microspheres: an overview
TRANSCRIPT
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MICROSPHERES: AN OVERVIEW
M. S. Chavan*, S. A. Nikam and P. R. Mahaparale
Dr. D. Y. Patil College of Pharmacy, Akurdi, Pune- 411 044, Maharashtra, India.
ABSTRACT
The aim of drug delivery system is to provide a therapeutic amount of
drug to the proper site in the body and then maintain the desired drug
concentration. The controlled drug delivery system can overcome few
drawbacks of conventional therapy and enhance therapeutic efficacy of
the given drug. There are various approaches in delivering therapeutic
substance to the target site in sustained and controlled release fashion.
One such approach is using microspheres as carriers for drug.
Microspheres or microparticles are small spherical particles, with
diameters in the micrometer range (typically 1 μm to 1000 μm).
Microspheres are prepared by synthetic and natural materials. These
are prepared by methods like Single emulsion, Double emulsion, Polymerization, Phase
separation, Emulsion solvent evaporation and solvent diffusion. Microspheres are having
wide range of applications because of controlled and sustained release. It is important carrier
for safe and effective in vivo drug delivery.
KEYWORDS: Microspheres, Characterization of microspheres, Controlled release, Target
site, Specificity, Therapeutic efficacy, Novel drug delivery.
DEFINITION[1]
Microspheres are small spherical particles, with diameters in the micrometer range (typically
1 μm to 1000 μm). Microspheres are sometimes referred to as micro particles. Microspheres
can be manufactured from various natural and synthetic materials. Glass microspheres,
polymer microspheres and ceramic microspheres are commercially available. Solid and
hollow microspheres vary widely in density and therefore, are used for different applications.
Hollow microspheres are typically used as additives to lower the density of a material.
World Journal of Pharmaceutical Research SJIF Impact Factor 7.523
Volume 6, Issue 7, 431-444. Review Article ISSN 2277– 7105
*Corresponding Author
Dr. M. S. Chavan
Dr. D. Y. Patil College of
Pharmacy, Akurdi, Pune- 411
044, Maharashtra, India.
Article Received on
03 May 2017,
Revised on 23 May 2017,
Accepted on 12 June 2017
DOI: 10.20959/wjpr20177-8618
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Chavan et al. World Journal of Pharmaceutical Research
PROPERTIES OF MICROSPHERES[1]
Table 1- Properties of Microspheres
Sr.No. Properties Consideration
1 Size Diameter/uniformity/distribution.
2 Composition
Density
Refractive index
Hydrophobicity/hydrophillicity
Non-specific binding
Autofluorescence
3 Surface chemistry Reactive group
Charge
4 Special properties Visible dye
Super paramagnetic.
MATERIAL FOR MICROSPHERE PREPARATION[2]
Polymers used in microspheres preparation are majorily classified in to two types:-
1. Natural polymers
These are obtained from different natural sources like carbohydrates proteins and chemically
modified Carbohydrates: Poly (acryl) dextran, Poly (acryl) starch
Ex. Carbohydrates likes Agarose, Carrageenan, Chitosan, Starch
Chemically modified Carbohydrates: Poly (acryl) dextran, Poly (acryl) starch
2. Synthetic Polymers
Ex. Non-biodegradable polymers such as Poly methyl methacrylate(PMMA), Acrolein,
Epoxy polymer.
Biodegradable polymers such latides and copolymer polyunhydride, Polyalkyl cyno acrylate
ADVANTAGES[2,3,4]
1. Microspheres provide constant and prolonged therapeutic effect.
2. It reduces the dosing frequency and finally improves the patient compliance.
3. They can be injected into the body due to the spherical shape and smaller size.
4. Better drug utilization will improve the bioavailability and reduce intensity of adverse
effects.
5. Microsphere morphology allows a controllable variability in degradation and drug release.
LIMITATION[3]
1. The modified release from the formulations.
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2. The release rate of the controlled release dosage form may vary from a variety of factors
like food and the rate of transit though gut.
3. Differences in the release rate from one dose to another.
4. Controlled release formulations generally contain a higher drug load and thus any loss of
integrity of the release characteristics of the dosage form may lead to potential toxicity.
5. Dosage forms of this kind should not be crushed or chewed.
TYPES OF MICROSPHERES[5,6]
A. Polymeric microspheres
The different types of polymeric microspheres can be classified as follows and they are
biodegradable polymeric microspheres and Synthetic polymeric microspheres.
Biodegradable polymeric microspheres
Natural polymers such as starch are used as they are biodegradable, biocompatible and also
bio adhesive in nature. It prolongs the residence time when come in contact with mucous
membrane because of its high degree of swelling property with aqueous medium, results gel
formation. The rate and extent of drug release is controlled by polymer concentration and
release in a sustained manner. The main drawback, its loading efficiency is very complex and
is difficult to control the drug release. However they provide wide range of application in
microsphere based treatment.
Synthetic polymeric microspheres
The synthetic polymeric microspheres are widely used for clinical application. It is used as
bulking agent, fillers, embolic particles, drug delivery vehicles etc. It is proved to be safe and
biocompatible. But the main disadvantage of these kinds of microspheres, are tendency to
migrate away from injection site and lead to potential risk, embolism and further organ
damage.
B. Bioadhesive microspheres
Adhesion can be defined as sticking of drug to the membrane by using the sticking property
of the water soluble polymers. Adhesion of drug delivery device to the mucosal membrane
such as buccal, ocular, rectal, nasal, oral etc can be termed as bio adhesion. That 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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C. 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, if the system is floating on gastric content and increases gastric residence and increases
fluctuation in plasma concentration. Moreover it also reduces chances of striking and dose
dumping, produces prolonged therapeutic effect and therefore reduces dosing frequencies.
Drug like ketoprofen is given through this form.
D. Radioactive microspheres
Radio remobilization therapy microspheres sized 10-30 nm are of larger than capillaries and
gets tapped in first capillary bed when they come across. They are injected to the aretries that
lead to tumor of interest. All these conditions radioactive microspheres deliver high radiation
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 typical distance and the different kinds of radioactive microspheres are α
emitters, β emitters, γ emitters.
E. Magnetic microspheres
This kind of delivery system is very important as it localizes 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 such as chitosan, dextran etc. It is divided into two types such as.
Diagnostic radioactive microspheres
Diagnostic studies with radiopharmaceuticals include dynamic and static imaging and in vivo
function tests. Dynamic imaging provides information about the biodistribution and
pharmacokinetics of drugs in organs. Performed with a γ-camera, dynamic studies are
generally carried over preset length of time and provide clues to the functioning of the organ
being examined. The first such microsphere in clinical use was red and white blood cells,
which were taken from a patient, labeled with 111In or 51Cr and then re-injected. Red blood
cells labeled with 51Cr commonly used for the measurement of red blood cell mass and
imaging of the spleen. Another common application of radiolabel led red blood cells is the
accurate determination of total systemic arterial flow or venous return, as well as for blood
flow determination within specific organs. 20 various diagnostic applications of radioactive
microspheres. It may be used for imaging liver metastases and also can be used to distinguish
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bowel loops from other abdominal structures by forming nano size particles supramagnetic
iron oxides.
Therapeutic magnetic microspheres
Magnetic targeting can be used to deliver chemotherapeutic drugs to liver tumors and also
therapeutic radio isotopes. Drugs like proteins and peptides can also be targeted through this
system. The advantage of this method over external beam therapy is that the dose can be
increased, resulting in improved tumor cell eradication, without harm to nearby normal
tissue. Magnetic targeted carriers which are more magnetically responsive iron carbon
particles have been radio labeled with isotopes. Similar to chemotherapeutic drugs, many
other drugs including peptides and proteins can be absorbed or encapsulated into magnetic
microspheres. A very recent development in the field of magnetic targeting is the use of
magnetically enhanced gene therapy. Advantages of such an approach are targeted gene
transfect ion at rapid speed and high efficiencies. The magnetic component in microspheres
can also be used for purposes other than targeting. This is possible by filling an additional
magnetic component into capsules or tablets. The speed of travel through the stomach and
intestines can then be slowed down at specific positions by an external magnet, thus changing
the timing and/or extent of drug absorption in stomach or intestines.
METHOD OF PREPARATION OF MICROSPHERES[1]
Polymerization Techniques
The polymerization technique conventionally used for the preparation of the microspheres are
classified as
1. Normal polymerization.
2. Interfacial polymerization.
1. Normal polymerization
The two processes are carried out in a liquid phase. Normal polymerization is carried out
using different techniques as bulk, suspension precipitation, emulsion and micelle
polymerization process.
In bulk polymerization, a monomer or a mixture of monomer along with the initiator is
usually heated to initiate the polymerization and carry out the process. The catalyst or the
inhibitor is added to the reaction mixture to facilitate or accelerate the rate of reaction. The
polymer so obtained may be molded to microsphere.
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The suspension of polymerization which is also referred as the bead or pearl polymerization
is carried out by heating the monomer or mixture of monomer as droplets dispersion in a
continuous aq. Phase. The droplets may also contain an initiator and other additives.
Emulsion polymerization differs from suspension polymerization as due to the presence
initiator in the aqueous phase, which later on diffuses to the surface of micelles.
2. 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. In this technique two reacting monomers are employed, one of
which is dissolved in the continuous phase while the other being dispersed in the continuous
phase the continuous phase is generally aq. in nature throughout which the second monomer
is emulsified. The polymerization reaction can be controlled by maintaining the concentration
of the monomers, which can be achieved by the addition of an excess of the continuous
phase. The monomer present in either phases diffuse rapidly at the interface. Two condition
arise depending upon the solubility of formed polymer in the emulsion droplets it will lead to
the formation of the monolithic type of the carrier is of capsular (reservoir) type. Drawback
which are associated with the process such as
1. Toxicity associated with the unreacted monomer.
2. High permeability of the film.
3. High degradation of the drug during the polymerization.
4. Fragility of microcapsules.
5. Non-biodegradability of the micro particles.
Double emulsion technique
It involves the formation of the multiple emulsions or the double emulsion of type w/o/w. It
is best suited to the water –soluble drugs peptides, proteins and the vaccines. This method can
be used both the natural as well as the synthetic polymers. The proteins solution is dispersed
in a lipophilic organic contain the active constituents phase. The continuous phase is
generally consisted of the polymer solution that eventually encapsulated of the protein
contained in dispersed aq. Phase. The primary emulsion is then subjected to the
homogenization or sonication before addition to the aq. solution of the polyvinyl alcohol
(PVP). This result in the formation of a double emulsion. The solvent evaporation is carried
out by maintaining emulsion at reduced pressure or by stirring the emulsion so that the
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organic phase evaporates out. In the latter case, the emulsion is added to the large quantity of
water [with or without surfactant] into which organic phase diffuse out. The solid
microspheres are obtained by filtration and washing a no. of hydrophilic drugs.
4. Emulsion solvent evaporation technique
In this technique the drug is dissolved in polymer which was previously dissolved in
chloroform and the resulting solution is added to aqueous phase containing 0.2% sodium of
PVP as emulsifying agent. The above mixture was agitated at 500 rpm then the drug and
polymer (eudragit) was transformed into fine droplet which solidified into rigid microspheres
by solvent evaporation and then collected by filtration and washed with demineralised water
and desiccated at room temperature for 24 hrs.
Emulsion cross linking method
In this method drug was dissolved in aqueous gelatin solution which was previously heated
for 1 hr at 40◦C. The solution was added drop wise to liquid paraffin while stirring the
mixture at 1500 rpm for 10 min at 35◦C, results in w/o emulsion then further stirring is done
for 10 min at 15◦ C. Thus microspheres were washed respectively three times with acetone
and isopropyl alcohol which then air dried and dispersed in 5ml of aqueous glutaraldehyde
saturated toluene solution at room temperature for 3 hrs for cross linking and then was treated
with 100ml of 10ml glycine solution containing 0.1%w/v of tween 80 at 37◦C for 10 min to
block untreated glutaraldehyde. Examples for this technique is Gelatin A microspheres.
Co-acervation method
In closed beaker with magnetic stirring for 6 hr at 500 rpm and the drug is dispersed in it and
stirring is continued for 15 mins. Then phase separation is done by petroleum benzoin 5 times
with continuous stirring. After that the microcapsules were washed with n-hexane and air
dried for 2 hr and then in oven at 50◦c for 4 hr. Specially designed for preparing the reservoir
type of the system, i.e., to encapsulate water soluble drugs e.g. peptides, proteins, matrix type
particularly, when the drug is hydrophobic in nature e.g., steroids. In matrix type device, the
drug or the protein is soluble in the polymer phase. The process is based on the principle of
decreasing the solubility of the polymer in the organic phase to affect the formation of the
polymer rich phase called the coacervates. The coacervation can be brought about by addition
of the third component to the system which results in the formation of the two phases.
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Spray drying and spray congealing technique
These methods are based on the drying of the mist of the polymer and drug in the air.
Depending upon the removal of the solvent or cooling of the solution, the two processes are
named spray drying and spray congealing respectively. The polymer is first dissolved in a
suitable volatile organic solvent such as dichloromethane, acetone, alcohol etc. The drug in
the solid form is then dispersed in the polymer solution under high speed homogenization.
This dispersion is then atomized in a stream of hot air. The atomization leads to the formation
of small droplets or fine mist from which the solvent evaporates instantaneously leading to
the formation of the microspheres in a size range 1- 100 µm. Microparticles are separated
from the hot air by means of the cyclone separator while the traces of solvent are removed by
vacuum drying. One of the major advantages of the process is feasibility of operation under
aseptic conditions.
Spray drying
The polymer is first dissolved in a suitable volatile organic solvent such as dichloromethane,
acetone, alcohol etc The drug in the solid form is then dispersed in the polymer solution
under high speed homogenization. This dispersion is then atomized in a stream of hot air. The
atomization leads to the formation of small droplets or fine mist from which the solvent
evaporates instantaneously leading to the formation of the microspheres in a size range 1- 100
µm. Microparticles are separated from the hot air by means of the cyclone separator while the
traces of solvent are removed by vacuum drying. One of the major advantages of the process
is feasibility of operation under aseptic conditions.
Figure 1- Spray drying method
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Emulsion-solvent diffusion technique
In order to improve the residence time in colon floating microparticles were prepared using
emulsion solvent diffusion technique. The drug polymer mixture was dissolved in a mixture
of ethanol and dichloromethane (1:1) and then the mixture was added drop wise to Sodium
Lauryl Sulphate (SLS) solution. The solution was stirred with propeller type agitator at room
temperature at 150 rpm for 1 hr. Thus the formed floating microspheres were washed and
dried in desiccators at room temperature. The microparticles were sieved and collected.
Multiple emulsion method
In this method the powdered drug was dispersed in solution (methyl cellulose) followed by
emulsification in ethyl cellulose solution in ethyl acetate. The primary emulsion was then re-
emulsified in aqueous medium. Under optimized condition discrete microspheres formed
during this phase.
Ionic gelation
Alginate/chitosan particulate system is used in this method. The solution of drug stirred
continuously in an aqueous solution of sodium alginate, to get the complete solution and after
that it was added drop wise to a solution containing Ca2+ /Al3
+ and chitosan solution in acetic
acid. Microspheres which formed are kept in original solution for 24 hr for internal
jellification followed by filtration for separation.
Figure 2- Ionic Gelation Method
Hydroxyl appetite (HAP) microspheres in sphere morphology
This was used to prepare microspheres with peculiar spheres in morphology.
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Microspheres prepared by o/w emulsion followed by solvent evaporation. At first o/w
emulsion was prepared by dispersing the organic phase in aqueous phase of surfactant. The
organic phase was dispersed in the form of tiny droplets which were surrounded by surfactant
molecules, this prevented the droplets from cosolvencing and helped them to stay individual
droplets. While stirring the organic phase slowly evaporated and the droplets solidify
individual to become microspheres.
CHARACTERIZATION/EVALUATION OF MICROSPHERES
Particle size analyzer
This is done by suspending the microsphere in distilled water (5ml) containing 2%w/v of
tween 80, to prevent microsphere aggregation, the above suspension is sonicated in water
bath and the particle size was expressed as volume mean diameter in micrometer.
Optical microscopy
This method was used to determine particle size by using optical microscope. The
measurement was done under 450x (10x eyepiece and 45x objective) and100 particles
calculated.
Scanning electron microscopy (SEM)
Surface morphology is determined by SEM. In this microcapsule is mounted directly on the
SEM sample slub with the help of double sided sticking tape and coated with gold film under
reduced pressure.
Swelling index
This technique is use for Characterization of sodium alginate microspheres is perform with
swelling index technique Different solution (100mL) is taken such as (distilled water, buffer
solution of pH(1.2, 4.5, 7.4) is take and alginate microspheres (100mg) is place in a wire
basket and keep on the above solution and swelling is allow at 370C and changes in weight
variation between initial weight of microspheres and weight due to swelling is measure by
taking weight periodically and soaking with filter paper.
Entrapment efficiency
Microspheres containing of drug are crushed and then dissolved in distilled water with the
help of ultrasonic stirrer for 3 hr, and is filter then assayed by UV -visible spectroscopy.
Entrapment efficiency is equal to ratio of actual drug content to theoretical drug content.
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X-ray diffraction
Change in crystalinity of drug can be determined by this technique. Microparticles and its
individual components are analyzed by the help of D & discover (Bruker, Germony).
Scanning range angle between 80C - 70
0C. Scan speed – 4
0/min Scintillation detector
Primary silt=1mm Secondary silt=0.6 mm.
Thermal analysis
Thermal analysis of microcapsule and its component can be done by using- Differential
Scanning Calorimetry (DSC). Accurately sample was weighed and heated on alumina pan at
constant rate of 10◦c/min under nitrogen flow of 40 ml/min.
FTTR (Fourier Transform Infra Red)
The drug polymer interaction and also degradation of drug while processing for
microencapsulation can be determined by FTIR.
Stability studies
By placing the microspheres in screw capped glass container and stored them at following
conditions:
1. Ambient humid condition
2. Room temperature (27+/-2 0C)
3. Oven temperature (40+/-2 0C)
4. Refrigerator (5 0C -80C).
It was carried out of a 60 days and the drug content of the microsphere is analyzed.
Zeta potential
The polyelectrolyte shell is prepared by incorporating chitosan of different molecular weight
into the W2 phase and the resulting particles were determined by zeta potential measurement.
APPLICATIONS OF MICROSPHERES[7]
The brief outlines of various applications of microspheres are explained as follows:
1. Microspheres in vaccine delivery
The prerequisite of a vaccine is protection against the microorganism or its toxic product.
Biodegradable delivery systems for vaccines that are given by parenteral route may overcome
the shortcoming of the conventional vaccines.
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2. Topical porous microspheres
These microsponges having capacity to entrap wide range of active ingredients such as
emollients, fragrances, essential oils etc., are used as the topical carries system further, these
porous microspheres with active ingredients can be incorporated into formulations such as
creams, lotions and powders.
3. Targeting using micro particulate carriers
The concept of targeting, i.e. site specific drug delivery is a well-established dogma, which is
gaining full attention. The therapeutic efficacy of the drug relies on its access and specific
interaction with its candidate receptors.
4. Surface modified microspheres
Different approaches have been utilized to change the surface properties of carriers to protect
them against phagocytic clearance and to alter their body distribution patterns. Protein
microspheres covalently modified by PEG derivatives show decreased immunogenicity and
clearance.
6. Imaging
The microspheres have been extensively studied and used for the targeting purposes. Various
cells, cell lines, tissues and organs can be imaged using radio labeled microspheres.
7. Monoclonal antibodies mediated microspheres
Monoclonal antibodies targeting microspheres are immunomicrospheres. This targeting is a
method used to achieve selective targeting to the specific sites.
Medicinal and radioactive application of microspheres
Medical application
1. Release proteins, hormones and peptides over extended period of time.
2. Gene therapy with DNA plasmids and also delivery of insulin.
5. Tumour targeting with doxorubicin and also treatments of leishmaniasis.
6. Magnetic microspheres can be used for stem cell extraction and bone marrow purging.
8. Used for various diagnostic tests for infectious diseases like bacterial, viral and fungal.
Radioactive microsphere’s application
1. Can be used for radioembolisation of liver and spleen tumors.
2. Used for radiosynvectomy of arthritis joint, local radiotherapy, interactivity treatment.
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3. Imaging of liver, spleen, bone marrow, lung etc and even imaging of thrombus in deep
vein Thrombosis can be done.
Marketed preparations of microspheres
Table 2- Marketed Preparation
Sr.No Marketed preparation Company Drug (API)
1 Lupron depot TAP Leuprolide
2 Enantone depot Takeda Leuprolide
3 Trenantone Takeda Leuprolide
4 Trelstar depot Pfizer Triptorelin
5 Decapeptyl Ferring Triptorelin
CONCLUSION
Microsphere is a short term but it is having wide applications in drug delivery systems. Most
important are the targeted drug delivery (Bioadhesive microspheres-nasal, ocular, buccal,
rectal etc., Magnetic microspheres and Radioactive micospheres – For tumours), Controlled
and sustained drug delivery (Polymeric microspheres, Floating microspheres). By combining
various strategies, microspheres will find central place in novel drug delivery mainly
particularly in cell sorting, diagnostics and Genetic engineering. From the study it is proved
that Microspheres act as effective carriers for the novel drug delivery system.
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