Drug Delivery System (FDDS)
In comparison to other systems floating drug delivery
system have less density that creates ability to float. Because of buoyancy it can remain lifted over
gastric contents and remains in stomach for extended time (3-4 hours). It is an
important approach towards sufficient drug bioavailability because of efficient
OF FLOATING DRUG DELIVERY SYSTEMS
delivery system should have:
· Slow Release:
It should discharge contents gradually and
act as reservoir.
· Specific Gravity: It
should keep specific gravity lower than gastric contents (1.003-4 to 1.01
· Gel barrier:
It must form well integrated gel barriers.
It is also
known as lesser density system.
OF FLOATING DRUG DELIVERY SYSTEMS:
The drug is discharged slowly at required proportion
from the system floating on the gastric contents.
After the drug is released the residual system is
emptied from the stomach.
Fig: Mechanism of Floating Systems
Floating force is required to keep dosage form buoyant
on the surface of gastric contents. A novel device is used to measure floating
force kinetics. This apparatus works by determining continuously the force “F” as
a function of time that is essential to retain the objects intermingle. The device
in accessing FDDS to stability and durability of floating forces produced in
order to prevent weaknesses of unexpected intra-gastric buoyancy ability of deviations.
F = F buoyancy – F gravity
= (D f – D s)
Where, F = Total vertical force
f = Fluid Density
s = Object Density
approach to design the floating dosage form there is a binary type of floating Dosage systems:
unit floating dosage system
unit floating dosage system
These two systems have been designed by using the
SINGLE UNIT DOSAGE FORMS
Low density approach;
As the name indicates in
low-density approach the globular shells with lower density than that of gastric
fluids are used as drug transporter for making single-unit floating dosage form
Popcorn, polystyrol and poprice have been used as drug transporters in coated
shells26. For the undercoating of these shells sugar polymeric materials such
as methacrylic polymer and cellulose acetate phthalate have been misused. These
shells are additionally coated with a combination of drug polymer. Depending
upon the type of discharge the polymer is ethyl cellulose or hydroxy propyl
cellulose. Product floats on the gastric fluid and slowly discharges the drug
for a extended period of time.
Fluid- filled floating chamber;
A gas-packed floatation chamber is blend into a microporous section that covers
the drug reservoir. Along the upper and bottom walls there is supply for
opening through which the GIT fluid enters into the device to dissolve the
drug. The side walls came in contact with the fluid is sealed to safeguard
un-dissolved drug remains in the device. Air, gas, liquid or solid that has
specific gravity and that should be inactive can be used as a system for
floatation. This scheme should be of swell able size. Device remains floating
within the stomach for a longer duration and slowly discharges the drug. After
the complete discharge of the drug, the shell unravel, goes to the intestine
and finally excreted from body.
Hydro-dynamically balanced systems (HBS);
These systems have more capacity of absorption because they are intended in a
way that they stays in GIT for long time. Drugs which are capable especially in
acidic environment and site-specific absorption in the upper part of GIT are
most appropriate for such systems. These dosages form must have more density of
? 1. It should preserve its structural probity should resolute release the
drug. The solubility of chlordiazepoxide hydrochloride29 is 150 mg/mL at pH 3-6
and is ~0.1 mg/ml at neutral pH. So, HBS capsule drug is better than conservative
to solve the solubility problem.
Bilayer and matrix tablets;
Some types of Bilayer and matrix tablets shows floatable characteristics. The polymers which have been misused are
sodium carboxymethyl cellulose (CMC), hydroxypropyl cellulose, hydroxypropyl
methylcellulose, ethyl cellulose and Crosspovidone.
As the advancements of asymmetric arrangement drug delivery system, 3-layer
principle has enhanced 3-layer principle helps to control the discharge extent
and for getting zero-order release kinetics. The design of the system works as
it floats on the stomach content and gastric ability to keep contents for
longer period which additional results in longer total transit period which
increases the absorptive capability and hence improved bioavailability is the
result. PH-dependent solubility’s drugs get benefit from it, drugs which are
absorbed by the active transport mechanism from the small intestine or the
drugs with small or thin absorption window.
Problems with single-unit formulations;
Major problem with this formulation is that the Single-unit formulations can
remain together or been clogged in the GIT, which can cause irritation or
MULTIPLE-UNIT DOSAGE FORMS
Multiple-unit dosage form is intended to create a formulation which should be
reliable that provide all the advantages of a single-unit form and to overwhelmed
the hazards of single-unit formulations. High loading capacity microspheres are
used in it. The polymers i.e. polyacrylamine, albumin, gelatin, starch, polymethacrylate
and polyalkylcyanoacrylate have been used to form microspheres. Because of its internal
hollow structure characteristic microspheres shows excellent in-vitro
floatability. After administration numerous devices of carbon dioxide multiple unit
oral formulations have been defined in the literatures with specific features .
CLASSIFICATION OF FLOATING DRUG DELIVERY
A) Effervescent system:-
In effervescent matrix type of system swell
able polymers especially methylcellulose and chitosan and effervescent
compounds mainly tartaric acid, citric acid, and sodium bicarbonate are used.
Liberation of Carbon dioxide occurs in these formulations when come in interaction
with gastric contents and gas is trapped in inflated hydrocolloids which
provide buoyancy to the dosage form.
Volatile liquid containing
In volatile liquid drug delivery system liquids are present
in the inflatable chambers, liquids mainly ether and cyclopentane, these
liquids causes inflammation in stomach when gasified at body temperature. This
matrix is comprising of a bio-erodible plug made up of PVA, Polyethylene etc.
that slowly liquefies and results in the discharge of gas from inflated chamber
and collapse after a predetermined period to allow the spontaneous discharge of
the inflatable systems from stomach.
Intra-gastric floating gastrointestinal drug delivery system
Intra-gastric floating gastrointestinal
drug delivery system: this system floats in fundus, because of the
floating chamber, which may be a vacuum filled with air or a harmless gas,
while drug reservoir is captured in a micro porous section.
Inflatable gastrointestinal delivery system
Inflatable gastrointestinal in
these systems inflatable unit is incorporated, which have liquid ether that
gasifies at body temperature to cause the compartment to inflatable in the
fundus. These systems are build by filling the chamber with drug reservoir,
which can be a drug infused polymeric matrix, than incorporated in a gelatin
capsule. After oral administration the drug’s reservoir is released due to
dissolving of capsule along with the inflatable chamber. The inflatable chamber
spontaneously inflates and retains the drug reservoir into the gastric fluid.
b) Gas generating systems:
In these systems effervescent reactions occurs between carbonates/bicarbonates
salts and tartaric/citric acids to liberate CO2, which gets
trapped in the gel matrix of the reservoir. Thus decrease in it specific
gravity and to make it float over the gastric fluid.
I) Floating pills:
These systems consists of two layers, inner effervescent film comprising tartaric
acid and sodium bicarbonate , the external
swell able polymeric membrane and the inner layer which is further divided into
two sub layers to avoid interaction between tartaric acid and sodium
bicarbonate. When this pill is submerged in buffer solution at 37°C, it settles
down at bottom and the buffer solution enters into the effervescent layer
through the outer swell able membrane. Generation of carbon dioxide forms
swollen pills or balloons as a result of chemical reaction between sodium
bicarbonates and tartaric acid. The carbon dioxide generation entrapped within
the delivery system to make the device float. These systems were found to float
completely within 10 minutes and have good floating ability independent of pH, controlled
viscosity of the medium and the drug is released.
II) Floating capsules:
Floating capsules are formed by mixing of sodium alginate and sodium bicarbonate
solution, generation of carbon dioxide make it to float, which gets entrapped
in the hydrating gel network when exposed to an acidic environment.
III) Floating systems with ion exchange resins:
These systems are formulated by using ion exchange resin which is loaded with
bicarbonate and by mixing the beads with sodium bicarbonate solution, to avoid
the sudden loss of carbon dioxide loaded beads are enclosed by semi permeable
membrane. When it came in interaction with gastric contents there is an
exchange of chloride and bicarbonate ions in result carbon dioxide generates
thereby carrying beads toward the top of gastric contents and producing a
floating layer of resin beads, which releases the drug at a determined quantity.
a) Intra-gastric single layer floating tablets or Hydrodynamic
ally balanced system:
These preparations have bulk density lower than gastric fluids and thus it float
in the stomach that cause increase in gastric emptiness proportion for a extended
period. These are formulated by closely mixing the gas (CO2) generating agents and the drug within the matrix
tablet. The drug is released at slow required proportion from the floating
system & the residues emptied from the stomach after the complete release
of the drug. This leads to and increases the gastric residence time & a
better control on fluctuations in plasma drug concentration.
b) Bi-layer tablet
Bi-layer tablet can also prepared by gas creating matrix in one layer and in
second layer with drug for its sustained discharge effect.
c) Triple layer tablet
Triple layer tablet also have first swell-able floating layer, second controlled
release layer of two drugs and third rapid dissolving layer
B) Non-effervescent systems:
This type of system after engulfing swells abandonment via Imbibition of
gastric fluid to an extent that it stops their discharge from the stomach. These
systems are discussed as the “plug type system” since they have capability to
remain bestow near the pyloric sphincter. One of the formulation methods of
these dosage forms involve the mixing of drug with a gel, which swells in
contact after oral administration and maintains a relative shape and a bulk
density of less than 1. This is based on the mechanism of swelling of polymer
or bio adhesion to mucosal layer in GIT. The most frequently used recipients
are gel forming materials such as polycarbonate, poly acryl ate, polystyrene
etc. this hydrocolloid starts to hydrate by first forming a gel at the surface
of the dosage form. The resulting gel structure then have control on the rate
of dispersion of solvent-in and drug-out of the dosage form. The various types
of this system are as follows:
Single layer floating tablets:
This can be produced by indirect mixing of drug with gel producing
hydrocolloid, which swells in and have contact with gastric fluid and maintain
bulk density of less than 1. The air trapped by the swollen polymer discusses
floating capacity to these dosage forms.
Bi-layer floating tablets:
A bi-layer tablet contains two layers, one is immediate release layer which
releases the initial dose from system while the other is sustained release
layer which absorbs the gastric fluid and maintains a bulk density of less than
1 and it remains floating in the stomach. Fassihi and Yang developed a
zero-order controlled release. Multilayer tablet consisting of at least 2
layers and one drug layer. All the layers are made of swell-able, erodible
polymers and the tablet was found to swell on having contact with aqueous
medium. As the tablet dissolved, the barrier layers eroded away to expose more
of the drug. Agents which evolve gases
are added in either of the barrier layers; this become the cause for tablet to
float and increased the retaining capability of tablet in a patient’s stomach.
Colloidal gel barrier systems:
It contains drug with gel forming hydrocolloids meant to remain floating on
stomach contents. This system assimilates a high level of one or more gel
forming highly swell-able cellulose type hydrocolloids. When it comes in
contact with gastric fluid, the hydrocolloids in the system hydrates and forms
a colloidal gel barrier around the gel surface. The air trapped by the inflated
polymer maintains a lesser density to this floating dosage forms.
Micro porous Compartment System
This technology is based on the encapsulation of drug reservoir inside a micro
porous compartment with aperture along its top and bottom wall. The marginal
walls of the drug reservoir compartments are closed to prevent it from direct interaction
of the gastric mucosal surface with the un-dissolved drug. In stomach the
floatation chamber consisting entrapped air causes the delivery system to float
over the gastric contents. Gastric fluid enters from apertures, dissolves the
drug, and carries the dissolved drug for constant transport it through the
intestine for absorption.
To develop Multi-unit floating dosage forms the freeze-dried calcium alginate
is used. Spherical beads of approximately 2.5 mm in diameter can be prepared
through precipitation of calcium alginate by drop wise addition of sodium
alginate solution into solution of calcium chloride. The beads are then detached
and frozen in liquid nitrogen, and freeze dried at -40°C for 24 hours, leading
to the formation of porous system, which can maintain a floating force over 12
Preparation of hollow microspheres is done through emulsion solvent diffusion
which (hollow microsphere) have drug in their outer polymer shelf. The ethanol:
dichloromethane solution of the drug andenteric acrylic polymers is poured in
to an agitated aqueous solution of PVA that was thermally controlled at 40°C.
The gas phase produced in dispersed
polymer droplet by evaporation of dichloromethane designed in internal cavity
in microspheres of the polymer with drug. The micro ballons floated constantly
over the surface of acidic dissolution media containing surfactant greater than
12 hours. The drug released has high pH 7.2. Hollow microspheres (micro
balloons), loaded with ibuprofen in their outer polymer shells were prepared by
a novel emulsion-solvent diffusion method.
o FACTORS AFFECTING GASTRIC RETENTION:
o A) PHYSIOLOGICAL FACTORS:-
o a) Density:
Gastric retention time of a dosage form floating is density dependent. A
buoyant dosage form having a density less than that of the gastric floating
fluid, since it is away from the pyloric sphincter, the dosage unit is retained
in the stomach for a longer period of time. A density having less than
1.004g/ml i.e. less than that of gastric contents has been reported.
o b) Size:
7.5mm diameter unit dosages are reported to have an increased gastric retention
time compared with those with a diameter of 9.9mm.
o c) Shape of dosage form:
Tetrahedron and ring shaped devices with a bend modulus of 49 pounds or 22.5
kilo pounds per square inch (KSI) are reported to have better gastric retention
time 90% to 100% retention at 24 hours compared with other shapes.
o B) BIOLOGICAL FACTORS:
o a) Fed or unfed state:
During fasting , GI motility have periods of strong motor activity or the
migrating myoelectric complex (MMC) that occurs every 1.5 to 2 hours. The MMC excretes
undigested material from the stomach. However, in the fed state, MMC delayed
and gastric retention time comparatively longer.
o b) Nature of meal:
Feeding of indigestible polymers or
fatty acid salts can change the motility rate of stomach, thus gastric emptying
rate is reduced and rate of drug release is prolonged.
o c) Caloric content:
Gastric retention time can be increased with the meal high in protein and fats
by 4 to 10 hours.
o d) Frequency of feed:
When successive meals are given in a single meal due to the low frequency of MMC
the gastric retention time can increase by over 400 minutes.
o e) Gender:
Mean GRT in males (3.4±0.6 hours) is
lesser in contrast to with their age and race matched female counterparts (4.6±1.2
hours), weight, height and body surface conditions not applied.
o f) Age:
Low gastric emptying time is observed in elders than do in younger subjects.
Intra subject and inter subject variations also are observed in gastric and
intestinal transit time. Elderly people, especially over 70 years have a
significantly longer GRT.
o g) Posture:
Gastric retention time can vary between supine and upright ambulatory states of
the patient. An upright position protects floating forms against postprandial
emptying because the floating form remains above the gastric contents regardless
of size. In supine subjects large dosage forms have prolonged retention. The
gastric retention of floating forms appear to floating anywhere between the low
and high twists of the stomach. On moving distally, these units may be moved
away by the peristatic movements that propel the gastric contents towards the
pylorus, leading to significant decrease in gastric retention time compared
with upright subjects.
o h) Concomitant drug administration:
Anti cholinergic like atropine and propentheline opiates like codeine and
prokinetic agents like meto clopramide and cisapride, affect the gastric
emptying and hence gastric residence time of an oral dosage form.
Methods for Preparing Floating
Direct compression technique
Involves tablets directly from powdered material without changing the physical
nature of the material itself. Direct compression carriers must have better flow
and compressible characters these properties are reported by predisposing these
vehicles to slugging, spray drying or crystallization. Most common carriers are
di calciumphosphate trihydrate, tri calcium phosphate etc.
Melt granulation technique:
This is a process by which the pharmaceutical powders are massed (making a
ball) by using a melt able binder and no water or organic solvents are required
for granulation. Because there is no step of drying, the process is less time
consuming and uses less energy. Granules were prepared in a lab scale high
shear mixer, using a jacket temperature of 60 °c and an impeller speed of 20000
Melt solidification technique:
This process involves emulsification of the molten mass in the aqueous phase
followed by its solidification by cooling. The carriers used for this technique
are lipids, waxes, polyethylene glycols. Drug is inserted into these carriers
to attain controlled release.
Wet granulation technique:
Wet granulation process involves the wet massing of powders, wet sizing or
milling and drying. Wet granulation forms the granules by attaching the powders
together with an adhesive instead of compaction. This method introduces the
binder depends on the solubility and on the components of the mixture since, in
general, the mass should merely be moist rather than wet, and there is a limit
to the amount of solvent that may be used. Once the granulating liquid is
added, mixing continues until a uniform dispersion is attained and all the
binder has been activated. Then the wet mass undergoes wet screening by passing
through a hammer mill or multi mill equipped with screens having large
perforation. The milled wet mass is dehydrated by either using tray drier or
fluidized bed drier, after completion, the drying lubrication materials is
blended with dried granules. This lubricated granule is made to experience compression.
The floating chamber of the drug delivery system filled with inert gas CO2 by
the effervescent reaction between organic acid citric acid and bicarbonate
Spray drying techniques:
It involves dispersing the core material in a liquefied coating material and solidification
effect of coating is done through spraying the core-coating mixture in
environment. Solidification is achieved by rapid evaporation of the solvent in
which coating material is dissolved.
Advantages of FDDS:
FDDS have many advantages in the treatment of gastric disorders, as the main
aimof such systems is to produce a gastro retentive product.
o Drugs with considerably short half life can be administered
by this method to get an appreciable therapeutic activity.
o Improvement of the bioavailability of drugs which are
bio-transformed in the upper GIT.
o They also have advantages over the conventional system as it
can be used to overcome the difficulties of gastric retention time as well as
the gastric emptying time.
o The duration of treatment through a single dose, which
releases an active ingredient over an extended period of time.
o The active drug is delivered to the site of action, thus
minimizing or eliminating the side effects.
Disadvantages of FDDS:
The major disadvantage of floating system is the necessity of 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 bio-adhesive polymers that easily adhere to the
mucosal lining of the stomach.
o Gastric retention influenced by many factors such as gastric
movement, pH and presence of food. These factors are not constant and hence the
floating cannot be predicted.
o Drugs that cause irritation to gastric mucosa are not
suitable to be formulated as floating drug delivery systems.
o High variability in gastric emptying time due to its all
(or) non-emptying process.
o Patients should not be dosed with floating forms just before
o Floating system is not suitable for those drugs that have
solubility (or) stability problem in gastric fluids.
o The dosage form should be administered with a minimum of
glass full of water (200-250 ml).
o The drugs, which are absorbed throughout GIT, which under go
first-pass metabolism (Nifedipine, Propranolol etc.) are not suitable priority.
Drug absorption in the gastrointestinal tract is a highly variable procedure
and increases gastric retention of the dosage form increase the time for drug
absorption. FDDS promises to be a potential approach for gastric retention.
Number of commercial products and patents issued in this field are the evidence
of it. The aim is to improve the bioavailability of the drug with less
absorption window in gastrointestinal tract region. By increasing the drug
staying time in GI region improves the solubility of drug that is less soluble
in high PH and decreases drug waste, reduction in plasma level fluctuation.
Although there are number of problems to be worked on to achieve prolonged
gastric retention, Now a day’s many companies have focus on commercializing