The document discusses magnetic microspheres, which are microparticles that can be guided to target sites in the body using external magnetic fields. They are typically made of polymers and magnetite. Methods for producing them include solvent evaporation and phase separation emulsion polymerization. Magnetic microspheres offer advantages like controlled drug release and reduced toxicity. They can be used to deliver drugs, vaccines, and antigens to specific areas for localized treatment. Characterization techniques evaluate their size, shape, composition and drug release profiles. Magnetic targeting allows microspheres to accumulate drugs at disease sites while avoiding uptake by the reticuloendothelial system.

1. MICROSPHERES-MAGNETIC MICROSPHERES
By:
Divya Rani Golla
(M.Pharmacy 2nd semester),
DEPARTMENT OF INDUSTRIAL PHARMACY,
UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES,
KAKATIYA UNIVERSITY, WARANGAL.

2. CONTENTS
• Introduction
• Polymers used for microspheres preparation
• Prerequisites for ideal microparticulate carriers
• General methods of preparation
• Release pattern of drug
• Advantages and disadvantages
• Applications
• Magnetic microspheres
• Characterization
• Conclusion
• References
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3. INTRODUCTION
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
for drugs.
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4. DEFINITION
• 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
fashion.
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5. 6/24/2014 5

6. POLYMERS USED IN THE MICROSPHERE
PREPARATION
 Synthetic Polymers
• Non-biodegradable
Acrolein
PMMA
Glycidyl methacrylate
Epoxy polymers
• Biodegradable
Lactides and Glycolides
copolymers
Polyalkyl cyanoacrylates
Polyanhydrides
Natural Materials
• Proteins
Albumins
Gelatin
Collagen
• Carbohydrates
Starch
agarose
Carrageenan
Chitosan
• Chemically modified carbohydrates
Poly (acryl) dextran
DEAE cellulose
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7. Prerequisites for Ideal Microparticulate Carriers
 Longer duration of action
 Control of content release
 Increase of therapeutic efficacy
 Protection of drug
 Reduction of toxicity
 Biocompatibility
 Sterilizability
 Relative stability
 Bioreabsorbability
 Water solubility or dispersibility
 Targetability
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 Polyvalent

8. 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
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9. I. Single emulsion technique
Aqueous
sol’n/suspension
of polymer
Dispersion in organic phase
Oil/CHCl3
Chemical Cross linking/heat denaturation
{Gluteraldehyde/
formaldehyde/butanol}
Aq.solution/suspe
nsion of polymer
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10. ii. Double emulsion technique
Aq.Solution of protein/polymer
Dispersion in oil/organic phase
Homogenization
First emulsion (W/O)
Addition of aq. Solution of PVA
Multiple emulsion
Addition to large aq. Phase
Denaturation/hardening
Microspheres in solution
Separation, Washing, Drying
MICROSPHERES
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11. B. Polymerization Techniques
i. Normal Polymerization
 Normal Polymerization is done by bulk, suspension, precipitation, emulsion and
miceller polymerization process.
Monomer +
bioactive
material +
initiator
Polymerization Polymer block
Mould/Mechanical
fragmentation
Microspheres
SCHEMATIC REPRESENTATION FOR BULK POLYMERIZATION
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Drug loading

12. SCHEMATIC REPRESENTATION OF SUSPENSION
POLYMERIZATION
Monomer Bioactive material Initiator
Dispersion in water and stabilizer
•Vigorous agitation
•Heat/radiation
Polymerization
DROPLETS
Separation and drying
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Microspheres

13. SCHEMATIC REPRESENTATION OF EMULSION
POLYMERIZATION
Microspheres
MONOMER AND
BIOACTIVE
MATERIAL
Aq. Sol’n of NaOH
+ initiator
+ surfactant above
CMC stabilizer
Micellar solution of polymer in
aq.medium
Polymerization
Separation
Washing &
Drying
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14. ii. INTERFACIAL POLYMERIZATION TECHNIQUE
 It involves the reaction of various monomers at interface
between the two immiscible liquid phases to form a film of
polymer.
 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
interface.
 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.
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15. D. PHASE SEPARATION COASERVATION
E. SPRAY DRYING
Salt addition
Non-solvent addition
Addition of
incompatible polymer
Change in pH
Removal of solvent
D. Phase separation E. Spray drying
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16. 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
water
(This process decreasing hardening time for microspheres)
Microspheres
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17. Advantages
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
and removal.
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.
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18. Disadvantages
1. Significant initial burst and unpredictable release in certain
cases.
2. The phagocytises of carriers, rapid clearance are common
disadvantage.
ROUTES OF ADMINISTRATION
Oral delivery
Parenteral delivery
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19. Release Profile Of Microspheres
 The release profile from microspheres depends on nature of
the polymer used in the preparation and nature of the active
drug.
 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.
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20. 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
hydrolytic bonds.
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21. APPLICATIONS
Vaccine delivery – Improved antigenecity, Antigen release,
Stabilization of Antigen.
Drug targeting
• Ocular: gelation with increased residence time
• Intranasal: protein and peptide delivery
• Oral
Magnetic microspheres
Immunomicrospheres
Chemoembolization
Imaging
Microsponges
Surface modified microspheres
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22. MAGNETIC 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
tesla.
 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.
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23. CONCEPT BEHIND MAGNETIC
TARGETING
 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.
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24. Representation of systemic drug
delivery and magnetic taargeting.
Magnetic drug targeting
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25.  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.
Endothelial cell
Microspheres
• Microspheres
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26. Magnetic microspheres
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27. • 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
suitable material.
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28. little access
Major pathway
Major pathway
little access
Principle of magnetic drug targeting
Target tissue
RES Organs
RES Organs
(liver/spleen/bone
(liver/spleen/bone
marrow)
marrow)
Phagocytosis
Phagocytosis
N
Target tissue
RES Organs
(liver/spleen/bone
marrow)
Drug/Carrier
Target tissue
Target tissue
S
RES Organs
(liver/spleen/bone
marrow)
Magnetic
Drug/Carrier
Circulation
Circulation
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29. SELECTION OF DRUGS
In the selection of drug for the formulation of magnetic
microspheres, following points are to be taken into
consideration :
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
therapeutic objective.
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.
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30. ADVANTAGES
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.
Reduce toxicity.
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.
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31. DISADVANTAGES
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
procedures.
Due to these limitations magnetic drug targeting is likely to be
approved only for severe diseases.
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32. 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
of thrombo-embolism.
Prepared mainly by two methods:
I. Continuous solvent evaporation (CSE)
II. Phase separation emulsion polymerization(PSEP)
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33. I. Continuous solvent evaporation method
Drug + Polymer + Magnetite
Dissolved in volatile organic solvent
STIRRING
Forms Homogeneous suspension known as
auxiliary solution
Volatile organic solvent evaporated at
22-30° C
Centrifugation
Microspheres
Freeze dried &
Stored at 4° C
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34. II. Phase separation emulsion polymerization
Drug + Polymer +
Drug + Polymer +
Magnetite
Vegetable oil
Emulsification by
magnetic stirrer
o15,000 rpm
o2 minutes
Temp: 100 – 150°C
Magnetite
Add cross linking agent drop wise to above emulsion
Washed
Freeze dried
Stored at 4°C
Stabilization
Vegetable oil
Droplets hardening
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Microspheres

35. CHARACTERIZATION
It helps to design a suitable carrier for the proteins, drug and antigen
delivery.
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.
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36. 6. Isoelectric point : Micro electrophoresis apparatus.
7. Capture efficiency or drug entrapment capacity :
Actual content
Theoretical content
% 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.
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37. 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
water.
• 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
particular drug.
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38. MARKETED PRODUCTS
TRADE NAME INCI NAME
EA-209 Ethylene/acrylic acid copolymer
Flo- beads SE-3107A(soft
beads A)
Ethylene /Methacrylate copolymer
Flo- beads SE-3107B(soft
beads B)
Ethylene /Methacrylate copolymer
BPD-800
BPD-500
BPD-500T
HDl/trimethylol hexyllactyl cross polymer (AND
silica)
BPA-500
MSP-822
Polymethyl Metharylate
BPA-500X
MSP-825
MSP-930
SUNPMMA-H
Methyl Methacrylate cross polymer
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39. APPLICATIONS
 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.
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40. CONCLUSION
 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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41. REFERENCES
 Vyas S.P, Khar R.K, Targeted & Controlled Drug Delivery novel
carrier systems, CBS Publishers & Distributers, first edition(2002)
pp:417-425, 441-444, 460.
 Jain N K, Controlled and novel drug delivery, CBS publishers &
Distributers, first edition,2002, pp: 236-237.
 Alagusundaram.M, Microspheres as a novel drug delivery system,
International Journal of ChemTech Research, ISSN : 0974-4290,
Vol.1, No.3 , pp 526-534,date : july 2009.
 Mukherjee S, Magnetic microspheres a latest approach in novel drug
delivery system, Journal of pharmaceutical and scientific innovation,
date: 04/01/2012.
 Salim Md, Magnetic microspheres as a magnetically targeted drug
delivery system, Journal of global pharma technology, ISSN0975-8542.
 Satinder kakar, A review on target drug delivery: Magnetic microspheres,
Journal of acute disease, date: 30/04/2013.
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