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e-ISSN 2249 7706
print-ISSN 2249 7714
International Journal of
Advanced Pharmaceutics
www.ijapjournal.com

A REVIEW ON ORAL CONTROLLED DRUG DELIVERY

P. Srikanth*, Narayana Raju
1
, S. Wasim Raja
2
, S. Brito Raj
1


1
Department of Pharmaceutics, Sri Venkateswara College of Pharmacy,
R.V.S. Nagar, Tirupati Road, Chittoor, Andhra Pradesh.
2
Department of Pharmacy Practice, Sri Venkateswara College of Pharmacy,
R.V.S. Nagar, Tirupati Road, Chittoor, Andhra Pradesh.

ABSTRACT
The process or method of administering a pharmaceutical compound for the purpose to create a therapeutic effect for
animals and humans is known as drug delivery. A drug delivery technology is a patented form of technology, which modifies
the absorption, drug release profile, elimination and distribution for the sake of enhancing the safety and efficacy of the product
to provide compliance and convenience to the patients. In recent years a wide variety of newer oral drug delivery system like
sustained/ controlled release dosage forms are designed and evaluated in order to overcome the limitation of conventional
therapy. These products are able to maintain steady drug plasma levels for extended periods of time as a result the variation of
the drug levels in the blood are prevented and minimized drug related side effects. This review mainly focused on oral drug
delivery system of drug.

Keywords: Controlled drug delivery, Diffusion controlled drug release, Dissolution controlled drug release.

INTRODUCTION
Controlled drug delivery is one which delivers the
drug at a predetermined rate, locally or systemically, for a
specified period of time. Continuous oral delivery of drugs
at predictable and reproducible kinetics for predetermined
period throughout the course of GIT. Recently, a new
generation of pharmaceutical products, called controlled
release drug delivery systems, such as those developed
from the osmotic pressure activated drug delivery system,
have recently received regulatory approval for marketing,
and their pharmaceutical superiority and clinical benefits
over the sustained release and immediate release
pharmaceutical products have been increased [1].
Controlled release drug administration means
not only prolongation of the duration of drug delivery,
similar to the objective in sustained release and prolonged
release, but the term also implies the predictability and
reproducibility of drug release kinetics. The basic rationale
of controlled drug delivery system is to optimize the
biopharmaceutical, pharmacokinetics and
pharmacodynamic properties of drug in such a way that its
utility is maximized through reduction in the side effects
and cure or control of condition in the shortest possible
time by the most suitable route.
Controlled release denotes that the system is able
to provide some actual therapeutic control, whether this is
of a temporal nature, spatial nature, or both.
Controlled drug delivery occurs when a polymer
is combined with a drug or active agent such that the
release from the bulk material is pre-designed.

Advantages of controlled drug delivery
Eliminate over or under dosing
Maintain drug levels in desired range
Need for less dosing
Increased patient compliance
Prevention of side effects

Design of controlled drug delivery system
Biopharmaceutical consideration:
Biopharmaceutical consideration Rate
limiting step of controlled release Rate limiting step of
conventional release

Corresponding Author:- P. Srikanth Email:- [email protected]
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1. Release from formulation
2. Movement within body during its passage to
site of action

Biopharmaceutical Characteristics of the Drug
Molecular weight, Aqueous solubility, Partition
coefficient, and Ionization, Route of administration, Drug
stability etc

Pharmacokinetic Characteristics of the Drug
Absorption rate, Elimination Half-Life, Rate of
metabolism etc.

Pharmacodynamic Characteristics of the Drug
Therapeutic Range, Therapeutic index, Plasma concentration
response relationship.

Drug release patterns
Drug disposition follows first order kinetics Rate
limiting step is in the absorptions rate of drug release
rapidly and completely absorbed.

Polymers for Controlled Release
These are some of the first materials selected for
delivery systems based on their intended non-biological
physical properties:
Polyurethanes for elasticity
Polysiloxanes for insulating ability
Polymethyl methacrylate for physical
strength and transparency
Polyvinyl alcohol for hydrophilicity and
swelling
Polyvinyl pyrrolidone for suspension
capabilities
Current Polymers used in Controlled Drug Delivery:
These polymers became usable in controlled
delivery due to their inert physical characteristics and
being free of leachable impurities
Poly 2-hydroxy ethyl methacrylate
Poly N-vinyl pyrrolidone
Polyvinyl alcohol
Polyacrylic acid
Polyethylene glycol
Polymethacrylic acid [2]

Approaches of oral controlled drug delivery system

1. Continuous release system Dissolution Controlled drug
release system
a. Matrix Dissolution Controlled system
b. Encapsulation/coating Dissolution Controlled
drug release system
2. Diffusion Controlled drug release system
a. Matrix Diffusion system
b. Reservoir devices
3. Dissolution and diffusion Controlled drug release system
4. Ion exchange resin drug complexes
5. pH depending formulation
6. Osmotic pressure Controlled system
7. Hydrodynamic pressure Controlled system [2,3].

1. Dissolution controlled drug release system
a. Matrix type
Also called as Monolithic dissolution controlled
system since the drug homogenously dispersed throughout
a rate controlling medium waxes (beeswax, carnauba wax,
hydrogenated castor oil etc) which control drug dissolution
by controlling the rate of dissolution
1. Altering porosity of tablet.
2. Decreasing its wettebility.
3. Dissolving at slower rate.
Exhibit First order drug release.
Drug release determined by dissolution rate of
polymer.

Fig 1. Monolithic dissolution controlled system

b. Encapsulation type
Also called as Coating dissolution controlled system
since the drug encapsulated, with slowly dissolving
material like cellulose, PEG, PMA (polymethylacrylates)
& waxes. Dissolution rate of coat depends upon stability &
thickness of coating.

Fig 2. Coating dissolution controlled system

2. Diffusion controlled drug release system
a. Matrix diffusion system
Rigid Matrix Diffusion
Materials used are insoluble plastics such as PVP &
fatty acids.
Swellable Matrix Diffusion
Also called as Glassy hydrogels. Popular for
sustaining the release of highly water soluble drugs.
Materials used are hydrophilic gums.
Examples : Natural: Guar gum, Tragacanth.
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Semi-synthetic: HPMC, CMC, Xantham gum.
Synthetic: Polyacrilamides.


Fig. 3. Matrix diffusion system

Drug and excipients are mixed with polymers
such as Hydroxypropyl methylcellulose
(HPMC) and Hydroxypropyl cellulose (HPC).
Tableted by conventional compression.
Release from the tablet takes place by
combination of water diffuses into the tablet,
swells the polymer and dissolves the drug may
diffuse out to be absorbed.

Reservoir System
Also called as laminated matrix device.
Hollow system containing an inner core
surrounded in water insoluble membrane.
Polymer can be applied by coating or micro
encapsulation.
Rate controlling mechanism - partitioning into
membrane with subsequent release into
surrounding fluid by diffusion.
Commonly used polymers - HPC, ethyl cellulose
& polyvinyl acetate.
Fig 4. Reservoir drug delivery system


3. Dissolution & Diffusion Controlled Release system

Drug encased in a partially soluble membrane.
Pores are created due to dissolution of parts of
membrane.
It permits entry of aqueous medium into core &
drug dissolution.
Diffusion of dissolved drug out of system.
Ethyl cellulose & PVP mixture dissolves in water
& create pores of insoluble ethyl cellulose
membrane

Fig 5. Dissolution & Diffusion Controlled Release
system


4. Ion-Exchange Resins Controlled Release Systems

Such system provides control release of an ionic
(ionisable) drug.
Ionisable drug is absorbed on ion-exchange resins
granules and then granules are coated with water
permeable polymers using spray drying
technique.
H
+
Cl
-
in the gastric fluid are exchange with
cationic and anionic drugs from the ion-
exchange resins.

5. P
H
depending formulation
The granules are designed for the oral controlled
release of basic or acidic drugs at a rate that is independent
of the p
H
in the gastrointestinal tract.
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They are prepared by mixing basic or acidic drugs
with one or more buffering agents granulating with
appropriate pharmaceutical excipients and finally coating
with a gastrointestinal fluid permeable film forming
polymer.

6. Osmotic pressure controlled system
Drug may be osmotically active, or combined
with an osmotically active salt (e.g., NaCl).
Semi-permeable membrane usually made from
Cellulose acetate.
Drug is pumped out continuously because of
osmotic pressure gradient.
More suitable for hydrophilic drug.
Provides zero order release

Fig 6. Osmotic pressure controlled system


7. Hydrodynamic pressure controlled system
One of the most feasible approaches for
achieving a prolonged and predictable drug delivery profile
in the GI tract is to control the gastric residence time i.e.
Gastroretentive Dosage Forms (GRDFs). These are
primarily controlled release drug delivery systems, which
gets retained in the stomach for longer periods of time,
thus helping in absorption of drug for the intended duration
of time. Gastric retentive drug delivery devices can be
useful for the spatial and temporal delivery of many drugs.
Thus, control of placement of a DDS in a specific region of
the GI tract offers numerous advantages, especially for
drug exhibiting an absorption window in the GI tract. The
intimate contact of the DDS with the absorbing membrane
and also the potential to maximize drug absorption may
influence the rate of drug absorption. These considerations
have led to the development of oral controlled release (CR)
dosage forms possessing gastric retention capabilities.
Drug may not be absorbed uniformly over the length of the
gastrointestinal tract, because dosage form may be rapidly
transported from more absorptive upper regions of the
intestine to lower regions where the drug is less absorbed
and drug absorption from colon is usually erratic and
inefficient. Moreover, certain drugs are absorbed only from
the stomach or the upper part of small intestine.
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, invitro floatability studies, in vivo floatability
studies in dogs, invitro drug release studies and stability
studies etc [4,5].

Gastro Retentive Drug Delivery System
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 bioavailability. 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
Microspheres
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 membrane.
Adhesion of bioadhesive drug delivery devices to the
mucosal tissue offers the possibility of creating an intimate
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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.

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 concentration.

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 [6,7].

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 Gastro Retention Time (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
inflammation 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 stomach.

b. Gas-generating Systems
These buoyant delivery systems utilize
effervescent reactions between carbonate/bicarbonate salts
and citric/tartaric acid to liberate CO
2
, which gets
entrapped in the gellified hydrocolloid layer of the systems
thus decreasing its specific gravity and making it to float
over chyme.

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. Colloidal gel barrier systems
Hydrodynamically balance system (HBS) was first
designed 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 forms.

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. Gelatin beads
Multiple unit floating dosage forms have been
developed from freeze-dried calcium Gelatin. Spherical
beads of approximately 2.5 mm in diameter can be
prepared by dropping a sodium Gelatin solution in to
aqueous solutions of calcium chloride, causing
precipitation of calcium Gelatin. The beads are then
separated 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 force over 12 h [8].

HOLLOW MICROSPHERES
Hollow Microspheres (microballons), loaded with
Ibuprofen in their outer polymer shells were prepared by a
novel emulsion-solvent diffusion method. The ethanol:
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
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continuously over the surface of acidic dissolution media
containing surfactant for greater than 12 h invitro

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
drugs. 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 [9].

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. 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
properties
.


List of Polymers used in Hollow Microspheres
Cellulose acetate, Chitosan, Eudragit, Acrycoat,
Methocil, Polyacrylates, Polyvinyl acetate, Gelatin, Agar,
Polyethylene oxide, Polycarbonates, Acrylic resins and
Polyethylene oxide [10].

Parenteral Controlled Release Systems
a.Injectables:
Solutions
Dispersions
Microspheres and Microcapsules
Nanoparticles and Niosomes
Liposomes and Pharmacosomes
Resealed erythrocytes
b. Implants
c. Infusion Device
Osmotic Pumps (Alzet)
Vapor Pressure Powered Pumps (Infusaid)
Battery Powered

Transdermal Drug Delivery Systems

Membrane permeation-controlled system
Transderm Scop (scopolamine; Ciba-Geigy)
Adhesive dispersion-type system
Deponit (nithroglycerin; Wyeth)
Matrix diffusion-controlled system
Nitrodur (nitroglycerin; Key)
Microresevoir dissolution-controlled system
Nitrodisc (Nitroglycerin; Searle)

Nasal and Pulmonary Drug Delivery Systems

Dry Powder Inhalations
Aerosols
Nasal Gels
Nasal Sprays [11-13].



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TYPES OF MICROPARTICLES
Microspheres are small spherical particles, with
diameters in the micrometer range (typically 1 m to
1000 m (1 mm)). Microspheres are sometimes referred to
as microparticles. There are two types of microparticles are
present
1. Microspheres
2. Microcapsules

Fig 7. Microscopic Photography of Hollow
Microspheres

Fig 8. Microcapsule

1. Microspheres
Microspheres can be manufactured from
various natural and synthetic materials. Glass
Microspheres, polymer Microspheres and ceramic
Microspheres are commercially available. Solid and
hollow Microspheres vary widely in density and, therefore,
are used for different applications. Hollow Microspheres
are typically used as additives to lower the density of a
material. Solid Microspheres have numerous applications
depending on what material they are constructed. The
Microspheres were characterized by shape, size, surface
morphology, size distribution, incorporation efficiency,
and invitro drug release studies. The outer surfaces of the
core and coated Microspheres, which were spherical in
shape, were rough and smooth, respectively. The size of
the core Microspheres ranged from 22 to 55 m, and the
size of the coated Microspheres ranged from 103 to 185
m.

2. Microcapsules
A microcapsule is a system that contains a well-
defined core and a well-defined envelope: the core can be
solid, liquid, or gas; the envelope is made of a continuous,
porous or nonporous, polymeric phase. The drug can be
dispersed inside the microcapsule as solid particulates with
regular or irregular shapes. Other forms may consist of a
pure or dissolved solution, suspension, emulsion, or a
combination of suspension and emulsion. Specific
applications sometimes require modifications, e.g., when
proteins are encapsulated they may contain stabilizers as
well as the active ingredient. Also, the core can be
something other than a chemical meant for release. An
interesting application is the encapsulation of gases for the
use of ultrasonic imaging [13-15].

CONCLUSION
Alternatively, a microsphere is a structure made
of a continuous phase of one or more miscible polymers in
which particulate drug is dispersed, at either the
macroscopic (particulates) or molecular (dissolution) level
However, the difference between the two systems is the
nature of the microsphere matrix, in which no well-defined
wall or envelope exists. Different methods of encapsulation
result, in most cases, in either a microcapsule or a
microsphere. For example, interfacial polymerization
almost always produces a microcapsule, whereas solvent
evaporation may result in a microsphere or a microcapsule,
depending on the amount of loading. Yet, one can use
solvent evaporation twice to create a sphere within a
sphere novel methods have been designed to use solvent
evaporation to create in one step a double-walled
microsphere, which is essentially a microcapsule.

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