A

Review
On

Microspheres technology and its application

By

Gunja Chaturvedi
(I.D no- 2008H146101)

Submitted in partial fulfilment of the course

PHA G632: Dosage Form Design

Date of Submission 01/04/2009

Submitted to

Dr. R. N Saha
(Instructor In-charge)

BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE, PILANI, RAJASTHAN – 333 031

April 2009
 REVIEW ON MICROSPHERES

Chaturvedi Gunja , Bhagav Prakash, Prof. R.N Saha

Birla Institute of Technology and Science, Pilani, Rajasthan (India)
3
Faculty of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan
4
Dean, Faculty Division-3, Birla Institute of Technology & Science, Pilani, Rajasthan (India)

Abstract :-
Nonideal pharmaceutical, pharmacokinetic, and therapeutic properties often combine to
reduce the effectiveness of certain compounds. For the vectoring of such compounds to target
areas, liposomes, nanoparticles, and microspheres have been suggested. Since organ
distribution of the latter is dependent upon their size and shape, it is reasonable to attempt
second-order targeting of microspheres on this basis.
The range of techniques for the preparation of microspheres offers a variety of opportunities
to control aspects of drug administration.This approach facilitates accurate delivery of small
quantities of potent drugs ,reduce 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.

Keywords: microspheres, formulation parameters, biodegradable polymers,matrix and

reservoir type microspheres, particle size, ,colonic drug delivery, ,nasal delivery.

Contents:-
 Introduction
 Definition and description
 History
 Potential use of microspheres
 Microspheres manufacture by different methods
 Approaches related to formulation and process parameters in microsphere
manufacturing
 Effect of process and formulation parameters on inernal morphology of
microspheres loaded with hydrophobic drug
 Proteins encapsulated in microspheres and its stability
 Preparation of Biodegradable Microspheres and Matrix Devices Containing
Naltrexone
● Approaches towards drug targeting using microspheres
 Nasal delivery
 Colonic drug delivery
● References

Introduction drugs in vivo can be manipulated by

The range of techniques for the
preparation of microspheres offers a
variety of opportunities to control aspects
of drug administration.This approach
facilitates the accurate delivery of small
quantity of the potent drugs ,reduced drug
concentration at the site other than the
target site and the protection of the labile
compound before and after the
administration and prior to appearance at
the site of action.The behaviour of the
coupling the drug to a carrier particle. The
clearance kinetics,tissue distribution,
metabolism and cellular interaction of the
drug are strongly influenced by the
behaviour of the carrier. The exploitation
of these changes in pharmacodynamics
behaviour may lead to enhanced
therapeutic effect. However ,an intelligent
approach to therapeutics employing drug
carriers technology requires a detailed
understanding of the carrier interaction
with critical cellular and organ systems THE POTENTIAL USE OF
and of the limitations of the systems with MCROSPHERES IN
respect to the formulation procedures and PHARMACEUTICAL INDUSTRY
stability. A variety of agents have been  Conversion of oils and other
used as drug carrier, including liquids to solids for ease of
immunoglobulins serum proteins handling
,liposomes, microspheres ,nanoparticles  Taste and odour masking
,microcapsules and even cells such as  Increasing the stability of the drug
erythrocytes. The characteristics of against the environmental
microspheres containing drug should be conditions
correlated with the required therapeutic  To delay the volatilisation
action and are dictated by the materials  Separation of incompatible
and the methods employed in the materials
manufacture of delivery systems. [1]  Improvement of flow properties of
powders
DEFINITION AND GENERAL  Safe handling of toxic substances
DESCRIPTION  Improve the solubility of water
Microspheres can be defined as solid,
insoluble substances by aiding in
approximately spherical particles ranging
dispersion of such material in
in size from 1 to 1000 µm.They are made
aqueous media
of polymeric,waxy or other protective
materials,that is biodegradable synthetic  Production of sustained
polymers and modified natural products release,controlled release and
such as starches,gums ,proteins,fats and targeted medications
waxes.The natural polymers include  Reduce the dose dumping
albumin and gelatine, the synthetic potential compared to large
polymer include polylactic acid and implantable devices. [1]
polyglycolic acid. The solvents used to
dissolve the polymeric materials chosen
according to the polymer and drug Microspheres manufacture
solubilities and stabilities ,process safety The most important physicochemical
and economic considerations. characteristics that may be controlled in
Microspheres are small and have large microsphere manufacture are:
surface-to-volume ratio. At the lower end - Partical size and
of their size range they have colloidal distribution
properties. The interfacial properties of - Polymer molecular weight
microspheres are extremely important - Ratio of drug to polymer
,often indicating their activity. [1] - Total mass of drug and
polymer
Different methods of microspheres
HISTORY
The concept of packaging microscopic manufacturing are:
quantities of materials within - Wax coating and hot
microspheres dates back to the 1930s and melt
the work of Bungenberg de Jong and - Spray coating and pan
coworkers on entrapment of substances coating
within coacervates. The first commercial - Coacervation
application of encapsulation was by the - Spray drying
National Cash Register Company for the - Solvent evaporation
manufacture of carbonless copying paper. and precipitation
The technology and applications have - Freeze drying
advanced over the last several dacades. [1] - Chemical and thermal
cross – linking
Wax coating and hot melt: wax may be
used to coat the core particles,
encapsulating the drug by dissolution or
dispersion in molten wax. The waxy
solution or suspension is dispersed by
high speed mixing into cold solution, such
as cold liquid paraffin. The mixture is
agitated for at least one hour. The external
phase (liquid paraffin) is then decanted
and the microspheres are suspended in a
non- miscible solvent and allowed to air
dry. Wax coated microspheres ,while
inexpensive and often used,release drug
more rapidly than polymeric microspheres.
Carnauba wax and beeswax can be used as
the coating materials and these can be
mixed in order to achieve desired
characteristics.
Spray coating and pan coating: spray
coating and pan coating employ heat-
jacketed coating pans in which the solid
drug core particles are rotated and into
which the coating material is sprayed. The
core particles are in size range of
micrometers upto few millimetres. The
coating material is usually sprayed at
angle from the side into the pan. The
process is continued until an even coating
is completed. Coating a large number of
particles may provide a safer and more
consistent release pattern than coated
tablets. In addition,several batches of
microspheres cab be prepared with
different coating thickness and mixed to
achieve specific controlled release pattern.
Coacervation : This process is a simple
separation of macromolecular solution
into two immiscible liquid phases,a dense
coacervate phase,which is relatively
concentrated in macromolecules and a
dilute equilibrium phase. In presence of
only one macromolecule this process is
referred to as simple coacervation. When
two or more macromolecules of opposite
charge are present ,it is referred to as
complex coacervation. Former one is
induced by various parameters like change
in temperature, addition of non-solvent or
microions , which results in dehydration of
macromolecules because they promote
polymer-polymer interactions over
polymer- solvent interaction. And the
latter is induced by large number of
variables like pH,ionic
strength,macromolecule
concentration,macromolecule ratio and
macromolecular weight which results in a
larger number of controllable parameters.
These can be manipulated to produce
microspheres with specific properties.
Spray drying: It is single step,closed-
system process applicable to wide variety
of materials,including heat-sensitive
materials. The drug and polymer coating
materials are dissolved in suitable
solvent(aqueous or non-aqueous) or the
drug may be present as a suspension in the
polymer solution. Alternatively, it may be
dissolved or suspended within an
emulsion or coacervate system. For
example,biodegradable polylactide
microspheres can be prepared by
dissolving the drug and the polymer in
methylene chloride. The microsphere size
is controlled by the rate of spraying,the
feed rate of the polymer drug solution,the
nozzle size ,the temperature in drying and
collecting chambers,and the size of the
two chambers. The quality of the spray
dried products are improved by the
addition of plasticizers that promote the
polymer coalescence and film formation
and enhance the formation of smooth
surfaced and spherical microspheres.
Solvent evaporation: For this method the
drug and the polymer must be soluble in
organic solvent,frequently methylene
chloride. The solution containing polymer
and drug may be dispersed in an aqueous
phase to form droplets. Continuous mixing
and elevated temperatures may be
employed to evaporate the more volatile
organic solvents and leave the solid
polymer-drug particles suspended in an
aqueous medium. The particles are finally
filtered from the suspension.
Precipitation : It is a variation on the
evaporation method. The emulsion
consists of polar droplets dispersed in a
non-polar medium. Solvent may be
removed from the droplets by the use of a
cosolvent. The resulting increase in the
polymer concentration causes precipitation
forming a suspension of microspheres.
Freeze Drying: This technique involves
the freezing of the emulsion and the
relative freezing points of the continuous
and dispersed phases are important. The
continuous phase solvent is usually
organic and is removed by sublimation at
low temperature and pressure. Finally the
dispersed phase solvent of the droplets is
removed by sublimation,leaving polymer-
drug particles.
Chemical and thermal cross- linking:
microspheres made from natural polymers
are prepared by a cross-linking process;
polymer include gelatin, albumin ,starch
and dextran. A water-oil emulsion is
prepared ,where the water phase is a
solution of polymer that contains drug to
be incorporated. The oil phase is a suitable
vegetable oil or oil - organic solvent
mixture containing an oil soluble
emulsifier. Once the desired water-oil
emulsion is formed ,the water soluble
polymer is solidified by thermal treatment
or addition of a chemical cross-linking
agent such as glutaraldehyde to form a
stable chemical cross link as in albumin. If
chemical or heat cross linking is used , the
amount of chemical and the period and
intensity of heating are critical in
determining the release rates and swelling
properties of the microspheres. [1],[2],[3],[4]
Approaches related to formulation and
process parameters in microsphere
manufacturing
1.Effect of process and formulation
parameters on inernal morphology of
microspheres loaded with a hydrophobic
drug: ABT627 is a newly synthesized
drug for the treatment of prostate cancer.
It is a lipophilic drug ,and taking it as a
model drug the effect of continuous phase/
dispersed phase ratio(CP/DP ratio),PLGA
concentration ,continuous phase pH
,polyvinyl alcohol concentration and initial
drug loading on the physicochemical
characteristics of the developed
microspheres was studied and internal
morphology of the microspheres was
analyzed by stereological method to
elucidate the distribution and the release
mechanism of the drug from microspheres.
Fig 1. structure of ABT627
From the above studies it was found that
for the encapsulation of the hydrophobic
substances into PLGA matrix, CP/DP ratio
is a crucial factor. It was observed that the
drug loading increased significantly with
increasing CP/DP ratio accompanied by
decreasing the burst effect. At the CP/DP
ratio 20,the microspheres with a core shell
structure were observed and the internal
porosity of the microspheres decreased
with increasing the CP/DP ratio.
Increasing the PLGA concentration
,increased particle size but decreased drug
release rate was observed. Increasing the
PVA concentration in continuous phase
from 0.1% to 0.5% increased the drug
release rate. The maximum solubility of
the drug in PLGA microspheres is
approximately 30% under which it was
dispersed in PLGA matrix in a molecular
state. Its release rate was decreased with
increasing the intial drug loading.
ABT627 was slowly released from the
PLGA microspheres over 30 days by a
combination of pore diffusion and polymer
degradation. During the first 13 days,it
was released mainly by diffusion
supported by unchanged internal
morphology of the microspheres after 7
days of release. Internal morphology
observation after incubating the
microspheres for 17 days indicated that
ABT627/PLGA microspheres were mainly
degraded by auto-catalyzation from
inside,as revealed by core-shell structure
of the microsphere at the release stage.
[5],[6],[7]
2.Reversible protein precipitation to
ensure stability during encapsulation
within PLGA microspheres: although the
purpose has been limited due to physical
and chemical instability. Due to relatively
high enzymatic susceptibility and short
half life,much attention has been paid to
their delivery from systems controlling
local release. Since a solid-state protein
exhibits restricted conformational
flexibility,non-aqueous encapsulation
approaches have emerged to ensure
protein stability upon encapsulation within
biodegradable polyester
microspheres.Various methods like spray-
drying or spray-freeze drying have been
reported for the preparation of small
protein particles. Although these methods
can generate protein particles ,they present
some drawbacks for microencapsulation
that they are technically complex and lead
to low protein recovery and also may
denature the proteins. The aim of this
study was to develop a non- denaturing
method to prepare protein particles. Freeze
–drying has often been used to obtain
protein particles without protein loss but it
induce the formation of large particles. To
obtain fine particles and preserve protein
integrity,proteins have been freeze- dried
with PEG which induces a two –phase
separation. This approach has been used
for protein microencapsulation by
solid/oil/water (s/o/w) and s/o/o
techniques. However ,the remaining
amount of PEG in the freeze-dried protein
products leads to an important initial burst
(20% in 1 hr) upon release from PLGA
microspheres, and so an adaptation of the
process was necessary. So in order to
obtain protein particles without these
disadvantages,from an aqueous solution
protein precipitation was induced via
isoelectric precipitation, reduction of
dielectric constant by addition of water-
miscible organic solvents ,the reduction of
the protein charge by changing the pH and
the addition of the polymers or salts. In
this study, an organic solvent ,Glycofurol
,was employed by preference to induce the
formation of fine protein particles. It was
chosen as a precipitant because it is non-
production of various proteins has become
possible with the recent advances in
biotechnology,their use for therapeutic
toxic PLGA solvent which could be used
to prepare PLGA microspheres. Moreover
,it is a protic solvent containing hydrogen
attached to oxygen so that it is able to
form hydrogen bonds or to donate a proton
such as in stabilizing PEG. The presence
of glucofurol induces a liquid –liquid
phase separation resulting in a protein –
rich phase and a protein –poor phase. The
addition of salt (sodium chloride) helped
in collecting the maximum amount of
protein precipitates by reducing the
electrostatic repulsive interactions between
charged proteins and promoting attractive
hydrophobic interactions. The reason
behind selecting sodium chloride was
related to its possible use in parenteral
pharmaceutical formulations and to its
intermediate location in the lyotrophic
series and also it decreases theprotein
solubility very little with minimal
denaturant effects. The various process
parameters discussed above were modified
to optimize the precipitation efficiency of
four model proteins : lysozyme,α-
chromotrypsin ,peroxidase and β-
galactosidase. As monitored by enzymatic
activity measurement of rehydrated
particles ,conditions to obtain more than
95% of the reversible precipitates were
defined for each protein. The study of the
rehydrated particles by absorbance
spectroscopy, fluorescence spectroscopy
and circular dichroism showed an absence
of structural- perturbation after
precipitation. The protein particles were
then microencapsulated within PLGA
microspheres using s/o/w technique. The
average encapsulation yield was around
80% and no loss of protein activity
occurred after the encapsulaton step.
Additionally , a lysozyme in vitro release
study showed that all of the released
lysozyme was biologically active. So this
method of protein precipitation is
appropriate for the encapsulation in
PLGA microspheres of various proteins
without inactivation. [8],[9],[10]
3. Preparation of Biodegradable antagonists. In this study ,poly(L-lactide)
Microspheres and Matrix Devices (PLA) microspheres containing naltrexone
Containing Naltrexone: Naltrexone is an prepared by sol-vent evaporation
opiate antagonist used mainly as an technique were compressed at
adjunct to prevent relapse in detoxified temperatures above the Tg of the polymer.
opioid-dependent patients. It is currently The effect of different process parameters,
given orally as tablets or capsules in a such as drug/polymer ratio and stirring
daily dose of 50 mg. Naltrexone is orally rate during preparation of micro-spheres,
active with a relatively short half-life and on the morphology, size distribution, and
subject to extensive hepatic first-pass in vitro drug release of microspheres was
metabolism.Naltrexone provides no studied.
euphoric effects, and there are no observ-
able pharmacological consequences when
a patient discontinues the drug. For
naltrexone treatment to be effective, a
sufficient level of the drug concentration
must be maintained. The minimum
effective concentra-tion of naltrexone for
the treatment of opiate addiction is
estimated to be in the range of 0.5 to 1.0
ng/mL. Detoxified patients are advised to
continue the naltrexone therapy for 4 to 8
months. This treatment typically requires
the patient to self-administer dosages of
the drug several times a week. The main
drawback in naltrexone treatment protocol
Fig.2.Effect of particle size on drug release
is patient compliance. A possible means of
from microspheres with 20% drug loading
improving patient compliance and
concomitant rehabilitation is the use of
controlled drug delivery systems of opioid

Fig.4. Effect of drug loading on drug release

from microspheres with the same size range

By increasing the stirring speed from 400

Fig.3. Effect of particle size on drug
release from microspheres with 40% drug
loading
to 1200 rpm, the mean diameter of
microspheres decreased from 251 μm to
104 μm. The drug release rate from
smaller microspheres was faster than from
larger microspheres. However, drug
release from microspheres with low drug
content (20% wt/wt) was not affected by
the particle size of microspheres.
Increasing the drug content of
microspheres from 20% to 50% wt/wt led
to signifi-cantly faster drug release from
microspheres. It was also shown that drug
release from matrix devices pre-pared by
compression of naltrexone microspheres is
much slower than that of microspheres. No
burst re-lease was observed with matrix
devices. Applying higher compression
force, when compressing micro-spheres to
produce tablets, resulted in lower drug re-
lease from matrix devices. The results
suggest that by regulating different
variables, desired release profiles of
naltrexone can be achieved using a PLA
micropar-ticulate system or matrix
devices. [16],[17],[18]
Approaches towards drug targeting
using microspheres
1.Spray –dried microspheres based on
methylpyrrolidinone chitosan as new
carrier for nasal administration of
metoclopramide : In recent years,chitosan
derivatives have been studied to improve
polymer solubility at different pH values
and to promote the permeability of anionic
drugs thereby avoiding the precipitation of
the drug –polymer complexes.5 –
methylpyrrolidinone chitosan (MPC) is a
chitosan derivative in which the amino
group of the glucosamine units of the
polysaccharide backbone are partially
substituted by methylpyrrolidinone(MP) in
position 5. It belongs to the class of the gel
–forming reabsorbable biopolymeric
substituted chitosans possessing
documented biological significance. This
chitosan derivative combines the
biocompatibility of chitosan and the
hydrophilic characteristics of the
pyrroilidinone moiety ,being particularly
susceptible to the hydrolytic action of
lysozyme.
Nasal delivery has generated interest as an
alternative route for the administration of
drugs and biomolecules that are
susceptible to enzymatic or acidic
degradation and first –pass hepatic
metabolism. Possible pathways for a drug
to permeate across the nasal mucosa are
passive transport ation ,carrier mediated
,transcytosis and transport through
intercellular tight junctions. However ,the
nasal delivery has limitations which have
restricted its use to the delivery of a few
drug molecules. The permeability of nasal
mucosa is normally low for the polar
molecules: for small polar drugs the
bioavailability is generally in the region of
10% and for the peptides such as
calcitonin and insulin normally not above
1%. Another factor of importance for the
low membrane transport is the general
rapid clearance of the administered
formulation from the nasal cavity due to
mucociliary clearance mechanism. It has
been shown that for both liquid and
powder formulations that are not
mucoadhesive ,the half life of clearance
are in order of 15 -20 mins. So in this
study chitosan derivative MPC is used to
produce microspheres for nasal delivery of
metoclopramide. The mechanism of action
of chitosan in improving the transport of
polar drugs across the epithelial
membrane is believed to be combination
of bioadhesion and transient opening of
tight junctions in the cell membrane to
enable the passage of the polar drugs. A
non –derivatized chitosan has been used as
comparison and metoclopramide
hydrochloride has been chosen as model
drug. The metoclopramide loaded MPC
microspheres were made by spray –drying
technique. They showed similar properties
of microparticles made by chitosan
chosen as reference with respect to size
and in vitro release behaviour. And the
microspheres based on MPC are
characterized by better
mucoadhesiveness,less swelling capability
and more prolonged ex –vivo permeation
profile than the particles containing
chitosan,moreover they are able to provide
a gel (when they come in contact with
aqueous solutions) which shows different
properties dependent upon the medium
used. These properties make microspheres
based on derivatized chitosan suitable for
nasal administration,infact the
mucoadhesiveness might prolong the
residential time of the formulation inside
the nasal cavity while a moderate swelling
could avoid potential mucosal damages or
inconveniences to the possible users.
[11],[12],[13]
2.Development of enteric –coated calcium
pectinate microspheres intended for
colonic drug delivery: Among the various
strategies proposed to target orally
administered drugs to the colon ,those
based on drug release triggered by colon
microflora are generally considered the
most effective regarding target selectivity.
And for this purpose the natural
biodegradable polymers such as pectins
are employed due to their ability to act as
specific substrate for colonic microflora
and also combined with their high
safety,non –toxicity and biocompatibility
characteristics. Most of the colon targeted
drug delivery system developed so far are
single –unit systems. On contrary ,multi –
particulate systems can offer several
advantages over single –unit formulations
like quick spread out on their arrival to the
colon,with a sharp increase in the surface
area exposed to bacterial breakdown that
produces rapid drug release and thereby
improves the drug absorption. In this study
enteric –coated calcium pectinate
microspheres are formulated as a colon –
targeted delivery system and
Theophylline is used as a model drug since
it is well absorbed in the large intestine in
humans and both its anti –asthma activity
and pharmacokinetic properties make it an
interesting candidate for such kind of
modified –release preparations. The
influence of pectine type ,calcium ion
concentration and cross –linking time on
both drug entrapment efficiency and dug
release pattern was investigated. And the
effect of varying the level of the pH –
dependent coating polymer (Eudragit
S100) was also evaluated. The Ca
pectinate microsphere(MS) prepared with
CF020 i.e low –methoxylated amidated
pectins were better than those obtained
with AU701 i.e low –methoxylated pectins
,for both their greater stability during
storage and more regular and
homogeneous morphological properties.
The shape of the former MS was poorly
influenced by the variations in Ca
concentrations maintaining a microencapsulation process employed.
homogeneous spherical form also at lower
Ca concentration.while the latter required
at least 20% w/v of Ca ion concentration
for obtaining MS of satisfactory and well
reproducible morphological properties.
This finding lead to an important
conclusion that the choice of the most
suitable pectin type is very essential
considering that increase in Ca amounts
gave rise to a decrease in rate of drug
release. From the release test performed
under pH gradient and in presence of
pectinolytic enzymes in simulated colonic
medium it was revealed that the Ca –
pectinate MS did not undergo any
selective colonic –microflora triggered
drug release mechanism and the observed
slowing down effect of free Ca ions in the
enzymatic degradation rate of the pectin
matrix can only partially concur to explain
the almost complete lack of activity shown
by pectinolytic enzymes. Inspite of this
unexpected result,the CF020 MS ,realized
with low Ca chloride concentration (2.5%
w/v) and coated with an appropriate
thickness pf a pH –dependent polymeric
film (100%w/v), demonstrated to be
suitable to adequately modulate drug
release through a mixed approach of pH
and transit –time control,completely
avoiding drug release during the first 2 h
in gastric ambient,limiting to less than
10% release in the following 2 h and
reaching 100% release in the colonic
simulated medium within less than 24
hours.[14],[15]
Conclusion:-
Drugs can be targeted to specific sites in
the body using microspheres. Degree of
targeting can be achieved by localization
of the drug to a specific area in the
body(for example in lungs),to a particular
group of cells(for example, kupffer cells)
and even to the intracellular
structures(such as lyzosomes or cell
nucleus). The rate of drug release from the
microspheres dictates their therapeutic
action. Release is governed by the
molecular structure of the drug and the
polymer,the resistance of the polymer to
degradation ,and the surface area
alongwith the porosity of the
microspheres. The internal structure of the
microspheres can vary as a function of the
Controlled drug release from microspheres
occurs by diffusion of the drug through a
polymeric excipient, diffusion of the
entrapped drug through the pores in the
polymeric microspheres. Microspheres
with high drug content release the active
ingredient more rapidly than with a low
load. Physicochemical properties of the
drug and excipient such as permeability of
one in the other, identity of the polymer,
degree of crystallinity ,inclusion of
plasticizers and fillers and thickness of the
polymer influences the drug release rate.
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