Formulation and-evaluation-of-microspheres

Novel Drug Delivery System

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. •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.
Contd.,

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 2mm.
•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. •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. SINGLE EMULSION BASED METHOD
Aq.Solution/suspension of polymer
Dispersion in organic phase
(Oil/Chloroform)
Microspheres in organic phase Microspheres in organic phase
MICROSPHERES
Stirring, Sonication
CROSS LINKING
Chemical cross linking
(Glutaraldehyde/Formal
dehyde/Butanol
Heat denaturation
Centrifugation, Washing, Separation

19. Aq.Solution of protein/polymer
First emulsion (W/O)
MICROSPHERES
Dispersion in oil/organic phase
Homogenization
Separation, Washing, Drying
Addition of aq. Solution of PVA
Addition to large aq. Phase
Denaturation/hardening
Multiple emulsion
Microspheres in solution
DOUBLE EMULSION BASED METHOD

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 dispersed or dissolved in polymer solution
MICROSPHERES
Drug
Separation, Washing, Drying
Hardening
Polymer rich globules
Microspheres in aq./organic phase

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. 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
The BRACE-Process

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 inGyricon
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 modifyviscosity.

45. Cancer research
•One useful discovery made from the research of
microspheres is a way to fightcanceron a molecular
level. According to Wake Oncologists, "SIR-Spheres
microspheres areradioactivepolymer spheres that emit
beta radiation. Physicians insert acatheterthrough the
groininto thehepatic arteryand deliver millions of
micropheres directly to the tumor site. The SIR-Spheres
microspheres target thelivertumors 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. Nanomitechnologies
•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 (50-
100 μm)
Biodegradable polymeric microspheres of
the same formulation fabricated by
microsieve™ emulsification (10 μm)

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

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
Expancel DU
(Unexpanded )
Expancel DET
(Expanded
75–200°C

51. BioMag® Protein A
•BioMag® ProteinA 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 PackHazards: 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 PackHazards: 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. cenospheresare marketed under the trade
nameCENOLITEand are available in the
following grades:
Size / GradeSinkersColour
0-300 micron<2% Off-white
0-150 micron<2% Off-white
0-90 micron<4% Off-white
Cenospheresaresmall,lightweight,inert,hollowspheres
comprisinglargelyofsilicaandaluminaandfilledwithlow
pressuregasses.Cenospheresareanaturallyoccurringby-
productoftheburningprocessatcoal-firedpowerplants.

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
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.236-255.

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 , 3
rd
edition volume-4 .
www.koboproducts.com
www.brace.com
www.wikipedia.org
[email protected]
www.harperintl.com.

58. THANK YOU