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Floating Microspheres : A Review

Submitted by punamgaba on Wed, 10/08/2008 - 01:35

Despite tremendous advancement in drug delivery, oral route remains the

preferred route for the administration due to higher levels of patient
compliance.

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.

One such approach is Floating Microspheres (Hollow Microspheres). Floating microspheres

are gastro-retentive drug delivery systems based on non-effervescent approach. Hollow
microspheres are in strict sense, spherical empty particles without core. These microspheres
are characteristically free flowing powders consisting of proteins or synthetic polymers,
ideally having a size less than 200 micrometer. Gastro-retentive floating microspheres are
low-density systems that have sufficient buoyancy to float over gastric contents and remain in
stomach for prolonged period. The drug is released slowly at desired rate resulting in
increased gastric retention with reduced fluctuations in plasma drug concentration. Floating
microspheres to improve patient compliance by decreasing dosing frequency, better
therapeutic effect of short half-life drugs can be achieved. Enhanced absorption of drugs
which solubilise only in stomach, Gastric retention time is increased because of buoyancy.
Floating microspheres are prepared by solvent diffusion and evaporation methods to create
the hollow inner core. Floating microspheres are characterized by their micromeritic
properties such as particle size, tapped density, compressibility index, true density and flow
properties including angle of repose, scanning electron microscopy, in vitro floatability
studies, in vivo floatability studies in dogs, in vitro drug release studies and stability studies
etc.

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,

Where, RW is total vertical force, Df is fluid density, Ds is object density, V is volume, g is

acceleration due to gravity.

Types Of Floating Drug Delivery System

FDDS can be divided into two systems:

1. Effervescent systems

2. Non-effervescent systems

1.Effervescent Systems

A. Volatile liquid containing systems

The GRT of a drug delivery system can be sustained by incorporating an inflatable chamber,
which contains a liquid e.g. ether, cyclopentane, that gasifies at body temperature to cause the
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 delivery systems utilize effervescent reactions between carbonate/bicarbonate

salts and citric/tartaric acid to liberate CO2, which gets entrapped in the gellified hydrocolloid
layer of the systems thus decreasing its specific gravity and making it to float over chyme 17,
18
.

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.

a. Colloidalgel barrier systems

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.

b. Microporous Compartment System

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

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

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

Hollow microspheres (microballons), loaded with ibuprofen in their outer polymer

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

Advantages Of Hollow Microspheres

1.Improves patient compliance by decreasing dosing frequency.

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

3.Gastric retention time is increased because of buoyancy.

4.Enhanced absorption of drugs which solubilise only in stomach

5.Drug releases in controlled manner for prolonged period.

6.Site-specific drug delivery to stomach can be achieved.

7.Superior to single unit floating dosage forms as such microspheres releases drug uniformly
and there is no risk of dose dumping.

8.Avoidance of gastric irritation, because of sustained release effect.

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

Development Of Floating Microspheres

Floating microspheres are gastro-retentive drug delivery systems based on non-effervescent

approach. Hollow microspheres are in strict sense, spherical empty particles without core.
These microspheres are characteristically free flowing powders consisting of proteins or
synthetic polymers, ideally having a size less than 200 micrometer. Solid biodegradable
microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the
potential for controlled release of drugs20. Gastro-retentive floating microspheres are low-
density systems that have sufficient buoyancy to float over gastric contents and remain in
stomach for prolonged period. As the system floats over gastric contents, the drug is released
slowly at desired rate resulting in increased gastric retention with reduced fluctuations in
plasma drug concentration.

Mechanism Of Floating Microspheres

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.

Methods Of Preparation Of Hollow Microspheres

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.

List Of Polymers Used In Hollow Microspheres

Cellulose acetate, Chitosan, Eudragit, Acrycoat, Methocil, Polyacrylates, Polyvinyl acetate,

Carbopol, Agar, Polyethylene oxide, Polycarbonates, Acrylic resins and Polyethylene oxide.

Characterization Of Hollow Microspheres

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.

The compressibility index was calculated using following formula:

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

The in-vivo floating behavior can be investigated by X-ray photography of hollow

microspheres loaded with barium sulphate in the stomach of beagle dogs. The in-vitro drug
release studies are performed in a dissolution test apparatus using 0.1N hydrochloric acid as
dissolution media. The in-vivo plasma profile can be obtained by performing the study in
suitable animal models (e.g. beagle dogs).

Applications Of Floating Microspheres

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.

3. Floating microspheres are especially effective in delivery of sparingly soluble and

insoluble drugs. It is known that as the solubility of a drug decreases, the time available for
drug dissolution becomes less adequate and thus the transit time becomes a significant factor
affecting drug absorption. For weakly basic drugs that are poorly soluble at an alkaline pH,
hollow microspheres may avoid chance for solubility to become the rate-limiting step in
release by restricting such drugs to the stomach. The positioned gastric release is useful for
drugs efficiently absorbed through stomach such as Verapamil hydrochloride. The gastro-
retentive floating microspheres will alter beneficially the absorption profile of the active
agent, thus enhancing its bioavailability.

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

Punam Gaba, Monika Gaba, Rajeev Garg and Dr. G. D. Gupta

Ms. Punam Gaba is working a lecturer cum research scholar in department of pharmaceutics
in ASBASJSM College of Pharmacy, Bela, Ropar, India. She had completed her graduation
and post graduation from ASBASJSM College of Pharmacy, Bela, Ropar, India. She has very
good academic and extra circular record.

For correspondence

Department of Pharmaceutics, ASBASJSM College of Pharmacy, Bela, Ropar, India

[email protected]; Ph No. 9872364239

Ms. Monika Gaba is working a lecturer cum research scholar in department of

pharmaceutical chemistry in ASBASJSM College of Pharmacy, Bela, Ropar , India . She had
completed her post graduation from Punjabi University , Patiala , India . She has very good
academic and extra circular record. Email: [email protected]: Ph No.
9872390321

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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