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MICROSPHERES-MAGNETIC MICROSPHERES 
By: 
Divya Rani Golla 
(M.Pharmacy 2nd semester), 
DEPARTMENT OF INDUSTRIAL PHARMACY, ...
CONTENTS 
• Introduction 
• Polymers used for microspheres preparation 
• Prerequisites for ideal microparticulate carrier...
INTRODUCTION 
The goal of any drug delivery system is to provide a 
therapeutic amount of drug to the proper site in the b...
DEFINITION 
• Microspheres are characteristically free flowing powders 
consisting of proteins or synthetic polymers which...
6/24/2014 5
POLYMERS USED IN THE MICROSPHERE 
PREPARATION 
 Synthetic Polymers 
• Non-biodegradable 
Acrolein 
PMMA 
Glycidyl methacr...
Prerequisites for Ideal Microparticulate Carriers 
 Longer duration of action 
 Control of content release 
 Increase o...
METHODS OF PREPARATION 
A. Solvent evaporation method 
i. -Single Emulsion technique 
ii. -Double emulsion technique 
B. P...
I. Single emulsion technique 
Aqueous 
sol’n/suspension 
of polymer 
Dispersion in organic phase 
Oil/CHCl3 
Chemical Cros...
ii. Double emulsion technique 
Aq.Solution of protein/polymer 
Dispersion in oil/organic phase 
Homogenization 
First emul...
B. Polymerization Techniques 
i. Normal Polymerization 
 Normal Polymerization is done by bulk, suspension, precipitation...
SCHEMATIC REPRESENTATION OF SUSPENSION 
POLYMERIZATION 
Monomer Bioactive material Initiator 
Dispersion in water and stab...
SCHEMATIC REPRESENTATION OF EMULSION 
POLYMERIZATION 
Microspheres 
MONOMER AND 
BIOACTIVE 
MATERIAL 
Aq. Sol’n of NaOH 
+...
ii. INTERFACIAL POLYMERIZATION TECHNIQUE 
 It involves the reaction of various monomers at interface 
between the two imm...
D. PHASE SEPARATION COASERVATION 
E. SPRAY DRYING 
Salt addition 
Non-solvent addition 
Addition of 
incompatible polym...
F. Solvent Extraction 
Drug is dispersed in organic solvent 
(water miscible organic solvent such as Isopropanol) 
Polymer...
Advantages 
1. Controlled release delivery Biodegradable microspheres are used to 
control drug release rates there by dec...
Disadvantages 
1. Significant initial burst and unpredictable release in certain 
cases. 
2. The phagocytises of carriers,...
Release Profile Of Microspheres 
 The release profile from microspheres depends on nature of 
the polymer used in the pre...
1. Osmotically driven burst mechanism :Water diffuses into the 
core through biodegradable or non-biodegradable coating, 
...
APPLICATIONS 
Vaccine delivery – Improved antigenecity, Antigen release, 
Stabilization of Antigen. 
Drug targeting 
• Ocu...
MAGNETIC MICROSPHERES 
 Definition : Magnetic microspheres are supramolecular particles that 
are small enough to circula...
CONCEPT BEHIND MAGNETIC 
TARGETING 
 Drug targeting is a specific form of drug delivery where the 
drug is directed to it...
Representation of systemic drug 
delivery and magnetic taargeting. 
Magnetic drug targeting 
6/24/2014 24
 When the microspheres are first pushed against the endothelial cells 
by the magnetic field, an endocytic response was t...
Magnetic microspheres 
6/24/2014 26
• It is also called as ferric ferrous oxide , Tri iron tetra oxide , 
and black iron oxide 
• A ferromagnetic material whe...
little access 
Major pathway 
Major pathway 
little access 
Principle of magnetic drug targeting 
Target tissue 
RES Organ...
SELECTION OF DRUGS 
In the selection of drug for the formulation of magnetic 
microspheres, following points are to be tak...
ADVANTAGES 
Increased duration of action. 
First pass effect can be avoided. 
Improved protein and peptide drug delivery. ...
DISADVANTAGES 
1. Major limitation : Drug cannot be targeted to deep-seated 
organism in the body. 
2. Unknown toxicity of...
METHOD OF PREPARATION 
 Magnetically responsive microspheres can be prepared 
by using albumin as a carrier of drug and m...
I. Continuous solvent evaporation method 
Drug + Polymer + Magnetite 
Dissolved in volatile organic solvent 
STIRRING 
For...
II. Phase separation emulsion polymerization 
Drug + Polymer + 
Drug + Polymer + 
Magnetite 
Vegetable oil 
Emulsification...
CHARACTERIZATION 
It helps to design a suitable carrier for the proteins, drug and antigen 
delivery. 
1. Particle size an...
6. Isoelectric point : Micro electrophoresis apparatus. 
7. Capture efficiency or drug entrapment capacity : 
Actual conte...
8. Angle of contact: wetting property is determined. 
9. Determination of drug content: UV visible spectrophotometer. 
10....
MARKETED PRODUCTS 
TRADE NAME INCI NAME 
EA-209 Ethylene/acrylic acid copolymer 
Flo- beads SE-3107A(soft 
beads A) 
Ethyl...
APPLICATIONS 
 They have wide application in the field of bio-medicine, bio 
engineering, biological and biomedical devel...
CONCLUSION 
 Over the years, microspheres and magnetic microspheres 
have been investigated for targeted drug delivery es...
REFERENCES 
 Vyas S.P, Khar R.K, Targeted & Controlled Drug Delivery novel 
carrier systems, CBS Publishers & Distributer...
6/24/2014 42
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Microspheres-Magnetic microspheres

  1. 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. 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 6/24/2014 2
  3. 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. 6/24/2014 3
  4. 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. 6/24/2014 4
  5. 5. 6/24/2014 5
  6. 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 6/24/2014 Poly(acryl)starch 6
  7. 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 6/24/2014 7  Polyvalent
  8. 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 6/24/2014 8
  9. 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 6/24/2014 9
  10. 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 6/24/2014 10
  11. 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 6/24/2014 Drug loading
  12. 12. SCHEMATIC REPRESENTATION OF SUSPENSION POLYMERIZATION Monomer Bioactive material Initiator Dispersion in water and stabilizer •Vigorous agitation •Heat/radiation Polymerization DROPLETS Separation and drying 6/24/2014 Microspheres
  13. 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 6/24/2014 13
  14. 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. 6/24/2014 14
  15. 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 6/24/2014 15
  16. 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 6/24/2014 16
  17. 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. 6/24/2014 17
  18. 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 6/24/2014 18
  19. 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. 6/24/2014 19
  20. 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. 6/24/2014 20
  21. 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 6/24/2014 21
  22. 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. 6/24/2014 22
  23. 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. 6/24/2014 23
  24. 24. Representation of systemic drug delivery and magnetic taargeting. Magnetic drug targeting 6/24/2014 24
  25. 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 6/24/2014 25
  26. 26. Magnetic microspheres 6/24/2014 26
  27. 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. 6/24/2014 27
  28. 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 6/24/2014 28
  29. 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. 6/24/2014 29
  30. 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. 6/24/2014 30
  31. 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. 6/24/2014 31
  32. 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) 6/24/2014 32
  33. 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 6/24/2014 33
  34. 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 6/24/2014 34 Microspheres
  35. 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. 6/24/2014 35
  36. 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. 6/24/2014 36
  37. 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. 6/24/2014 37
  38. 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 6/24/2014 38
  39. 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. 6/24/2014 39
  40. 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 6/24/2014 40
  41. 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. 6/24/2014 41
  42. 42. 6/24/2014 42

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