Microsphere-A Novel Drug Delivery System

Abstract

Microspheres are characteristically free flowing powders having particle size ranging from 1-1000 μm consisting of proteins or synthetic polymers. Microspheres are used in drug delivery systems which are prepared to obtain prolonged or controlled drug delivery to improve bioavailability, stability and action at the specific site to predetermined rate. Microsphere are spherical in shape so, therapeutic efficacy of microspheres containing drug depends upon their characteristics that can be altered in required terms by altering materials, methods, polymers or techniques used. These delivery systems offer numerous advantages compared to conventional dosage forms, which include improved efficacy, reduced toxicity, improved patient compliance and convenience. Microsphere can be manufactured by various type of material such as glass, polymers, and ceramic microspheres. Microspheres are various types like Bioadhesive microspheres, Magnetic microspheres, Floating microspheres, radioactive microspheres, Polymeric microspheres, Biodegradable polymeric microspheres, Synthetic polymeric microspheres and are prepared by methods like Spray Drying, Solvent Evaporation, Single emulsion technique, Double emulsion technique, Phase separation coacervation technique, Spray drying and spray congealing, Solvent extraction, Quassi emulsion solvent diffusion. Microspheres have wide range of applications because of controlled and sustained release.
Keywords: microspheres, method of preparation, patents, recent advancement, marketing formulation

Full text

Review Article
Microsphere- A Novel Drug Delivery System
Ritu Verma1*, Shubham Verma2, Sokindra Kumar3
1. R V Northland Institute, Dadri, Greater Noida, UP, India
2. Saraswathi College of Pharmacy, Hapur, U.P, India
3. ABESIT College of Pharmacy, Ghaziabad, U.P, India
Introduction
Microspheres may be defined as microspheres
are the substances or compounds which having free
flowing property (powders).Microspheres are consisting
of proteins or synthetic polymers which are biodegradable
in nature and ideally having a particle size from 1-1000μm.
Microspheres are also called as microparticals.
Microsphere can be manufactured by various type of
material such as glass, polymers, and ceramic
microspheres. They are used in different applications,
their use depends on their material and particle size used
in construction. Micro sphere are two types microcapsules
and micrometrics, which are described as, micro-capsules
are those in which entrapped substance is distinctly
surrounded by distinct capsule wall. And micrometrics in
which entrapped substance is dispersed throughout the
matrix (see figure 1). Microsphere plays an important role
to improve bioavailability of conventional drugs and
minimizing side effect [1, 2].
Figure 1. Types of microsphere
Advantage of microspheres
1. Particle size reduction enhances the solubility of the
poorly soluble drug.
2. Microsphere provides constant and prolonged
therapeutic effect.
3. Provide constant drug concentration in blood thereby
increasing patent compliance.
4. Decrease dose and toxicity.
5. Protect the drug from enzymatic and photolytic
cleavage hence found to be best for drug delivery.
6. Reduce the dosing frequency and thereby improve the
patient compliance.
Abstract
Microspheres are characteristically free flowing powders having particle size ranging from
1-1000 μm consisting of proteins or synthetic polymers. Microspheres are used in drug delivery systems which are
prepared to obtain prolonged or controlled drug delivery to improve bioavailability, stability and action at the specific
site to predetermined rate. Microsphere are spherical in shape so, therapeutic efficacy of microspheres containing
drug depends upon their characteristics that can be altered in required terms by altering materials, methods,
polymers or techniques used. These delivery systems offer numerous advantages compared to conventional dosage
forms, which include improved efficacy, reduced toxicity, improved patient compliance and convenience. Microsphere
can be manufactured by various type of material such as glass, polymers, and ceramic microspheres. Microspheres are
various types like Bioadhesive microspheres, Magnetic microspheres, Floating microspheres, radioactive
microspheres, Polymeric microspheres, Biodegradable polymeric microspheres, Synthetic polymeric microspheres and
are prepared by methods like Spray Drying, Solvent Evaporation, Single emulsion technique, Double emulsion
technique, Phase separation coacervation technique, Spray drying and spray congealing, Solvent extraction, Quassi
emulsion solvent diffusion. Microspheres have wide range of applications because of controlled and sustained release.
Keywords: microspheres, method of preparation, patents, recent advancement, marketing formulation
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Research Chronicle in Health Sciences 2019;5(1):5-14
ISSN 2395-552X
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Article History:
Article received: April, 2019; Article revised: May, 2019; Article published: July, 2019
Corresponding Author: Ritu Verma R V Northland Institute, Dadri, Greater Noida, UP, India

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7. Better drug utilization will improve the bioavailability
and reduce the incidence or intensity of adverse
effects.
8. Protects the GIT from irritant effects of the drug.
9. Biodegradable microspheres have the advantage over
large polymer implants in that they do not require
surgical procedures for implantation and removal.
10. Controlled release delivery biodegradable
microspheres are used to control drug release rates
thereby decreasing toxic side effects and also decrease
the problems of repeated injections
11. Taste and odor masking.
12. Conversion of oils and other liquids to solids for easy of
handling.
13. Protection of drugs against the environment
(moisture, light etc.).
14. Improvement of flow of powders.
15. Aid or helps in the dispersion of water-insoluble
substances in aqueous media [3].
Disadvantage of microsphere-
1. The costs of the materials and processing of the
controlled release preparation, are substantially higher
than those of standard formulations.
2. The fate of polymer matrix and its effect on the
environment.
3. The fate of polymer additives such as plasticizers,
stabilizers, antioxidants and fillers.
4. Reproducibility is less.
5. Process conditions like change in temperature, pH,
solvent addition, and evaporation/agitation may
influence the stability of core particles to be
encapsulated.
6. The environmental impact of the degradation
products of the polymer matrix produced in response
to heat, hydrolysis, oxidation, solar radiation or
biological agents [4].
Ideal properties of microspheres-
1. The ability to incorporate reasonably high
concentrations of the drug.
2. Stability of the preparation after synthesis with a
clinically acceptable shelf life.
3. Controlled particle size and dispersability in aqueous
vehicles for injection.
4. Release of active reagent with a good control over a
wide time scale.  Biocompatibility with a controllable
biodegradability.
5. Susceptibility to chemical modification [3].
Benefits of microsphere in drug delivery system
Microspheres are used as controlled drug delivery
systems for a variety of applications including
chemotherapy, cardiovascular disease, hormone therapy,
therapeutic protein delivery, and vaccine development.
Delivery of drugs through biodegradable
microspheres has numerous applications compared to
conventional delivery systems. While in conventional
systems the drug is usually released shortly after delivery
of drug and stops the working after a brief period of time,
biodegradable polymer offers a way to provide sustained
release over a longer time, thus eliminating the need for
multiple doses and ensuring sustained and controlled drug
delivery over weeks or months.
Use of biodegradable polymers minimizes the
possibility of toxicity problems, but does produce by-
products that must be tolerated without adverse
reactions.
Applications of microspheres.
Localized delivery of drug: These are the product can
be implied directly at the site where drug action is
required (needed) and hence, systemic exposure of the
drug can be reduced. This is becomes important especially
for toxic drugs which are related to various systemic side
effects (such as the chemotherapeutic drugs).
Sustained delivery of drugs: The drug in the form of
encapsulated is released over extended periods and
hence, reduce the need for multiple injections. This
feature can improve patient compliance especially for
drugs for chronic indications, requiring frequent injections
(such as for deficiency of certain proteins).
Stabilization of the drug: The polymer can protect the
drug from the physiological environment and hence
improve its stability in vivo. This particular feature makes
this technology attractive for the delivery of labile drugs
such as proteins [3,4].
Types of Microspheres:
1. Bioadhesive microspheres
2. Magnetic microspheres
3. Floating microspheres
4. Radioactive microspheres
5. Polymeric microspheres
i) Biodegradable polymeric microspheres
ii) Synthetic polymeric microspheres
1. Bioadhesive microspheres:
Adhesion can be defined as sticking of drug to the
membrane by using the sticking property of the water-

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soluble polymers. Adhesion of drug delivery device to the
mucosal membrane such as buccal, ocular, rectal, nasal
etc. can be termed as bio adhesion. These kinds of
microspheres shows a prolonged action time at the site
of application and causes intimate contact with the
absorption site and produces better therapeutic
action[5,6].
2. Magnetic microspheres:
This kind of delivery system is very much
important which localises the drug to the disease site. In
this larger amount of freely circulating drug can be
replaced by smaller amount of magnetically targeted
drug. Magnetic carriers receive magnetic responses to a
magnetic field from incorporated materials that are used
for magnetic microspheres are chitosan, dextran etc. The
different types of
a. Therapeutic magnetic microspheres used to deliver
chemotherapeutic agent to liver tumour. Drugs like
proteins and peptides can also be targeted through this
system.
b. Diagnostic microspheres, used for imaging liver
metastases and also can be used to distinguish bowel
loops from other abdominal structures by forming nano
size particles supramagnetic iron oxides[7,8].
3. Floating microspheres:
In floating types the bulk density is less than the
gastric fluid and so remains buoyant in stomach without
affecting gastric emptying rate. The drug is released
slowly at the desired rate, and the system is found to be
floating on gastric content and increases gastric residence
and increases fluctuation in plasma concentration.
Moreover it also reduces chances of dose dumping. It
produces prolonged therapeutic effect and therefore
reduces dosing frequencies. Drug (ketoprofen) is given in
the form of floating microspheres [9,10,11].
4. Radioactive microspheres:
Radio embolization therapy microspheres sized
10-30nm are of larger than the diameter of the capillaries
and gets tapped in first capillary bed when they come
across. They are injected in the arteries that leads them to
tumour of interest so all these conditions radioactive
microspheres deliver high radiation dose to the targeted
areas without damaging the normal surrounding tissues. It
differs from drug delivery system, as radio activity is not
released from microspheres but acts from within a
radioisotope typical distance and the different kinds of
radioactive microspheres are α emitters, β emitters, γ
emitters [12,13].
5. Polymeric microspheres:
The different types of polymeric microspheres
can be classified as follows and they are biodegradable
polymeric microspheres and Synthetic polymeric
microspheres [13].
i) Biodegradable polymeric microspheres:
Natural polymers such as starch are used with the
concept that they are biodegradable, biocompatible, and
also bio adhesive in nature. Biodegradable polymers
prolongs the residence time when contact with mucous
membrane due to its high degree of swelling property
with aqueous medium , results gel formation.The rate and
extent of drug release is controlled by concentration of
polymer and the release pattern ina sustained manner.
The main drawback is, in clinical use drug loading
efficiency of biodegradable microspheres is complex and
is difficult to control the drug release. However they
provide wide range of application in microsphere based
treatment [14].
ii) Synthetic polymeric microspheres:
Synthetic polymeric microspheres are widely used
in clinical application, moreover that also used as bulking
agent, fillers, embolic particles, drug delivery vehicles etc.
and proved to be safe and biocompatible but the main
disadvantage of these kind of microspheres, are tend to
migrate away from injection site and lead to potential risk,
embolism and further organ damage[15].
Method of Preparation
1. Spray Drying
2. Solvent Evaporation
3. Single emulsion technique
4. Double emulsion technique
5. Phase separation coacervation technique
6. Spray drying and spray congealing
7. Solvent extraction
8. Quassi emulsion solvent diffusion [16,17,18].
1. Spray Drying
In Spray Drying technique, firstly the entire
polymer are dissolved in a suitable volatile organic solvent
such as dichloromethane, acetone, etc. and then the drug
in the solid form is dispersed in the polymer solution with
high-speed homogenization. This dispersion is then
atomized in a stream of hot air. The atomization leads to
the formation of the small droplets or the fine mist from
which the solvent evaporates instantaneously leading the

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formation of the microspheres in a size range 1-100μm
(figure 2). Micro particles are separated from the hot air
by means of the cyclone separator while the trace of
solvent is removed by vacuum drying. One of the major
advantages of this process is feasibility of operation under
aseptic conditions.
Figure 2. Spray drying technique
2. Solvent Evaporation:
This process are carried out in vehicles in this the
two phases aqueous and organic phase that process
called as emulsification i.e. o/w type emulsion after this
the solvent evaporate and remains raw nanospheres of
microspheres (figure 3).
Figure 3. Solvent evaporation
3. Single emulsion technique:
In this technique aqueous solution of polymer are
dispersed in organic phase oil/chloroform with continuous
stirring this process called as sonification. After this
microsphere can be prepared by two ways, first heat
denaturation and chemical crosslinking and centrifuge the
product and washing or finally separation to produce
microspheres (figure 4)
Figure 4. Single emulsion method
4. Double emulsion technique:
In this method aqueous solution of polymer and
drug are dispersed in organic phase which produce first
emulsion after addition of aq. Solution of PVA and make
multi emulsion in solution separation, washing and drying
to produce microspheres (figure 5).
Figure 5. Double emulsion method
5. Phase separation coacervation technique;
In this technique aqueous/organic solution of
drug dissolved in polymer solution that forms polymer rich
globules or droplets and Harding in aqueous/organic
phase, separation, of microspheres washing and then
drying to pure form of microspheres (figure 6).

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Figure 6. Phase separation method.
6. Spray drying and spray congealing:
Polymer dissolved in suitable volatile organic
solvent such as acetone, chloroform, etc. dissolved in
polymer solution under high speed homogenization
atomized in stream of hot air and this lead to formation of
small droplets and then solidifying and form of minute
particles (figure 7).
Figure 7. Spray drying and spray congealing.
7. Solvent extraction:
In the solvent extraction polymer and drug must
be soluble in organic solvent which forms a solution that
called aq. Phase and extract this solution with water
missible organic solvent to produce microsphere in
aqueous media (figure 8).
Figure 8. Solvent extraction.
8. Quassi emulsion solvent diffusion:
A novel quasi-emulsion solvent diffusion method
to manufacture the controlled release microspheres of
drugs with acrylic polymers has been reported in the
literature. Microsponges can be manufactured by a quasi-
emulsion solvent diffusion method using an external
phase containing distilled water and polyvinyl alcohol. The
internal phase consists of drug, ethanol and polymer. The
concentration of polymer is in order to enhance plasticity.
At first, the internal phase is manufactured at 60.C and
then added to the external phase at room temperature.
After emulsification process, the mixture is continuously
stirred for 2 hours. Then the mixture can be filtered to
separate the microsponges. The product is then washed
and dried by vacuum oven at 40o C.
Evaluation Parameters of Microsphere
1. Particle size and shape The most widely used
procedures to visualize micro particles are conventional
light microscopy (LM) and scanning electron microscopy
(SEM).
2. Electron spectroscopy for chemical analysis: The
surface chemistry of the microspheres can be determined
using the electron spectroscopy for chemical analysis
(ESCA)[19].
3. Density determination: The density of the
microspheres can be measured by using a multi volume
pycnometer [20].
4. Isoelectric point: The micro electrophoresis is used to
measure the electrophoretic mobility of microspheres
from which the isoelectric point can be determined [21].
5. Angle of contact: The angle of contact is measured to
determine the wetting property of a micro particulate
carrier [22].
6. In vitro methods: Release studies for different type of
microspheres are carried out by using different suitable
dissolution media, mostly by rotating paddle apparatus
(USP / BP) [23].
7. Drug entrapment efficiency: Drug entrapment
efficiency can be calculated using following equation, %
Entrapment = Actual content/Theoretical content x 100.
8. Swelling index: The swelling index of the microsphere
was calculated by using the formula, Swelling index=
(mass of swollen microspheres - mass of dry
microspheres/mass of dried microspheres) [24].

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Application of Microspheres
a. Vaccine delivery
b. Monoclonal antibodies
c. Imaging
d. Topical porous microsphere
e. Nasal drug delivery
f. Oral drug delivery
g. Targeting drug delivery
h. Gastroretentive controlled delivery system
i. Bio-medical application
j. Pharmaceutical application
k. Other applications are given in table no.1.
Table 1. Other applications of microspheres
Category
Drug
Use
Method
Result
NSAID
Acelofenac25
anti-inflammatory
By dissolving drug in
polymer
Controlled release and minimize
local side effect
Antibiotic
Amoxicillin26
Gentamicin27
for helicobacter pylori
infection
eliminating infection
Crosslinking double
emulsion technique
Slow release rate
Controlled release
Anti-
inflammatory
Indomethacin28
Diclofennac29
Ketoprofen30
Anti-inflammatory
………..
………..
Co-matrix method
Coacevation phase
separation
Multiple emulsion o/w/o
Decrease in release rate
Suppress the release rate
Modulate drug release
Cardiac agent
Nifedipine31,32
Propanolol31,32
Dilitazam33
Calcium channel blockers
…….
Calcium channel blockers
Encapsulation
Emulsification
coacevation technique
Controlled coacevation
technique
More drug entrapment efficiency
Enhance drug encapsulation
efficiency
Retard drug release
Steroidal
Progesterone34
Steroid
Crosslinking
Maintain plasma drug
concentration
Antidiabatic
agent
Insulin35
Antihyperglycemic
…..
Improve systemic absorption
Diuretics
Furosemide36
Diuretic
Crosslinking
Reduce affect of external
variables
Anticancer
Fluoroucil37
Cisplatin38
Mitoxantrone
Oxantrazol
For targeted delivery to treat
cerebral tumors
Antitumors activity
Antitumor
anticancer
Dry-in-oil
w/o emulsion system
crosslinking technique
combined emulsion
Slow down of release rate of
drug
Reduse release rate
Minimize drug toxicity &
minimize therapeutic efficacy
Enhance the delivery of drug in
brain 100 times
Marketed formulation of microspheres: marketing formulation are given in table No.2
Table 2. Marketing formulation.
SN
Brand name
Drug
company
Treatment
Ref.
1
Protonix
Pantoprazole
Wyeth pharmaceutical inc..
Germany
Gastric ulcer
51
2
Lumason
Sulfur hexafluoride lipid
microsphere
Bracco Diagnostics Inc
Diagnosis and Investigation
52
3
Altinac, Atralin,
Avita, etc
Tretinoin
Janssen cilag pharmaceuticals
inc..
Skin renew
53
4
Definity
Perflutren Lipid Microsphere
Ultrasound
54
5
Bellafill
dermal filler
Suneva Medical Inc.
Correction of Nasolabial Folds and
Acne Scars
55
6
Optison
human albumin microspheres
GE healthcare as oslo, norway
ultrasound imaging procedures
56
7
Zilretta
Triamcinolone Acetonid
Flexion therapeutic inc.
inflammatory conditions(knee pain
e.t.c)
57
Patent of microsphere: patent of microsphere are given in table no.3.

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Table 3. Patent of microspheres.
Patent
no.
Filed
Date of
patent
inventor
Work
Ref.
10195149
May 15,
2014
February
5,2019
Yi Mi Kim, Sun Kyung Lim, Mi
Ran Park, Young Joon Park,
Seung Hee Baek, Hyun Woo
Shin
The present invention relates to a continuous process
for preparing microspheres and microspheres
prepared thereby, and in particular, a process for
preparing microspheres
39
10201633
December
7, 2015
February
12,2019
Paul M.Weinberger, William
D. Hill,George G Wicks
Glass composites for tissue augmentation,biomedical
and cosmetic applications
40
9050843
June 9,2015
June 30,
2008
Franciscus gerardus henricus
duijnhoven van, franciscus
wilhemus maria gelissen,
Microsphere comprising a polymer core, a shell and
an absorber
41
9944778
April
17,2018
October 16,
2013
Franciscus Wilhelmus Maria
Gelissen, Franciscus Gerardus
Henricus Van Duijnhoven
The present invention relates to microspheres and to
their use, preferably as laser absorbing additive, and
to a process for their production.
42
5017378
May 21,
1991
May 1,1989
Terry L. Turner, Stuart S.
Howards
Intraorgan injection of biologically active compounds
contained in slow-release microcapsules or
microspheres
43
7931918
April 26,
2011
July 2, 2008
Barbara Pui Chan, Ming
Cheuk Chan, Kwok Fai So.
Collagen-based microspheres and methods of
preparation and uses.
44
8338428
December
25, 2012
March 15,
2012
Josiah Brown
Methods for administering aripiprazole
45
8334013
December
18, 2012
November
3, 2008
Dimiter N Petsev, Erin
Derbins, Sergio Mendez,
Shailendra Rathod, Nick
Carroll, David A. Weitz
Mesoporous metal oxide microspheres and method
for forming same
46
8728817
May 20,
2014
March 10,
2011
Roy Clinton Ogle, Edward A.
Botchwey, III, Rebekah A.
Neal
Compositions and methods for making and using
laminin nanofibers
47
4452773
June 5,
1984
April 5,
1982
Robert S. Molday
Magnetic iron-dextran microspheres
48
7879304
February 1,
2011
January 16,
2008
Timothy L Ward, Jaime
Bravo, Abhaya Datye, Gabriel
Lopez, Hien Pham,
Shailendra Rathod, Venkata
Goparaju
Monodisperse mesoporous silica microspheres
formed by evaporation-induced self-assembly of
surfactant templates in aerosols
.49
6991779
January 31,
2006
January 17,
2003
Solomon S. Steiner, Cohava
Gelber, Robert S. Feldstein,
Roderike Pohl
Compositions for treatment or prevention of
bioterrorism
50
Recent advancements of microspheres: Recent advancements of microspheres are given in Table No.4.
Table no. 4. Recent advancements of microspheres.
SN
Author
Recent work
Year
Reference
1
Zhang T, Sun W, Xue J, Chen J, Jiang Q, Mou
L, Du H.
Podocytic infolding glomerulopathy (PIG) is a newly
proposed disease
march
2019
58
2
Lu D, Li J, Lin C, Liao J, Feng Y, Ding Z, Li Z,
Liu Q, Li H.
Microspheres, A High Performance Catalyst to Hydrolyze
Ammonia Borane for Hydrogen Production.
march
2019
59
3
Braat AJAT, Kappadath SC, Ahmadzadehfar
H, Stothers CL, Frilling A, Deroose CM,
Flamen P, Brown DB, Sze DY, Mahvash A,
Lam MGEH.
Radioembolization with Y Resin Microspheres of
Neuroendocrine Liver Metastases
March
2019
60
4
Pan SD, Chen XH, Shen HY, Li XP, Cai MQ,
Zhao YG, Jin MC
Rapid and effective sample cleanup based on graphene
oxide-encapsulated core-shell magnetic microspheres for
determination.
2019
61
5
Bastiaannet R, Kappadath SC, Kunnen B,
Braat AJAT, Lam MGEH, de Jong HWAM.
The physics of radioembolization.
2018
62

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6
Baltatzis M, Siriwardena AK.
Liver Resection for Colorectal Hepatic Metastases after
Systemic Chemotherapy and Selective Internal Radiation
Therapy with Yttrium-90 Microspheres
2018
63
7
Delicque J, Guiu B, Boulin M, Schwanz H,
Piron L, Cassinotto C.
Liver chemo-embolization of hepatocellular carcinoma
using TANDEM microspheres
2018
64
8
Thakur S, Riyaz B, Patil A, Kaur A, Kapoor B,
Mishra V.
Novel drug delivery systems for NSAIDs in management
of rheumatoid arthritis
2018
65
9
Zemánek J, Michálek T, Hurák Z.
Phase-shift feedback control for dielectrophoretic
micromanipulation.
2018
66
10
Wong CY, Al-Salami H, Dass CR.
Microparticles, microcapsules and microspheres: A
review of recent developments and prospects for oral
delivery of insulin.
2018
67
Conclusion
The concept of microsphere drug delivery
systems offers certain advantages over the conventional
drug delivery systems such as controlled and sustained
delivery. As well as microspheres also allow drug targeting
to various systems such as ocular , intranasal , oral and IV
route . Novel technologies like magnetic microspheres,
immune-microspheres offer great advantages and uses
than conventional technologies. Marketing preparation
such as protonix, zilretta, lumson, definity etc. are famous
preparation, therefore microsphere are offers great
affinity to the preparation to make them efficient and
enhance the therapeutic effect.
Acknowledgement
Authors are highly thankful to Department of
Pharmacy, R V Northland Institute, Dadri, Greater Noida, G
B Nagar, India for proving library facility during my
literature survey.
Conflict of interest:
There are no conflict of interest.
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How to cite: Verma R, Verma S, Kumar S. Microsphere- A Novel Drug Delivery System.
Research Chronicle in Health Sciences 2019;5(1):5-14.