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FORMULATION AND EVALUATION OF

MICROSPHERES

PRESENTED BYDADHICHI K THAKKAR

M.PHARM

SEMISTER -I

Guided by :-Dr UPENDRA PATELDEPARTMENT OF PHARMACUETICAL TECHNOLOGY

 ARIHANT COLLEGE OF PHARMACYGUJARAT TECHNICAL UNIVERSITY..

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CONTENTS

      INTRODUCTION

     CLASSIFICATION OF POLYMERS.

     METHODS OF PREPARATION.

     CHARACTERIZATION.

     APPLICATIONS.

     CONCLUSION.

     REFERENCES

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INTRODUCTION The oral route is considered as the most promising

route of drug delivery. Conventional drug delivery systemachieves as well as maintains the drug concentration

within the therapeutically effective range needed for 

treatment, only when taken several times a day.

This results in a significant fluctuation in drug levels. A

well defined controlled drug delivery system can

overcome some of the problems of conventional therapy

and enhance the therapeutic efficacy of a given drug..

There are various approaches in delivering a

therapeutic susbstance to the target site in sustained

controlled release fashion using microspheres as carrier 

for drug

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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.,

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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

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Ideally, microspheres are completely spherical and

homogeneous in size

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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 hollowform. Hollow microspheres are used as additives tolower the density of a material.

Solid biodegradable microspheres incorporating a drugdispersed or dissolved throughout particle matrix havethe 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.

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     Advantages

Controlled release for longer period of time(like 1-3 months).

Frequency is reduced and hence patientcompliance is increased.

Constant release and hence no peaks andtroughs 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 dilutioneffect)

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     Disadvantages

Intended mainly for parenteral route whichcauses pain.

Forms a depot in tissue or muscle for longer 

period and hence may produce pain whenmuscle activities are done.

Once administered, it is difficult to take back thedose.

Polymer may produce toxic effects. High cost.

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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 inaqueous media, and Production of SR, CR, and targetedmedications.

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Polymers used in the

Microsphere preparationSynthetic Polymers

     N on-biodegradable

PMMA

Acrolein Epoxy polymers

     Biodegradable

Lactides and Glycolides copolymers Polyalkyl cyanoacrylates

Polyanhydrides

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Natural Materials

     Proteins

Albumins

Gelatin

Collagen

     Carbohydr ates Starch agarose

Carrageenan

Chitosan

     Chemically modified carbohydrates Poly(acryl)dextran

Poly(acryl)starch

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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

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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

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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 

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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

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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/Formald

ehyde/ButanolHeat denaturation

Centrifugation, Washing, Separation

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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

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Interfacial Polymerization technique

When two reactive monomers are dissolved inimmiscible solvents, the monomers diffuse to the oil-water interface where they react to form a polymericmembrane that envelopes dispersed phase.

Drug is incorporated either by being dissolved in thepolymerization medium or by adsorption onto thenanoparticles after polymerization completed.

The nanoparticle suspension is then purified to removevarious stabilizers and surfactants employed for polymerization by ultracentrifugation and re- suspendingthe particles in an isotonic surfactant-free medium.

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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

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Salting-out process

An aqueous phase saturated with electrolytes (e.g.,magnesium acetate, magnesium chloride) andcontaining PVA as a stabilizing and viscosity increasingagent is added under vigorous stirring to an acetone

solution of polymer.

In this system, the miscibility of both phases is preventedby the saturation of the aqueous phase with electrolytes,according to a salting-out phenomenon.

The addition of the aqueous phase is continued until aphase inversion occurs and an o/w emulsion is formed

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Emulsification-Solvent

evaporation method

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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 ³drying´ and³congealing´, respectively.

The polymer dissolved in a suitable volatile organicsolvent (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 whichsolvent 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 microspheresby solidifying the melted mass of drug and polymer in the

form of minute particles.

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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

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The BRACE-Process

A liquid is gently pumped through a vibrating nozzlesystem whereupon exiting the fluid stream breaks up intouniform droplets.

The surface tension of these droplets moulds them intoperfect spheres in which gelation is induced during ashort period of free fall.

Solidification can be induced in a gaseous and/or liquidmedium through cooling, drying, or chemical reaction.

There are no constraints on the type of liquid²moltenmaterials, solutions, dispersions, sols, or suspensionscan be used to manufacture perfectly sphericalMicrospheres.

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DRUG LOADING

During the preparation of microspheres or after the

formation of microspheres by incubating.

Loading into preformed microspheres has an advantageof removing all impurities from microsphere preparation

before the drug is incorporated.

High loading can be achieved by insitu loading.

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ROUTE OF ADMINISTRATION

     ORAL DELIVERY

     PARENTERAL DELIVERY

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CHARACTERIZATION

      PARTICLE SIZE.

      PARTICLE SHAPE.

      DENSITY DETERMINATION.

      ISOELECTRIC POINT.

      CAPTURE EFFICIENCY.

      RELEASE STUDIES.

      ANGLE OF CONTACT.

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PARTICLE SIZE AND SHAPE

Particle size and distribution can be determined by

conventional light microscopy

scanning electron microscopy

Confocal laser scanning microscopyConfocal fluorescence microscopy

Laser light scattering and multisize coulter counter 

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PARTICLE SIZE

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PARTICLE SHAPE

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DENSITY DETERMINATION

Measured by using a Multivolumepsychnometer.

ISOELECTRIC POINTThe microelectrophoresis is an apparatus

used to measure the electophoretic mobility

of microspheres from which isoelectric

point can be determined.

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CAPTURE EFFICIENCY

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RELEASE STUDIES

Rotating paddle apparatus

Dialysis method

ANGLE OF CONTACT

     Determine wetting property of  microparticulate carrier.

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APPLICATIONS

      MICROSPHERES IN VACCINE DELIVERY.

Eg ; Diphtheria toxoid , Tetanus toxoid.

      TARGETED DRUG DELIVERY.Eg ; ocular, eye (cornea).etc

      CONTROLLED RELEASE.

Eg ; luprodine (prostate cancer).

      CHEMOEMBOLIZATION.

      Gene delivery

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OTHER APPLICATIONS

Microcapsules are also extensively used as diagnostics,

for example, temperature-sensitive microcapsules for thermographic detection of tumors.

In the biotechnology industry microencapsulatedmicrobial cells are being used for the production of 

recombinant proteins and peptides.

Encapsulation of microbial cells can also increase thecell-loading capacity and the rate of production inbioreactors.

A feline breast tumor line, which was difficult to grow inconventional culture, has been successfully grown inmicrocapsules.

Microencapsulated activated charcoal has been used for 

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Modified release microspheres of indomethacin were

prepared by the emulsion solvent diffusion techniqueusing a synthetic polymer, Acrycoat s100.

Microspheres of diltiazem hydrochloride were

formulated using combination of polyethylene glycol6000 and Eudragit RS 100 and Eudragit RS 100 aloneby solvent evaporation and non-solvent additionmethods with an aim to prolong its release

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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-Spheresmicrospheres are radioactive polymer spheres that emit

beta radiation. Physicians insert a catheter through thegroin into the hepatic artery and deliver millions of microspheres directly to the tumor site. The SIR-Spheresmicrospheres target the liver tumors and spare healthyliver tissue. Approximately 55 physicians in the United

States use Sirtex¶s SIR-Spheres microspheres in morethan 60 medical centers.

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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 asocular , intranasal , oral and IV route .

     Novel technologies like magnetic microspheres,

immunomicrospheres offer great advantages and

uses than conventional technologies.

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     Further more in future by combining various

other strategies, microspheres will find thecentral 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 genetherapy.

     This area of novel drug delivery has

innumerable applications and there is aneed for more research to be done in thisarea.

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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.

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     Donald L.Wise, Handbook of pharmaceutical controlledrelease technology.

     James Swarbrick, James C.Boylan ,Encyclopedia of pharmaceutical technology Editors, volume-10.

     Patrick B.Deasy, Microencapsulation and related drugdelivery processes edited by.

     James Swarbrick, Encyclopedia of pharmaceutical

technology , 3rd

edition volume-4 .     www.koboproducts.com

     www.brace.com

     www.wikipedia.org

     info@polysciences.com

     www.harperintl.com.     www.pharmacy2011foru.blogspot.com

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THANK YOU