1. MICROSPHERES
Submitted to: Submitted by:
Mr. Santosh Kumar Singh P. Swetha.
Sugunan
M.Pharm,
Pharmceutics,
2nd sem.
2. CONTENT
Introduction
Advantages
Polymer used for preparation
General method of preparation
Release of drug from microspheres
Characterization of microspheres
Applications
3. INTRODUCTION
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.
Types of Microspheres
Microcapsule Micromatrix
Spherical particle with size
varying from 50 nm to 2 mm.
4. ADVANTAGES
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,
• Production of SR, CR, and targeted medications.
5. PHARMACEUTICAL
APPLICATIONS
Microencapsulated products currently on the market, such
as aspirin, theophylline & its derivatives, vitamins,
pancrelipase, antihypertensive, potassium chloride,
progesterone, and contraceptive hormone combinations.
Microencapsulated KCl is used to prevent gastrointestinal
complications associated with potassium chloride.
Microspheres have also found potential applications as
injection, or inhalation products.
Most encapsulation processes are expensive and require
significant capital investment for equipment.
An additional expense is due to the fact that most
microencapsulation processes are patent protected.
6. .
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.
Paramedical uses of microcapsules include bandages with
microencapsulated anti-infective substances.
8. 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
9. 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
10. GENERAL METHODS OF
PREPARATION
• Single Emulsion techniques
• Double emulsion techniques
• Polymerization techniques
- Normal polymerization
- Interfacial polymerization
• Coacervation phase separation techniques
• Spray drying and spray congealing
• Solvent extraction
11. SIMPLE EMULSION BASED METHOD
Aq.Solution/suspension of polymer
Stirring, Sonication
Dispersion in organic phase
(Oil/Chloroform)
Chemical cross linking
(Glutaraldehyde/Formalde
Heat denaturation CROSS LINKING hyde/ Butanol)
Microspheres in organic phase Microspheres in organic phase
Centrifugation, Washing, Separation
MICROSPHERES
12. 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
13. INTERFACIAL DEPOSITION TECHNIQUE
First, the polymer is dissolved in acetone,
then a phospholipid mixture (e.g., Epikuron'")
and benzyl benzoate are added to this
solution.
The resulting organic solution is poured into
an aqueous phase containing a surfactant
(e.g., poloxamer 188) under moderate stirring.
Acetone diffuses immediately into the
aqueous phase, inducing the deposition and
the precipitation of the polymer around the
oily droplets.
Once the microcapsules are formed, acetone is eliminated under
reduced pressure.
Drugs intended to be encapsulated by this method must have a high
solubility in the organic-oily phase, otherwise they diffuse from the oily
solution and precipitate in the aqueous medium during particle formation.
14. A)NORMAL POLYMERIZATION
Normal Polymerization is done by bulk, suspension, pption,emulsion and
polymerization process.
1. Bulk polymerization:
Monomer Bioactive material Initiator
Heated to initiate polymerization
Initiator accelerate rate of reaction
Polymer(Block)
Moulded/fragmented
Microspheres
15. B)SUSPENSION POLYMERIZATION
Monomer Bioactive material Initiator
Dispersion in water & stabilizer
Droplet
Vigorous ,Aggitation Polymerization by Heat
Hardened microspheres
Separation & Drying
MICROSPHERES
16. C)EMULSION POLYMERISATION
Monomer/ Aq.Solution of NaOH,
Bioactive material Initiator, Surfactant , Stabilizer
Dispersion with vigorous stirring
Micellar sol. Of Polymer in aqueous medium
Polymerization
Microspheres formation
MICROSPHERES
17. 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.
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.
This technique has been reported for making polybutylcyanoacrylate or
poly (alkylcyanoacrylate) nanoparticles.
18. PHASE SEPARATION METHOD
Aqueous/Organic Solution of polymer
Drug
Drug dispersed or dissolved in polymer solution
Phase seperation induced by various means
Polymer rich globules
Hardening
Microspheres in aq./organic phase
Separation, Washing, Drying
MICROSPHERES
19. E) SPRAY DRYING
Polymer dissolve in volatile organic solvent
(acetone, dichloromethane)
Drug dispersed in polymer solution under high speed
homogenization
Atomized in a stream of hot air
Due to solvent evaporation small droplet or fine mist form
Leads to formation of Microspheres
Microspheres separated from hot air by cyclone
separator, Trace of solvent are removed by vacuum drying
20. 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)
Hardened microspheres
21. PREPARATION OF MICROSPHERES BY DESOLVATION
OF ALBUMIN
Gelatin and albumin nanospheres can be
produced by the slow addition of a
desolvating agent (neutral salt or
alcohol) to the protein solution.
Upon this addition, a progressive
modification of the protein tertiary
Structure is induced leading (when a
certain degree of desolvation is
obtained), to the formation of protein
aggregates.
Nanospheres are obtained by subsequent crosslinking of these
aggregates with glutaraldehyde.
To obtain small and monodispersed particles, it is important to
maintain the system at a point just before coacervation is initiated.
The addition of the desolvating agent is monitored by turbidimetry
measurements of the system and must be stopped as soon as the
turbidity increases, otherwise aggregates that are too large will be
formed.
22. 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.
Then, a sufficient amount of pure water is added to disrupt the
equilibrium between the two phases and to allow complete diffusion of
acetone into water, leading to polymer precipitation in the form of
spherical nanospheres
23. PREPARATION OF MICROSPHERES BY THERMAL
DENATURATION OF ALBUMIN
Once a high degree of dispersion is
achieved, the emulsion is added
dropwise.
Immediate vaporization of the water
contained in the droplets and to the
irreversible denaturation of the albumin
which coagulates in the form of solid
nanospheres.
The suspension is then allowed to cool down
at room temperature or in an ice bath.
Subsequently, the particles are submitted to
several washings using large amounts of
organic solvent
(e.g., ether, ethanol, acetone) for complete
removal of the oil.
24. Release pattern of drug from
microspheres
Naltroxone (vivitrol TM) microspheres (PLA-PLGA)
the first approved alcohol dependence medication in
USA:
MECHANISM: The release pattern of naltroxone as a
result of:
absorbing water and swelling immediately after
injection where the near surface drug is released first
-as water absorption continues hydrolysis starts and
after several days physical erosion begins.
-further drug diffuse to the surrounding resulting in
sustained release of medication with the elimination
of water and carbon dioxide as degradation product
of polymer matrix.
26. CHARACTERIZATION OF MICROSPHERES
YIELD VALUES AND LOADING EFFICIENCY:
Yield value = 100 x Obtained wgt. Of microspheres
Theoretical wgt to be prepared
Loading = 100 x actual amt. of drug obtained by extraction
effeciency theoretical wgt. of drug added in preparation
MICROSPHERE MORPHOLOGY:In this the
prepared loaded microsphere is analyzed by
scanning electronic microscope(SEM)after
palladium/gold coating of the samples on an
aluminium strip.
27. MICROSPHERE SIZE DISTRIBUTION: Mean size
is determined by methods like Laser
diffractometry method.
BULK DENSITY MEASUREMENT: By dipping
method.
MEASUREMENT OF GLASS TRANSITION TEMP
(Tg) BY DSC: Tg is measured by DSC for the
blank (unloaded) and the prepared loaded
microspheres.
SURFACE CHEMISTRY BY ELECTRON
SPECTROSCOPY: Done for chemical analysis.
Provides means of determination of atomic
composition of the surface.
28. RELEASE STUDY: Carried out in phosphate saline
buffer Ph 7.4. Two methods-
1. Rotating paddle dissolution appratus.
2. Dialysis method.
ISOELECTRIC POINT: Microelectrophoresis
apparatus is used to measure electrophoretic
mobility of microspheres from which isoelectric
point can be determined.
DEGREE OF HYDRATION: Measured to evaluate
water uptake by the system as a first step in
biodegradation.
29. RECENT ADVANCEMENT
SWINE FLU INFLUENZA DNA VACCINE
ENCAPSULATED IN PLGA MICROSPHERE
DNA vaccine against Swine flu influenza
encapsulated in poly(D,L)lactic co glycolic
acid(PLGA) microspheres.
Prepared by Emulsion evaporation method using
PLGA as biodegradable matrix formic polymer.
PLGA microspheres containing DNA vaccine can
be used to achieved prolonged released of
plasmid DNA.
30. s-PLLA/IBUPROFIN MICROSPHERES(2010)
These are star shaped poly(L- lactide)loaded
ibuprofen (s-PLLA/IBU) microspheres.
Prepared using Solvent evaporation method
IBU could combine with s-PLLA well and part of
PLLA were degraded after releasing.
The drug encapsulating efficiency of s-PLLA/IBU
microspheres is high and release of ibuprofen from
microspheres is slow and effective.
31. APPLICATION
S Vaccine delivery – Improved antigenecity, Ag release,
Stabilization of Ag
Drug targeting
◦ Ocular: gelation with increased residence time
◦ Intranasal: protein and peptide delivery
◦ Oral
Magnetic microspheres
Immunomicrospheres
Chemoembolization
Imaging
Microsponges
Surface modified microspheres
