M pharm
Department of Pharmaceutics
Associate Professor
Department of Pharmaceutics
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MICROSPHERES
Microspheres are defined as solid, spherical particles ranging in size from
1- 1000 µm, made up of polymeric, waxy or other protective materials.
➢ They are spherical free flowing particles consisting of proteins or synthetic
polymers which are biodegradable in nature.
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• 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.
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ADVANTAGES OF MICROSPHERES:
1.Particle size reduction for enhancing solubility of the poorly soluble drug.
2. Provide constant and prolonged therapeutic effect.
3. Decrease dose and toxicity.
4. Protect the drug from enzymatic and photolytic cleavage hence found to be best
for drug delivery
5. Reduce the dosing frequency and thereby improve the patient compliance
6. Better drug utilization will improve the bioavailability and reduce the incidence or
intensity of adverse effects.
7. Protects the GIT from irritant effects of the drug.
8. Biodegradable microspheres have the advantage over large polymer implants
because they do not require surgical procedures for implantation and removal.
9. Controlled release delivery biodegradable microspheres are used to control drug
release rates there by decreasing toxic side effects, and eliminating the
inconvenience of repeated injections.
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DISADVANTAGES:-
1. The costs of the materials and processing of the controlled release
preparation, are substantially higher than those of standard formulations.
2. The fate of polymer additives such as plasticizers , stabilizers, antioxidants,
fillers, polymer matrix and its effect on the environment.
3. Reproducibility is less.
4. Process conditions like change in temperature, pH, solvent addition, and
evaporation/agitation may influence the stability of core particles to be
encapsulated.
5. The environmental impact of the degradation products of the polymer
matrix produced in response to heat, hydrolysis, oxidation, solar radiation
or biological agents.
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BIOADHESIVE MICROSPHERES:-
• Adhesion of drug delivery device to the mucosal membrane such as buccal,
ocular, rectal, nasal etc. can be termed as bio adhesion.
• These kinds of microspheres exhibit a prolonged residence time at the site of
application and causes intimate contact with the absorption site and produces
better therapeutic action
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MAGNETIC MICROSPHERES:
• This kind of delivery system is very much important which localises the drug to
the disease site.
• In this larger amount of freely circulating drug can be replaced by smaller
amount of magnetically targeted drug.
• Magnetic carriers receive magnetic responses to a magnetic field from
incorporated materials that are used for magnetic microspheres are chitosan ,
dextran etc.
The different types of magnetic microspheres:
a. Therapeutic magnetic microspheres:- used to deliver chemotherapeutic
agent to liver tumors. Drugs like proteins and peptides can also be targeted
through this system.
b. Diagnostic microspheres:- used for imaging liver and also can be used to
distinguish bowel loops from other abdominal structures by forming micron size
particles Ex:supra magnetic iron oxides.
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FLOATING MICROSPHERES:
➢ In floating types the bulk density is less than the gastric fluid and so remains
buoyant in stomach without affecting gastric emptying rate.
➢ The drug is released slowly at the desired rate, and the system is found to be
floating on gastric content and increases gastric residence and decreases
fluctuation in plasma concentration.
➢ Moreover it also reduces chances of dose dumping.
➢ It produces prolonged therapeutic effect and therefore reduces dosing
frequencies.
Ex: Drug (ketoprofen)is given in the form of floating microspheres
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RADIOACTIVE MICROSPHERES:-
• Radio embolization therapy microspheres sized 10-30mm are of larger than the
diameter of the capillaries and gets tapped in capillary bed.
• They are injected in the arteries that leads them to tumour of interest so
these radioactive microspheres deliver high dose to the targeted areas without
damaging the normal surrounding tissues.
• It differs from drug delivery system, as radio activity is not released from
microspheres but acts from within a radioisotope.
• The different kinds of radioactive microspheres are α emitters, β emitters, γ
emitters.
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POLYMERIC MICROSPHERE:-
The various types of polymers are used for preparation of
microspheres
e.g:- Albumin microspheres
Gelatin microspheres
Starch microspheres
Dextran microspheres
Carrageenan microspheres
Alginate microspheres
Poly (alkyl cyanoacrylate ) microspheres etc.,
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POLYMERS USED IN MICROSPHERE
PREPARATION:-
They are classified into two types:
➢ Synthetic Polymers
➢ Natural polymers
Synthetic polymers are divided into two types.
a) Non-biodegradable polymers:- Poly methyl methacrylate (PMMA), Acrolein,
Glyceryl methacrylate, Epoxy polymers
b) Biodegradable polymers:-Lactides, Glycolides & their co polymers, Poly alkyl
cyanoacrylates, Poly anhydrides
Natural polymers obtained from different sources like proteins, carbohydrates
and chemically modified carbohydrates
• Proteins: Albumin, Gelatin, Collagen
• Carbohydrates: Agarose, Carrageenan, Chitosan, Starch
• Chemically modified carbohydrates: Poly (acryl) dextran, Poly(acryl)starch
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PREPERATION METHODS:-
1) SOLVENT EVAPORATION METHOD
2) SINGLE EMULSION TECHNIQUE
3) DOUBLE EMULSION TECHNIQUE
4) POLYMERISATION TECHNIQUE
a. NORMAL POLYMERISATION
• Bulk polymerization
• Suspension polymerization
• Emulsion polymerization
b. INTERFACIAL POLYMERISATION
5) COACERVATION PHASE SEPERATION TECHNIQUE
6) SPRAY DRYING
7) SOLVENT EXTRACTION
8) AIR SUSPENSION
9) PRECIPITATION
10) FREEZE DRYING
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Criteria for selection of method of
preparation
The ability to incorporate reasonably high concentrations of the
drug.
Stability of the preparation after synthesis with a clinically acceptable shelf
life.
Controlled particle size and dispersability in aqueous vehicles
for injection.
Release of active reagent with a good control over a wide time
scale
Susceptibility to chemical modification
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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Prerequisites for Ideal Microparticulate
Carriers
• Longer duration of action
• Control release
• Increase of therapeutic efficacy
• Protection of drug
• Reduction of toxicity
• Biocompatibility
• Sterilizability
• Relative stability
• Water solubility or dispersibility
• Targeting
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Spray drying and spray congealing
These methods are based on the drying of mist of the
polymer & drug in the air either by,
• removal of solvent (spray drying)or
• cooling of the solution(spray congealing).
Advantages:
Feasibility of operation in aseptic condition.
Suitable for both bath & bulk mfg.
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Preparation of BSA loaded PLGA
microspheres
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SUSPENSION POLYMERIZATION:-
Suspension polymerization also referred as bead or pearl polymerization.
It is carried out by heating the monomer or composition of monomers as
droplets/ dispersion in a continuous aqueous phase.
Droplets may also contain an initiator and other additives
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EMULSION POLYMERIZATION
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INTERFACIAL POLYMERIZATION
• Interfacial polymerization essentially precedes involving reaction of various
monomers at the interface between the two immiscible liquid phases to
form a film of polymer that essentially envelops the dispersed phase.
• The monomers present in either phases diffuse rapidly and polymerize
rapidly at the interface.
• Monomer droplet, the formed carrier is of capsular (reservoir)type.
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PHASE SEPARATION & COACERVATION
METHOD
Specially designed for preparation of reservoir type of the system, also used
for matrix type devices.
Coacervation is induced by subjecting the biphasic system to
conditions which brings coalescence of the polymer by withdrawing the
solvent away from colloidal particles under controlled conditions.
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1)Simple coacervation:
Occurs in presence of only one macromolecule. E.g. water/gelatin
Induced by-
• Non solvent addition
• Salt addition
• Temp. change
• Incompatible polymer addition
2) Complex coacervation:
Two or more macromolecules of opposite charges.
E.g. Solution of positively charged Gelatin with negatively charged Gum
Arabica.
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Solvent extraction:
➢ This method involves removal of the organic phase by extraction of non
aqueous solvent.
➢ It involves water miscible organic solvents like isopropanol .
➢ Organic phase can be removed by extraction with water. This process
decreases the hardening time for the microspheres.
➢ One variation of the process involves direct incorporation of the drug or
protein to polymer organic solution.
➢ Rate of solvent removal by extraction method depends on the temperature of
water, ratio of emulsion volume to the water and solubility profile of polymer.
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Solvent Extraction
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Wax coating & Hot melt technique
In this method, Wax is used to coat the core particles
Ex: Carnauba wax ,Bees wax.
Polyanhydrides
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Air Suspension
• Prof. Dale E. Wurster.
• It consist of dispersing the solid particulate core material in supporting
air stream.
Process variable parameter:-
1) Application rate of coating material.
2) Coating material conc.
3) Core material properties.
Precipitation
➢ An emulsion is formed, which consists of polar droplets dispersed in a
non-polar medium.
➢ Solvent may be removed from the droplets by the use of a co-solvent.
➢ The resulting increase in the polymer-drug concentration causes a
precipitation forming a suspension
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Freeze Drying
• This method involves the freezing of emulsion.
• The continuous-phase solvent is usually organic and is removed by
sublimation at low temperature and pressure.
• Finally, the dispersed-phase solvent of the droplets is removed by
sublimation, leaving polymer-drug particles.
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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
• free flowing, porous, large surface area,soft or rigid
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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.
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EVALUATION OF MICROSPHERES:
1. Particle size and shape:
The most widely used procedures to visualize microparticles are:
➢ Conventional light microscopy
➢ Scanning electron microscopy (SEM).
➢ Confocal laser scanning microscopy
➢ Confocal fluorescence microscopy
➢ Laser light scattering and multisize coulter counter
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2. Degradation behavior:
The surface chemistry of the microspheres can be determined using the electron
spectroscopy for chemical analysis (ESCA). This method determines the atomic
composition of surface. The spectra of ESCA is used to determine surface
degradation of biodegradable microspheres.
3. Density determination:
The density of the microspheres can be measured by using a multi volume
pycnometer.
4. Isoelectric point:
The microelectrophoresis is used to measure the electrophoretic mobility of
microspheres from which the isoelectric point can be determined.
The mean velocity at different pH values ranging from 3-10 is calculated by
measuring time for particle movement over 1mm distance. Using this data
electrical mobility can be determined.
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5.Bulk density measurement: By dipping method.
6.Measurement of glass transition temp (Tg) by DSC: Tg is
measured by DSC for the blank (unloaded) and the prepared loaded
microspheres.
7. Angle of contact:
The angle of contact is measured to determine the wetting property of a
micro particulate carrier.
The angle of repose was calculated by the following equation
tan θ =h/r
where h & r are the height band radius of the heap.
8. Drug entrapment efficiency:
Drug entrapment efficiency it is the percentage of drug that is successfully
entrapped within microspheres, it can be determined by allowing washed
microspheres to lyse. The lysate is then subjected to determination of
active constituents as per monograph. The % encapsulation is calculated
using following equation,
% Entrapment = Actual content/Theoretical content x 100.
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9. Swelling index :
• It is conducted in a phosphate buffer of pH 6.8.
• The diameter is measured periodically by using laser particle size distribution
analyzer until they were decreased by erosion and dissolution.
• The swelling index of the microsphere was calculated by using the formula,
Swelling index= (mass of swollen microspheres – mass of dry microspheres) x100
(mass of dried microspheres)
10. In vitro methods:
Release studies- for different type of microspheres are carried out by using
suitable dissolution media(phosphate buffer pH 7.4), mostly by rotating paddle
apparatus (USP)
• Agitated with 100 rpm, samples were collected at specific time intervals and
replaced by same amount and analyzed.
2. Dialysis method-Carried out in phosphate saline buffer Ph 7.4.
11. Adhesion property:
• Freshly cut piece of pig intestine is used (5 cm long),clean and wash it with
isotonic saline solution.
• Accurate weight of microspheres was placed on mucosal surface, phosphate
buffer of pH 6.8 is warmed at 37 °c was peristaltically pumped at a rate of 5 ml/
min over the tissue.
• The duration of complete washing of microspheres from pig intestine was
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APPLICATIONS
➢ Vaccine delivery – Improved antigenecity, Ag release, Stabilization of Ag.
Eg : Diphtheria toxoid , Tetanus toxoid.
➢ Drug targeting
◦ Ocular: gelation with increased residence time
◦ Intranasal: protein and peptide delivery
◦ Oral
➢ Magnetic microspheres
➢ Immunomicrospheres
➢ Chemoembolization
➢ Imaging
➢ Microsponges
➢ Surface modified microspheres.
➢ Gene delivery
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Cont….
• 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.
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PHARMACEUTICAL
APPLICATIONS
Microencapsulated products currently on the market, such as aspirin,
theophylline & its derivatives, vitamins, antihypertensive, potassium chloride,
progesterone, and contraceptive hormone combinations.
Microencapsulated KCl is used to prevent gastrointestinal complications
associated with potassium chloride.
Microspheres have also found potential applications as injection, or
inhalation products.
Most encapsulation processes are expensive and require significant capital
investment for equipment.
An additional expense is due to the fact that most microencapsulation
processes are patent protected.
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OTHER APPLICATIONS
Microcapsules are also extensively used as diagnostics.
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 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.
Paramedical uses of microcapsules include bandages with
microencapsulated anti-infective substances.
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QUESTIONS:
1. Short notes on magnetic microspheres. 5M
2. Enlist the different methods of preparation of microspheres. Explain any
2 methods. 10M x 2
3. Write a note on types of microspheres. 5M
4. Evaluation of microspheres and give its applications. 10M
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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.
➢ N.K.Jain ,Controlled and novel drug delivery edited by reprint 2007
pg.no.236-255.
➢ Review article by Kadam N.R and Suvarna
➢ IMAGE SOURCE:- WWW.GOOGLE.COM
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