FORMULATION AND EVALUATION OF MICROSPHERES PRESENTED BY DADHICHI K THAKKAR M.PHARM SEMISTER -I Guided by :-Dr UPENDRA PA TEL DEP ARTMENT OF PHARMACUETICAL TECHNOLOGY ARIHANT COLLEGE OF PHARMACY GUJARAT TECHNICAL UNIVERSIT Y . .
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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
www.harperintl.com. www.pharmacy2011foru.blogspot.com
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THANK YOU