Divya Rani Golla
(M.Pharmacy 2nd semester),
DEPARTMENT OF INDUSTRIAL PHARMACY,
UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES,
KAKATIYA UNIVERSITY, WARANGAL.
• Polymers used for microspheres preparation
• Prerequisites for ideal microparticulate carriers
• General methods of preparation
• Release pattern of drug
• Advantages and disadvantages
• Magnetic microspheres
The goal of any drug delivery system is to provide a
therapeutic amount of drug to the proper site in the body
and then maintain the desired drug concentration.
A well designed controlled drug delivery system can
overcome some of the problems of conventional therapy and
enhance the therapeutic efficacy of a given drug.
There are various approaches in delivering a therapeutic
substance to the target site in a sustained controlled release
fashion. One such approach is using microspheres as carriers
• 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 200 μm.
• This is the important approach in delivering therapeutic
substance to the target site in sustained and controlled release
Prerequisites for Ideal Microparticulate Carriers
Longer duration of action
Control of content release
Increase of therapeutic efficacy
Protection of drug
Reduction of toxicity
Water solubility or dispersibility
METHODS OF PREPARATION
A. Solvent evaporation method
i. -Single Emulsion technique
ii. -Double emulsion technique
B. Polymerization techniques
i. Normal polymerization
o Bulk polymerization
o Suspension polymerization
o Emulsion polymerization
ii. Interfacial polymerization
C. Coacervation phase separation techniques
D. Spray drying and spray congealing
E. Solvent extraction
I. Single emulsion technique
Dispersion in organic phase
Chemical Cross linking/heat denaturation
nsion of polymer
ii. Double emulsion technique
Aq.Solution of protein/polymer
Dispersion in oil/organic phase
First emulsion (W/O)
Addition of aq. Solution of PVA
Addition to large aq. Phase
Microspheres in solution
Separation, Washing, Drying
B. Polymerization Techniques
i. Normal Polymerization
Normal Polymerization is done by bulk, suspension, precipitation, emulsion and
miceller polymerization process.
Polymerization Polymer block
SCHEMATIC REPRESENTATION FOR BULK POLYMERIZATION
SCHEMATIC REPRESENTATION OF SUSPENSION
Monomer Bioactive material Initiator
Dispersion in water and stabilizer
Separation and drying
SCHEMATIC REPRESENTATION OF EMULSION
Aq. Sol’n of NaOH
+ surfactant above
Micellar solution of polymer in
ii. INTERFACIAL POLYMERIZATION TECHNIQUE
It involves the reaction of various monomers at interface
between the two immiscible liquid phases to form a film of
In this technique two reacting monomers are employed ,one
of which is dissolved in the continuous phase while other
being dispersed in continuous phase.
The continuous phase is aqueous in nature throughout which
the second monomer is emulsified.
The monomers present in either phases diffuse rapidly at the
If the polymer is soluble in droplet it will lead to the
formation of the monolithic type of carrier.
If the polymer is insoluble in monomer droplet, the formed
carrier is of capsular.
D. PHASE SEPARATION COASERVATION
E. SPRAY DRYING
Change in pH
Removal of solvent
D. Phase separation E. Spray drying
F. Solvent Extraction
Drug is dispersed in organic solvent
(water miscible organic solvent such as Isopropanol)
Polymer in organic solvent
Organic phase is removed by extraction with
(This process decreasing hardening time for microspheres)
1. Controlled release delivery Biodegradable microspheres are used to
control drug release rates there by decreasing toxic side effects, and
eliminating the inconvenience of repeated injections.
2. Biodegradable microspheres have the advantage over large polymer
implants in that they do not require surgical procedures for implantation
3. Taste and odor masking.
4. Conversion of oils and other liquids to solids for ease of handling
5. Improvement of flow of powders.
6. They provide protection for unstable drug before and after administration,
prior to their availability at the site of action.
7. They enable controlled release of drug.
Ex: narcotic antagonist, steroid hormones.
1. Significant initial burst and unpredictable release in certain
2. The phagocytises of carriers, rapid clearance are common
ROUTES OF ADMINISTRATION
Release Profile Of Microspheres
The release profile from microspheres depends on nature of
the polymer used in the preparation and nature of the active
Drugs could be released through microspheres by any one of
the 3 methods :
1. Osmotically driven burst mechanism
2. Pore diffusion mechanism
3. Erosion or degradation of polymer.
1. Osmotically driven burst mechanism :Water diffuses into the
core through biodegradable or non-biodegradable coating,
creating sufficient pressure that ruptures the membrane.
2. Pore diffusion method : Here penetrating water front continue
to diffuse towards the core.
The dispersed drug/protein dissolves creating a water filled
pore network and diffuses out in controlled manner
3. Erosion of polymer : It begins with changes in the micro
structure of carrier as water penetrates within it leading to
plasticization of matrix. Plasticization leads to cleavage of
Vaccine delivery – Improved antigenecity, Antigen release,
Stabilization of Antigen.
• Ocular: gelation with increased residence time
• Intranasal: protein and peptide delivery
Surface modified microspheres
Definition : Magnetic microspheres are supramolecular particles that
are small enough to circulate through capillaries without producing
embolic occlusion (<4μm) but are sufficiently
susceptible(ferromagnetic) to be captured in micro vessels and
dragged in to the adjacent tissues by magnetic field of 0.5 to 0.8
Magnetic drug delivery by particulate carriers is a very efficient
method of delivering a drug to a localized disease site.
Magnetic microspheres developed to overcome two major problems
encountered in drug targeting namely:
I. To decrease RES clearance and
II. Increase target site specificity.
CONCEPT BEHIND MAGNETIC
Drug targeting is a specific form of drug delivery where the
drug is directed to its site of action or absorption.
A drug or therapeutic radioisotope is encapsulated in a
magnetic compound, injected into patient’s blood stream
through large arteries & then stopped with a powerful
magnetic field in the target area (systemic and magnetic
drug delivery shown in fig).
Depending on the type of drug, it is then slowly released
from magnetic carriers and gives a local effect, thus it
reduces the loss of drug as freely circulating in body.
Representation of systemic drug
delivery and magnetic taargeting.
Magnetic drug targeting
When the microspheres are first pushed against the endothelial cells
by the magnetic field, an endocytic response was triggered with
continuous magnetic influence over certain period of time.
Microspheres migrated from endothelial cells into the interstitial
compartment and formed a depot for sustained release over an
extended period of time.
• It is also called as ferric ferrous oxide , Tri iron tetra oxide ,
and black iron oxide
• A ferromagnetic material when incorporated into
microspheres makes them magnetically responsive so that
they can be concentrated to the desired site by applying
some external magnetic field.
• Iron is strong ferromagnetic material but due to its local
tissue irritation and other toxic manifestation it cannot be
included into microspheres.
• But such a problem is not seen when magnetite which is
chemically ferrous ferric oxide (Fe3O4) biologically
compatible and also its ultra fine particle size makes it
Principle of magnetic drug targeting
SELECTION OF DRUGS
In the selection of drug for the formulation of magnetic
microspheres, following points are to be taken into
1. The drug is so dangerous or labile that we cannot allow it to
circulate freely in the blood stream.
2. The agent is so expensive, that we cannot afford to waste
99.9% of it.
3. Requires a selective, regional effect to meet localized
4. Requires an alternative formulation essential to continue
treatment in patient whose systemic therapy must be
temporarily discontinued due to life threatening toxicity
directed at selective organs.
Increased duration of action.
First pass effect can be avoided.
Improved protein and peptide drug delivery.
They enable controlled release of drug.
Ex: narcotic antagonist, steroid hormones.
Ability to bind and release high concentration of drugs.
Patient compliance is good.
Method of preparations is simple.
Can be injected into the body using hypodermic needle.
Difference occurs maximally in capillary network so efficient delivery of
drug to diseased tissue is achieved.
Linear blood velocity in capillaries is 300 times less as compared to
arteries, so much smaller magnetic field is sufficient to retain them in the
capillary network of the target area.
1. Major limitation : Drug cannot be targeted to deep-seated
organism in the body.
2. Unknown toxicity of magnetic beads.
3. A large fraction(40-60%) of the magnetite, which is
entrapped in carriers, is deposited permanently in tissues.
4. It is an expensive, technical approach and requires
specialized manufacture and quality control system.
5. It needs specialized magnet for targeting, advanced
techniques for monitoring, and trained personnel to perform
Due to these limitations magnetic drug targeting is likely to be
approved only for severe diseases.
METHOD OF PREPARATION
Magnetically responsive microspheres can be prepared
by using albumin as a carrier of drug and magnetite.
Size of microspheres is kept between 1-2 μm, so that
they can be injected into blood vessels without problem
Prepared mainly by two methods:
I. Continuous solvent evaporation (CSE)
II. Phase separation emulsion polymerization(PSEP)
I. Continuous solvent evaporation method
Drug + Polymer + Magnetite
Dissolved in volatile organic solvent
Forms Homogeneous suspension known as
Volatile organic solvent evaporated at
Freeze dried &
Stored at 4° C
II. Phase separation emulsion polymerization
Drug + Polymer +
Drug + Polymer +
Temp: 100 – 150°C
Add cross linking agent drop wise to above emulsion
Stored at 4°C
It helps to design a suitable carrier for the proteins, drug and antigen
1. Particle size and shape: Conventional light microscopy(LM),
Scanning electron microscopy(SEM), Confocal laser scanning
microscopy(CLSM), Confocal fluorescence microscopy, Laser
light scattering and Multisize coulter counter.
2. Electron spectroscopy for chemical analysis(EMCA): Surface
chemistry of microspheres , Atomic composition, Surface
degradation of biodegradable microspheres.
3. Attenuated total reflectance Fourier transform-infrared
spectroscopy(ATR-FTIR): degradation of polymeric matrix of
the carrier system and surface composition.
4. Density determination: Multivolume pichnometer.
5. Flow properties: Angle of repose, Hausner ratio.
6. Isoelectric point : Micro electrophoresis apparatus.
7. Capture efficiency or drug entrapment capacity :
% Entrapment = ×100
7. Release studies : in phosphate saline buffer of pH7.4
a) Rotating paddle apparatus &
b) Dialysis method.
Rotating paddle apparatus : sample agitated at 100rpm,
samples are taken out at specific time intervals and replaced
by same amount of saline.
The api is analyzed as per monograph.
Dialysis method: The microspheres are kept in a dialysing bag or
tube with membrane, the dialysing media is continuously
stirred and samples of dialysate are taken estimated for drug
content & Replaced with fresh buffer.
8. Angle of contact: wetting property is determined.
9. Determination of drug content: UV visible spectrophotometer.
10. Determination of solubility :
• Take excess quantity of microspheres in 50ml vials filled with
• Shake the vials on a magnetic stirrer.
• Filter the solution through whatmann paper no.1 and drug
concentration determined at particular λ max value for
They have wide application in the field of bio-medicine, bio
engineering, biological and biomedical developments.
It is used in enzyme immobilization, cell isolation, protein
purification and targeted drugs.
Drug discovery, molecular targeting, and undergoing the
pathway of cell cycle regulation.
High throughput DNA isolation.
They can be used for stem cell extraction.
It is used as chemotherapeutic agent.
Magnetic vehicles are used for delivery of therapeutic agent as
they can be targeted to specific location in the body through
the application of magnetic field.
Over the years, microspheres and magnetic microspheres
have been investigated for targeted drug delivery especially
magnetic targeted chemotherapy due to their better tumor
targeting. Targeted Drug delivery is an effective method to assist
the drug molecule to reach preferably to the desired site. The main
advantage of this technique is the reduction in the dose & side
effects of the drug.
It is a challenging area for future research in the drug
targeting so more researches, long term toxicity study, and
characterization will ensure the improvement of magnetic drug
delivery system. The future holds lot of promises in magnetic
microspheres and by further study this will be developed as novel
and efficient approach for targeted drug delivery system
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Salim Md, Magnetic microspheres as a magnetically targeted drug
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Satinder kakar, A review on target drug delivery: Magnetic microspheres,
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