Floating Microspheres-A Review
Floating Microspheres-A Review
Floating Microspheres-A Review
net/reviews/floating-microspheres-review
But conventional oral dosage forms offer no control over drug delivery, leading to
fluctuations in plasma drug level. These have a disadvantage of a release all or nothing
emptying process while the multiple unit particulate system pass through the GIT to avoid the
vagaries of gastric emptying and thus release the drug more uniformly. Various approaches
have been worked out to improve the retention of oral dosage form in the stomach, e.g.
floating systems, swelling and expanding systems, bioadhesive systems, high density
systems.
Introduction
Gastric emptying of dosage form is extremely variable process and ability to prolong and
control the emptying time is valuable asset for dosage forms, which reside in the stomach for
a long period of time than conventional dosage forms. Several difficulties are faced in
designing controlled released systems for better absorption and enhanced the bioavailability1.
Conventional oral dosage forms such as tablets, capsules provide specific drug concentration
in systemic circulation without offering any control over drug delivery and also cause great
fluctuations in plasma drug levels. Although single unit floating dosage forms have been
extensively studied, these single unit dosage forms have the disadvantage of a release all or
nothing emptying process while the multiple unit particulate system pass through the GIT to
avoid the vagaries of gastric emptying and thus release the drug more uniformly. The uniform
distribution of these multiple unit dosage forms along the GIT could result in more
reproducible drug absorption and reduced risk of local irritation; this gave birth to oral
controlled drug delivery and led to development of Gastro-retentive floating microspheres2, 3.
Three decades, various attempts have been done to retain the dosage form in the stomach as a
way of increasing retention time:
1. Bio/Mucoadhesive Systems:
The term bioadhesion describe materials that bind to the biological substrates, such as
mucosal memberes. Adhesion of bioadhesive drug delivery devices to the mucosal tissue
offeres the possibility of creating an intimate and prolonged contact at the site of
administration.This prolonged residence time can result in the enhanced absorption and in
combination with a controlled release of drug also improved patient compliance by reducing
the frequency of administration. The epithelial adhesive properties of mucin have been
applied in the development of gastro retentive drug delivery systems 4, 8.
2. Floating Systems:
Floating systems are low-density systems that have sufficient buoyancy to float over the
gastric contents and remain in the stomach for a prolonged period. While the system floats
over the gastric contents, the drug is released slowly at the desired rate, which results in
increased gastro-retention time and reduces fluctuation in plasma drug concentration9-11.
3. Swelling Systems:
These are capable of swelling to a size that prevents their passage through the pylorus; as a
result, the dosage form is retained in the stomach for a longer period of time. Upon coming in
contact with gastric fluid, the polymer imbibes water and swells 12-14.
Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so
remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged
period of time. While the system is floating on the gastric contents. The drug is released
slowly at the desired rate from the system. After release of drug, the residual system is
emptied from the stomach. This results in an increased GRT and a better control of the
fluctuations in plasma drug concentration. However, besides a minimal gastric content
needed to allow the proper achievement of the buoyancy retention principle, a minimal level
of floating force (F) is also required to keep the dosage form reliably buoyant on the surface
of the meal. To measure the floating force kinetics, a novel apparatus for determination of
resultant weight (RW). The RW apparatus operates by measuring continuously the force
equivalent to F (as a function of time) that is required to maintain the submerged object. The
object floats better if RW is on the higher positive side. This apparatus helps in optimizing
FDDS with respect to stability and durability of floating forces produced in order to prevent
the drawbacks of unforeseeable intragastric buoyancy capability variations 15.
RW or F = F buoyancy - F gravity = (Df - Ds) gV,
1. Effervescent systems
2. Non-effervescent systems
1.Effervescent Systems
The GRT of a drug delivery system can be sustained by incorporating an inflatable chamber,
which contains a liquid e.g. ether, cyclopentane, that gasifies at body temperature to cause the
inflatation of the chamber in the stomach. The device may also consist of a bioerodible plug
made up of PVA, Polyethylene, etc. that gradually dissolves causing the inflatable chamber to
release gas and collapse after a predetermined time to permit the spontaneous ejection of the
inflatable systems from the stomach16.
B. Gas-generating Systems
These buoyant systems utilize matrices prepared with swellable polymers like methocel,
polysaccharides like chitosan, effervescent components like sodium bicarbonate, citric acid
and tartaric acid or chambers containing a liquid that gasifies at body temperature. The
optimal stoichiometric ratio of citric acid and sodium bicarbonate for gas generation is
reported to be 0.76:1. The common approach for preparing these systems involves resin
beads loaded with bicarbonate and coated with ethylcellulose. The coating, which is insoluble
but permeable, allows permeation of water. Thus, carbon dioxide is released, causing the
beads to float in the stomach .Other approaches and materials that have been reported are
highly swellable hydrocolloids and light mineral oils, a mixture of sodium alginate and
sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested,
floating minicapsules with a core of sodium bicarbonate, lactose and polyvinyl pyrrolidone
coated with hydroxypropyl methylcellulose (HPMC), and floating systems based on ion
exchange resin technology, etc.
2. Non-Effervescent Systems
This type of system, after swallowing, swells unrestrained via imbibition of gastric fluid to an
extent that it prevents their exit from the stomach. These systems may be referred to as the
„plug-type systems‟ since they have a tendency to remain lodged near the pyloric sphincter.
One of the formulation methods of such dosage forms involves the mixing of drug with a gel,
which swells in contact with gastric fluid after oral administration and maintains a relative
integrity of shape and a bulk density of less than one within the outer gelatinous barrier. The
air trapped by the swollen polymer confers buoyancy to these dosage forms.
Hydrodymamically balance system (HBS) was first design by Sheth and Tossounian in 1975.
Such systems contains drug with gel forming hydrocolloids meant to remain buoyant on
stomach contents. This system incorporate a high level of one or more gel forming highly
swellable cellulose type hydrocolloids e.g. HEC, HPMC, NaCMC, Polysacchacarides and
matrix forming polymers such as polycarbophil, polyacrylates and polystyrene, incorporated
either in tablets or in capsules. On coming in contact with gastric fluid, the hydrocolloid in
the system hydrates and forms a colloidal gel barrier around the gel surface. The air trapped
by the swollen polymer maintains a density less than unity and confers buoyancy to this
dosage forms19.
c. Alginate beads
Multiple unit floating dosage forms have been developed from freeze-dried calcium alginate.
Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping a sodium
alginate solution in to aqueous solutions of calcium chloride, causing precipitation of calcium
alginate. The beads are then separated snap and frozen in liquid nitrogen, and freeze dried at -
40° for 24 h, leading to the formation of porous system, which can maintain a floating fource
over 12 h.
d. Hollow microspheres
7.Superior to single unit floating dosage forms as such microspheres releases drug uniformly
and there is no risk of dose dumping.
When microspheres come in contact with gastric fluid the gel formers, polysaccharides, and
polymers hydrate to form a colloidal gel barrier that controls the rate of fluid penetration into
the device and consequent drug release. As the exterior surface of the dosage form dissolves,
the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air
trapped by the swollen polymer lowers the density and confers buoyancy to the microspheres.
However a minimal gastric content needed to allow proper achievement of buoyancy 21, 22.
Hollow microspheres of acrylic resins, eudragit, polyethylene oxide, and cellulose acetate;
polystyrene floatable shells; polycarbonate floating balloons and gelucire floating granules
are the recent developments.
Hollow microspheres are prepared by solvent diffusion and evaporation methods to create
the hollow inner core. Polymer is dissolved in an organic solvent and the drug is either
dissolved or dispersed in the polymer solution. The solution containing the drug is then
emulsified into an aqueous phase containing polyvinyl alcohol to form oil in water emulsion.
After the formation of a stable emulsion, the organic solvent is evaporated either by
increasing the temperature under pressure or by continuous stirring. The solvent removal
leads to polymer precipitation at the o/w interface of droplets, forming cavity and thus
making them hollow to impart the floating properties23,24.
Floating microspheres are characterized by their micromeritic properties such as particle size,
tapped density, compressibility index, true density and flow properties 25. Particle size is
measured using an optical microscopy and mean particle size was calculated by measuring
200 to 300 particles with the help of calibrated ocular micrometer. True density is
determined by liquid displacement method; tapped density and compressibility index are
calculated by measuring the change in volume using a bulk density apparatus; angle of repose
is determined by fixed funnel method. The hollow nature of microspheres is confirmed by
scanning electron microscopy26-28.
I = Vb –Vt / Vb x 100
Where, Vb is the bulk volume and Vt is the tapped volume. The value given below 15%
indicates a powder with usually give rise to good flow characteristics, whereas above 25%
indicate poor flow ability.
Floating Behavior
Fifty milligrams of the floating microspheres were placed in 100 ml of the simulated gastric
fluid (SGF, pH 2.0) containing 0.02% w/v Tween 20. The mixture was stirred at 100 rpm
with a magnetic stirrer. After 8 hours, the layer of buoyant microspheres was pipetted and
separated by filtration. Particles in the sinking particulate layer were separated by filtration.
Particles of both types were dried in a desiccator until constant weight was achieved. Both the
fractions of microspheres were weighed and buoyancy was determined by the weight ratio of
floating particles to the sum of floating and sinking particles29.
Buoyancy (%) = Wf / Wf + Ws
Where, Wf and Ws are the weights of the floating and settled microparticles
In-Vitro Release Studies
The release rate of floating microspheres was determined in a United States Pharmacopoeia
(USP) XXIII basket type dissolution apparatus. A weighed amount of floating microspheres
equivalent to 50 mg drug was filled into a hard gelatin capsule (No. 0) and placed in the
basket of dissolution rate apparatus. Five hundred milliliters of the SGF containing 0.02%
w/v of Tween 20 was used as the dissolution medium. The dissolution fluid was maintained
at 37 ± 1° at a rotation speed of 100 rpm. Perfect sink conditions prevailed during the drug
release study. 5ml samples were withdrawn at each 30 min interval, passed through a 0.25
μm membrane filter (Millipore), and analyzed using LC/MS/MS method to determine the
concentration present in the dissolution medium. The initial volume of the dissolution fluid
was maintained by adding 5 ml of fresh dissolution fluid after each withdrawal. All
experiments were run in triplicate.
In-Vivo Studies
1. The floating microspheres can be used as carriers for drugs with so-called absorption
windows, these substances, for example antiviral, antifungal and antibiotic agents
(Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and
Tetracyclines) are taken up only from very specific sites of the GI mucosa.
2. Hollow microspheres of non-steroidal anti inflammatory drugs are very effective for
controlled release as well as it reduces the major side effect of gastric irritation; for example
floating microspheres of Indomethacin are quiet beneficial for rheumatic patients.
4. Hollow microspheres can greatly improve the pharmacotherapy of the stomach through
local drug release, leading to high drug concentrations at the gastric mucosa, thus eradicating
Helicobacter pylori from the sub-mucosal tissue of the stomach and making it possible to
treat stomach and duodenal ulcers, gastritis and oesophagitis. 31
5. The drugs recently reported to be entrapped in hollow microspheres include Prednisolone,
Lansoprazole, Celecoxib, Piroxicam, Theophylline, Diltiazem hydrochloride, Verapamil
hydrochloride and Riboflavin, Aspirin, Griseofulvin,Ibuprofen, Terfenadine.
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About Authors
For correspondence
Mr. Rajeev Garg is working a lecturer cum research scholar in department of pharmaceutics
in ASBASJSM College of Pharmacy, Bela, Ropar , India . He had completed his graduation
from Rameesh institutions, Greater Noida and post graduation from B.N.College of
pharmacy, Udaipur , Raj. He has very good academic and extra circular record.
Dr.G.D.Gupta is working as a professor and principal in ASBASJSM College of Pharmacy,
Bela, Ropar , India . Dr. Gupta has author of number of books and published more than 100
Research Paper / Abstract in National and International conferences.
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2008