Mucoadhesive Microencapsulation: A New Tool in Drug Delivery Systems

WORLD
Santosh et al. JOURNAL OF PHARMACY

World AND PHARMACEUTICAL
Journal of Pharmacy SCIENCES
and Pharmaceutical Sciences
SJIF Impact Factor 6.041
Volume 5, Issue 12, 1410-1470. Review Article ISSN 2278 – 4357
MUCOADHESIVE MICROENCAPSULATION: A NEW TOOL IN

DRUG DELIVERY SYSTEMS
*R. Santosh Kumar, G.V. Radha and T. Naga Satya Yagnesh
GITAM Institute of Pharmacy, GITAM University, Rushikonda, Visakhapatnam,

A.P-530045.
Article Received on
ABSTRACT
19 October. 2016, The microencapsulation has a major role in solving the problems
Revised on 09 Nov. 2016,
Accepted on 29 Nov. 2016 regarding targeting of drug to a specific organ tissue and controlling
DOI: 10.20959/wjpps201612-8149 the rate of drug delivery to the target site. Microencapsulated drug
delivery system plays a major role in developing oral controlled release
*Corresponding Author systems. Microspheres constitute an important part of novel drug

R. Santosh Kumar delivery system by virtue of their small size and efficient carrier
GITAM Institute of capacity. Due to their short residence time, bioadhesive characteristics
Pharmacy, GITAM
can be coupled to microspheres to develop mucoadhesive
University, Rushikonda,
microspheres. Mucoadhesive microspheres have advantages like
Visakhapatnam, A.P-
530045. efficient absorption and enhanced bioavailability of the drugs due to a
high surface to volume ratio, a much more intimate contact with the
mucus layer, controlled and sustained release of drug from dosage form and specific targeting
of drugs to the absorption site. The present review provides an overview of various aspects of
mucoadhesive microsphere based on various polymers, methodology of preparation of
mucoadhesive microspheres, method of evaluation and their applications in drug delivery.
KEYWORDS: Microencapsulation, Mucoadhesion, Polymers, Applications.
INTRODUCTION
Microencapsulation is a rapidly expanding technology. It is the process of applying relatively
thin coatings to small particles of solids or droplets of liquids and dispersions.
Microencapsulation provides the means of converting liquids to solids, of altering colloidal
and surface properties, of providing environmental protection and of controlling the release
characteristics or availability of coated materials. Microencapsulation is receiving
considerable attention fundamentally, developmentally and commercially.[1]
www.wjpps.com Vol 5, Issue 12, 2016. 1410

Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences
The term microcapsule is defined as a spherical particle with size varying from 50nm to
2mm, containing a core substance. Microspheres are in strict sense, spherical empty particles.
However the terms microcapsule and microsphere are often used synonymously. The
microspheres are characteristically free flowing powders consisting of proteins or synthetic
polymers, which are biodegradable in nature and ideally having a particle size less than
200nm. Solid biodegradable microcapsules incorporating a drug dispersed or dissolved
throughout the particle matrix have the potential for the controlled release of drug. These
carriers received much attention not only for prolonged release but also for the targeting of
the anticancer drug to the tumor.
The concept of microencapsulation[2] was initially utilized in carbonless copy papers. More
recently it has received increasing attention in pharmaceutical and biomedical applications.
The first research leading to the development of microencapsulation procedures for
pharmaceuticals was published by Bungenburg de Jong and Kass in 1931 and dealt with the
preparation of gelatin spheres and the use of gelatin coacervation process for coating. In the
late 1930s, Green and co-workers of National cash register co. Dayton, Ohio, developed the
gelatin coacervation process. Since then may other coating materials and processes of
application have been developed bythe pharmaceutical industry for the microencapsulation of
drugs. Over the last 25 years numerous patents have been taken out by pharmaceutical
companies for microencapsulated drugs.
Fundamental Considerations
Microencapsulation often involves a basic understanding of the general properties of
microcapsules, Such as the nature of the core and coating materials, the stability and release
characteristics of the coated materials and the microencapsulation methods. The intended
physical characters of the encapsulated product and the intended use of the final product must
also be considered. (Leon Lachman et.al).
a. Core Material
The core material, defined as the specific material to be coated, can be liquid or solid in
nature. The composition of the core material can be varied as the liquid core can include
dispersed and/or dissolved material. The solid core can be a mixture of active constituents,
stabilizers, diluents, excipients and release rate retardants or accelerators.

b. Coating Materials
The coating material should be capable of forming a film that is cohesive with the core
materials, be chemically compatible and non reactive with the core material and provide the
desired coating properties such as strength, flexibility impermeability, optical properties and
stability. The total thickness of the coatings achieved with microencapsulation techniques is
microscopic in size.
c. Selected Stability, Release and Other Properties

Three important areas of current microencapsulation application are the stabilization of core
materials, the control of the release or availability of core materials and separation of
chemically reactive ingredients within a tablet or powder mixture. A wide variety of
mechanisms is available to release encapsulated core materials; such as disruption of the
coating can occur by pressure, shear or abrasion forces, permeability changes brought about
enzymatically etc, improved gastro tolerability of drugs can be obtained by
microencapsulation.
d. Physical Character of the Final Product

Microcapsules should have desirable physical properties like ability to flow, to be compacted
or to be suspended and the capsule wall must be capable of resisting the pressure during
compression etc.
Coating Materials[3]
A number of different substances both biodegradable as well as non-biodegradable have been
investigated for the preparation of microcapsules. These materials include the polymers of
natural and synthetic origin and also modified natural substances. Some of the polymers used
in the preparation of the microcapsules are classified and listed below.
Synthetic Polymers
Non-biodegradable
 PMMA
 Acrolein
 Glycidyl methacrylate
 Epoxy polymers

Biodegradable
 Lactides and glycolides and their copolymers
 Polyalkyl cyano acrylates
 Polyanhydrides
 Carbopol
Natural Materials
Proteins
 Albumins
 Gelatin
 Collagen
Carbohydrates
 Starch
 Agarose
 Carragenan
 Chitosan
Chemically modified carbohydrates

 DEAE cellulose
 Poly (acryl) dextran
 Poly (acryl) starch
Prerequisites for Ideal Microparticulate Carriers

The materials utilized for the preparation of microparticulates should ideally fulfill the
following prerequisites:
 Longer duration of action
 Control of content release
 Increase of therapeutic efficiency
 Protection of drug
 Reduction of toxicity
 Biocompatibility
 Sterilizability
 Relative stability
 Water solubility or dispersability

 Bioresorbability
 Targetability
 Polyvalent
Methods of Microencapsulation[4]
Preparation of microcapsules as prolonged action dosage form can be achieved by various
techniques under following headings.
1. Coacervation phase separation

a. By temperature change
b. By incompatible polymer addition
c. By non-solvent addition
d. By salt addition
e. By polymer-polymer interaction
f. By solvent evaporation
2. Multi orifice centrifugal process.
3. Pan coating
4. Air suspension coating
5. Spray drying and spray congealing
6. Polymerization
7. Melt dispersion technique.
1. Coacervation Phase Separation

Microencapsulation by coacervation phase separation is generally attributed to the national
cash register (NCR) corporation and the patents of Green et.al. The general outline of the
processes consists of three steps carried out under continuous agitation.
1. Formation of three immiscible chemical phases.
2. Disposition of the coating and
3. Rigidization of the coating
a. By thermal change: Phase separation of the dissolved polymer occurs in the form of
immiscible liquid droplets and if a core material is present in the system, under proper
polymer concentration, temperature and agitation conditions, the liquid polymer droplets
coalesce around the dispersed core material particles, thus forming the embryonic
microcapsules. As the temperature decreases, one phase becomes polymer-poor (the

microencapsulation vehicle phase) and the second phase. (the coating material phase)
becomes polymer-rich.
b. By incompatible polymer addition: It involves liquid phase separation of a polymers

coating material and microencapsulation can be accomplished by utilizing the
incompatibility of dissimilar polymers existing in a common solvent.
c. By non-solvent addition: A liquid that is a non-solvent for a given polymer can be added
to a solution of the polymer to induce phase separation. The resulting immiscible liquid
polymer can be utilized to effect microencapsulation of an immiscible core material.
d. By salt addition: There are two types of coacervation: simple and complex. Simple
coacervation involves the use of only one colloid, e.g. gelatin in water and involves
removal of the associated water from around the dispersed colloid by agents with a
greater affinity for water, such as various alcohols and salts. The dehydrated molecules of
polymer tend to aggregate with surrounding molecules to form the coacervate. Complex
coacervation involves the use of more than one colloid. Gelatin and acacia in water are
most frequently used and the coacervation is accomplished mainly by charge
neutralization of the colloids carrying opposite charges rather than by dehydration.
e. By polymer-polymer interaction: The interaction of oppositely charged poly electrolytes

can result in the formation of a complex having such reduce solubility that phase
separation occurs.
f. By solvent evaporation: The processes are carried out in a liquid manufacturing vehicle.
The microcapsule coating is dispersed in a volatile solvent, which is dispersed in volatile
solvents, which is immiscible with the liquid manufacturing vehicle phase. A core
material to be microencapsulated is dissolved or dispersed in the coating polymer
solution. With agitation, the core material mixture is dispersed in the liquid
manufacturing vehicle phase to obtain the appropriate size microcapsule. The mixture is
then heated if necessary to evaporate the solvent for the polymer. In the case in which the
core material is dissolved in the coating polymer solution, matrix type microcapsules are
formed. The solvent evaporation technique to product microcapsules is applicable to a
wide variety of core materials. The core materials may be either water soluble or water
insoluble materials.

2. Multiorifice – Centrifugal Process

The South-West research institute (SWRI) has developed a mechanical process for producing
microcapsules that utilizes centrifugal forces to hurl, a core material particle through an
enveloping microencapsulation membrane therapy effecting mechanical microencapsulation.
Processing variables include the rotational speed of the cylinder, the flow rate of the core and
coating materials, the concentration and viscosity of the coating material and the viscosity
and surface tension of the core material. This method is capable of microencapsulating
liquids and solids of varied size ranges, with diverse coating materials.
3. Pan Coatings
The microcapsulation of relatively large particles by pan coating method has become wide
spread in the pharmaceutical industry and solid particles greater than 600 μg in size are
generally considered essential for effective coating. The coating is applied as a solution or as
an automized spray to the desired solid core passed over the coated materials during coatings
is being applied in the coating pans.
4. Air Suspension Coating

The process consists of the dispersing of solid particulate core materials in a supporting air
stream and the spray coating of the air suspended particles. Within coating chambers,
particles are suspended on an upward moving air stream. The design of the chamber and its
operating parameters effect a recirculating flow of the particles through the coating zone
portion of the chamber, where a coating material, usually a polymer solution is spray-applied
to the moving particles.
5. Spray Drying and Spray Congealing

Spray drying and spray congealing processes are similar in that both involve dispersing the
core material in liquified coating substance and spraying or introducing the core coating
mixture into some environmental condition, whereby relatively rapid solidification of the
coating is affected. The principle difference between the two methods is the means by which
coating solidification is accomplished. Coating solidification in the case of spray drying is
effected by rapid evaporation of solvent in which the coating material is dissolved. Coating
solidification in spray congealing method, however, is accomplished by thermally congealing
a molten coating material or by solidifying the dissolved coating by introducing the coating
core material mixture into a nonsolvent. Removal of the nonsolvent or solvent from the
coated product is then accomplished by sorption extraction or evaporation techniques.

6. Polymerization
The method involve the reaction of monomeric unit located at the interface existing between
a core material and a continuous phase in which the core material is dispersed. The
continuous or core material supporting phase is usually a liquid or gas and therefore the
polymerization reaction occurs at a liquid-liquid, liquid-gas, solid-liquid or solid-gas interface
e.g, microcapsules containing protein solutions by incorporating the protein in the aqueous
diamine phase.
7. Melt-Dispersion Technique
In this technique the coating material is melted by heating upto 80oC. The drug is suspended
in it and then emulsified in water containing emulsifying agent at 80 oC under stirring.
Microcapsules are formed as the temperature of the system reaches to room temperature.
Applications of Microencapsulation: (Chowdary, 1992)

Pharmaceutical
 To mask the taste of bitter drugs.
 To provide protection to the core material against atmospheric effects.
 In the design of controlled and sustained release dosage form.
 To reduce gastric and other G.I. tract irritation.
 To decrease the volatility
 To reduce toxic hazards.
 To reduce hygroscopicity.
 To increase flow properties.
 For the separation of incompatible substances.
 For liquid-solid conversions.
Biomedical
 As artificial cells: to remove or convert unwanted metabolites or toxins from the body; for
the treatment of chronic renal failure and congenital enzyme deficiency.
 Liposomes: entrapment of enzymes with in concentric layers of lipids; used for the
entrapment of enzyme for enzyme studies, for enzyme and drug targeting.
 Magnetic microcapsules: for drug targeting.
Characterization of Microcapsules (Vyas etal,2002)

The characterization of microcapsule carrier is an important phenomenon, which helps to

design a suitable carrier for the proteins, drug or antigen delivery. The parameters that are
generally evaluated for characterization of microcapsules are:
1. Particle Size and Shape

The most widely used procedure to visualize microcapsule are conventional light microscopy,
and Scanning electron microscopy (SEM). Both techniques can be used to determine the
shape and outer structure of microcapsule. SEM provides higher resolution in contrast to the
light microscopy. It allows investigation of the microsphere surfaces and after particles are
cross sectioned, it can also be used for the investigation of double walled systems. Confocal
laser scanning microscopy (CLSM) is applied as a nondestructive visualization technique,
which allows characterization of structures not only on surface, but also inside particle.
2. Fourier Transform – Infrared Spectroscopy: (FTIR)

FTIR is used to determine the degradation of the polymeric matrix of the carrier system, and
also interaction between drug and polymer system if present.
3. Density Determination
The density of the microcapsule can be measured by using a multi volumepychnometer.
Accurately weighed sample in a cup is placed in pychnometer, helium is introduced at a
constant pressure in chamber and allowed to expand. The expansion results in a decrease in
pressure within the chamber. From two pressure readings the volume and hence density of
microcapsule can be determined.
4. Isoelectric point
The micro electrophoresis is an apparatus used to measure electrophoretic mobility of
microsphere from which the isoelectric point can be determined. The electrophoretic mobility
can be related to surface contained charge, ionisable behavior or ion absorption nature of
microsphere.
5. Capture Efficiency
The capture efficiency of microcapsule or the percent drug entrapment can be determined by
allowing washed microcapsule to lyse. The lysate is then subjected to determination of active
constituents as per monograph. The percent encapsulation efficiency is calculated using
following equation

% Entrapment = Actual content X 100

Theoritical content
6. Contact Angle
The angle of contact is measured to determine the wetting property of microcapsule. It
determines the nature of microsphere in terms of hydrophilicity or hydrophobicity. The angle
of contact is measured at the solid/air/water surface by placing a droplet in circular cell
mounted above the objective of inverted microscope. Contact angle is measured at 20oC
within a minute of decomposition of microsphere.
7. In-Vitro Release Studies

Release studies for microcapsules can be carried out in different pH condition like pH 1.2 and
pH 7.4 using USP rotating basket or paddle apparatus. The samples are taken at specific time
intervals and are replaced by same amount of fresh medium. The samples withdrawn are
analyzed as per the monograph requirement and release profile is determined using the plot of
amount released as a function of time.
Kinetics of Drug Release

Release of the active constituent is an important consideration in case of microcapsules.
Many theoretically possible mechanisms may be considered for the release of the drug from
the micro particulates.
1. Liberation due to polymer erosion or degradation
2. Self diffusion through the pore
3. Release from the surface of the polymer.
4. Pulsed delivery initiated by the application of an oscillating or sonic field.
In most of the cases, a combination of more than one mechanism for drug release may
operate, so the distinction amongst the mechanisms is not always trivial. The release profile
from the microcapsules depends on the nature of the polymer used in the preparation as well
as on the nature of the active drug.
Attempts to model drug release from microcapsule have been reported and in the treatment of
their data, it was assumed that drug release was confined to any of the order such as zero
order or first order processes. One indication of mechanism can be obtained using a plot of
log of cumulative percentage of drug remaining in the matrix against time.

First order release5 would be linear as predicted by following equation.

Log C = Log Co - Kt /2.303 ————————(1)
Where,
C = Amount of drug left in the matrix
Co = Initial amount of drug in the matrix
K = First order rate constant, (time –1)
t = Time, either in hours or minutes
The in vitro drug release data obtained from selected batch of microcapsules was treated
according to equation (1) by plotting log of cumulative % of drug remaining against time.
Next, an attempt was made to see whether the drug release is by diffusion. For system, which
will release the drug by diffusion, were proposed by
Higuchi.[6]
Q = [DЄ – Є Cs) Cs t]1/2----------------- (2)
Where,
Q = Weight in grams of drug released per unit surface area.
D = Diffusion co-efficient of drug in the release medium.
ε = Porosity of the matrix.
Cs = Solubility of drug in the microcapsule expressed as gm/ml.
A = Total concentration of drug in matrix
=Tortuosity of the matrix
t = Time
The assumption made in the deriving equation (2) is as follows:

 A pseudo steady state is maintained during release.
 A » Cs i.e, excess solute is present.
 C = 0 solution at all times (perfect sink).
 Drug particles are much smaller than those in the matrix.
 The diffusion coefficient remains constant.
 No interaction between the drug and the matrix occurs.
For the purpose of data treatment, equation is usually reduced to,
Q = Kt1/2 ---------------(3)

Therefore a plot of amount of drug released verses the square root of time should be linear if
the drug release from the matrix is diffusion controlled.
Precisely, to know the exact mechanism of drug release, whether it is by diffusion or with
combination of diffusion and erosion control, the data has also been plotted according to
equation as suggested by Korsemeyer[7], they used a simple empirical equation to describe the
general solute release behavior from control release polymer matrices.
Mt
= Ktn
M∞
Mt
= the fraction of drug release
M∞
K = Kinetic rate constant
t = Release time
n = Diffusional exponent for drug release.
The value of 'n' gives an indication of the release mechanism. For non –Fickian release, the
‘n’ value falls between 0.5 and 1.0, while in the case of Fickian diffusion, n ≤ 0.5 for zero
order release (case II transport) n = 1 and for super case II transport n > 1.
The in-vitro drug release data obtained from microcapsules was treated according to equation
(4) by plotting log cumulative percentage of drug release Vs log time.
Table 1.1: Examples of Some Microencapsulated Drugs.

Characteristic Purpose of
Active moiety Final product form
Property encapsulation
Taste masking, sustained
Slightly soluble in
Aspirin release, reduced in Tablet or capsule
water
gastric irritation,
Slightly soluble in
Paracetamol Taste masking Tablet
water
Sustained normalization
Islet of Langerhans Viable cells Injection
of diabetic condition
Isosorbide dinitrate Water soluble Sustained release Capsule
Slightly soluble in
Progesterone Sustained release Varied
water
Reduction in volatility,
Menthol Volatile solution Lotion
Sustained release
Highly soluble in Reduction in gastric
Potassium chloride Capsule
water irritation

Perm selectivity of
Water soluble
Urease enzyme, substrate and Dispersion
enzyme
reaction
Vit.A Palmitate Nonvolatile liquid Stabilization to oxidation Dry powder
Practically insoluble Prevention from
Nifedipine Dry powder
in water photoinstability
Mucoadhesive Microspheres and Microcapsules

Drug delivery systems (DDS) that can precisely control the release rates or target drugs to a
specific body site have had an enormous impact on the health care system. Carrier technology
offers an intelligent approach for drug delivery by coupling the drug to a carrier particle such
as microspheres, Nanoparticles and liposomes, which modulate the release and absorption
characteristics of the drug. Microspheres constitute an important part of these particulate
DDS by virtue of their small size and efficient carrier characteristics. However, the success of
these novel DDS is limited due to their short residence time at the site of absorption. It
would, therefore, be advantageous to have means for providing an intimate contact of the
DDS with absorbing membranes. It can be achieved by coupling mucoadhesion
characteristics to microspheres and developing novel delivery systems referred to as
mucoadhesive microspheres.
Mucoadhesion and Mucoadhesive Drug Delivery Systems

Mucoadhesive drug delivery systems are delivery systems which utilize the property of
bioadhesion of certain polymers which become adhesive on hydration[9] and hence can be
used for targeting a drug to a particular region of the body for extended periods of time.[10]
Bioadhesion is a phenomenon in which two materials, at least one of which is biological, are
held together by means of interfacial forces.[11] The attachment could be between an artificial
material and biological substrate, such as adhesion between a polymer and a biological
membrane. In the case of polymer attached to the mucin layer of a mucosal tissue, the term
mucoadhesion is used. The mucosal layer lines a number of regions of the body including the
gastrointestinal tract, the urogential tract, the airways, the ear, nose and eye. These represent
potential sites for attachment of bioadhesive system and hence, the mucoadhesive drug
delivery systems could be designed for buccal, oral, vaginal, rectal, nasal and ocular routes of
administration.
Advantages of Mucoadhesive Systems
Mucoadhesive systems have three distinct advantages when compared to conventional dosage
forms. First the mucoadhesive systems are readily localized in the region applied to improve

and enhance the bioavailability of drugs. Greater bioavailability of piribedit[12], testosterone

and its esters[13], vasopressin[14], dopamine[15], insulin[16] and gentamycin[17] was observed
from mucoadhesive dosage systems. Second, these dosage forms facilitate intimate contact of
the formulation with underlying absorption surface. This allows modification of tissue
permeability for absorption of macromolecules such as peptides and proteins. Inclusion of
penetration enhancers such as sodium glycocholate[18], sodium taurocholate and L-
lysophosphatidyl choline (LPC)[19] and protease inhibitors in the mucoadhesive dosage forms
resulted in the better absorption of peptides and proteins and third, the mucoadhesive dosage
forms also prolong residence time of the dosage form at the site of application and absorption
to permit once or twice a day dosing.[20]
Mucoadhesive Microspheres
Mucoadhesive microspheres include microparticles and microcapsules (having a core of the
drug) of 1-1000 µm in diameter and consisting either entirely of a mucoadhesive polymer or
having an outer coating of it, respectively.[21] Microspheres in general, have the potential to
be used for targeted and controlled release drug delivery; but coupling of mucoadhesive
properties to microspheres has additional advantages, e.g. efficient absorption and enhanced
bioavailability of the drugs due to a high surface to volume ratio, a much more intimate
contact with the mucus layer, specific targeting of drug to the absorption site achieved by
anchoring plant lectins, bacterial adhesives and antibodies on the surface of the microspheres.
Mucoadhesive microspheres can be tailored to adhere to any mucosal tissue including those
found in eye, nasal cavity, urinary and gastrointestinal tract, thus offering the possibilities of
localized as well as systemic controlled release of drugs. Application of mucoadhesive
microspheres to the mucosal tissues of ocular cavity, gastric and colonic epithelium is used
for administration of drugs for localized action. Prolonged release of drugs and a reduction in
frequency of drug administration to the ocular cavity can highly improve the patient
compliance. The latter advantage can also be obtained for drugs administered intra-nasally
due to the reduction in mucociliary clearance of drugs adhering to nasal mucosa.
Microspheres prepared with mucoadhesive and bioerodable polymers undergo selective
uptake by the M cells of Peyer patches in gastrointestinal (GI) mucosa. This uptake
mechanism has been used for the delivery of protein and peptide drugs, antigens for vac-
cination and plasmid DNA for gene therapy. Moreover, by keeping the drugs in close
proximity to their absorption window in the GI mucosa, those mucoadhesive microspheres

improve the absorption and oral bioavailability of drugs like furosemide and riboflavin. The
concept of a non-invasive single shot vaccine, by means of mucosa, immunization, offers
controlled release of antigens and thus forms another exquisite application of mucoadhesive
microspheres.
Polymers Used for Mucoadhesive Microspheres

The properties of the mucoadhesive microspheres, e.g. their surface characteristics, force of
mucoadhesion, release pattern of the drug and clearance, are influenced by the type of
polymers used to prepare them. Suitable polymers that can be used to form mucoadhesive
microspheres include soluble and insoluble, non-biodegradable and biodegradable polymers.
These can be hydrogels or thermoplastics, homopolymeres, copolymers or blends, natural or
synthetic polymers.
Classification of Polymers
Hydrophilic polymers, Hydrogels and Thermoplastic polymers:
Hydrophilic polymers are the water-soluble polymers that swell indefinitely in contact with
water and eventually undergo complete dissolution. Hydrogels are water swellable materials,
usually a cross-link polymer with limited swelling capacity. Thermoplastic polymers include
the non-erodible neutral polystyrene and semi crystalline bioerodible polymers, which
generate the carboxylic acid groups as they degrade, e.g. polyanhydrides and polylactic acid.
Various synthetic polymers used in mucoadhesive formulations include polyvinyl alcohol,
polyamides, polycarbonates, polyalkylene glycols, polyvinyl ethers, esters and halides,
polymethacrylic acid, polymethylmethacrylic acid, methylcellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose and sodium carboxymethylcetlulose.
Various biocompatible polymers used in mucoadhesive formulations include cellulose-based

polymers, ethylene glycol polymers and its copolymers, oxyethylene polymers, polyvinyl
alcohol, polyvinyl acetate and esters of hyaluronic acid. Various biodegradable polymers
used in rnucoadhesive formulations are poly (lactides), poly (glycolides), poly (lactide-co-
glycolides), polycaprolactones and polyalkyl cyanoacrylates. Polyorthoesters,
polyphosphoesters, polyanhydrides, polyphosphazenes are the recent additions to these poly-
mers.

Specific Site Directed Bioadhesives- The Next Generation

The specific mucosal surfaces can be targeted using site-specific chemical agents that are
anchored onto the polymeric DDS. The first generation mucoadhesive polymers lack
specificity and can bind to any mucosal surface. This limits their use for fabrication of
mucoadhesive drug delivery system for a particular tissue However, the development of
polymers and microspheres grafted with mucus or cell-specific ligands have increased
therapeutic benefit and made site-specific drug delivery possible Table 1.2. Any ligand with a
high binding affinity for mucin can be covalently linked to the microspheres and be expected
to influence the binding of microspheres. Targeting of the drugs can be achieved by using the
following ligands.
Table 1.2: Specific Ligands to the Glycosal Groups on Cell Membranes for Targeting
Mucoadhesive Microspheres.
Glycosyl groups on
Specific ligands Specific site
cell membranes
Epithelial cells in stomach,
Mannose Galanthus nivalis agglutinin (GNA)
caecum and colon
Epithelial cells in stomach,
Wheat germ agglutinin (WGA) caecum, colon and absorptive
N-acetylglucosamine enterocytes in small intestine
Lycopersiconesculentum or tomato
Strong binding to M cells
lectin (LEA)
Endocytosed by villus enterocytes
N-Acetylglucosamine Lectin ML-1 from Visum album and goblet cells strong bindmg to
epithelial cells in small intestine
Phytohaemagglutinin Phaseolus vulgans isoagglutinin Surface cells of the stomach
Specific binding and transcytosis
Fucose Aleuria aurentia agglutinin (AAA)
by M cells
Lectins
Lectins can be defined as proteins of non-immune origin that bind to carbohydrates
specifically and non-covalently. Lectins can increase the adherence of microparticles to the
intestinal epithelium and enhance penetration of drugs. They may be used to target therapeu-
tic agents for different gut components or even for different cells (e.g. complex-specific
lectins for parietal cells or fucose-specific lectins for M cells). A bioinvasive mechanism has
beendescribed for the activity of lectins as targeting moieties. After binding to specific cells
the lectins undergo cellular uptake and subsequently can also exhibit strong binding to
nuclear pore membrane.[22] Polystyrene microparticles coated with tomato lectin were shown
to be specifically adhesive to enterocytes.[23] Tomato lectin is a potential targeting moiety due

to its low toxicity and high specificity, but its inactivation due to cross-reactivity with mucus
limits its usefulness. The potential of tomato lectin can, however, be tapped by exploiting its
cellular uptake for drug delivery.[24] The other useful lectin ligands include lectins isolated
from: Abrus precatroius, Agaricus bisporus, Anguilla anguilla, Amchis hypogaea,
Pandeiraea simplicifolia, and Bauhinia purpurca. Lectin-mediated drug delivery is being
regarded as a promising approach for peroral specific mucoadhesive formulations. The use of
lectins for targeting drugs to tumor tissue is currently under intensive investigation as the
humancarcinoma celllines exhibit higher lectin binding capacity than the normal human
colonocyte.[23]
Bacterial Adhesions
Bacteria are able to adhere to epithelial surfaces of the enterocytes with the aid of fimbriae.
Fimbriae are long, lectin like proteins found on the surface of many bacterial strains. Their
presence has been correlated with pathogenicity, e.g acherence of Eschericia coli to the brush
border of epithelial cells mediated by K99 limbriae is a prerequisite for subsequent
production and cellular uptake of E. coli enterotoxin. Thus, the DDS based on bacterial adhe-
sion factors could be an efficient mechanism to increase adhesion of mucoadhesive
microspheres to epithelial surface.[25] Another study[26] envisaging the importance of bacterial
adhesion has been carried out using invasion, which is a membrane protein from Yersinia
pseudotuberculosis.
Cellular uptake of polymeric nanospheres functionalized with invasion has been observed
using confocal laser scanning microscopy.
Amino Acid Sequences

Certain amino acid sequences have complementary parts on the cell and mucosal surfaces
and when attached to microparticles can promote binding to specific cell surface
glycoproteins. The cell surface glycoproteins are altered in the presence of disease conditons
and these altered protein sequences can be targeted by complementary amino acid sequences
attached to the drug delivery device.
Antibodies
Antibodies can be produced against selected molecules present on mucosal surfaces. Due to
their high specificity, antibodies can be a rational choice as a polymeric ligand for designing
site-specific mucoadhesives. This approach can be useful for targeting drugs to tumor tissues.

Preparation of Mucoadhesive Microspheres

Various methods for preparation of mucoadhesive microspheres are,
 Solvent evaporation
 Hot melt microencapsulation
 Solvent removal
 Hydrogel microspheres
 Spray drying
 Phase inversion microencapsulation
Solvent Evaporation
It is the most extensively used method of microencapsulation, first described by Ogawa et
al.[27] A buffered or plain aqueous solution of the drug (may contain a viscosity building or
stabilizing agent) is added to an organic phase consisting of the polymer solution in solvents
like dichloromethane (or ethyl acetate or chloroform) with vigorous stirring to form the
primary water in oil emulsion. This emulsion is then added to a large volume of water
containing an emulsifier like PVA or PVP to form the multiple emulsions (w/o/w). The
double emulsion, so formed, is then subjected to stirring until most of the organic solvent
evaporates, leaving solid microspheres. The microspheres can then be washed, centrifuged
and lyophilize to obtain the free flowing and dried microspheres.
Hot Melt Microencapsulation

This method was first used by Mathiowitz and Langer[28] to prepare microspheres of
polyanhydride copolymer of poly[bis(p-carboxy phenoxy) propane anhydride] with sebacic
acid. In this method, the polymer is first melted and then mixed with solid particles of the
drug that have been sieved to less than 50 µm. The mixture is suspended in a non-miscible
solvent (like silicone oil), continuously stirred, and heated to 50C above the melting point of
the polymer. Once the emulsion is stabilized, it is cooled until the polymer particles solidify.
The resulting microspheres are washed by decantation with petroleum ether. The primary
objective for developing this method is to develop a microencapsulation process suitable for
the water labile polymers, e.g. polyanhydrides. Microspheres with diameter of 1-1000 pm can
be obtained and the size distribution can be easily controlled by altering the stirring rate. The
only disadvantage of this method is moderate temperature to which the drug is exposed.
Solvent Removal
It is a non-aqueous method of microencapsulation, particularly suitable for water labile

polymers such as the ployanhydrides. In this method, drug is dispersed or dissolved in a

solution of the selected polymer in a volatile organic solvent like methylene chloride. This
mixture is then suspended in silicone oil containing span 85 and methylene chloride.[29] After
pouring the polymer solution into silicone oil, petroleum ether is added and stirred until
solvent is extracted into the oil solution. The resulting microspheres can then be dried in
vacuum.
Hydrogel Microspheres
Microspheres made of gel-type polymers, such as alginates are produced by dissolving the
polymer in an aqueous solution, suspending the active ingredient in the mixture and extruding
through a precision device, producing micro droplets which fall into a hardening bath that is
slowly stirred. The hardening bath usually contains calcium chloride solution, whereby the
divalent calcium ions crosslink the polymer forming gelled microspheres. The method in-
volves an all-aqueous system, which eliminates residual solvents in microspheres. Lim and
Moss[30] developed this method for encapsulation of live cells, as it doesnot involve harsh
conditions, which could kill the cells. The surface of these microspheres can be further
modified by coating them with polycationic polymers, like polylysine after fabrication. The
particle size of microspheres can be controlled by using various size extruders or by varying
the polymer solution flow rates.
Spray Drying
In this process, the drug may be dissolved or dispersed in the polymer solution and spray
dried. The quality of spray- dried microspheres can be improved by the addition of plas-
ticizers, e.g. citric acid, which promote polymer coalescence on the drug particles and hence
promote the formation of spherical and smooth surfaced microspheres. The size of
microspheres can be controlled by the rate of spraying, the feed rate of polymer drug
solution, nozzle size and the drying temperature. This method of microencapsulation is
particularly less dependent on the solubility characteristics of the drug and polymer and is
simple, reproducible, and easy to scale up.[31]
Phase Inversion Microencapsulation

The process involves addition of drug to a dilute solution of the polymer (usually 1-5% w/v
in methylene chloride). The mixture is poured into an unstirred bath of strong non-solvent
(petroleum ether) in a solvent to non-solvent ratio of 1:100, resulting in the spontaneous
production of microspheres in the size range of 0.5-5.0 pm can then be filtered, washed with

petroleum ether and dried with air.[32] This simple and fast process of microencapsulation
involves relatively little loss of polymer and drug.
Evaluation of Mucoadhesive Microspheres

The best approach to evaluate mucoadhesive microspheres is to evaluate the effectiveness of
mucoadhesive polymer to prolong the residence time of drug at the site absorption, thereby
increasing absorption and bioavailability of the drug. The methods used to evaluate
mucoadhesive microspheres include the following.
Measurement of Adhesive Strength

The quantification of the mucoadhesive forces between polymeric microspheres and the
mucosal tissue is a useful indicator for evaluating the mucoadhesive strength of
microspheres. In vitrotechniques have been used to lest the polymeric microspheres against a
variety of synthetic and natural mucus, frozen and freshly excised tissue etc. The different in
vitromethods include the following.
Tensile Stress Measurement, Wilhelmy Plate Technique

The wilhelmy plate technique is traditionally used for the measurement of dynamic contact
angles and involves the use of a microtensiometer or microbalance. The Cahn dynamic
contact angle analyzer (model DCA 322, Cahn Instruments, Cerritos) has been modified to
perform adhesive micro force measurements. The OCA 322 system consists of an IBM
compatible computer and microbalance assembly.[33] The microbalance unit consists of
stationary sample and tare loops and a motor powered translation stage. The instrument
measures the mucoadhesive force between mucosal tissue and a single microsphere mounted
on a small diameter metal wire suspended from the sample loop in microtesiometer.[34] The
tissue, usually rat jejunum, is mounted within the tissue chamber containing Dulbecco's
phosphate buffered saline containing 100 mg/dl glucose and maintained at the physiologic
temperature. The chamber rests on a mobile platform, which is raised until the tissue comes
in contact with the suspended microsphere. The contact is held for 7 min, at which time the
mobile stage is lowered and the resulting force of adhesion between the polymer and mucosal
tissue recorded as a plot of the load on rnicrosphere versus mobile stage distance or deforma-
tion. The plot of output of the instrument is unique in that it displays both the compressive
and the tensile portions of the experiment. By using the Cahn software system, three essential
mucoadhesive parameters can be analyzed. These include the fracture strength, deformation
to failure and work of adhesion.

Fracture strength is the maximum force per unit surface area required to break the adhesive
bond. Deformation to failure is the distance required to move the stage before complete
separation occurs. This parameter is dependent on the material stiffness and the intensity of
strength of adhesion. Work of adhesion is a function el both the fracture strength and the
deformation to failure. It tends to be the strongest indicator of the bioadhesive potential.
This technique allows the measurement el mucoadhesive properties of a candidate material in

the exact geometry of the proposed microsphere delivery device and the use of a
physiological tissue chamber mimics the in vitroconditions. From a single tensile experiment,
11 mucoadhesive parameters can be analyzed out of which 3 are direct predictors of the
bioadhesive potential.[35]
The Cahn instrument, although a powerful tool has inherent limitations in its measurement
technique, makes it better suited for largo microspheres (with a diameter of more than 300
pm) adhered to tissue in vitro. Therefore, many new techniques have been developed to
provide quantitative information of mucoadhesive interactions of the smaller microspheres.
Novel Electromagnetic Force Transducer (EMFT)

The EMFT is a remote sensing instrument that uses a calibrated electromagnetic to detach a
magnetic loaded polymer microspheres from a tissue sample36. It has the unique ability to
record remotely and simultaneously the tensile force information as well as high
magnification video images of mucoadhesive interactions at near physiological conditions.
The EMFT Measures tissue adhesive forces by monitoring the magnetic force required to
exactly oppose the mucoadhesive force. To test a microsphere it must first be attached to the
sample of tissue; magnetic force is then generated by an electromagnet mounted on the
microscope vertically above the tissue chamber. After the computer has calculated the
position of microsphere, the tissue chamber is slowly moved down, away from the magnet
tip. As the tissue slowly descends away from the magnet, the video analysis continuously
calculates the position of microsphere until the latter is completely pulled free of the tissue
the computer can display the results either as raw data or convert it to a force versus
displacement graph. The primary advantage of the EMIT is that no physical attachment is
required between the force transducer and the microsphere. This makes it possible to perform
accurate mucoadhesive measurements on the small microspheres, which have been implanted
in vitroand then excised (along with the host tissue) for measurement. This technique can also
be used to evaluate the mucoadhesion of polymers to specific cell types and hence can be

used to develop MODS to target- specific tissues.
Shear Stress Measurement

The shear stress measures the force that causes a mucoadhesive to slide with respect to the
mucus layer in a direction parallel to their plane of contact.[37] Adhesion tests based on the
shear stress measurement involve two glass slides coated with polymer and a film of mucus.
Mucus forms a thin film between the two polymer coated slides, and the test measures the
force required to separate the two surfaces. Mikos and Peppas[38] designed the in vitromethod
of flow chamber. The flow chamber made of Plexi glass is surrounded by a water jacket to
maintain a constant temperature. A polymeric microsphere placed on the surface of a layer of
natural mucus is placed in a chamber. A simulated physiologic row of fluid is introduced in
the chamber and movement of microsphere is monitored using video equipment attached to a
goniometer, which also monitors the static and dynamic behavior of the microparticle.[35]
Adhesion Number
Adhesion number for mucoadhesive microspheres is determined as the ratio of the number of
particles attached to the substrate to the total number of applied particles expressed as a
percentage. The adhesion strength increases with an increase in the adhesion number.
Falling Liquid Film Method

It is a simple, quantitative in situ method wherein an excised intestinal segment cut
lengthwise, is spread on a plastic flute and positioned at an incline. The suspension of
microsphere is allowed to flow down the intestinal strip. Particle concentrations entering the
segment from the dilute suspension reservoir and leaving the intestinal segment can be
determined with the help of coulter counter to quantify the steady state fraction of particles
adhered to the intestinal mucosa. The percent of particles retained on the tissue is calculated
as an index of mucoadhesion.[39]
Everted Sac Technique

The everted intestinal sac technique is a passive test for mucoadhesion and involves
polymeric microspheres and a section of the everted intestinal tissue. It is performed using a
segment of intestinal tissue excised from the rat, everted, ligated at the ends and filled with
saline. It is then introduced into a tube containing a known amount of the microspheres and
saline and agitated while incubating for 30 min. Sac is then removed, microspheres are
washed and lyophilized and the percentage of binding to the sac is calculated from difference

in the weight of the residual spheres from the original weight of the microspheres.
The advantage of the technique is that no external force applied to the microspheres being
tested; microspheres are freely suspended in buffer solution and made to come in contact with
the everted intestinal tissue randomly. The Cahn technique and the everted intestinal sac
technique, both predict the strength of mucoadhesion in a very similar manner. Santos et al[34]
established a correlation between the two in vitromucoadhesion assay methods which thereby
allows one to confidentially utilize a single mucoadhesion assay to scan a variety of
mucoadhesive polymers.
In vitro Techniques of Evaluation

Measurement of the Residence Time
Measurements of the residence time of mucoadhesives at the application site provide
quantitative information on their mucoadhesive properties. The GI transit times of many
mucoadhesive preparations have been examined using radioisotopes and fluorescent labeling
techniques.
GI Transit Using Radio-Opaque Microspheres

It is a simple procedure involving the use of radio- opaque markers, e.g. barium sulfate,
encapsulated in mucoadhesive polymers to determine the effects of mucoadhesive polymers
on GI transit time. Faeces collection (using an automated faeces collection machine) and X-
ray inspection provide a non-invasive method of monitoring total GI residence time without
affecting normal GI Motiiity. Mucoadhesives labeled with Cr-51, Tc-99m, In-113m, or I-123
have been used to study the transit of the microspheres in the GI tract.[40]
Gamma Scintigraphy Technique

Distribution and retention time of the mucoadhesive intravaginal microspheres can be studied
using the gamma scintigraphy technique. A study has reported the intensity and distribution
of radioactivity in the genital tract after administration of technetium labeled hyaluronic acid
esters (HYAFF) microspheres. Dimensions of the vaginal cavity of the sheep can be outlined
and imaged using labeled gellan gum and the data collected is subsequently used to compare
the distribution of radiolabelled HYAFF formulations. The retention of mucoadhesive -
radiolabelled microspheres based on HYAFF polymer was found to be more for the dry
powder formulation than for the pessary formulation after 12 h of administration to vaginal
epitheliu.[41]

The combination of sheep model and gamma scintigraphy method has been proved to be an
extremely useful tool for evaluating the distribution, spreading and clearance of vaginally
administered mucoadhesive drug delivery systems (MDDS), including microbicides.
Surface Characterization of the Mucoadhesive Microspheres

Surface morphology of microspheres and the morphological changes produced through
polymer degradation can be investigated and documented using scanning electron
microscopy (SEM), electron microscopy and scanning tunneling microscopy (STM). To
assess the effect of surface morphology on the mucoadhesive properties, the microsphere
samples are lyophilized and analyzed under SEM at 150X and 1000X. The smooth texture of
the microsphere surface leads to weak mucoadhesive properties, while the coarser surface
texture improves the adhesion through stronger mechanical interactions. The morphological
surfaces changes occurring due to the hydrolytic degradation of the polymers, e.g.
polyanhydrides can be studied after incubating the microspheres in the PBS buffer for
different intervals of time.[40]
Recent Mucoadhesive Microsphere and Microcapsule Research

During the last one decade much research work has been done on mucoadhesive
microspheres and microcapsules for various routes of drug administration. The primary
objectives are to provide an intimate contact of dosage form with the absorbing surface and to
increase the residence time of the dosage form at the absorbing surface to prolong drug
action. Though oral route is the most commonly employed route of drug administration, it is
not suitable for drugs which are susceptible to gut and/or hepatic metabolism and also for
drugs which cause gastrointestinal side effects. As such mucoadhesive dosage forms are
developed for other routes of drug administration such as buccal, nasal and vaginal routes
which avoid the disadvantages of oral route. The bioavailability and duration of action of
drugs administered by these routes are increased by use of the principle of mucoadhesion.
Research work on mucoadhesive microspheres and microcapsules is summarized in Table1.3.
Table 1.3: Research Work on Mucoadhesive Microspheres and Microcapsules.

Drug Polymer Route Purpose of Result
Acyclovir[42] Chitosan Ocular Slow release rates increased AUC
Slow release rates, sustained drug
Methyl prednisolone[43] Hyaluronic acid Ocular
concentration in tear fluids
[44]
Gentamicin DSM+ LPC Nasal Increase nasal absirption
Effective delivery of insulin into tha
Insulin[44] DSM+ LPC Nasal
systemic circulation via nasal route

Human growth
DSM+ LPC Nasal Rapid and increased absorption
harmone (hGH)[45]
Addition of LPC causes a five folds
[46]
Desmopressin Starch Nasal increase in Cmax and two folds
increase in bioavailability
Haemagglutinin (HA) With mucosal adjuvant:-ed serum IgG
obtained from HYAFF Nasal antibody response as compared to i.m.
influenza A virus[47] immunization
Beclomethasone[48] HPC Nasal Increasing the bioavailability
Gentamicin[49] HA/Chitosan Nasal Improving the bioavailability
Gentamicin[50] HPMC Nasal Increasing the absorption
Increased bioavailability
Higher AUC
Furosimide[51] AD-MMS (PGEFs) GI
Effective absorption from the
absorption window
Riboflavin AD-MMS (PGEFs) GI ----------------
Amoxicillin AD-MMS (PGEFs) GI Greater anti H. Pylori Activity
MRT of drugs is increased plasma
Delapril Hydrochloride
PEGFs GI concentrations of the active metabolite
(Prodrug)[52]
are sustained
Polycarbapol /
Amoxicillin[53] Carbapol934/ ion GI Greater anti H. Pylori Activity
exchange resin
Cephradine[54] Chitosan/ ethylcellulose GI Prolong the intestinal absorption
PGEF coated with Well absorbed even without absorption
Vancomycin[55] Clonic
Eudragit S 100 enhancers
PGEF coated with Absorbed only in the presence of
Insulin[55] Clonic
Eudragit S 100 absorptions enhancers e.g. EDTA salts
Increased absorption from HYAFF
Nerve growth factor
HYAFF Vaginal microspheres as compared to aqueous
(nGF)[56]
solution of the drugs
Insulin[57] HYAFF Vaginal microspheres as compared to aqueous
solutions of the drugs
Salmon Calcitonin[41] HYAFF Vaginal microspheres as compared to aqueous
solution of the drugs
Ous MC/ Sodium CMC/
Vaginal Controlled release
Acriflavine[58] Alginate/ Carbapol 974
CMC as
mucopolysaccharide+
Pipedimic acid[59] Vesical -----------------------
Eudragit RL as matrix
polymer
Alginate+ Sodium
Indomethacin[60] CMC/ MC/ Carbopol/ Oral Slow release rate
HPMC
Alginate+ Sodium
Glipizide[61] CMC/ MC/ Carbopol/ Oral Slow release rates
HPMC

Table 1.4: Recent Literature on Microencapsulation.

Name of The Reason for Coating
S.No Category Technology Used Result Reference
Drug Microencapsulation Polymers Used
Entrapment efficiency,
To study entrapment
Cross linking particle size and drug [62]
1 Aceclofenac NSAID efficiency, micro pellet size, Gelatin.
technique. release were found to be
Drug release characteristics.
increased.
Olibanum resin was found
to be a new and efficient
microencapsulating agent
for controlled release
microcapsules and the
To evaluate Olibanum resin Emulsion solvent
olibanum resin coated [63]
2 Aceclofenac NSAID as coat for controlled drug evaporation Olibanum resin.
microcapsules exhibited
delivery. technique.
good controlled release
characteristics and were
found suitable for oral
controlled release of
Aceclofenac over 24hrs.
To formulate characterize
Meltable emulsified
and study the in vitro drug Formulation F3 showed
dispersion cooling [64]
3 Aceclofenac NSAID release from wax Carnauba Wax. 77.20% drug release in
induced solidification
microspheres loaded with 8hours.
technique.
aceclofenac.
To investigate the stability of
chitosan microspheres as
The chitosan microspheres
Calcium nasal delivery system and
Amlodipine Simple emulsification have potential to deliver [65]
4 Channel also to study the influence of Chitosan.
Besylate cross linking method. the drug following
Blocker the process variables in the
intranasal administration.
preparation of the
microspheres.

To develop alginate MC8 formulation with

mucoadhesive microcapsules Alginate:HPMC(K4M)
of atenolol by orifice-ionic ratio 5:1 containing 4%
Anti- Orifice ionic gelation HPMC 50cps, [66]
5 Atenelol gelation process using w/w Magnesium Stearate
hypertensive method. HPMC K4M.
HPMC 50cps and HPMC has shown promising
K4M as mucoadhesive results. Released 72.16%
polymers. in 8hours.
Spray drying technology
can be used to generate
inhaled particles like
To design dry powder inhaler
Anti- Chitosan, microspheres and porous [67]
6 Budesonide (DPI) formulations for Spray drying.
inflammatory Gelatin. particles with improved
pulmonary drug delivery.
pulmonary deposition as
compared to conventional
DPI formulations.
To prepare microspheres
containing 4-chlorocurcumin Result suggests the body
using spray drying technique weight normalization with
with ethyl cellulose as 4-chlorocurcumin. Thus,
polymer. To evaluate the in the study a new
4-chloro Hepato pharmacokinetics and molecule with a new [68]
7 Spray drying. Ethyl cellulose.
curcumin protective hepatoprotective activity delivery system for use in
after intraperitoneal the treatment of cirrhosis
administration of the and associated liver
developed formulation disorders has been
containing 4- developed.
chlorocurcumin.
To investigate on the Oxidation of
Soluble soya
microencapsulation of the Canthaxanthin was slower
bean [69]
8 Canthaxanthin Antioxidant Canthaxanthin from Spray drying method. for the microparticles with
polysaccharide
microbial source with lower ratios of
(SSPS).
different concentrations of CAN/SSPS. The best

SSPS by spray drying formulation was obtained

method and also investigate with ratio of CAN/SSPS at
the properties of a maximum level of 0.25.
microcapsules and their
storage stabilities at light and
dark conditions.
Microspheres exhibited
good mucoadhesive
Alginate,
property. The release is
HPMC,
slow and extended over a
Carbopol 934,
To achieve controlled release Emulsification ionic long period of time. [70]
9 Captopril ACE inhibitor Chitosan,
and drug targeting. gelation process. Alginate-Carbopol 934 &
Cellulose
Alginate-Chitosan
Acetate
microcapsules were found
Pthalate.
suitable for oral controlled
release.
PLGA appears to be
Alginate, superior micro carrier for
Steroid To produce long acting Ionic Gelation Chitosan, preparing Centchroman [71]
10 Centchroman
Contraceptive biodegradable microspheres. method. Albumin, microspheres, then
PLGA. Alginate, Albumin,
&Chitosan.
Gelatin, being
To develop a long term
biodegradable, can be used
injectable suspension of
for designing long term
Chloroquine microspheres containing Cold congealing [72]
11 Anti Malarial Gelatin. delivery systems.
Phosphate Chloroquine prepared using method.
Formaldehyde was
biodegradable polymer like
selective as cross linking
cross linked gelatin.
agent.

Results suggest that self

cross linked gelatin
To achieve a better microcapsules for
Coacervation and
Chlorpromazine therapeutic profile through Chlorpromazine [73]
12 Anti psychotic phase separation Gelatin.
hydrochloride self cross linked gelatin hydrochloride may reduce
technique.
microcapsules. the occurrence of degree
of extrapyramidal side
effects.
Calcium alginate is more
effective than Sodium
alginate in delaying drug
Sodium
release. Sodium alginate is
To improve stability. Ionic Gelation Alginate, [74]
13 Ciprofloxacin Antibacterial more superior to Calcium
To delay drug release. method. Calcium
alginate in improving
Alginate.
stability. Thus these two
can be used in sustained
release dosage forms.
Under optimal conditions
Aminoalkyl
80% microencapsulation
To investigate the feasibility methacrylate(Eu
was achieved. This yield
Clarithromycin & of microencapsulating two dragit L30D), [75]
14 Antibiotic Spray drying method. was achieved at
Erythromycin macrolide antibiotics using a Cellulose
drug:excipient ratio of 5%
spray drying process. acetate phthalate
for Clarithromycin and
(CAP).
30% for Erythromycin.
A formulation was
developed for better drug
To prepare brain targeted
distribution, increasing
Benzodiazepin gelatin chitosan Emulsion cross Gelatin, [76]
15 Clonazepam therapeutic index &
e mucoadhesive microspheres linking method. Chitosan.
reducing side effects.
to rapid onset of action.
Chitosan contributed
towards good release.

Increase in Albumin
decreases release rate.
For localization of drug at Emulsion 1200rpm produced
Diclofenac [77]
16 NSAID the site of inflammation. polymerization Albumin. maximum release rate.
Sodium
Specific targeting. technique. Increase in stabilization
temperature decreases
release rate.
Among the solvents
employed Chloroform was
To evaluate influence of Emulsion solvent
Diclofenac found to be more suitable [78]
17 NSAID three solvents employed in evaporation Ethyl cellulose.
Sodium for slow release of
preparation of drug release. technique.
Diclofenac from Ethyle
cellulose microspheres.
Solvent deposition
technique may be used for
complexation of sparingly
To formulate an oral and slightly water soluble
sustained release dosage drugs, and then can be
Coacervation and
Diclofenac form using a combination of microencapsulated to [79]
18 NSAID phase separation Ethyl cellulose.
Sodium two techniques like sustain the action. On the
method.
complexation & other hand physical
microencapsulation. mixture can be used for
comlexation of freely
water soluble drugs for
sustaining the action.
Gelatin microspheres
To identify the formulation
containg diclofenac
and processing variables
Diclofenac Emulsion cross sodium could be [80]
19 NSAID affecting the characteristics Gelatin.
Sodium linking method. successfully prepared
of gelatin microspheres
using native glucose as a
crosslinked with sugars.
crosslinking agent.
[81]
20 Diclofenac NSAID To study the factors Solvent evaporation Ethyl cellulose. The presence of Span60

Sodium influencing the technique. was found to be essential

characterization of modified reducing aggregation
release microspheres of microspheres. Stirring
Diclofenac sodium. speed, polymer to drug
ratio & concentration of
Ethyl cellulose solution
were found to be affecting
drug release.
Sustained release
To develop sustained release
diclofenac sodium
diclofenac sodium
microcapsules could be
microcapsules using ethyl Emulsion solvent
Diclofenac formulated by using ethyl [82]
21 NSAID cellulose as a release evaporation Ethyl cellulose.
Sodium cellulose as release
retarding material by technique.
retardant by emulsion
emulsion solvent evaporation
solvent evaporation
technique.
technique.
Non solvent addition
phase separation is a
To prepare Diclofenac
useful technique for the
Diclofenac sodium-Ethyl cellulose Non solvent addition [83]
22 NSAID Ethyl cellulose. microencapsulation of
Sodium microspheres with modified technique.
diclofenac sodium with
drug release properties.
ethyl cellulose for
sustained release.
Dissolution test results
show that increase in
Microcapsules of Diltiazem
concentration of Eudragit
were formulated using
Calcium Solvent evaporation RS100 decreased rate of
combination of PEG 6000 & PEG 6000, [84]
23 Diltiazem Channel & non solvent drug release where as
Eudragit RS 100and Eudragit Eudragit RS100.
Blocker addition. increasing PEG 6000
RS 100 alone with the aim to
actually increased drug
prolong its release.
release. Comparisonof test
formulations with

marketed diltiazem
hydrochloride sustained
release capsules showed
that F-VI exhibited similar
release pattern of marketed
SR capsules.
The release profile using
optimized formulation was
found to be quite regulated
for controlled release
purposes (t80%=9.5h) with
Calcium To design, develop and
Emulsion solvent little dose dumping [85]
24 Diltiazem Channel optimize controlled release Ethyl cellulose.
evaporation method. (release up to 16hours ≈
Blocker of Diltiazem microcapsules.
99%).
Dissolution profiles of
Diltiazem : Rosin at 1:8 &
1:10 ratios show that
Calcium Emulsion solvent
To develop sustained release cumulative drug release [86]
25 Diltiazem Channel evaporation Rosin.
formulation. was very slow giving a
Blocker technique.
sustained release of 22-
24h. Span 80 was used to
prevent aggregation.
To design and evaluate micro The microspheres
adhesive microcapsules of Sodium consisting of Sodium
Calcium Emulsification
Diltiazem HCl using alginate, alginate alone & in [87]
26 Diltiazem Channel internal gelation
mucoadhesive polymers for HPMC, combination with HPMC
Blocker technique.
prolonged gastrointestinal Carbopol 934P. and Carbopol exhibited
absorption. good mucoadhesive

properties compared to
non mucoadhesive, Ethyl
cellulose polymers.
The release profiles of
formulation DS3 and PS3
were highest and lowest
(86.21% & 73.11). It is
observed that
To increase bioavailability.
Emulsification cross Domperidone is released [88]
27 Domperidone Antiemetic To avoid first pass effect. Starch.
linking technique. in sustained release
For nasal drug delivery.
manner.
Release of drug from
microcapsules is
proportional to
concentration of drug.
Probably the presence of
Quaternary ammonium
groups in Eudragit RL100
To explore the possibility of stabilized the controlled
Eudragit RL100 dispersion & microspheres
microspheres for site specific could form even in [89]
28 5-Flouro Uracil Anticancer Condensation. Eudragit RL100.
delivery of 5-Flouro Uracil absence of surfactants.
by the process of passive Colloidal nature of
targeting. microspheres indicates use
of these microspheres as
colloidal DDS.
Release was sustained for

To achieve colonic drug Solvent evaporation EudragitS100, upto 20hrs in formulation [90]
29 5-Flouro Uracil Anticancer
delivery. technique. Alginate. with core microsphere to
EudragitS100 ratio 1:7.
[91]
30 5-Flouro Uracil Anticancer To achieve colon drug Emulsion Chitosan. Release of drug in

delivery. polymerization physiological environment

method. of colon was due to
dehydration of chitosan by
colonic bacteria.
Carbopol 934,
To evaluate the efficacy of Microcapsules employing
HPMC,
combined polymers in sustained release polymers
Orifice ionic gelation Sodium CMC, [92]
31 Famotidine Antiulcer designing the sustained used in combination
method. Methyl
release mucoadhesive exhibited slow release of
cellulose,
microcapsule formulation. Famotidine over 9hours.
Guar gum.
Among 8 formulations F2
was considered best
because it showed delayed
release & drug release in
To formulate and evaluate a pH 7.2 buffer was found to
Cellulose
delayed release Emulsion solvent be (98%) complete & [93]
32 Flubriprofen NSAID acetate
microparticular dosage form evaporation method. sustained. HPMC
phthalate.
of Flubriprofen. phthalate exhibits positive
influence and Eudragit
L100, Eudragit S100
exhibit negative effect on
drug release.
Release data from
microspheres showed
To investigate complexation
significant improvement
of Fluticasone with 2-
Antiasthma, Spray and freeze of the dissolution rate of [94]
33 Fluticasone hydroxy propyl β CD and Albumin.
Corticosteroid. drying methods. Fluticasone and a
albumin for improved
controlled release was
delivery to lungs.
obtained in presence of
higher amount of albumin.
Antiasthma, To evaluate in vitro lung Modified spray The microspheres showed [95]
34 Fluticasone Poloxamer.
Corticosteroid. deposition pattern and anti drying method. improved dissolution

asthmatic efficacy of profile and sustained

sustained release Fluticasone release of Fluticasone for
microparticles for improved more than 60hours.
therapy of asthma. Microparticles showed
lung retention along with
sustained action.
To develop sustained drug The microspheres were
Antiasthma, Gelatin, [96]
35 Fluticasone delivery directly to the lungs. Spray drying. shown to extend drug
Corticosteroid. Chitosan.
To minimize dose frequency. release upto 4hours.
All the batches sustained
To sustain the release of the Ionotropic gelation Calcium [97]
36 Furosemide Diuretic the drug for more than
drug. technique. alginate.
8hours.
Optimized formulation
was obtained with 2%
Gentamicin sulphate
Gentamicin For effective wound healing Emulsification cross [98]
37 Antibiotic Chitosan. concentration, 2% w/v
sulphate by localized drug delivery. linking technique.
sodium tripoly phosphate
concentration and 3%w/v
chitosan concentration.
To develop and optimize
The microcapsules showed
Gliclazide loaded Alginate- Alginate,
prolonged release of [99]
38 Gliclazide Antidiabetic Methyl cellulose Ionotropic gelation. Methyl
gliclazide over a period of
mucoadhesive cellulose.
8hours.
microcapsules.
Glipizide release from the
To develop an industrially microcapsules was slow
feasible technique of Emulsion solvent Ethyl vinyl and extended over a period [100]
39 Glipizide Antidiabetic
microencapsulation by EVA evaporation method. acetate. of more than 12hours and
copolymer. depended on core:coat
ratio.
To prepare and evaluate Emulsion solvent The hypoglycemic effect [101]
40 Glipizide Antidiabetic Ethyl cellulose.
Ethyl cellulose microspheres evaporation. of glipizide was sustained

of Glipizide with the over a period of 6days

objective of achieving with microspheres MC2
parenteral controlled release administered
over long periods of time. subcutaneously.
The hypoglycemic effect
of Glipizide could be
To develop characterize and
sustained over a period of
evaluate mucoadhesive
Orifice ionic gelation 14hours with [102]
41 Glipizide Antidiabetic microcapsules of Glipizide Alginate.
process. microcapsules MC7 that
employing various
contained
mucoadhesive polymers.
Alginate:Carbopol (9:1) as
coat.
Increase in gum Damar
concentration decreases
To investigate gum Damar as
the drug release rate. Gum
novel microencapsulating Emulsion solvent [103]
42 Ibuprofen NSAID Gum damar. Damar effectively
agent material for therapeutic evaporation.
sustained the drug release
substances.
rates for longer period of
time.
MCII batch are most
The study is an attempt to
satisfactory microcapsules
prepare calcium induced
Ionotropic gelation with regard to recovery, [104]
43 Ibuprofen NSAID alginate microcapsules of Alginate.
method. encapsulation efficiency,
Ibuprofen by ionotropic
mean diameter and release
gelation process.
rate after 8hours.
Polymer:drug ratio 1:2
shows better loading
To study the feasibility of encapsulation efficiency &
[105]
44 Ibuprofen NSAID polystyrene microspheres for Solvent evaporation. Polystyrene. release pattern. It controls
oral controlled drug delivery. drug release over 20hrs
and found more suitable
among all batches for

controlled drug delivery.

Indomethacin release from
microcapsules was slow
and spread over a period
To evaluate the resin Emulsification
of more than 24hrs and [106]
45 Indomethacin NSAID extracted from Olibanum as solvent evaporation Olibanum resin.
depended on core:coat
a coat in microencapsulation. method.
ratio. As the proportion of
the coat increased release
rate was decreased.
The order of increasing
To study the effects of four
permeability of EVA
solvents namely Chloroform,
microcapsules prepared by
Cyclohexane,
solvents was Cyclohexane
Dichloromethane and 1-2
< dichloromethane < 1-2
dichloromethane employed Emulsification Ethyl vinyl [107]
46 Indomethacin NSAID dichloromethane
in the preparation of EVA solvent evaporation. acetate.
<Chloroform.
microcapsules on
High permeability and
permeability and drug
complete drug release in
release from microcapsules
12hrs was observed with
was studied.
Chloroform as solvent.
Microcapsules MC1 &
MC2 of size 20/35
fulfilled the official
dissolution rate test
To study the feasibility of specifications of
preparing EVA Emulsion solvent Ethyl vinyl Indomethacin extended [108]
47 Indomethacin NSAID
microcapsules by emulsion evaporation. acetate. release capsules.
solvent evaporation method. Thus spherical
microcapsules of EVA
should be prepared by
emulsion solvent
evaporation technique.

Sodium CMC,
To study release kinetics & Carbopol, Alginate-Methyl cellulose
ulcerogenic activity of methyl and Alginate-Sodium
Emulsification ionic [109]
48 Indomethacin NSAID Indomethacin from cellulose, CMC microcapsules were
gelation.
mucoadhesive HPMC, found suitable for oral
microcapsules. Alginate,Oliban controlled release.
um.
Indomethacin release from
Alginate-Methyl cellulose
To develop and evaluate
Alginate, (MC2) & Alginate-
mucoadhesive Indomethacin
Sodium CMC, Sodium CMC (MC1) was
containing microcapsules
Emulsification ionic Carbopol, slow and extended over a [110]
49 Indomethacin NSAID enjoying various
gelation. methyl period of 12hours and
mucoadhesive polymers
cellulose, suitable for controlled
designed for oral controlled
HPMC. release.
release.
MC-2 also fulfilled USP
requirements.
Insulin microspheres
prepared with Eudragit
To develop an oral dosage
L100, 1% aprotinin, 1%
form for Insulin which is
sodium glycocholate
designed to deliver Insulin Solvent diffusion Eudragit L100 [111]
50 Insulin Hormone showed prolonged
into intestine in the presence technique. and S100.
hypoglycemic effect for
of protease inhibitor and bile
3hours when compared to
salts.
intravenous injection of
Bovine Insulin.
DG1E(1ml crosslinking
To prepare mucoadhesive agent) and DC1E(1ml
Chitosan microspheres for Emulsification crosslinking agent) [112]
51 Insulin Hormone Chitosan.
non-invasive delivery of method. formulations were found
Insulin. to be better and selected as
optimized formulations for

further study. It was

further observed
Glutaraldehyde cross
linked microspheres are
better than citric acid cross
linked microspheres.
Release studies were
carried out in 0.1 HCl and
To investigate the possibility 88.1, 83.8, 79.3, 73.0% of
of obtaining a prolonged, drug was released from
relatively constant effective Glutaraldehyde cross 0.5, 1.0, 1.5 & 2.0% of [113]
52 Isoniazid Antitubercular Chitosan.
level of Isoniazid from linking method. Chitosan microspheres
microspheres using Chitosan respectively after 8 hours.
as carrier. Increase in concentration
of chitosan causes
decrease in release.
The Ketoprofen loaded
microspheres were found
To reduce the gastric to be less ulcerogenic and
irritation mainly caused due Solvent diffusion Eudragit S, they protected the stomach [114]
53 Ketoprofen NSAID
to presence of free technique. Eudragit L. probably bypreventing the
carboxylic acid group. intimate contact of
ketoprofen with gastric
mucosa.
To study the feasibility of Polystyrene was found to
using mixtures of be highly impermeable to
Polystyrene and poly vinyl Emulsion solvent Polystyrene, drug release. [115]
54 Ketoprofen NSAID
pyrrolidine to modulate evaporation. PVP. Incorporation of PVP
release characteristics of easily modulated drug
Ketoprofen. release.
Ketorolac Analgesic, To study poly(lactic acid) Phase separation Poly(lactic Drug release decreased [116]
55
tromethamine Anti microspheres of Ketorolac coacervation, non acid). with increase in polymer

inflammotory tromethamine which were solvent addition. ratio. This may due to the
prepared for administering as low permeability of
controlled release prolong polymer to the drug.
dosage forms. Drug release was found to
be in a controlled manner
releasing up to 80% of
drug within 36hours.
Drug to Chtosan ratio 1:1
To develop a sustained
showed good
release system of HPMC,
Antiulcer, incorporation efficiency
Lansaprazole to increase its Emulsion solvent Methyl [117]
56 Lansaprazole Proton pump and high percentage
residence time in stomach diffusion technique. cellulose,
inhibitor. release.
without contact with the Chitosan.
Prepared micropellets
mucosa.
floated more than 12hrs.
The release pattern
obtained shows an
extended release up to
Chitosan,
To observe the suitability of 2hrs in formulation II and
HPMC,
spray drying as a technique up to 4hrs in formulation
Hydroxy proplyl [118]
57 Levocitrizine Antihistamine for formulation of the Spray drying. III.
cellulose,
mucoadhesive microspheres Study shows that it is
Sodium
for nasal delivery. possible to prepare
alginate.
mucoadhesive
microspheres using spray
drying technique.
Microspheres showed 40-
Poly ε 60% of drug in first 12hrs.
The objective is to develop Emulsion solvent caprolactone, An increase in release rate
[119]
58 Levenorgestrel Contraceptive biodegradable microspheres evaporation Poly(di lactide was observed with
of Levenorgestrel. technique. coglycollide) increased drug loading.
PLGA. Release of drug decreased
with increased PLGA

ratio. This could be

explained by low
permeability of PLGA to
steroids.
There is no significant
release of drug at gastric
pH from wax/fat
To minimize the unwanted microspgeres. At the end
Bees wax,
toxic effects by kinetic Meltable emulsified of the 8th hour, drug
Cetosteryl
Lithium control of drug release, it dispersion cooling release from Cetosteryl [120]
59 Anti maniac alcohol,
carbonate was entrapped into gastro induced solidification alcohol (84.68%), Cetyl
Spermaceti,
resistant, biodegradable technique. alcohol (78.49%)
Cetyl alcohol.
waxes and fats. microspheres was faster
than Bees wax (75.85%),
Spermaceti (67.75%)
microspheres.
F4, F5, F6 were the
To achieve controlled optimized formulations
Eudragit RS
release. with Eudragit RS100 and
Losartan Antihypertensi Solvent evaporation 100, [121]
60 To minimize side effects. Eudragit RL100 as coating
potassium ve technique. Eudragit RL
To minimize inactivation of polymers. They have
100.
drug. shown 83-87% release
over a period of 12hrs.
Release of the drug
showed biphasic release
To improve its oral pattern with non-Fickian
Mebeverine bioavailability and Emulsion solvent Eudragit S100, diffusion release in 12hrs. [122]
61 Antispasmodic
hydrochloride possibility to redirect its evaporation method. Eudragit L100. On basis of drug content,
absorption only to the colon. particle size, in vitro
release, formulation F3
was found to be optimal.
[123]
62 Mesalamine Antiulcer To achieve sustained release Emulsion solvent Eudragit S100, Formula MES100EC10

and to overcome rapid evaporation method. Ethyl cellulose. showed the most suitable
absorption. characters for sustained
To overcome unwanted release.
effects. It exhibits highest yield &
encapsulation efficiency.
Release is extended over a
period of 16hrs.
Microsphres made of both
polymers at 1:1 ratios
To design sustained release (total 10% w/w) exhibited
Cellulose
Metformin Antihyperglyc gastric floating Emulsion solvent satisfactory drug release. [124]
63 acetate butyrate,
hydrochloride emic microspheres, to increase evaporation method. 73-77% & 77-81% drug
Eudragit RL100.
gastric retention. released in 8-10hrs in 0.1N
HCl & phosphate buffer
repectively.
Ideal batch (batch C)
showed maximum
To investigate the process
percentage of drug
variables in the formulation
targeting (47%) to lungs.
of Methotraxate loaded [125]
64 Methotrexate Anticancer Heat stabilization. Albumin. In vitro evaluation of ideal
albumin microspheres and to
batch (batch C), it showed
evaluate itsin vitro and in
only low percent drug
vitro characteristics.
localization (15.8%) after
36hrs.
To study the therapeutic The MTX-IMS group was
application and carrier more effective in terms of
mediated specificity of better cell affinity and
Emulsion cross [126]
65 Methotrexate Anticancer immune microcapsules Albumin. binding capacity than the
linking method.
through anticancer agents in MTX-MS and free MTX
site specific drug delivery and control groups, against
systems for cancer therapy. selected cancer cells.
[127]
66 Metoclopromide Antiemetic To optimize, characterize & Emulsion phase Chitosan As polymer to drug ratio

evaluate mucoadhesive separation technique. increases, the percentage

microspheres of mucoadhesion also
Metoclopromide. increases.
In batches A2 to A4 the
percentage mucoadhesion
was above 20% even after
8hrs.
1:1 ratio showed
maximum percentage
To design & evaluate
Phase separation yield 88.1% and 1:2 ratio
Antihypertensi Chitosan microspheres of [128]
67 Metoprolol emulsification Chitosan. showed highest drug
ve Metoprolol tartrate for
technique. entrapment of 72.1% w/w.
sustained release.
Release was found to be
sustained.
F5 (containing 1% w/w of
drug loaded microcapsules
Antibiotic, To prolong the release. Solvent evaporation Ethyl cellulose, [129]
68 Metronidazole and 0.6% w/w carbopol
Antiprotozoal. To reduce dose frequency. method. Carbopol.
974) was found to sustain
Metronidazole over 36hrs.
The microspheres
prepared at optimum speed
(400rpm) with 2% protein
To encapsulate the drug in
Heat stabilization & concentration with a cross
Antibiotic, albumin microspheres to [130]
69 Metronidazole chemical stabilization Albumin. linking agent (A1
Antiprotozoal. sustain the release of the
process. formulation) shows good
drug.
percentage drug
entrapment and sustained
release.
Antidepressant To microencapsulate a newer Emulsification. Then It has taken 7hrs for 100%
, multiple serotonin receptor micronized spray in drug release from 100:1 [131]
70 Mianserine Albumin.
Anxiolytic, modulator, Mianserine in a denaturation solvent formulation, 5hrs from
Hypnotic. narrow particle size environment. 50:1 formulation and 3hrs

distribution. from 10:1 formulation.

Among the different
polymer-drug ratios C2
To provide more uniform formulation (1:0.3) is
Antihyperlipid Emulsion solvent [132]
71 Niacin distribution with reduced Ethyl cellulose. selected as it shows
emic diffusion method.
dose dumping. optimum prolonged
release (68% within 10hrs
and 100% within 18hrs).
Release from the
To evaluate the resin microcapsules was slow
obtained from Olibanum as and spread over a period [133]
72 Nifedipine channel solvent evaporation Olibanum.
coating material in of more than 24hrs and
blocker technique.
microencapsulation. depended on core: coat
ratio.
Microcapsules containing
Microencapsulated with solvent deposited systems
Cellulose acetate to obtain Cellulose as core gave slow, [134]
73 Nifedipine channel solvent evaporation
sustained release of acetate. sustained and complete
blocker method.
Nifedipine. release of Nifedipine over
a period of 12hrs.
To prepare Nimesulide Increase in polymer
microspheres using concentration as well as
optimization methodology. A Calcium cross linking agent
23 factorial was employed to Ionotropic Gelation alginate, concentration causes a [135]
74 Nimesulide NSAID
study various effective method. Sodium decrease in drug release.
factors such as polymer alginate. Increase in drug
conc, drug conc, cross-linker concentration causes an
conc. increase in release.
Microcapsules prepared with Lipids- Among the 12
the aim of targeting the drug Modified solvent Glyceryl preparations maximum [136]
75 Nimesulide NSAID
to the site of inflammation evaporation method. tristearate, yield (93.2%) & highest
and for controlled release. Cholesterol. drug entrapment (68.1%)

was obtained with

Glyceryl tristearate
(SEGL1) microspheres.
Drug released over 12days
with maximum release of
74%.
To design and evaluate a The second formulation
drug delivery system of (1:1) showed the best
Nitrofurantoin for achieving Emulsification release profile with longest
Bactericidal [137]
76 Nitrofurantoin sustained serum and urinary solvent evaporation Ethyl cellulose. steady state phase,
agent
levels over a prolonged technique. releasing more than 95%
period of time but without of the drug and a sustained
side effects. action for more than 8hrs.
70-80% of the drug was
Bactericidal To sustain the drug release. Ionic Gelation Alginate, [138]
77 Nitrofurantoin released over a period of
agent To minimize the side effects. method. Chitosan.
6hrs.
Release of drug from
A comparative study of two Gelatin microcapsules was
Simple coacervation Gelatin,
Antibacterial polymers that is Gelatin and found to be very rapid [139]
78 Norfloxacin and complex Cellulose
agent Cellulose acetate was when compared to
emulsion technique. acetate.
undertaken. Cellulose acetate
microcapsules.
A2 (2% w/v calcium
chloride) formulation
Antibacterial Sodium showed best sustained [140]
79 Norfloxacin To sustain the drug release. Ionotropic gelation.
agent alginate. release amongst the three
formulations releasing
about 40.51% in 5hrs.
Formulation (F2)
Emulsion solvent Ethyl cellulose,
Ofloxacin Antibacterial To achieve gastro retentive containing Ethyl cellulose [141]
80 evaporation PVP-K90,
hydrochloride agent drug delivery. 1% showed maximum
technique. PVA.
drug release after 6hrs.

Formulation B1 was
HPMC,
Emulsion solvent considered as best
Proton pump To develop gastro resistant Sodium [142]
81 Pantoprazole evaporation formulation as drug
inhibitor drug delivery system. alginate,
technique. release was found to be
Eudragit RS100.
91.352% in 14hrs.
To prepare poly
In the in vitro release
study, formulation F2
Xanthine containing Pentoxyfilline to Solvent evaporation Poly ε [143]
82 Pentoxyfilline (1:4) showed 90.34% drug
derivative achieve a controlled drug method. caprolactone.
release at 15hrs and found
release profile for peroral
to be sustained.
administration.
Increase in miotic
response duration and
AUC of 1% PN
To increase the ocular
microspheric suspension
contact time and hence the
Pilocarpine Miotic, Protein gelation as compared to solutions. [144]
83 drug bioavailability by Albumin.
nitrate Antiglaucoma. process. Results showed that egg
addition of suitable
albumin microspheres
polymers.
have potential to deliver
PN for prolonged period
of time.
Microencapsulation was
96.34-104.30% in case of
To prepare and evaluate Ethyl cellulose, EC and 95.0-101.25% in
Ethyl cellulose and EVA Emulsification Ethyl vinyl case EVA. Pioglitazone [145]
84 Pioglitazone Antidiabetic
microcapsules for controlled solvent evaporation. acetate release from
release. copolymer. microcapsules was slow
over 24hrs depends on
core : coat ratio.
To systemically analyze the Emulsion solvent Formulations F2, F4 and
Antihypertensi Cellulose [146]
85 Propronalol effect of different evaporation A2 were found to comply
ve acetate butyrate.
formulation variables on the technique. with drug release test-1 for

microcapsule properties extended release. Drug

using a response surface release is prolonged over a
methodology & to develop period of 24hrs.
optimized formulation.
To avoid first pass Formulation MS4(D) and
metabolism, to improve MS5(E) were relatively
patient compliance, to us an smooth and uniform which
Antihypertensi Emulsion cross [147]
86 Propronalol alternative therapy to Gelatin. is suitable for intranasal
ve linking method.
conventional dosage from, to administration.
achieve controlled blood Formulation MS5 showed
level profiles. maximum mucoadhesion.
Percentage release of
protein from microspheres
To investigate the in one week was 68.13,
preparation of microspheres 59.81, 51.66, & 38.31 %
Double emulsion Poly (D,L-
Protein (Bovine as potential carriers for for RG502H, RG503, [148]
87 Antigen solvent evaporation lactide co
serum albumin) proteins, intended for RG503H, RG504,
method. oglycollide).
controlled release respectively. Release
formulation. studies showed that PLGA
microspheres showed
sustained release.
Formulation RM5 was
found to be best among all
To increase gastric retention Solvent evaporation Chotosan, [149]
88 Repaglinide Antidiabetic formulations since it
of the drug. method. Eudragit RS100.
showed good
mucoadhesion properties.
The formulation MC1 with
To develop microcapsules a coating ratio of 1:1
Sodium
utilizing blend of polymers Emulsification ion (Sodium alginate : [150]
89 Rifampicin Antitubercular alginate,
for delivery of anti gelation method. Carbopol974P) was found
Carbopol 974P.
micobacterial drug. to be suitable for oral
controlled release.

Results showed that the

surface adhering drug was
found to release
To develop a sustained
immediately and a
release dosage form by Extrusion method &
constant release was [151]
90 Theophylline Antiasthamtic formulating Theophylline disperse phase Agar.
obtained up to 5hrs from
embedded agar microbeads congealing.
all the batches. Release of
with hydrocolloid.
drug decrease as
concentration of
hydrocolloid increased.
Ratio 1:1:2 showed
To design and evaluate
maximum yield of 82%
Albumin-Chitosan
Heat stabilization Albumin, and pH 1.2 and 92.4% at [152]
91 Theophylline Antiasthamtic microspheres of
method. Chitosan. pH 7.4 after 8hrs and
Theophylline for sustained
showed highest drug
release.
entrapment.
To evaluate
microencapsulated controlled Results showed that an
release preparations of increase in the ratio of
Tolmetin using Ethyl drug: polymer (0.5:1)
Double emulsion
cellulose as retardant resulted in a reduction in [153]
92 Tolmetin NSAID solvent diffusion Ethyl cellulose.
material. the release rate of the drug
method.
To improve loading which may be attributed to
efficiency of water soluble hydrophobic nature of the
drugs and modulate release polymer.
properties.
Drug release was steady
To alleviate the dose related
with almost 50% drug was
problems and to reduce the
Antihypertensi Coacervation phase released within 2hrs & [154]
93 Triflouperazine frequency of multiple dosing Ethyl cellulose.
ve separation. remaining drug was
and there by improve patient
released in sustaining
compliance.
fashion for a period of

12hrs. Formulation TMC2

was found to have better
drug loading efficiency.
To prepare mononucleated
The optimum
microencapsulated ion-
concentration of coating
exchange resin beads Amberlite,
Emulsion solvent material was 3%, plasticity [155]
94 Venlafaxine Antidepressent containing Venlafaxine Eudragit RS100,
diffusion method. agent was 5%, and ratio of
hydrochloride with sustained Eudragit RL100.
drug-resin complexes to
release properties and
coating materials was 8:1.
offering complete release.
Of all the formulations F3,
To develop a suitable Sodium
F6 and F9 were found to
microparticulate system of alginate,
Antihypertensi Ionotropic gelation show satisfactory results. [156]
95 Verapamil Verapamil hydrochloride for HPMC,
ve technique. Micropellets showed
prolonged release delivery Hydroxy propyl
prolonged release over a
system. cellulose.
period of 6hrs.
Highest entrapment (54%)
was shown with ratio
To prepare and evaluate oral
increasing from 1:0.25 to
controlled release
1:0.5.
microparticulate drug
Double emulsion 1:0.5 showed optimum [157]
96 Zidovudine Antiretroviral delivery system of AZT Ethyl cellulose.
solvent diffusion. capacity for drug
using ethyl cellulose by
encapsulation.
w/o/o double emulsion
As concentration of
solvent diffusion method.
Span80 increased a faster
drug release was observed.

CONCLUSION
The microencapsulation approach offers a wide variety of opportunities such as protection
and masking, reduced dissolution rate, facilitation of handling, and spatial targeting of the
active ingredient. This approach facilitates accurate delivery of small quantities of potent
drugs, reduced drug concentrations at sites other than the target organ or tissue and protection
of labile compounds before and after administration and prior to appearance at the site of
action. Microencapsulation system offers potential advantages over the conventional drug
delivery systems. Microspheres and microparticales are a unique carrier system for various
pharmaceuticals dosage form. Hence, microspheres and microparticales are not only used for
controlled release but also for the target delivery of the drug to the specific site in to the body.
The microencapsulation approach also beneficial for those drugs which required to dissolved
in to the intestine not in the stomach. Therefore, this safe and efficient particular system
should be developed in future.
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Mucoadhesive Microencapsulation: A New Tool in Drug Delivery Systems

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Santosh et al. JOURNAL OF PHARMACY

Volume 5, Issue 12, 1410-1470. Review Article ISSN 2278 – 4357

MUCOADHESIVE MICROENCAPSULATION: A NEW TOOL IN

*R. Santosh Kumar, G.V. Radha and T. Naga Satya Yagnesh

GITAM Institute of Pharmacy, GITAM University, Rushikonda, Visakhapatnam,

*Corresponding Author systems. Microspheres constitute an important part of novel drug

KEYWORDS: Microencapsulation, Mucoadhesion, Polymers, Applications.

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c. Selected Stability, Release and Other Properties

d. Physical Character of the Final Product

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Chemically modified carbohydrates

Prerequisites for Ideal Microparticulate Carriers

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1. Coacervation phase separation

1. Coacervation Phase Separation

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b. By incompatible polymer addition: It involves liquid phase separation of a polymers

e. By polymer-polymer interaction: The interaction of oppositely charged poly electrolytes

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2. Multiorifice – Centrifugal Process

4. Air Suspension Coating

5. Spray Drying and Spray Congealing

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Applications of Microencapsulation: (Chowdary, 1992)

Characterization of Microcapsules (Vyas etal,2002)

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The characterization of microcapsule carrier is an important phenomenon, which helps to

1. Particle Size and Shape

2. Fourier Transform – Infrared Spectroscopy: (FTIR)

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% Entrapment = Actual content X 100

7. In-Vitro Release Studies

Kinetics of Drug Release

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First order release5 would be linear as predicted by following equation.

The assumption made in the deriving equation (2) is as follows:

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Table 1.1: Examples of Some Microencapsulated Drugs.

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Mucoadhesive Microspheres and Microcapsules

Mucoadhesion and Mucoadhesive Drug Delivery Systems

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and enhance the bioavailability of drugs. Greater bioavailability of piribedit[12], testosterone

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Polymers Used for Mucoadhesive Microspheres

Various biocompatible polymers used in mucoadhesive formulations include cellulose-based

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Specific Site Directed Bioadhesives- The Next Generation

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Amino Acid Sequences

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Preparation of Mucoadhesive Microspheres

Hot Melt Microencapsulation

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polymers such as the ployanhydrides. In this method, drug is dispersed or dissolved in a

Phase Inversion Microencapsulation

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Evaluation of Mucoadhesive Microspheres

Measurement of Adhesive Strength