MICROSPHERES: AN OVERVIEW

www.wjpr.net Vol 6, Issue 7, 2017.

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Chavan et al. World Journal of Pharmaceutical Research

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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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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MICROSPHERES: AN OVERVIEW