1. FORMULATION AND EVALUATION OF MICROSPHERES
PRESENTED BY
GEETHA.R
M.PHARM
II - SEMISTER
DEPARTMENT OF PHARMACEUTICS
UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCE
KAKATIYA UNIVERSITY, WARANGAL .

2. CONTENTS INTRODUCTION CLASSIFICATION OF POLYMERS.
METHODS OF PREPARATION.
CHARACTERIZATION.
APPLICATIONS.
CONCLUSION.
REFERENCES

3. INTRODUCTION POWDERS AND GRANULATES
Free-flowing powders and granulates are needed for a variety of industrial processes. These, however, do not always meet the exacting standards which modern manufacturing demands of them, due to their varying grain size distribution and odd shapes.
These properties are detrimental to efficient processing and lead to agglomeration, inexact dosage, abrading with loss of material, or low reproducibility of castings.
Pharmaceutical applications require highly reproducible dosage and the controlled release of active agents, which can not be achieved with conventional powders and Granulates.

4. Contd.,
The use of small and perfectly round Microspheres with exactly the same size circumvents all of the disadvantages that are encountered while using powders and granulates.
These Microspheres are free-flowing and roll with practically no friction, that means there is no abrasion, guaranteeing a dust-free environment. Pharmaceuticals embedded in the Microsphere matrix are released continuously and at a constant rate.

5. Contd.,
Administration of drugs in the form of microspheres usually improves the treatment by providing the localization of the active substances at the site of action & by prolonging the release of drugs.

6. Definition of microspheres
Microparticles or microspheres are defined as small, insoluble, free flowing spherical particles consisting of a polymer matrix and drug. and sized from about 50 nm to about 2 mm.
The term nanospheres is often applied to the smaller spheres (sized 10 to 500 nm) to distinguish them from larger microspheres

7. Ideally, microspheres are completely spherical and homogeneous in size

8. Microspheres are made from polymeric , waxy or protective materials that is biodegradable synthetic polymers and modified natural products.
Microspheres are manufactured in both solid and hollow form. Hollow microspheres are used as additives to lower the density of a material.
Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of the drug.
These carriers received much attention not only for prolonged release but also for the targeting anti cancer drugs to the tumour.

9. Advantages
Controlled release for longer period of time (like 1-3 months).
Frequency is reduced and hence patient compliance is increased.
Constant release and hence no peaks and troughs in concentration of drug.
Low dose and hence toxic effect is less.
Targeting the tissue is possible.
Other organ toxicity is less.
No distribution through out the body (no dilution effect)

10. Disadvantages Intended mainly for parenteral route which causes pain.
Forms a depot in tissue or muscle for longer period and hence may produce pain when muscle activities are done.
Once administered, it is difficult to take back the dose.
Polymer may produce toxic effects.
High cost.

11. Potential use of microspheres in the pharmaceutical industry
Taste and odor masking.
Conversion of oils and other liquids to solids for ease of handling.
Protection of drugs against the environment (moisture, light etc.).
Separation of incompatible materials (other drugs or excipients).
Improvement of flow of powders.
Aid in dispersion of water-insoluble substances in aqueous media, and Production of SR, CR, and targeted medications.

12. Polymers used in the Microsphere preparation
Synthetic Polymers
Non-biodegradable
PMMA
Acrolein
Epoxy polymers
Biodegradable
Lactides and Glycolides copolymers
Polyalkyl cyanoacrylates
Polyanhydrides

13. Chemically modified carbohydrates
Natural Materials
Proteins
Albumins
Gelatin
Collagen
Carbohydrates
Starch agarose
Carrageenan
Chitosan
Chemically modified carbohydrates
Poly(acryl)dextran
Poly(acryl)starch

14. 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
Water solubility or dispersibility
Bioresorbability
Targetability
Polyvalent

15. Types of Microspheres
Microcapsule: consisting of an encapsulated core particle. Entrapped substance completely surrounded by a distinct capsule wall.
Micromatrix: Consisting of homogenous dispersion of active ingredient in particle.
Microcapsule
Micromatrix
Types of Microspheres

16. MICROSPHERE MANUFACTURE
Most important physicochemical characteristics that may be controlled in microsphere manufacture are:
Particle size and distribution
Polymer molecular weight
Ratio of drug to polymer
Total mass of drug and polymer

17. GENERAL METHODS OF PREPARATION
Single Emulsion techniques
Double emulsion techniques
Polymerization techniques
- Normal polymerization.
- Interfacial polymerization
Coacervation phase separation techniques
Emulsification-solvent evaporation method
Spray drying and spray congealing
Brace process

18. Dispersion in organic phase
SINGLE EMULSION BASED METHOD
Aq.Solution/suspension of polymer
Dispersion in organic phase
(Oil/Chloroform)
Microspheres in organic phase
MICROSPHERES
Stirring, Sonication
CROSS LINKING
Chemical cross linking (Glutaraldehyde/Formaldehyde/Butanol
Heat denaturation
Centrifugation, Washing, Separation

19. DOUBLE EMULSION BASED METHOD
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

20. Interfacial Polymerization technique
When two reactive monomers are dissolved in immiscible solvents, the monomers diffuse to the oil- water interface where they react to form a polymeric membrane that envelopes dispersed phase.
Drug is incorporated either by being dissolved in the polymerization medium or by adsorption onto the nanoparticles after polymerization completed.
The nanoparticle suspension is then purified to remove various stabilizers and surfactants employed for polymerization by ultracentrifugation and re- suspending the particles in an isotonic surfactant-free medium.

22. PHASE SEPARATION METHOD
Aqueous/Organic.Solution of polymer
Drug
Drug dispersed or dissolved in polymer solution
Polymer rich globules
Hardening
Microspheres in aq./organic phase
Separation, Washing, Drying
MICROSPHERES

23. Salting-out process
An aqueous phase saturated with electrolytes (e.g., magnesium acetate, magnesium chloride) and containing PVA as a stabilizing and viscosity increasing agent is added under vigorous stirring to an acetone solution of polymer.
In this system, the miscibility of both phases is prevented by the saturation of the aqueous phase with electrolytes, according to a salting-out phenomenon.
The addition of the aqueous phase is continued until a phase inversion occurs and an o/w emulsion is formed

25. Emulsification-Solvent evaporation method

26. Spray drying and spray congealing method
These methods are based on drying of the mist of polymer and drug in air. Depending on the removal of solvent or cooling the solution are named as “drying” and “congealing”, respectively.
The polymer dissolved in a suitable volatile organic solvent (dichloromethane,acetone,etc)
The drug in the solid form is then dissolved in polymer solution under high speed homogenization.
This dispersion is atomized in a stream of hot air.
This leads to formation of small droplets from which solvent evaporates leading to the formation of microspheres.
These are then separated from hot air by means of cyclone separator.
Spray congealing involves the formation of microspheres by solidifying the melted mass of drug and polymer in the form of minute particles.

27. The BRACE-Process Ultra Spherical Microspheres
Microspheres with a monodisperse grain size distribution and the smallest divergence are manufactured by BRACE.
• perfectly spherical Microspheres
• monodisperse grain size, narrow size distribution with diameters between 50µm and 5000µm
• nonabrading, therefore dust-free
• free flowing, porous, large surface area,soft or rigid

28. The BRACE-Process
A liquid is gently pumped through a vibrating nozzle system whereupon exiting the fluid stream breaks up into uniform droplets.
The surface tension of these droplets moulds them into perfect spheres in which gelation is induced during a short period of free fall.
Solidification can be induced in a gaseous and/or liquid medium through cooling, drying, or chemical reaction.
There are no constraints on the type of liquid—molten materials, solutions, dispersions, sols, or suspensions can be used to manufacture perfectly spherical Microspheres.

30. DRUG LOADING
During the preparation of microspheres or after the formation of microspheres by incubating.
Loading into preformed microspheres has an advantage of removing all impurities from microsphere preparation before the drug is incorporated.
High loading can be achieved by insitu loading.

31. ROUTE OF ADMINISTRATION
ORAL DELIVERY
PARENTERAL DELIVERY

32. CHARACTERIZATION PARTICLE SIZE. PARTICLE SHAPE. DENSITY DETERMINATION.
ISOELECTRIC POINT.
CAPTURE EFFICIENCY.
RELEASE STUDIES.
ANGLE OF CONTACT.

33. PARTICLE SIZE AND SHAPE
Particle size and distribution can be determined by
conventional light microscopy
scanning electron microscopy
Confocal laser scanning microscopy
Confocal fluorescence microscopy
Laser light scattering and multisize coulter counter

34. PARTICLE SIZE

35. PARTICLE SHAPE

36. DENSITY DETERMINATION
Measured by using a Multivolume psychnometer.
ISOELECTRIC POINT
The microelectrophoresis is an apparatus used to measure the electophoretic mobility of microspheres from which isoelectric point can be determined.

37. CAPTURE EFFICIENCY

38. RELEASE STUDIES Rotating paddle apparatus Dialysis method
ANGLE OF CONTACT
Determine wetting property of microparticulate carrier.

39. APPLICATIONS MICROSPHERES IN VACCINE DELIVERY.
Eg ; Diphtheria toxoid , Tetanus toxoid.
TARGETED DRUG DELIVERY.
Eg ; ocular, eye (cornea).etc
CONTROLLED RELEASE.
Eg ; GI tumors, Bone tumors.
CHEMOEMBOLIZATION.
IMMUNO MICROSPHERES

40. Contd.,

41. OTHER APPLICATIONS
Microcapsules are also extensively used as diagnostics, for example, temperature-sensitive microcapsules for thermographic detection of tumors.
In the biotechnology industry microencapsulated microbial cells are being used for the production of recombinant proteins and peptides.
Encapsulation of microbial cells can also increase the cell-loading capacity and the rate of production in bioreactors.
A feline breast tumor line, which was difficult to grow in conventional culture, has been successfully grown in microcapsules.
Microencapsulated activated charcoal has been used for hemoperfusion.

42. Modified release microspheres of indomethacin were prepared by the emulsion solvent diffusion technique using a synthetic polymer, Acrycoat s100.
Microspheres of diltiazem hydrochloride were formulated using combination of polyethylene glycol 6000 and Eudragit RS 100 and Eudragit RS 100 alone by solvent evaporation and non-solvent addition methods with an aim to prolong its release

44. New applications for microspheres are discovered everyday, below are just a few:
Assay - Coated microspheres provide meassuring tool in biology and drug research
Ceramics - Used to create porous ceramics used for filters (microspheres melt out during firing, polyetheylene)
Cosmetics - Opaque microspheres used to hide wrinkles and give color, Clear microspheres provide "smooth ball bearing" texture during application (polyethylene)
Drug Delivery - Miniture time release drug capsule (polymer)
Electronic paper - Dual Functional microspheres used in Gyricon electronic paper
Personal Care - Added to Scrubs as an exfoilating agent (Polyethylene)
Spacers - Used in LCD screens to provide a precision spacing between glass panels (glass)
Standards - monodispere microspheres are used to calibrate particle sieves, and particle counting apparatus.
Thickening Agent - Added to paints and epoxies to modify viscosity.

45. Cancer research
One useful discovery made from the research of microspheres is a way to fight cancer on a molecular level. According to Wake Oncologists, "SIR-Spheres microspheres are radioactive polymer spheres that emit beta radiation. Physicians insert a catheter through the groin into the hepatic artery and deliver millions of micropheres directly to the tumor site. The SIR-Spheres microspheres target the liver tumors and spare healthy liver tissue. Approximately 55 physicians in the United States use Sirtex’s SIR-Spheres microspheres in more than 60 medical centers.

46. MARKETED PRODUCTS

47. Nanomi technologies Product examples
1| Monodisperse biodegradable polymeric microspheres for drug delivery. 2| Monodisperse fluorescent polymeric markers. 3| Monodisperse PLGA microspheres with encapsulated fluorescent protein. 4| Hollow biodegradable capsules. 5| Monodisperse microspheres with vitamine B12. 6| Monodisperse magnetic particles.
Biodegradable polymeric microspheres fabricated by conventional technology ( μm)
Biodegradable polymeric microspheres of the same formulation fabricated by microsieve™ emulsification (10 μm)

48. ) Monodisperse PLGA microspheres with encapsulated fluorescent protein) 
Monodisperse PLGA microspheres with encapsulated fluorescent protein
Monodisperse fluorescent red polymeric markers (≈ 10μm)
Hollow biodegradable capsules after core-liquid removal
Monodisperse microspheres with vitamine B12

49. The product
EXPANCEL® microspheres are small spherical plastic particles. The microspheres consist of a polymer shell encapsulating a gas. When the gas inside the shell is heated, it increases its pressure and the thermoplastic shell softens, resulting in a dramatic increase in the volume of the microspheres. When fully expanded, the volume of the microspheres increases more than 40 times. The product range includes both unexpanded and expanded microspheres. Unexpanded microspheres are used as blowing agents in many areas such as printing inks, paper, textiles, polyurethanes, PVC-plastics and more. The expanded microspheres are used as lightweight fillers in various applications

50. SEM Unexpanded to Expanded Microspsheres
HEAT
75 – 200°C
Expancel DU (Unexpanded )
Expancel DET (Expanded

51. BioMag® Protein A
BioMag® Protein A Particles Available in New Package Size - 2ml
Concentration: 5mg/ml Binding Capacity: 1ml (5mg) of BioMag® Protein A will bind a minimum of 0.2mg of rabbit IgG
Requires:  Cold Pack Hazards: Harmless-use normal precautions
Handling: Exercise normal care
Storage: Store at 4 degrees celsius, Do not permit to freeze
Code: A2dm - (hazard/handling/storage codes)

52. BioMag® Protein G
BioMag® Protein G Particles Available in New Package Size - 2ml
Concentration: 5mg/ml Binding Capacity: 1ml (5mg) of BioMag® Protein G will bind a minimum of 0.2mg of rabbit IgG
Requires:  Cold Pack Hazards: Harmless-use normal precautions
Handling: Exercise normal care
Storage: Store at 4 degrees celsius, Do not permit to freeze
Code: A2dm - (hazard/handling/storage codes)

53. cenospheres are marketed under the trade name CENOLITE and are available in the following grades:
Size / Grade
Sinkers
Colour
0-300 micron
<2%
Off-white
0-150 micron
0-90 micron
<4%
Cenospheres are small, lightweight, inert, hollow spheres comprising largely of silica and alumina and filled with low pressure gasses. Cenospheres are a naturally occurring by-product of the burning process at coal-fired power plants.

54. CONCLUSION
The concept of microsphere drug delivery systems offers certain advantages over the conventional drug delivery systems such as controlled and sustained delivery. Apart from that microspheres also allow drug targeting to various systems such as ocular , intranasal , oral and IV route .
Novel technologies like magnetic microspheres, immunomicrospheres offer great advantages and uses than conventional technologies.

55. Further more in future by combining various other strategies, microspheres will find the central place in novel drug delivery, particularly in diseased cellsorting ,diagnostics, gene and genetic materials, safe,targated and effective invivo delivery which may have implications in gene therapy.
This area of novel drug delivery has innumerable applications and there is a need for more research to be done in this area.

56. REFERENCES Review: Radioactive Microspheres for Medical Applications.
S.P.Vyas., R.K.Khar, International Journal for Targeted & Controlled Drug Delivery Novel Carrier Systems.,
First Edition :2002.,Reprint :2007 page no:417,453.
Review: Radioactive Microspheres for Medical Applications.
International journal of Pharmaceutics 282 (2004) 1-18,Review polymer microspheres for controlled drug release.
N.K.Jain ,Controlled and novel drug delivery edited by reprint 2007 pg.no

57. Donald L.Wise, Handbook of pharmaceutical controlled release technology.
James Swarbrick, James C.Boylan ,Encyclopedia of pharmaceutical technology Editors, volume-10.
Patrick B.Deasy, Microencapsulation and related drug delivery processes edited by.
James Swarbrick, Encyclopedia of pharmaceutical technology , 3rd edition volume-4 .

58. THANK YOU