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MICROSPHERES
Submitted to: Submitted by:
Mr. Santosh Kumar Singh P. Swetha.Sugunan
M.Pharm,Pharmceutics,2nd sem.
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CONTENT
Introduction
Advantages
Polymer used for preparationGeneral method of preparation
Release of drug from
microspheresCharacterization of microspheres
Applications
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INTRODUCTION
Microspheres are characteristically freeflowing powders consisting of proteins orsynthetic polymers which are biodegradablein nature and ideally having a particle size
less than 200 m.μ
Spherical particle withsize varying from 50nm to 2 mm.
Microcapsule Micromatrix
Types of Microspheres
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ADVANTAGES
Potential use of microspheres in the pharmaceuticalindustry
• Taste and odor masking
• Conversion of oils and other liquids to solids for easeof 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 dis ersion of water-insoluble substances in
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PHARMACEUTICALAPPLICATIONS
Microencapsulated products
currently on the market, such asaspirin, theophylline & its
derivatives, vitamins,
pancrelipase, antihypertensive,potassium chloride,
progesterone, and contraceptive
hormone combinations.
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.
OTHER APPLICATIONS
Microcapsule
s are alsoextensively
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Synthetic Polymers
Non-biodegradable
PMMA
Acrolein
Epoxy polymers
Biodegradable
Lactides and Glycolides
copolymers
Polyalkyl cyanoacrylates
Polyanhydrides
Natural Materials
Proteins
Albumins
Gelatin
Collagen
CarbohydratesStarch agarose
Carrageenan
Chitosan
Chemically modified
carbohydrates
Poly (acryl) dextran
Poly(acryl)starch
DEAE cellulose
POLYMERS USED IN THE MICROSPHEREPREPARATION
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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
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MICROSPHEREMANUFACTURE
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
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GENERAL METHODS OFPREPARATION• Single Emulsion techniques
• Double emulsion techniques
• Polymerization techniques
- Normal polymerization
- Interfacial polymerization
• Coacervation phase separationtechniques
• Spray drying and spray congealing
• Solvent extraction
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SIMPLE EMULSION BASED METHOD
Aq.Solution/suspension of polymer
Dispersion in organic
phase(Oil/Chloroform)
Microspheres inorganic phase Microspheres inorganic phase
MICROSPHE
RES
Stirring,Sonication
CROSSLINKING
Chemical crosslinking(Glutaraldehyde/Formaldehyde/Butanol)
Heatdenaturati
on
Centrifugation,Washing, Separation
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DOUBLE EMULSION BASEDMETHODAq.Solution of
protein/polymer
First emulsion(W/O)
MICROSPHERES
Dispersion in oil/organicphaseHomogenization
Separation, Washing,Drying
Addition of aq. Solution
of PVA
Addition to large aq.PhaseDenaturation/hardening
Multipleemulsion
Microspheres insolution
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First, the polymer is dissolved inacetone,
then a phospholipid mixture (e.g.,Epikuron'") and benzyl benzoate areadded to this solution. The resulting organic solution ispoured into an aqueous phase
containing a surfactant (e.g.,poloxamer 188) under moderatestirring.Acetone diffuses immediately into theaqueous phase, inducing thedeposition and the precipitation of thepolymer around the oily droplets.
Drugs intended to be encapsulated by this method must havea high solubility in the organic-oily phase, otherwise theydiffuse from the oily solution and precipitate in the aqueousmedium during particle formation.
Once the microcapsules are formed, acetone is eliminatedunder reduced pressure.
INTERFACIAL DEPOSITIONTECHNIQUE
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A)NORMAL POLYMERIZATION
Normal Polymerization is done by bulk, suspension, pption,emulsion and polymerization process.
1. Bulk polymerization:
Monomer Bioactive materialInitiator
Heated to initiate polymerization
Initiator accelerate rate
of reaction
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B)SUSPENSIONPOLYMERIZATION
Monomer Bioactive material Initiator
Dispersion in water &stabilizer
Droplet
Vigorous ,Aggitation Polymerization by Heat
Hardened microspheres
Separation & Drying
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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
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When two reactivemonomers are
dissolved in immisciblesolvents,
the monomers diffuse tothe oil-
water interface where
they react toform a polymericmembrane.
Drug is incorporatedeither by
being dissolved in thepolymerization mediumor by
adsorption onto thenanoparticles
after polymerizationcompleted.
This technique has been reported for making
polybutylcyanoacrylate or poly
INTERFACIAL POLYMERIZATIONTECHNIQUE
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PHASE SEPARATIONMETHOD
Aqueous/Organic
Solution of polymer
Drug dispersed or dissolved inpolymer solution
MICROSPHERES
Drug
Separation, Washing,Drying
Phase seperation induced by various
means
Hardening
Polymer richglobules
Microspheres inaq./organic phase
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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 orfine mist form
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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
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Gelatin and albumin nanospherescan be produced by the slowaddition of a desolvating agent(neutral salt or alcohol) to theprotein solution.Upon this addition, a progressivemodification of the protein
tertiaryStructure is induced leading(when a certain degree of desolvation is obtained), to theformation of protein aggregates.
To obtain small and monodispersed particles, it isimportant to maintain the system at a point just beforecoacervation is initiated. The addition of the desolvating agent is monitored byturbidimetry measurements of the system and must be
stopped as soon as the turbidity increases, otherwisea re ates that are too lar e will be ormed.
Nanospheres are obtained by subsequent crosslinkingof these aggregates with glutaraldehyde.
PREPARATION OF MICROSPHERES BY DESOLVATION OF ALBUMIN
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An aqueous phase saturated with
electrolytes (e.g., magnesiumacetate, magnesium chloride) andcontaining PVA as a stabilizing andviscosity increasing agent is addedunder vigorous stirring to an acetonesolution of polymer.
In this system, the miscibility of bothphases is prevented by the saturationof the aqueous phase withelectrolytes, according to a salting-outphenomenon.
The addition of the aqueous phase iscontinued until a phase inversionoccurs and an o/w emulsion is formed.
Then, a sufficient amount of pure water is added to disruptthe equilibrium between the two phases and to allowcomplete diffusion of acetone into water, leading to
polymer precipitation in the form of spherical nanospheres
SALTING-OUT PROCESS
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Once a high degree of dispersionis achieved, the emulsion isadded dropwise.
Immediate vaporization of thewater contained in the dropletsand to the irreversibledenaturation of the albumin whichcoagulates in the form of solidnanospheres.
The suspension is then allowed tocool down at room temperature or in
an ice bath. Subsequently, theparticles are submitted to severalwashings using large amounts of organic solvent (e.g., ether, ethanol,acetone) for complete removal of theoil.
PREPARATION OF MICROSPHERES BY THERMAL DENATURATION OF ALBUMIN
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Release pattern of drugfrom microspheres
Naltroxone (vivitrol TM) microspheres(PLA-PLGA) the first approved alcoholdependence medication in USA:
MECHANISM: The release pattern of naltroxone as a result of:
absorbing water and swellingimmediately after injection where the near
surface drug is released first-as water absorption continues hydrolysis
starts and after several days physicalerosion begins.
-further drug diffuse to the surrounding
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CHARACTERIZATION OFMICROSPHERES
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CHARACTERIZATION OFMICROSPHERES 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 byextraction
effeciency theoretical wgt. of drug added inpreparation
MICROSPHERE MORPHOLOGY:In this theprepared loaded microsphere isanalyzed by scanning electronic
microscope(SEM)after palladium/gold
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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 byDSC for the blank (unloaded) and theprepared loaded microspheres.
SURFACE CHEMISTRY BY ELECTRONSPECTROSCOPY: Done for chemicalanalysis. Provides means of determination of atomic composition of the surface.
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RELEASE STUDY: Carried out in
phosphate saline buffer Ph 7.4. Twomethods-
1. Rotating paddle dissolution appratus.
2. Dialysis method.ISOELECTRIC POINT: Microelectrophoresis
apparatus is used to measureelectrophoretic mobility of microspheres
from which isoelectric point can bedetermined.
DEGREE OF HYDRATION: Measured to
evaluate water uptake by the system as
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RECENT ADVANCEMENT
SWINE FLU INFLUENZA DNA VACCINEENCAPSULATED IN PLGAMICROSPHERE
DNA vaccine against Swine flu influenzaencapsulated in poly(D,L)lactic co glycolicacid(PLGA) microspheres.
Prepared by Emulsion evaporation
method using
PLGA as biodegradable matrix formicpolymer.
PLGA microspheres containing DNA
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s-PLLA/IBUPROFIN
MICROSPHERES(2010) These are star shaped poly(L-lactide)loaded ibuprofen (s-PLLA/IBU)microspheres.
Prepared using Solvent evaporationmethod
IBU could combine with s-PLLA well andpart of PLLA were degraded after releasing.
The drug encapsulating efficiency of s-PLLA/IBU
microspheres is high and release of
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APPLICATIONS
Vaccine delivery – Improved antigenecity, Ag
release,Stabilization of Ag
Drug targeting
◦ Ocular: gelation with increased residencetime
◦ Intranasal: protein and peptide delivery
◦ Oral
Magnetic microspheres Immunomicrospheres
Chemoembolization
Imaging
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REFERENCES
www.google.com
www.wikipedia.com
www.autorsteam.com
www.informahealthcare.com
www.en.cnki.com.cn
www.pharmainfo.net
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