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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

http://www.google.com/

http://www.wikipedia.com/

http://www.autorsteam.com/

http://www.informahealthcare.com/

http://www.en.cnki.com.cn/

http://www.pharmainfo.net/


http://www.en.cnki.com.cn/

http://www.informahealthcare.com/

http://www.autorsteam.com/

http://www.wikipedia.com/

http://www.google.com/

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