Multiple-unit oral floating drug delivery system. (B) Working principle of

effervescent floating drug delivery system.

Ichikawa et al 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

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between the gastric juices and the gas-generating agents.29 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. Two parameters were evaluated: the time for the pills to be floating

(TPF) and rate of pills floating at 5 hours (FP5h). It was observed that both the TPF and FP5h

increased as the percentage of swellable membrane layer coated on pills having a

effervescent layer increased. As the percentage of swellable layer was increased from 13% to

25% (wt/wt), the release rate was decreased and the lag time for dissolution also increased.

The percentage of swellable layer was fixed at 13% wt/wt and the optimized system showed

excellent floating ability in vitro (TPF ~10 minutes and FP5h ~80%) independent of pH and

viscosity of the medium(Ichikawa et al )

Yang et al developed a swellable asymmetric triple-layer tablet with floating ability to

prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, and

clarithromycin) in Helicobacter pylori–associated peptic ulcers using hydroxy propyl methyl

cellulose (HPMC) and poly (ethylene oxide) (PEO) as the rate-controlling polymeric

membrane excipients. The design of the delivery system was based on the swellable

asymmetric triple-layer tablet approach. Hydroxypropylmethylcellulose and poly(ethylene

oxide) were the major rate-controlling polymeric excipients. Tetracycline and metronidazole

were incorporated into the core layer of the triple-layer matrix for controlled delivery, while

bismuth salt was included in one of the outer layers for instant release. The floatation was

accomplished by incorporatinga gas-generating layer consisting of sodium bicarbonate:

calcium carbonate (1:2 ratios) along with the polymers. The in vitro results revealed that the

sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved

while the tablet remained afloat. The floating feature aided in prolonging the gastric residence

time of this system to maintain high-localized concentration of tetracycline and

metronidazole (Yang et al)(Figure 2).

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Figure 2.  Schematic presentation of working of a triple-layer system. (A) Initial

configuration of triple-layer tablet. (B) On contact with the dissolution medium the bismuth

layer rapidly dissolves and matrix starts swelling. (C) Tablet swells and erodes. (D) and (E)

Tablet erodes completely.

Ozdemir et al developed floating bilayer tablets with controlled release for furosemide. The

low solubility of the drug could be enhanced by using the kneading method, preparing a solid

dispersion with β cyclodextrin mixed in a 1:1 ratio. One layer contained the polymers HPMC

4000, HPMC 100, and CMC (for the control of the drug delivery) and the drug. The second

layer contained the effervescent mixture of sodium bicarbonate and citric acid. The in vitro

floating studies revealed that the lesser the compression force the shorter is the time of onset

of floating, ie, when the tablets were compressed at 15 MPa, these could begin to float at 20

minutes whereas at a force of 32 MPa the time was prolonged to 45 minutes. Radiographic

studies on 6 healthy male volunteers revealed that floating tablets were retained in stomach

for 6 hours and further blood analysis studies showed that bioavailability of these tablets was

1.8 times that of the conventional tablets. On measuring the volume of urine the peak diuretic

effect seen in the conventional tablets was decreased and prolonged in the case of floating

dosage form(Ozdemir et al ).

Choi et al prepared floating alginate beads using gas-forming agents (calcium carbonate and

sodium bicarbonate) and studied the effect of CO2 generation on the physical properties,

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morphology, and release rates. The study revealed that the kind and amount of gas-forming

agent had a profound effect on the size, floating ability, pore structure, morphology, release

rate, and mechanical strength of the floating beads. It was concluded that calcium carbonate

formed smaller but stronger beads than sodium bicarbonate. Calcium carbonate was shown to

be a less-effective gas-forming agent than sodium bicarbonate but it produced superior

floating beads with enhanced control of drug release rates. In vitro floating studies revealed

that the beads free of gas-forming agents sank uniformly in the media while the beads

containing gas-forming agents in proportions ranging from 5:1 to 1:1 demonstrated excellent

floating (100%).( Choi et al)

Li et al evaluated the contribution of formulation variables on the floating properties of a

gastro floating drug delivery system using a continuous floating monitoring device and

statistical experimental design. The formulation was conceived using taguchi design. HPMC

was used as a low-density polymer and citric acid was incorporated for gas generation.

Analysis of variance (ANOVA) test on the results from these experimental designs

demonstrated that the hydrophobic agent magnesium stearate could significantly improve the

floating capacity of the delivery system. High-viscosity polymers had good effect on floating

properties. The residual floating force values of the different grades of HPMC were in the

order K4 M~ E4 M~K100 LV> E5 LV but different polymers with same viscosity, ie, HPMC

K4M, HPMC E4M did not show any significant effect on floating property. Better floating

was achieved at a higher HPMC/carbopol ratio and this result demonstrated that carbopol has

a negative effect on the floating behavior(Li et al).

Penners et al developed an expandable tablet containing mixture of polyvinyl lactams and

polyacrylates that swell rapidly in an aqueous environment and thus reside in stomach over

an extended period of time. In addition to this, gas-forming agents were incorporated. As the

gas formed, the density of the system was reduced and thus the system tended to float on the

gastric contents(Penners et al).

Fassihi and Yang developed a zero-order controlled release multilayer tablet composed of at

least 2 barrier layers and 1 drug layer. All the layers were made of swellable, erodible

polymers and the tablet was found to swell on contact with aqueous medium. As the tablet

dissolved, the barrier layers eroded away to expose more of the drug. Gas-evolving agent was

added in either of the barrier layers, which caused the tablet to float and increased the

retention of tablet in a patient’s stomach (Fassihi and Yang).

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Talwar et al developed a once-daily formulation for oral administration of ciprofloxacin.

The formulation was composed of 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03%

xanthum gum, 13.7% sodium bicarbonate, and 12.1% cross-linked poly vinyl pyrrolidine.

The viscolysing agent initially and the gel-forming polymer later formed a hydrated gel

matrix that entrapped the gas, causing the tablet to float and be retained in the stomach or

upper part of the small intestine (spatial control). The hydrated gel matrix created a tortuous

diffusion path for the drug, resulting in sustained release of the drug (temporal delivery)

( Talwar et al).

Two patents granted to Alza Corporation revealed a device having a hollow deformable unit

that was convertible from a collapsed to expandable form and vice versa. The deformable

unit was supported by a housing that was internally divided into 2 chambers separated by a

pressure-sensitive movable bladder. The first chamber contained the therapeutic agent and the

second contained a volatile liquid (cyclopentane, ether) that vaporized at body temperature

and imparted buoyancy to the system. The system contained a bioerodible plug to aid in exit

of the unit from the body.

Baumgartner et al developed a matrix-floating tablet incorporating a high dose of freely

soluble drug. The formulation containing 54.7% of drug, HPMC K4 M, Avicel PH 101, and a

gas-generating agent gave the best results. It took 30 seconds to become buoyant. In vivo

experiments with fasted state beagle dogs revealed prolonged gastric residence time. On

radiographic images made after 30 minutes of administration, the tablet was observed in

animal’s stomach and the next image taken at 1 hour showed that the tablet had altered its

position and turned around. This was the evidence that the tablet did not adhere to the gastric

mucosa. The MMC (phase during which large nondisintegrating particles or dosage forms are

emptied from stomach to small intestine) of the gastric emptying cycle occurs approximately

every 2 hours in humans and every 1 hour in dogs but the results showed that the mean

gastric residence time of the tablets was 240 ± 60 minutes (n = 4) in dogs. The comparison of

gastric motility and stomach emptying between humans and dogs showed no big difference

and therefore it was speculated that the experimentally proven increased gastric residence

time in beagle dogs could be compared with known literature for humans, where this time is

less than 2 hours(Baumgartner et al).

Moursy et al developed sustained release floating capsules of nicardipine HCl. For floating,

hydrocolloids of high viscosity grades were used and to aid in buoyancy sodium bicarbonate

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was added to allow evolution of CO2. In vitro analysis of a commercially available 20-mg

capsule of nicardipine HCl (MICARD) was performed for comparison. Results showed an

increase in floating with increase in proportion of hydrocolloid. Inclusion of sodium

bicarbonate increased buoyancy. The optimized sustained release floating capsule

formulation was evaluated in vivo and compared with MICARD capsules using rabbits at a

dose equivalent to a human dose of 40 mg. Drug duration after the administration of

sustained release capsules significantly exceeded that of the MICARD capsules. In the latter

case the drug was traced for 8 hours compared with 16 hours in former case(Moursy et al).

Atyabi and coworkers developed a floating system using ion exchange resin that was

loaded with bicarbonate by mixing the beads with 1 M sodium bicarbonate solution. The

loaded beads were then surrounded by a semipermeable membrane to avoid sudden loss of

CO2. Upon coming in contact with gastric contents an exchange of chloride and bicarbonate

ions took place that resulted in CO2 generation thereby carrying beads toward the top of

gastric contents and producing a floating layer of resin beads (Figure 3) .The in vivo behavior

of the coated and uncoated beads was monitored using a single channel analyzing study in 12

healthy human volunteers by gamma radio scintigraphy. Studies showed that the gastric

residence time was prolonged considerably (24 hours) compared with uncoated beads (1 to 3

hours)( Atyabi and coworkers).

Figure 3.  Pictorial presentation of working of effervescent floating drug delivery system

based on ion exchange resin.

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Non-effervescent floating dosage forms use a gel forming or swellable cellulose type of

hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate,

polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a simple

approach of thoroughly mixing the drug and the gel-forming hydrocolloid. After oral

administration this dosage form swells in contact with gastric fluids and attains a bulk density

of < 1. The air entrapped within the swollen matrix imparts buoyancy to the dosage form.

The so formed swollen gel-like structure acts as a reservoir and allows sustained release of

drug through the gelatinous mass.

Thanoo et al developed polycarbonate microspheres by solvent evaporation technique.

Polycarbonate in dichloromethane was found to give hollow microspheres that floated on

water and simulated biofluids as evidenced by scanning electron microscopy (SEM). High

drug loading was achieved and drug-loaded microspheres were able to float on gastric and

intestinal fluids. It was found that increasing the drug-to-polymer ratio increased both their

mean particle size and release rate of drug (Thanoo et al).

Nur and Zhang developed floating tablets of captopril using HPMC (4000 and 15 000 cps)

and carbopol 934P. In vitro buoyancy studies revealed that tablets of 2 kg/cm2 hardness after

immersion into the floating media floated immediately and tablets with hardness 4 kg/cm2

sank for 3 to 4 minutes and then came to the surface. Tablets in both cases remained floating

for 24 hours. The tablet with 8 kg/cm2 hardness showed no floating capability. It was

concluded that the buoyancy of the tablet is governed by both the swelling of the

hydrocolloid particles on the tablet surface when it contacts the gastric fluids and the

presence of internal voids in the center of the tablet (porosity). A prolonged release from

these floating tablets was observed as compared with the conventional tablets and a 24-hour

controlled release from the dosage form of captopril was achieved(Nur and Zhang).

Bulgarelli et al studied the effect of matrix composition and process conditions on casein

gelatin beads prepared by emulsification extraction method. Casein by virtue of its

emulsifying properties causes incorporation of air bubbles and formation of large holes in the

beads that act as air reservoirs in floating systems and serve as a simple and inexpensive

material used in controlled oral drug delivery systems. It was observed that the percentage of

casein in matrix increases the drug loading of both low and high porous matrices, although

the loading efficiency of high porous matrices is lower than that of low porous matrices.

(Bulgarelli et al)

23

Fell et al prepared floating alginate beads incorporating amoxycillin. The beads were

produced by dropwise addition of alginate into calcium chloride solution, followed by

removal of gel beads and freeze-drying. The beads containing the dissolved drug remained

buoyant for 20 hours and high drug-loading levels were achieved(Fell et al).

Streubel et al prepared single-unit floating tablets based on polypropylene foam powder and

matrix-forming polymer. Incorporation of highly porous foam powder in matrix tablets

provided density much lower than the density of the release medium. A 17% wt/wt foam

powder (based on mass of tablet) was achieved in vitro for at least 8 hours. It was concluded

that varying the ratios of matrix-forming polymers and the foam powder could alter the drug

release patterns effectively(Streubel et al ).

Asmussen et al invented a device for the controlled release of active compounds in the

gastrointestinal tract with delayed pyloric passage, which expanded in contact with gastric

fluids and the active agent was released from a multiparticulate preparation. It was claimed

that the release of the active compound was better controlled when compared with

conventional dosage forms with delayed pyloric passage(Asmussen et al).

El-Kamel et al prepared floating microparticles of ketoprofen, by emulsion solvent diffusion

technique. Four different ratios of Eudragit S 100 with Eudragit RL were used. The

formulation containing 1:1 ratio of the 2 above-mentioned polymers exhibited high

percentage of floating particles in all the examined media as evidenced by the percentage of

particles floated at different time intervals. This can be attributed to the low bulk density,

high packing velocity, and high packing factor(El-Kamel et al ).

Illum and Ping developed microspheres that released the active agent in the stomach

environment over a prolonged period of time. The active agent was encased in the inner core

of microspheres along with the rate-controlling membrane of a water-insoluble polymer. The

outer layer was composed of bioadhesive (chitosan). The microspheres were prepared by

spray drying an oil/water or water/oil emulsion of the active agent, the water-insoluble

polymer, and the cationic polymer(Illum and Ping).

Streubel et al developed floating microparticles composed of polypropylene foam, Eudragit

S, ethyl cellulose (EC), and polymethyl metha acrylate (PMMA) and were prepared by

solvent evaporation technique. High encapsulation efficiencies were observed and were

24

independent of the theoretical drug loading. Good floating behavior was observed as more

than 83% of microparticles were floating for at least 8 hours. The in vitro drug release was

dependent upon the type of polymer used. At similar drug loading the release rates increased

in the following order PMMA < EC < Eudragit S. This could be attributed to the different

permeabilities of the drug in these polymers and the drug distribution within the system

(Streubel et al).

Sheth and Tossounian developed an HBS system containing a homogeneous mixture of

drug and the hydrocolloid in a capsule, which upon contact with gastric fluid acquired and

maintained a bulk density of less than 1 thereby being buoyant on the gastric contents of

stomach until all the drug was released (Sheth and Tossounian)(Figure4).

Figure 4.  Working principle of hydrodynamically balanced system.

25

Sheth and Tossounian developed hydrodynamically balanced sustained release tablets

containing drug and hydrophilic hydrocolloids, which on contact with gastric fluids at body

temperature formed a soft gelatinous mass on the surface of the tablet and provided a water-

impermeable colloid gel barrier on the surface of the tablets. The drug slowly released from

the surface of the gelatinous mass that remained buoyant on gastric fluids. (Sheth and

Tossounian)

Figure 5.  Intragastric floating tablets. (A) United States patent 4 167 558, September 11,

1979. (B) United States patent 4 140 755, February 20, 1979.

Ushomaru et al developed sustained release composition for a capsule containing mixture of

cellulose derivative or a starch derivative that formed a gel in water and higher fatty acid

glyceride and/or higher alcohol, which was solid at room temperature. The capsules were

filled with the above mixture and heated to a temperature above the melting point of the fat

components and then cooled and solidified (Ushomaru et al).

Bolton and Desai developed a noncompressed sustained release tablet that remained afloat

on gastric fluids. The tablet formulation comprised 75% of drug and 2% to 6.5% of gelling

agent and water. The noncompressed tablet had a density of less than 1 and sufficient

mechanical stability for production and handling(Bolton and Desai).

26

Kawashima et al prepared multiple-unit hollow microspheres by emulsion solvent diffusion

technique. Drug and acrylic polymer were dissolved in an ethanol-dichloromethane mixture,

and poured into an aqueous solution of PVA with stirring to form emulsion droplets. The rate

of drug release in micro balloons was controlled by changing the polymer-to-drug ratio.

Microballoons were floatable in vitro for 12 hours when immersed in aqueous media.

Radiographical studies proved that microballoons orally administered to humans were

dispersed in the upper part of stomach and retained there for 3 hours against peristaltic

movements.( Kawashima et al)

Dennis et al invented a buoyant controlled release pharmaceutical powder formulation filled

into capsules. It released a drug of a basic character at a controlled rate regardless of the pH

of the environment. PH-dependent polymer is a salt of a polyuronic acid such as alginic acid

and a pH-independent hydrocarbon gelling agent, hydroxypropylmethyl cellulose(Dennis et

al).

Spickett et al invented an antacid preparation having a prolonged gastric residence time. It

comprised 2 phases. The internal phase consisted of a solid antacid and the external phase

consisted of hydrophobic organic compounds (mono-, di-, and triglycerides) for floating and

a non-ionic emulsifier(Spickett et al).

Franz and Oth described a sustained release dosage form adapted to release of the drug

over an extended period of time. It comprised a bilayer formulation in which one layer

consisted of drug misoprostal and the other had a floating layer. The uncompressed bilayer

formulation was kept in a capsule and was shown to be buoyant in the stomach for 13 hours.

The dosage form was designed in such a way that all the drug was released in the stomach

itself(Franz and Oth ).

Wu et al developed floating sustained release tablets of nimodipine by using HPMC and

PEG 6000. Prior to formulation of floating tablets, nimodipine was incorporated into

poloxamer-188 solid dispersion after which it was directly compressed into floating tablets. It

was observed that by increasing the HPMC and decreasing the PEG 6000 content a decline in

in vitro release of nimodipine occurred(Wu et al).

Wong et al developed a prolonged release dosage form adapted for gastric retention using

swellable polymers. It consisted of a band of insoluble material that prevented the covered

27

portion of the polymer matrix from swelling and provided a segment of a dosage form that

was of sufficient rigidity to withstand the contractions of the stomach and delayed the

expulsion of the dosage form from the stomach(Wong et al).

Mitra developed a sustained release multilayered sheet-like medicament device. It was

buoyant on the gastric contents and consisted of at least 1 dry, self-supporting carrier film of

water-insoluble polymer. The drug was dispersed or dissolved in this layer and a barrier film

overlaid the carrier film. The barrier film was compsosed of 1 water-insoluble layer and

another water-soluble and drug-permeable polymer or copolymer layer. The 2 layers were

sealed together in such a way that plurality of small air pockets were entrapped that gave

buoyancy to the formulation(Mitra).

Harrigan developed an intragastric floating drug delivery system that was composed of a

drug reservoir encapsulated in a microporous compartment having pores on top and bottom

surfaces. However, the peripheral walls were sealed to prevent any physical contact of the

drug in the reservoir with the stomach walls(Harrigan).

Joseph et al developed a floating dosage form of piroxicam based on hollow polycarbonate

microspheres. The microspheres were prepared by the solvent evaporation technique.

Encapsulation efficiency of ~95% was achieved. In vivo studies were performed in healthy

male albino rabbits. Pharmacokinetic analysis was derived from plasma concentration vs time

plot and revealed that the bioavailability from the piroxicam microspheres alone was 1.4

times that of the free drug and 4.8 times that of a dosage form consisting of microspheres plus

the loading dose and was capable of sustained delivery of the drug over a prolonged

period(Joseph et al).

28

PHYSICOCHEMICAL CHARACTERISTICS

Physicochemical Characteristics Of Drug Molecules are

l. pKa

2. Solubility and Dissolution Rate

Solubility

Dissolution Rates

Factors Affecting Solubility and Dissolution Rates

3. Chemical Stability

4. Complexation

5. Adsorption

Dosage Form Design Considerations

1. Liquid versus Solid Dosage Forms

2. Modulation of Gastric Emptying

3. Enteric-Coated Products

1. Rationale

2. Definition

3. Henderson-Hassel balch-Equations

The majority of drugs are either weak acids or weak bases. Each weak acid/base has a

pKa value. The pKa value is the single most important parameter that permeates the

entire learning process in pharmaceutics. It will remain to be a necessary part of your

professional practice as well. You will meet it again, again, and again.unionized form

affects drug's solubility, permeability, binding, and other. Why is it so important? It is

because pKa affects the proportion of drug • molecules in the ionized and unionized

forms.

The ratio of ionized over characteristics.

Definition

29

Ka and KB are originally defined as the equilibrium constant of the dissociation

process of an acid and a base, respectively. pKa (pKb) is equal to -logKa (-log Kb).

W For Acids: For Bases:.

f HA <--> H+ + A' NaOH <--> OH" + Na+ *•

Ka = [H+][A']/[HA] Kb = [OH'] [Na+]/[NaOH]

For weak acids, the higher the [FT1"] or the stronger the acid, the higher the Ka, the

higher the logKa, but the lower the -logKa or pKa. For weak bases, the higher the [OH'J

or stronger the base, the higher the Kb, the higher the logKb, but the lower the-pKb.

Henderson-Hassel balch Equations

• One of the best known set of equations in the pharmaceutics, it will permeate all

the classes that deal with dosage forms.

• pH - pKa = log [A"]/[HA] ——The world famous Henderson-Hasselbalch equation

for acids.

• pH - pKa = log [B]/[BH+] ——The world famous Henderson-Hasselbach

equation for bases

Solubility and Dissolution Rate

1 Solubility

Solubility is the concentration of drug molecules in a particular dissolution media.

Solubility is measured after drug of interest has had sufficient contact time (how ever

long it takes) with the dissolution media. They are two types of solubility: one is called

intrinsic solubility, the other the apparent solubility. The intrinsic solubility is defined as

concentration of drug in pure water. It is often derived from calculation, and is a single

numeric number microgram/milliliter) that is independent of the environmental factors .

The apparent solubility is dependent on the environmental factors such as pH and ionic

strength. This number may be obtained with experimental C measurement.

30

C o The relationship: Cs = Cs* (1+Ka/fH*]) for weak acids

Cs (l+[FT]/Ka) for weak bases.

2 Dissolution Rate

Dissolution rate is the rate at which drug solids dissolve in a dissolution media. For

drugs whose absorption rates are faster than the dissolution rates (e.g., steroids), the rate-

limiting step in the absorption process is often the dissolution rate. Because of a limited

residence time at the absorption site, drugs that are not dissolved before they are removed

from intestinal absorption site are considered useless. Therefore, the rate of dissolution

has a major impact on the performance of drugs that are poorly soluble. Because of this

factor, the dissolution rate of drugs in solid dosage forms is an important, routine, quality

control parameter used in the drug manufacturing process. o Dissolution rate = K S (CS-

C)

31

where K is dissolution rate constant, S is the surface area, Cs is the

apparent solubility, and C is the concentration of drug in the dissolution

4. media.

For rapid drug absorption, CS-C is approximately equal to Cs T.' f

Therefore, Dissolution rate = KS (Cs)

Factors Affecting Dissolution Rates:

• Factors affecting apparent solubility of acids and bases.

Cs = [HA] + [A'] + [A'] for weak acids

Cs = [B] + [BH+] = C* + [BH+] for weak bases where Cs* is the intrinsic solubility of

the unionized form. These equations indicate that pH will affect the solubility of weak

acids/bases. Because the ionized form has higher apparent solubility than the

unionized form, manipulation of pH is an effective means of changing a drug's

apparent solubility. This strategy is commonly used in the development of parenteral

drugs, where salt form of the drug molecules are frequently used.

Factors affecting K

Chemical form: Salt forms generally have a higher solubility and dissolution

rate than their acidic and basic counterparts.

Crystal form: The amorphous form generally has a higher solubility than the

rystalline form.

Wettability: For poorly soluble drugs that are difficult to wet, wetting agents

(e.g., surfactants) may be useed to increase the solubtility.

32

Factors affecting

Particle size: The smallest particle size/unit weight has the largest surface area/unit

weight.

Chemical Stability

Chemical stability at the absorption site is seldom a problem for modern

p. pharmaceuticals. However, instability in the stomach has prevented many drugs to

be developed, including many peptide and nucleotide-like drugs that were very potent.

Chemical instability can sometimes be circumvented by using prodrugs to mask the

unstable functional group(s).Documented examples of chemical instability in the GI

tract are: penicillin G, digoxin, and certain ester analogs of erythromycin.

Complexation

• Complexation of a drug in the GI fluid/tract may significantly alter the absorption

characteristics of the drugs. Documented examples include:

• Intestinal mucus, which contains the polysaccharide mucin, can avidly bind

streptomycin and dihydrostreptomycin. These binding may contribute to the poor

absorption of antibiotics.

• Bile salts may interact with certain drugs such as tubocurarine, neomycin, and

kanamycin to form insoluble, nonabsorble complexes.

• Tetracycline form insoluble complexes with Ca.

• Complexes are sometimes used to increase or decrease solubility. Hydroquinone has

been used to form a complex with digoxin for increased solubility, which results in

increased absorption rate.

33

Adsorption

• Adsorption of drug molecules to certain components of dosage forms or to L0

macromolecular resin could be both beneficial and detrimental to achieving 4

desirable outcomes.

• Charcoal is a strong absorber, and a common antidote in drug intoxication.It is

effective in decreasing the absorption of promazine, by forming a strong

complex of promazine and charcoal.

• Absorption of lincomycin has been shown to be less when taken with a ^

commercial kaolin-pectin mixture for diarrhea, because the mixture binds

strongly with lincomycin.

• Cholestyramine and colestipol are resin that binds to bile salts and cholesterol

metabolites to make them not available for absorption. Unfortunately, they

may' also bind to other drugs. Cholestyramine has been shown to decrease the

If absorption of thyroxine, warfarin, phenoprocoumon, and digoxin.

Dosage Form Design Considerations

• Liquid versus Solid Dosage Forms

o The absorption of drugs delivered as liquid dosage forms is generally much

faster than the absorption of drugs delivered as the solid dosage forms.

o The faster absorption is the result of faster gastric emptying and/or faster

dissolution. The latter is only relevant if the liquid dosage form has co-solvents

which enhance drug solubility. In other words, the drug may precipitate into

fine particles, which require subsequent dissolution before they are absorbed.

o Absorption of solid dosage forms may also be decreased by various factors that

decrease the gastric emptying of intact doage forms. These factors include: size

of the dosage forms, presence or absence of food, and density of the dosage

forms. In general, larger and lighter dosage forms are emptied slower, whereas

the presence of food (especially those that are rich in sugar and fat) slows down

the emptying of the dosage form.

Modulation of Gastric Emptying

o Solid dosage forms can be designed to slow the gastric emptying to achieve

sustained release of drugs. These dosage forms include:

34

• Floating devices

o Natural floating tablets: wafer

The retention potentials of dosage forms depends on their design,

o Balloon device

o Swelling device

• Sandwich

• Hydrogel: Experimental

• Hydrogels expand greatly in volume when it gains contact with water.

• Bioadhesive polymers

This delivery strategy uses ionic attraction between negative charge (biomembrane)

and positive charge (polymer) to improve the retention of the dosage forms in the

stomach.Other devices Shape of dosage forms have a significant effect on their gastric

emptying. It has been shown that dosage forms with rigid bulky structures have higher

retention in the stomach than those with more flexible linear structures.

Enteric-Coated Products

Enteric-coated products are not disintegraded in the stomach. It will be emptied intact

into the small intestine, where it will disintegrate, dissolve, IP and eventually be

absorbed.Enteric-coated products typically have slower onset. Therefore, enteric-

coated products are mainly used for drugs that are unstable in, or cause irritation to the

stomach. Therefore, enteric-coated products cannot be cut or physically altered,

because the intactness of the coat is critical to its desirable performance.

35

List of Drugs Formulated as Floating Drug

Delivery Systems

Dosage form

Example

Tablets

Capsules

Chlorpheniramine maleate

Theophylline

Furosemide

Ciprofloxacin

Captopril

Acetylsalisylic acid

Amoxycillin tryhydrate

Verapamil HCL

Isosorbide dinitrate

Sotalol

Atenolol

Ampicillin

Diltiazem

Florouracil

Prednisolone

Riboflavin-5' phosphate

Nicardipine

L-dopa and benserzide

Chlordizepoxide

Furosemide

Misoprostal Diazepam Propranolol

Microspheres Verapamil

Aspirin Iboprufen

36

Granules Indomethacin

Diclofenac sodium Prednisolone

Films Drug delivery device

Cinnarizine

Powders Several basic drugs

37

Marketed Preparations of Floating Tablets

Product active ingredient

Madopar levodopa and benserzide

Valrelease diazepam

Topalkan aluminium magnesium antacid

Almagate flatcoat antacid

Liquid gavison alginic acid and sodium bicarbonate

38

Some of the marketed formulations are listed as follows:

Table → Marketed Products of GRDDS

Brand name Delivery system Drug (dose) Company name

Valrelease® Floating capsule Diazepam (15mg) Hoffmann-LaRoche,

USA

Madopar® HBS

(Prolopa® HBS)

Floating, CR capsule Benserazide (25mg) and

L-Dopa (100mg)

Roche Products, USA

Liquid Gaviscon® Effervescent Floating

liquid  alginate

preparations

Al hydroxide (95 mg),

Mg Carbonate (358 mg)

GlaxoSmithkline, India

Topalkan® Floating liquid  alginate

preparation

Al – Mg  antacid Pierre Fabre Drug,

France

Almagate Flot

coat®

Floating dosage form Al – Mg  antacid -----------

Conviron® Colloidal gel forming

FDDS

Ferrous sulphate Ranbaxy, India

Cytotech® Bilayer floating capsule Misoprostol

(100µg/200µg)

Pharmacia, USA

Cifran OD® Gas-generating floating

form

Ciprofloxacin (1gm) Ranbaxy, India

39

INGREDIENTS OF FLOATING TABLETS

ACTIVE INGREDIENTS:-

Food supplement, vitamins, minerals, trace elements, active drug substances.

HIGHLY SWELLING SUBSTANSES:-

Water soluble-: alginates, pectins, dextran, chitin, gelatin, hemicellulose,

methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,

hydroxyethylcellulose, corboxy methylcellulose, polyacrylic acid polyvinyl

alcohol, etc.

Lipophilic-: steryl alcohol, stearic acid, glycerides, fatty alohol esters, cellulose

acetate, acrylic acetate, etc.

EXCIEPIENTS:-

Lubricants-: stearates of alluminium, calcium, magnesium, tin, magnesium

silicates, etc. Binders-: starch, alginates, corboxymethyl cellulose, polyvinyl

pyrolidone, etc. Disintegrates-: starch, starch paste, microcrystalline cellulose, etc.

Flow regulators-: talc, colloidal silica, starch, free flowingmicrocrystaline

cellulose, etc. Stabilizers-: microcrystaline cellulose, corboxymethyl cellulose, etc.

Bulking agents-: alluminium oxide, magnesium oxide, silicon oxide, titanium

oxide, calcium carbonate, etc.

40

MECHANISM OF FLOATING TABLETSAfter intake of the slow-release dosage form it reaches the stomach, where it is

normally transported after 0.5-3 h into the small intestine. The time to pass through the

small intestine is usually 3-6 h. The result of this is that absorption of the active

ingredient must be complete within about 3-6 h because most active ingredients are

absorbed in the colon to only a negligible extent or not at all. It is therefore possible to

adjust a longer release-slowing period only with difficulty. The bioavailability of active

ingredients which are not completely absorbed in this period decreases because part of the

dose is lost. An additional factor is that certain active ingredients have an absorption

window, which is very quickly passed through with conventional dosage forms, in the

small intestine.

A system which remains in the stomach for a longer time and continuously

releases active ingredient would avoid these disadvantages, since the active ingredient

would continuously pass through the pylorus in dissolved form and could be taken up in

the small intestine. It is possible in this way on the one hand to extend the bioavailability

but also, on the other hand, to extend the duration of action, for example of a drug

product.

There have been frequent approaches to extending the residence time by tablets

which swell in the stomach and become so large that they are no longer able to pass

through the pylorus. All these forms have the disadvantage that they may block the outlet

from the stomach and may cause health problems. In addition, the swelling depends

greatly on the contents of the stomach and the osmolarity of the medium. These

eventually also influence the release-slowing action and the residence time.

Another possibility for extending the residence time in the stomach is to produce

floating forms. These float on the contents of the stomach and, because the pylorus is

located in the lower part of the stomach, are not discharged into the small intestine for a

lengthy period.

41

APPROACHES & METHOD

Several approaches have been attempted in the preparation of gastro-retentive drug

delivery systems. These include floating systems, swell able and expandable systems,

high density systems, bioadhesive systems, altered shape systems, gel forming solution or

suspension systems and sachet systems. Various approaches have been followed to

encourage gastric retention of an oral dosage form. Floating systems have low bulk

density so that they can float on the gastric juice in the stomach. The problem arises when

the stomach is completely emptied of gastric fluid. In such a situation, there is nothing to

float on. Floating systems can be based on the following:   

1. Hydrodynamically balanced systems (HBS) – incorporated buoyant materials

enable the device to float;

2. Effervescent systems – gas-generating materials such as sodium bicarbonates or

other carbonate salts are incorporated. These materials react with gastric acid and

produce carbon dioxide, which entraps in the colloidal matrix and allows them to

float;

3. Low-density systems -- have a density lower than that of the gastric fluid so they

are buoyant;

4. Bioadhesive or mucoadhesive systems – these systems permit a given drug

delivery system (DDS) to be incorporated with bio/mucoadhesive agents, enabling

the device to adhere to the stomach (or other GI) walls, thus resisting gastric

emptying. However, the mucus on the walls of the stomach is in a state of constant

renewal, resulting in unpredictable adherence.

5. High-density Systems - sedimentation has been employed as a retention

mechanism for pellets that are small enough to be retained in the rugae or folds of

the stomach body near the pyloric region, which is the part of the organ with the

lowest position in an upright posture. Dense pellets (approximately 3g/cm3)

trapped in rugae also tend to withstand the peristaltic movements of the stomach

wall. With pellets, the GI transit time can be extended from an average of 5.8–25

hours, depending more on density than on diameter of the pellets, although many

conflicting reports stating otherwise also abound in literature.

42

Methods

1. Using gel forming hydrocolloids such as hydrophilic gums, gelatin, alginates,

cellulose derivatives, etc.

2. Using low density enteric materials such as methacrylic polymer, cellulose acetate

phthalate.

3. By reducing particle size and filling it in a capsule.

4. By forming carbon dioxide gas and subsequent entrapment of it in the gel network.

5. By preparing hollow micro-balloons of drug using acrylic polymer and filled in

capsules.

6. By incorporation of inflatable chamber which contained in a liquid e.g. solvent

that gasifies at body temperature to cause the chambers to inflate in the stomach.

43

Fig: 1 is showing the floating drug delivery in stomach and fig: 2 demonstrate the

mechanism of floating drug delivery systems.

44

FACTORS AFFECTING

1. Density – gastric retention time (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 7.5 mm are reported to

have an increased GRT compared with those with a diameter of 9.9 mm;

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 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 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;

5. 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 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 longe

6. 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;

7. Caloric content – GRT can be increased by four to 10 hours with a meal that is

high in proteins and fats;

8. 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;

9. Gender – mean ambulatory GRT in males (3.4±0.6 hours) is less compared with

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

weight, height and body surface);

10. Age – elderly people, especially those over 70, have a significantly longer GRT;

45

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

patient;

12. Concomitant drug administration – anticholinergics like atropine and

propantheline, opiates like codeine and prokinetic agents like metoclopramide and

cisapride; can affect floating time.

13. Biological factors – diabetes and Crohn’s disease, etc.

46

LIMITATIONS

ØThe major disadvantage of floating system is requirement of a sufficient high level of

fluids in the stomach for the drug delivery to float. However this limitation can be

overcome by coating the dosage form with the help of bioadhesive polymers that easily

adhere to the mucosal lining of the stomach

ØFloating system is not feasible for those drugs that have solubility or stability problem

in gastric fluids.

ØThe dosage form should be administered with a minimum of glass full of water (200-

250 ml).

ØThe drugs, which are absorbed throughout gastro-intestinal tract, which under go first-

pass metabolism (nifedipine, propranolol etc.), are not desirable candidate.

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

47

PRODUCTION OF FLOATING TABLETSVarious processes are known for producing sustained release dosage forms or floating

tablets. Thus, it is possible to incorporate substances which have per se a low density,

such as, for example, fats, oils or waxes. However, relatively large amounts are necessary

for this and increase the volume of the dosage forms and makes them more difficult to

swallow and, in addition, these substances have a very disadvantageous effect on the

strength of the shaped products. Compression results in tablets with low harnesses, and

the tablets frequently adhere to the punch during production. Fat-containing mixtures

which are packed into a capsule and must be heated for solidification. This is complicated

and entirely unsuitable for temperature-labile active ingredients. Shaped articles are

produced by cooling and gelling and drying. This process is even more elaborate.

Another method makes use of the evolution of gas from salts of carbonic acid. This

entails these salts being incorporated together with gel formers into the dosage forms and,

after exposure to gastric acid, produced and inflates the form and leads to the floating. In

order to be independent of gastric acid there is frequently incorporation of physiologically

tolerated acids such as, for example, citric acid or tartaric acid. These preparations are

very sensitive to moisture, so that humidity must be low during \ production and no

water-containing excipients can be employed. The packaging material for the dosage

forms must be very leakproof so that the forms do not effervesce even during storage.

The evolution of gas on contact with acid often also affects the structure of the dosage

forms and the release-slowing effect is reduced. Since these preparations are often

difficult to compress, and tablets with adequate mechanical stability are not obtained,

such preparations are frequently and inconveniently packed in hard or soft if gelatin

capsules. Besides the disadvantages already mentioned above, with these tablets there are

enormous problems with reproducibility of the release. It is generally known that the gel-

forming capacity and the gel strength of polysaccharides varies from batch to batch

because of the variation in the chain length and the degree of substitution, and this is

exacerbated by the disturbance of the gel structure through evolution of C02 In

addition, T the gel formers react very sensitively to differences in the qsmolarity of the

release * media, with alterations in the release.

48

Some other methods

The tablets of this invention have a density of less than one and will float on gastric

fluid in vivo. They are sustained release dosage units, i.e. they release their

medicaments over an extended period of time. The actual rate of release varies with

the amount of exposed surface area and, therefore, with size and shape of the tablet.

The non-compressed tablets of the present invention may be prepared by the following

method:

1. Prepare a solution of the hydrocolloid gelling agent and excipients, if any, in

hot water;

2. Prepare a mixture of a therapeutic agent and therapeutically acceptable inert oil;

3. Cool the solution of gelling agent, but not to the point where gelation takes place, and

combine the solution and the mixture from step (2) with stirring, while maintaining

the temperature above the gelation temperature;

4. Pour the mixture from step (3) into a tablet mold and allow to stand in the mold to

form a gel; and

5. Dry the molded gel tablets to reduce the water content. The solution temperature for

the gelling agent is generally about 70 degree.

The specific temperature depends upon the gelling agent used in the formulation. The

following examples are given by way of illustration only to have idea about the

formulation of floating tablet.

EXAMPLE-1 (www.patentgenius.com/patent/4814179.html)

Theophylline tablets were prepared from the following formulation, using agar as

gelling

Ingredients grams %

Theophylline 9.0 42

Light mineral oil 2.0 9.

Agar 0.2 0.9

Water 10.

49

The theophylline and mineral oil were charged into a beaker and stirred. Water and

agar were placed in a separate beaker, stirred and heated to boiling to effect solution.

The agar solution was cooled to TO.degree. C. and gradually added to the

theophylline-oil mixture with vigorous stirring to form an oil-in-water emulsion. The

warm emulsion was poured at 50.degree.-55.degree. C. into a tablet mold in which the

cylindrical holes had a height of about 0.46 cm and a diameter of about 1.10 cm. The

compositions in the holes, were allowed to cool and gelled in about 5 minutes. The

tablets were removed from the mold and air dried for 24 hours. The average density of

the tablets (average of 10 tablets) was 0.70.

The release of theophylline from the tablets was determined using the U.S.

Pharmacopeia basket method at 50 rpm and 37.degree. C. The dissolution medium

was either at pH 1.2

50

(concentrated HC1 diluted withwater) or pH 7.4 (buffer solution containing sodium

hydroxide, potassium phosphate and distilled water, as described in U.S.P. XX).

EXAMPLE -2

Theophylline tablets were prepared as described in Example 1, using iota carrageenan as

the gelling agent, in the following formulation:

Ingredients grams %

Theophylline 6.0 32.8

Iota carrageenan 0.3 1.6

Mineral oil 2.0 10.9

Water 10.0 54.6

After 24 hours air drying, the l.ll.times.0.48 cm tablet weighed 234 mg, the hardness was

6.2 kg and the density was 0.576.

EXAMPLE-3

Theophylline tablets were prepared as described in Example 1, using kappa carrageenan

as the gelling agent, in the following formulation:

Ingredients grams %

Theophylline 6.0 32.8

Kappa carrageenan 0.3 1.6

Mineral oil 2.0 : 10.9

Water 10.0 54.6

51

V

After 24 hours air drying, the l.ll.times.0.48 cm tablet weighed 237 mg, the hardness was

5.2 kg and the density was 0.580.

EXAMPLE -4

Theophylline tablets were prepared as described in Example 1, using a mixture of iota

carrageenan and locust bean gum as gelling agent in the following formulation:

Ingredients grams %

Theophylline 6.0 32.8

Iota carrageenan 0.2 1.1

Locust bean gum 0.1 0.5

Mineral oil 2.0 10.9

Water 10.0 54.6

After 24 hours air drying, the l.ll.times.0.48 cm tablet weighed 221 mg, the hardness

was 7.9 kg and the density was 0.546.

EXAMPLE - 5

Theophylline tablets were prepared as described in Example 1, using a mixture of alginic T

acid and locust bean gum as gelling agent, in the following formulation:

Ingredients grams % *

Theophylline 6.0 32.8

Alginic acid 0.2 1.1

Locust bean

gum

0.1 0.5

Mineral oil 2.0 10.9

Water 10.0 54.6

After 24 hours air drying, the 1.11=0.48 cm tablet weighed 226 mg and the hardness was

7.4 kg. The density of the tablet was 0.554.

52

EXAMPLE - 6

Ampicillin floating tablets were prepared using agar as the gelling agent, according to the

following formulation:

Ingredients grams

Ampicillin, 90.0 32.5

anhydrous

Light mineral oil 16.0 5.8

Agar 3.2 1.15

Sodium citrate 8.0 2.9

Water 160.0 57.7

53

This formulation was used to make a batch of 300 tablets. The mineral oil was added to

the ampicillin previously charged into a 500 ml beaker and mixed thoroughly with a glass

rod. In a separate beaker, the water was heated to 90.degree. C. and the sodium citrate

was dissolved therein with stirring. The agar was added to the aqueous solution and

stirred while heating until the agar dissolved. The ampicillin-oil mixture which was in the

form of a powder was added in portions to the agar solution at 70.degree.C. and mixed

with an electric whisk until a smooth, creamy suspension was obtained. The suspension

was poured into a tablet mold at 48.degree.-50.degree. C. The suspension gelled after

cooling for 10 minutes. The excess was scraped off the top of the molds, the tablets were

pushed out of the molds and air dried at room temperature for 24 hours.

EXAMPLE - 7

Captopril tablets were prepared in the same manner as described in Example 6, using agar

as gelling agent, according to the following recipe:

Ingredients grams %

Captopril 7.0 35.7

Light mineral Oil 1.0 5.1

Agar 0.3 1.5

Lactose 1.0 5.1

Calcium Gluconate 0.3 1.5

Water 10.0 51.0

The captopril-oil mixture was added to the aqueous solution containing agar, lactose and

calcium gluconate at 70.degree. C. and after mixing thoroughly was poured into the tablet

mold at 50.degree. C. The molded gel tablets were air dried for 36 hours. The size of the

dried tablet was 0.95.times.0.32 cm and the average tablet weight was 134 mg. The

hardness was 9.9 kg and the average tablet density was 0.817. A friability test showed a

loss of 0.84%.

54

Development of floating drug dosage form

Development of a multifunctional matrix drug delivery system surrounded by an

impermeable cylinder

A multifunctional drug delivery system based on hydroxypropyl methylcellulose

(HPMC)-matrices (tablets) placed within an impermeable polymeric cylinder (open at

both ends) was developed. Depending on the configuration of the device, extended

release, floating or pulsatile drug delivery systems could be obtained. The release

( behaviour of the different devices was investigated as a function of HPMC viscosity C

grade, HPMC content, type of drug (chlorpheniramine maleate or ibuprofen), matrix

weight, position of the matrix within the polymeric cylinder, addition of various fillers

(lactose, dibasic calcium phosphate or microcrystalline cellulose) and agitation rate of the

release medium. The drug release increased with a reduced HPMC viscosity grade, higher

aqueous drug solubility, decreased HPMC content and increased surface area of the

matrix. The release was fairly independent of the agitation rate, the position of the tablet

within the polymeric cylinder and the length of the cylinder. With the pulsatile device, the

lag time prior to the drug release could be controlled through the erosion rate of the

matrix (matrix weight and composition).

55

OPTIMISATION OF FLOATING MATRIX

TABLETS AND EVALUATION OF THEIR

GASTRIC RESIDENCE TIME Effervescent FDDS investigation concerns the development of the floating matrix

tablets, which after oral administration are designed to prolong the gastric residence time,

increase the drug bioavailability and diminish the side effects of irritating drugs. The

importance of the composition optimization, the technological process development for

the preparation of the floating tablets with a high dose of freely soluble drug and

characterization of those tablets (crushing force, floating properties in vitro and in vivo,

drug release) was examined. Tablets containing hydroxypropyl methylcellulose (HPMC),

drug and different additives were compressed. The investigation shows that tablet

composition and mechanical strength have the greatest influence on the floating

properties and drug release. With the incorporation of a gas-generating agent together

with microcrystalline cellulose, besides optimum floating (floating lag time, 30 s;

duration of floating, '(8 h), the drug content was also increased. The drug release from

those tablets was sufficiently sustained (more than 8 h) and non-Fickian transport of the

drug :from tablets was confirmed. Radiological evidence suggests that, that the

formulated tablets did not adhere to the stomach mucus and that the mean gastric

residence time was prolonged.

FDDS buoyant delivery systems utilize matrices prepared with swellable polymers

such as hypromellose 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. 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 to float on the chyme. The carbonates, in addition to imparting buoyancy to these

formulations, provide the initial alkaline microenvironment for polymers to gel.

Moreover, the release of CO2 helps to accelerate the hydration of the floating tablets,

which is essential for the formation of a bioadhesive hydrogel. This provides an

additional mechanism („bioadhesion‟) for retaining the dosage form in the stomach, apart

56

from floatation. Floating dosage forms with an in situ gas generating mechanism are

expected to have grater buoyancy and improved drug release characteristics. However,

the optimization of the drug release may alter the buoyancy and, therefore, it is

sometimes necessary to separate the control of buoyancy from that of drug release

kinetics during formulation optimization. From the results of resultant-weight

measurements of various excipients, it is concluded that higher molecular weight

polymers and slower rates of polymer hydration are usually associated with enhanced

floating behavior. Hence, the selection of high molecular weight and less hydrophilic

grades of polymers seems to improve floating characteristics.

57

EVALUATION OF FLOATING TABLETS

Invitro evaluation of SR formulation are done for two purposes:

(1) As a guide to formulation during development stage.

(2) To ensure batch to batch uniformity

Invitro evalution:

Assay: To ensure drug content, the SR formulations are assayed by Colorimetric and

Spectrophotometric methods.

Dissolution : dissolution testing for SR formulations are limited to USP dissolution

testing methods, using either the rotating basket method (apparatus 1) and the

paddle type (apparatus 2) .

Apparatus 1: it is basically a close compartment, beaker type of a cylinder glass

vessel

with hemispherical bottom of 1 liter capacity partially immersed in water bath to

maintain temperature at 37 C. a cylindrical basket made of mesh no 22 to hold the

dosage form is located centrally in the vessel at a distance of 2 cm from bottom and

rotated by a variable speed motor through a shaft.

Apparatus 2: The assembly is same as that of apparatus 1 except that the rotating

basket is replaced with a paddle which act as a stirrer.

The SR tablets are first kept in 0.1 N HCL for specific time (stimulated gastric fluid)

and followed by a media of pH 7.2 (simulated intestinal fluid) for specific time.

58

Beside the USP dissolution testing apparatus the rotating bottle, stationary basket

and rotating filter, Sartorius absorption and solubility stimulater, and column

type flow through apparatus are aso used.

Rotating bottle : The Rotating bottle apparatus consists of a rotating bottle of capacity 90

ml. 60 ml of fluid is kept at 37 C and rotetas at a speed of 40 rpm. The tablet which has to

be evaluated is introtruced onto the samples are withdrawal at regular interval and is

analysed.

Sartorius device : the Sartorius device consists of an artificial lipid membrane which

separates the dissolution chamber from a simulated plasma compartment in which drug

concentration are measured. The time of testing may vary from 6-12 hours. Sink

condition can obtained by recirculating the media and thus the cumulative release can be

obtained. In certain case, the drug is exposed to media of pH 4-5, considering the

transition between gastric and intestinal pH Stability studies are completed since

accelerated stability studies may induce changes in the system. For a sustained release

product, the stability testing dependson the dosage -form and its composition.

In vivo evaluation:

In vivo Mesurment of drug availability: In vivo testing for drug is done in human

beings or animal models like dogs during the product development stage, animal models

are preferred. In vivo drug availability for SR formulation are done either by periodic

blood level determination or urinary excretion data.

In vivo measurements are done to find out release rate of drug and to notice the drug

dumping. If drug level cannot be measured in biological fluids, the pharmacological

effect must be observed.

59

APPLICATIONS OF FLOATING TABLETS

Floating drug delivery offers several applications for drugs having poor bioavailability

dosage form at the site of absorption and thus enhances the bioavailability. These are

summarized as follows.

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 this system.

These systems have 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.

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 (Shours).

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 release was essentially complete in less than 30

minutes in the latter case.

60

Site Specific Drug Delivery

• These systems are particularly advantageous for drugs that are specially absorbed

for

stomach or the proximal part of the small intestine, e.g. riboflavin and fiirosemide.

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.

A bilayer floating capsule was developed for local delivery of misoprostol, which is a

synthetic analog of prostaglandin El 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 reduced.

Absorption enhancement

Drugs that have poor bioavailability because of site specific absorption from the upper

part of the GIT are potential candidates to be formulated as floating drug delivery

systems, thereby maximizing their absorption.

A significant increase in the bioavailability of floating dosage forms (42.95%) could

be achieved as compared with commercially available LASIX tablets (33.4%) and

enteric coated LASIX long product (29.5%).

The absorption of bromocriptine is limited to 30% from the GIT tract, however an

HBS of the same can enhance the absorption.

61

Floating tablets as a new approach to the treatment of Helicobacter

pylori infections

Floating tablets offer a new possibility of treating the stomach infected with Helicobacter

pylori. The objective of this study was to select suitable materials for the formulation of

floating tablets with sustained drug release properties. In the preformulation studies the

differences between cellulose polymer (HEC, HPC, HPMC K4M, Avicel) isotherms were

estimated using the DVS method and the disappearance of gas-generating agent at higher

relative humidities was observed. The correlation between wettability and the floating lag

time proves that the first contact with water is not essential for good floating. Tablets with

an incorporated drug stored at high relative humidity have a lower crushing force, the

floating lag time increased, but the release profile did not change. Optimally designed

tablets with ciprofloxacin hydrochloride monohydrate have good resistance to crushing, a

floating lag time of less than 1 minute, float longer than 24 hours. The fact that they

enable a more than 8-hour-long controlled drug release from non-disintegrated matrices

plays an important role in prolonging gastric residence time.

62

CONCLUSION

In recent years scientific and technological advancements have been made in the research and development of

controlled release oral drug delivery systems by overcoming physiological adversities like short gastric

residence times and unpredictable gastric emptying times. Floating tablets are the systems which are retained in

the stomach for a longer period of time and thereby improve the bioavailability of drugs. Floating tablets were

prepared using directly compression technique using polymers like HPMC K4M and HPMCK100M for their

gel-forming properties.

63

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