Formulation and evaluation of microspheres

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FORMULATION AND EVALUATION OF
MICROSPHERES
PRESENTED BY
GEETHA.R
M.PHARM
II - SEMISTER
DEPARTMENT OF PHARMACEUTICS
UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCE
KAKATIYA UNIVERSITY, WARANGAL .
CONTENTS
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INTRODUCTION
CLASSIFICATION OF POLYMERS.
METHODS OF PREPARATION.
CHARACTERIZATION.
APPLICATIONS.
CONCLUSION.
REFERENCES
INTRODUCTION
POWDERS AND GRANULATES
• Free-flowing powders and granulates are needed for a
variety of industrial processes. These, however, do not
always meet the exacting standards which modern
manufacturing demands of them, due to their varying
grain size distribution and odd shapes.
• These properties are detrimental to efficient processing
and lead to agglomeration, inexact dosage, abrading
with loss of material, or low reproducibility of castings.
• Pharmaceutical applications require highly reproducible
dosage and the controlled release of active agents,
which can not be achieved with conventional powders
and Granulates.
Contd.,
• The use of small and perfectly round
Microspheres with exactly the same size
circumvents all of the disadvantages that are
encountered while using powders and
granulates.
• These Microspheres are free-flowing and roll
with practically no friction, that means there is no
abrasion, guaranteeing a dust-free environment.
Pharmaceuticals embedded in the Microsphere
matrix are released continuously and at a
constant rate.
Contd.,
• 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.
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
• Ideally, microspheres are completely spherical and
homogeneous in size
• 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 hollow
form. Hollow microspheres are used as additives to
lower the density of a material.
• Solid biodegradable microspheres incorporating a drug
dispersed or dissolved throughout particle matrix have
the 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.
 Advantages
• Controlled release for longer period of time
(like 1-3 months).
• Frequency is reduced and hence patient
compliance is increased.
• Constant release and hence no peaks and
troughs 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 dilution
effect)
 Disadvantages
• Intended mainly for parenteral route which
causes pain.
• Forms a depot in tissue or muscle for longer
period and hence may produce pain when
muscle activities are done.
• Once administered, it is difficult to take back the
dose.
• Polymer may produce toxic effects.
• High cost.
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, and Production of SR, CR, and targeted
medications.
Polymers used in the
Microsphere preparation
Synthetic Polymers
 Non-biodegradable
• PMMA
• Acrolein
• Epoxy polymers
 Biodegradable
• Lactides and Glycolides copolymers
• Polyalkyl cyanoacrylates
• Polyanhydrides
• Natural Materials
 Proteins
• Albumins
• Gelatin
• Collagen
 Carbohydrates
• Starch agarose
• Carrageenan
• Chitosan
 Chemically modified carbohydrates
• Poly(acryl)dextran
• Poly(acryl)starch
Prerequisites for Ideal Microparticulate
Carriers
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

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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
Types of Microspheres
• Microcapsule: consisting of an encapsulated core particle.
Entrapped substance completely surrounded by a distinct
capsule wall.
Types of Microspheres
Microcapsule
Micromatrix
• Micromatrix: Consisting of homogenous dispersion of active
ingredient in particle.
MICROSPHERE MANUFACTURE
• Most important physicochemical characteristics that may
be controlled in microsphere manufacture are:
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Particle size and distribution
Polymer molecular weight
Ratio of drug to polymer
Total mass of drug and polymer
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
SINGLE EMULSION BASED METHOD
Aq.Solution/suspension of polymer
Stirring, Sonication
Dispersion in organic phase
(Oil/Chloroform)
Heat denaturation
CROSS LINKING
Microspheres in organic phase
Chemical cross linking
(Glutaraldehyde/Formal
dehyde/Butanol
Microspheres in organic phase
Centrifugation, Washing, Separation
MICROSPHERES
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
Interfacial Polymerization technique
• When two reactive monomers are dissolved in
immiscible solvents, the monomers diffuse to the oilwater interface where they react to form a polymeric
membrane that envelopes dispersed phase.
• 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.
PHASE SEPARATION METHOD
Aqueous/Organic.Solution of polymer
Drug
Drug dispersed or dissolved in polymer solution
Polymer rich globules
Hardening
Microspheres in aq./organic phase
Separation, Washing, Drying
MICROSPHERES
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
Emulsification-Solvent
evaporation method
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 “drying” and “congealing”, respectively.
• The polymer dissolved in a suitable volatile organic solvent
(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 which solvent
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 microspheres by
solidifying the melted mass of drug and polymer in the form of
minute particles.
The BRACE-Process
 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

A liquid is gently pumped through a vibrating nozzle
system whereupon exiting the fluid stream breaks up into
uniform droplets.

The surface tension of these droplets moulds them into
perfect spheres in which gelation is induced during a
short period of free fall.

Solidification can be induced in a gaseous and/or liquid
medium through cooling, drying, or chemical reaction.

There are no constraints on the type of liquid—molten
materials, solutions, dispersions, sols, or suspensions
can be used to manufacture perfectly spherical
Microspheres.
DRUG LOADING
• During the preparation of microspheres or after the
formation of microspheres by incubating.
• Loading into preformed microspheres has an advantage
of removing all impurities from microsphere preparation
before the drug is incorporated.
• High loading can be achieved by insitu loading.
ROUTE OF ADMINISTRATION
 ORAL DELIVERY
 PARENTERAL DELIVERY
CHARACTERIZATION
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PARTICLE SIZE.

PARTICLE SHAPE.

DENSITY DETERMINATION.

ISOELECTRIC POINT.

CAPTURE EFFICIENCY.

RELEASE STUDIES.

ANGLE OF CONTACT.
PARTICLE SIZE AND SHAPE
• Particle size and distribution can be determined by
conventional light microscopy
 scanning electron microscopy
Confocal laser scanning microscopy
Confocal fluorescence microscopy
Laser light scattering and multisize coulter counter

PARTICLE SIZE
PARTICLE SHAPE
DENSITY DETERMINATION
Measured by using a Multivolume
psychnometer.
ISOELECTRIC POINT
The microelectrophoresis is an apparatus
used to measure the electophoretic mobility
of microspheres from which isoelectric
point can be determined.
CAPTURE EFFICIENCY
RELEASE STUDIES
• Rotating paddle apparatus
• Dialysis method
ANGLE OF CONTACT
Determine wetting property of
microparticulate carrier.
APPLICATIONS

MICROSPHERES IN VACCINE DELIVERY.
Eg ; Diphtheria toxoid , Tetanus toxoid.

TARGETED DRUG DELIVERY.
Eg ; ocular, eye (cornea).etc

CONTROLLED RELEASE.
Eg ; GI tumors, Bone tumors.

CHEMOEMBOLIZATION.

IMMUNO MICROSPHERES
Contd.,
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.
• Modified release microspheres of indomethacin were
prepared by the emulsion solvent diffusion technique
using a synthetic polymer, Acrycoat s100.
•
Microspheres of diltiazem hydrochloride were
formulated using combination of polyethylene glycol
6000 and Eudragit RS 100 and Eudragit RS 100 alone
by solvent evaporation and non-solvent addition
methods with an aim to prolong its release
• New applications for microspheres are discovered
everyday, below are just a few:
• Assay - Coated microspheres provide meassuring tool in biology and
drug research
• Ceramics - Used to create porous ceramics used for filters
(microspheres melt out during firing, polyetheylene)
• Cosmetics - Opaque microspheres used to hide wrinkles and give color,
Clear microspheres provide "smooth ball bearing" texture during
application (polyethylene)
• Drug Delivery - Miniture time release drug capsule (polymer)
• Electronic paper - Dual Functional microspheres used in Gyricon
electronic paper
• Personal Care - Added to Scrubs as an exfoilating agent (Polyethylene)
• Spacers - Used in LCD screens to provide a precision spacing between
glass panels (glass)
• Standards - monodispere microspheres are used to calibrate particle
sieves, and particle counting apparatus.
• Thickening Agent - Added to paints and epoxies to modify viscosity.
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-Spheres
microspheres are radioactive polymer spheres that emit
beta radiation. Physicians insert a catheter through the
groin into the hepatic artery and deliver millions of
micropheres directly to the tumor site. The SIR-Spheres
microspheres target the liver tumors and spare healthy
liver tissue. Approximately 55 physicians in the United
States use Sirtex’s SIR-Spheres microspheres in more
than 60 medical centers.
MARKETED
PRODUCTS
 Nanomi technologies
•
•
Product examples
1| Monodisperse biodegradable polymeric microspheres for drug delivery.
2| Monodisperse fluorescent polymeric markers.
3| Monodisperse PLGA microspheres with encapsulated fluorescent protein.
4| Hollow biodegradable capsules.
5| Monodisperse microspheres with vitamine B12.
6| Monodisperse magnetic particles.
•
Biodegradable polymeric microspheres
fabricated by conventional technology (50 100 μm)
Biodegradable polymeric microspheres of
the same formulation fabricated by
microsieve™ emulsification (10 μm)
• )
Monodisperse fluorescent red polymeric
markers (≈ 10μm)
Hollow biodegradable capsules after
core-liquid removal
Monodisperse PLGA microspheres
with encapsulated fluorescent protein
Monodisperse microspheres with
vitamine B12
The product
EXPANCEL® microspheres
are small spherical plastic particles. The
microspheres consist of a polymer shell
encapsulating a gas. When the gas
inside the shell is heated, it increases its
pressure and the thermoplastic shell
softens, resulting in a dramatic increase
in the volume of the microspheres. When
fully expanded, the volume of the
microspheres increases more than 40
times.
The product range includes both
unexpanded and expanded
microspheres. Unexpanded
microspheres are used as blowing
agents in many areas such as printing
inks, paper, textiles, polyurethanes, PVCplastics and more. The expanded
microspheres are used as lightweight
fillers in various applications
SEM Unexpanded to Expanded
Microspsheres
HEAT
75 – 200°C
Expancel DU
(Unexpanded )
Expancel DET
(Expanded
BioMag® Protein A
• BioMag® Protein A Particles Available in New
Package Size - 2ml
• Concentration: 5mg/ml
Binding Capacity: 1ml (5mg) of BioMag® Protein A will
bind a minimum of 0.2mg of rabbit IgG
• Requires: Cold Pack Hazards: Harmless-use normal
precautions
• Handling: Exercise normal care
• Storage: Store at 4 degrees celsius, Do not permit to
freeze
• Code: A2dm - (hazard/handling/storage codes)
BioMag® Protein G
• BioMag® Protein G Particles Available in
New Package Size - 2ml
• Concentration: 5mg/ml
Binding Capacity: 1ml (5mg) of BioMag® Protein
G will bind a minimum of 0.2mg of rabbit IgG
• Requires: Cold Pack Hazards: Harmless-use
normal precautions
• Handling: Exercise normal care
• Storage: Store at 4 degrees celsius, Do not
permit to freeze
• Code: A2dm - (hazard/handling/storage codes)
 cenospheres are marketed under the trade
name CENOLITE and are available in the
following grades:
Size / Grade
Sinkers
Colour
0-300 micron
<2%
Off-white
0-150 micron
<2%
Off-white
0-90 micron
<4%
Off-white
 Cenospheres are small, lightweight, inert, hollow spheres
comprising largely of silica and alumina and filled with low
pressure gasses. Cenospheres are a naturally occurring byproduct of the burning process at coal-fired power plants.
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 as
ocular , intranasal , oral and IV route .
 Novel technologies like magnetic microspheres,
immunomicrospheres offer great advantages and
uses than conventional technologies.
 Further more in future by combining various
other strategies, microspheres will find the
central 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 gene
therapy.
 This area of novel drug delivery has
innumerable applications and there is a
need for more research to be done in this
area.
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.
 Donald L.Wise, Handbook of pharmaceutical controlled
release technology.
 James Swarbrick, James C.Boylan ,Encyclopedia of
pharmaceutical technology Editors, volume-10.
 Patrick B.Deasy, Microencapsulation and related drug
delivery processes edited by.
 James Swarbrick, Encyclopedia of pharmaceutical
technology , 3rd edition volume-4 .
 www.koboproducts.com
 www.brace.com
 www.wikipedia.org
 [email protected]
 www.harperintl.com.
THANK YOU
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