MICROSPHERES A MAGICAL NOVEL DRUG DELIVERY SYSTEM: A … · Drug delivery systems (DDS) that can precisely control the release rates or target drugs to a specific body site have had

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Preeti et al. World Journal of Pharmacy and Pharmaceutical Sciences

MICROSPHERES A MAGICAL NOVEL DRUG DELIVERY SYSTEM:

A REVIEW

*Preeti Agrawal1, Sarlesh Rajput1, Ashish pathak1, Nikhil Shrivastava2, Satyendra

Singh Baghel2, Rajendra singh Baghel2

1Department of Pharmaceutics, ShriRam College of Pharmacy, Morena, M.P., India

2Department of Pharmacology, ShriRam College of Pharmacy, Morena, M.P., India

ABSTRACT

Drug delivery systems (DDS) that can precisely control the release

rates or target drugs to a specific body site have had an enormous

impact on the health care system. So the concept of targeted drug

delivery is designed for attempting to concentrate the drug in the

tissues of interest while reducing the relative concentration of the

medication in the remaining tissues. As a result, drug is localized on

the targeted site. Hence, surrounding tissues are not affected by the

drug. So, carrier technology offers an intelligent approach for drug

delivery by coupling the drug to a carrier particle such as

microspheres, nanoparticles, liposomes, etc which modulates the

release and absorption characteristics of the drug. Among these drug

delivery system we are selecting microspheres of various types which

will be controlled release and which can be made specific site targeted

by giving some specific characteristic to it like mucoadhesion character or by inserting any

magnetic or radioactive material as a result of which it will show site specific action. So this

article emphasis on different types of microspheres as a controlled and targeted drug delivery

system.

Keywords: Microsphere, target site, Specificity, controlled release.

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Article Received on 25 May 2012, Revised on 02 June 2012, Accepted on 07 June 2012

*Correspondence for

Author:

* Preeti Agrawal

Department of Pharmaceutics

ShriRam College of Pharmacy.

Banmore, Morena M.P. India.

[email protected]

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INTRODUCTION

The method by which a drug is delivered can have a significant effect on its efficacy. Some

drugs have an optimum concentration range within which maximum benefit is derived, and

concentrations above or below this range can be toxic or produce no therapeutic benefit at

all.[1] On the other hand, the very slow progress in the efficacy of the treatment of severe

diseases, has suggested a growing need for a multidisciplinary approach to the delivery of

therapeutics to targets in tissues. From this, new ideas on controlling the pharmacokinetics,

pharmacodynamics, non-specific toxicity, immunogenicity, biorecognition, and efficacy of

drugs were generated. These new strategies, often called drug delivery systems (DDS), are

based on interdisciplinary approaches that combine polymer science, pharmaceutics,

bioconjugate chemistry, and molecular biology.

To minimize drug degradation and loss, to prevent harmful side-effects and to increase drug

bioavailability and the fraction of the drug accumulated in the required zone, various drug

delivery and drug targeting systems are currently under development. Among drug carriers

one can name soluble polymers, microparticles made of insoluble or biodegradable natural

and synthetic polymers, microcapsules, cells, cell ghosts, lipoproteins, liposomes, and

micelles. The carriers can be made slowly degradable, stimuli-reactive (e.g., pH- or

temperature-sensitive), and even targeted (e.g., by conjugating them with specific antibodies

against certain characteristic components of the area of interest.[1, 2]

Controlled drug release and subsequent biodegradation are important for developing

successful formulations. Potential release mechanisms involve:

Desorption of surface-bound /adsorbed drugs;

Diffusion through the carrier matrix;

Diffusion (in the case of nanocapsules) through the carrier wall;

Carrier matrix erosion; and

A combined erosion /diffusion process.

A well designed controlled drug delivery system can overcome some of the problems of

conventional therapy and enhance the therapeutic efficacy of a given drug.

To obtain maximum therapeutic efficacy, it becomes necessary to deliver the agent to the

target tissue in the optimal amount in the right period of time there by causing little toxicity

and minimal side effects.

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There are various approaches in delivering a therapeutic substance to the target site in a

sustained controlled release fashion. One such approach is using microspheres as carriers for

drugs.[3, 4]

Drug delivery systems (DDS) that can precisely control the release rates or target drugs to a

specific body site have had an enormous impact on the health care system.[5] The ideal drug

delivery system delivers drug at rate decided by the need of the body throughout the period of

treatment and it provides the active entity solely to the site of action.

The concept of targeted drug delivery is designed for attempting to concentrate the drug in

the tissues of interest while reducing the relative concentration of the medication in the

remaining tissues. As a result, drug is localized on the targeted site. Hence, surrounding

tissues are not affected by the drug. In addition, loss of drug does not happen due to

localization of drug, leading to get maximum efficacy of the medication.

So, carrier technology offers an intelligent approach for drug delivery by coupling the drug to

a carrier particle such as microspheres, nanoparticles, liposomes, etc which modulates the

release and absorption characteristics of the drug.

Microspheres constitute an important part of these particulate DDS by virtue of their small

size and efficient carrier characteristics. These are characteristically free flowing powders

consisting of proteins or synthetic polymers which are biodegradable in nature and ideally

having a particle size less than 200µm

.

Figure -1 Microscopic view of Microspheres

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Figure-2 SEM View of Microspheres

Properties of an Ideal microsphere

Preparation of microspheres should satisfy certain criteria:

1. The ability to incorporate reasonably high concentrations of the drug.

2. Stability of the preparation after synthesis with a clinically acceptable shelf life.

3. Controlled particle size and dispersability in aqueous vehicles for injection.

4. Release of active reagent with a good control over a wide time scale.

5. Biocompatibility with a controllable biodegradability and

6. Susceptibility to chemical modification.

TYPES OF MICROSPHERE

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I. 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 etc can be termed as bioadhesion.[8] The term

“bioadhesion” describes materials that bind to biological substrates, such as mucosal

membranes. Adhesion of bioadhesive drug delivery devices to the mucosal tissue offers the

possibility of creating an intimate and prolonged contact at the site of administration. This

prolonged residence time can result in enhanced absorption and in combination with a

controlled release of drug also improved patient compliance by reducing the frequency of

administration.

Bioadhesive microspheres can be tailored to adhere to any mucosal tissue including those

found in eye, nasal cavity, urinary, colon and gastrointestinal tract, thus offering the

possibilities of localized as well as systemic controlled release of drugs.[7]

II. 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 type are Therapeutic magnetic microspheres: Are used to deliver

chemotherapeutic agent to liver tumour.

Diagnostic microspheres: Can be used for imaging liver metastases and also can be used to

distinguish bowel loops from other abdominal structures by forming nano size particles

supramagnetic iron oxides.[8]

The aim of the specific targeting is to enhance the efficiency of drug delivery & at the same

time to reduce the toxicity & side effects. Magnetic drug transport technique is based on the

fact that the drug can be either encapsulated into a magnetic microsphere or conjugated on

the surface of the microsphere. When the magnetic carrier is intravenously administered, the

accumulation take place within area to which the magnetic field is applied & often

augmented by magnetic agglomeration. The accumulation of the carrier at the target site

allow them to deliver the drug locally. Efficiency of accumulation of magnetic carrier on

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physiological carrier depends on physiological parameters eg. particle size, surface

characteristic, field strength, & blood flow rate etc. The magnetic field helps to extravasate

the magnetic carrier into the targeted area. Very high concentration of chemotherapeutic

agents can be achieved near the target site without any toxic effect to normal surrounding

tissue or to whole body. It is possible to replace large amounts of drug targeted magnetically

to localized disease site, reaching effective and up to several fold increased drug levels. This

technique which requires only a simple injection, is far less invasive than surgical methods of

targeted drug delivery. Another advantage is that particles in the magnetic fluid interact

strongly with each other, which facilitates the delivery of high concentrations of drug to

targeted areas.

Magnetic microspheres can be filled with drugs or radioactive materials to treat a variety of

illnesses. Magnets applied outside the body attract the spheres to the disease site where they

deliver therapeutics in a targeted way. The magnets attract the microspheres to the immediate

area of the wound site and stop them there. The spheres gradually break down and release

growth factors over a period of weeks, allowing blood vessels and damaged tissues to re-

grow and repair.

Small amounts of drug targeted magnetically to localized sites can replace large doses of drug

that, using traditional administration methods, freely circulate in the blood and hit the target

site in a generalized way only.[9]

III. 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. One another way it produces prolonged therapeutic effect and therefore reduces

dosing frequencies. Drug (ketoprofen) given through this form.[8]

IV. Radioactive microspheres

Radio emobilisation therapy microspheres sized 10-30nm are of larger than capillaries and

gets tapped in first capillary bed when they come across. They are injected to the arteries that

lead to tumor of interest. So all these conditions radioactive microspheres deliver high

radiation dose to the targeted areas without damaging the normal surrounding tissues. It

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differs from drug delivery system, as radioactivity 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.

It offer new solutions for patients who need drugs delivered directly to tumors, diabetic ulcers

and other disease sites.[8]

V. Mucoadhesive microspheres

Mucoadhesive microspheres which are of 1-1000mm in diameter and consisting either

entirely of a mucoadhesive polymer or having an outer coating of it, respectively.

Microspheres, in general, have the potential to be used for targeted and controlled release

drug delivery; but coupling of mucoadhesive properties to microspheres has additional

advantages, e.g. efficient absorption and enhanced bioavailability of the drugs due to a high

surface to volume ratio, a much more intimate contact with the mucus layer, specific

targeting of drug to the absorption site achieved by anchoring plant lectins, bacterial

adhesions and antibodies, etc. on the surface of the microspheres.

Mucoadhesive microspheres can be tailored to adhere to any mucosal tissue including those

found in eye, nasal cavity, urinary and gastrointestinal tract, thus offering the possibilities of

localized as well as systemic controlled release of drugs.

Advantages of mucoadhesive system

Mucoadhesive systems have three distinct advantages when compared to conventional dosage

forms.

The mucoadhesive systems are readily localized in the region applied to improve and

enhance the bioavailability of drugs. Greater bioavailability of piribedit, testosterone

and its esters, vasopressin, dopamine, insulin and gentamycin was observed from

mucoadhesive dosage systems.

These dosage forms facilitate intimate contact of the formulation with underlying

absorption surface. This allows modification of tissue permeability for absorption of

macromolecules, such as peptides and proteins. Inclusion of penetration enhancers

such as sodium glycocholate, sodium taurocholate and L-lysophosphotidyl choline

(LPC) and protease inhibitors in the mucoadhesive dosage forms resulted in the

better absorption of peptides and proteins.

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Mucoadhesive dosage forms also prolong residence time of the dosage form at the

site of application and absorption to permit once or twice a day dosing.[5]

METHOD OF PREPRATION

Various methods employed in its preparation are

Single Emulsification Technique

Double Emulsification Technique

Normal Polymerization Technique

Bulk polymerization

Suspension polymerization

Emulsion polymerization

Interfacial Polymerization Technique

Phase Separation Coacervation Technique

Spray Drying and Spray Congealing Technique

Solvent Extraction Method

Solvent Evaporation

Wet Inversion Technique

Complex Coacervation

Hot Melt Microencapsulation

1. Single emulsion technique

The micro particulate carriers of natural polymers i.e. those of proteins and carbohydrates are

prepared by single emulsion technique. The natural polymers are dissolved or dispersed in

aqueous medium followed by dispersion in non-aqueous medium like oil. Next cross linking

of the dispersed globule is carried out. The cross linking can be achieved either by means of

heat or by using the chemical cross linkers. The chemical cross linking agents used are

glutaraldehyde, formaldehyde, di acid chloride etc. Heat denaturation is not suitable for

thermolabile substances. Chemical cross linking suffers the disadvantage of excessive

exposure of active ingredient to chemicals if added at the time of preparation and then

subjected to centrifugation, washing, separation.[3]

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Fig 3: Processing scheme for microspheres-preparation by single emulsion technique.

2. Double emulsion technique

Double emulsion method of microspheres preparation involves the formation of the multiple

emulsion or the double emulsion of type w/o/w and is best suited to water soluble drugs,

peptides, proteins and the vaccines. This method can be used with both the natural as well as

synthetic polymers. The aqueous protein solution is dispersed in a lipophilic organic

continuous phase. This protein solution may contain the active constituents. The continuous

phase is generally consisted of the polymer solution that eventually encapsulates of the

protein contained in dispersed aqueous phase. The primary emulsion is subjected then to the

homogenization or the sonication before addition to the aqueous solution of the poly vinyl

alcohol (PVA). This results in the formation of a double emulsion. The emulsion is then

subjected to solvent removal either by solvent evaporation or by solvent extraction a number

of hydrophilic drugs like leutinizing hormone releasing hormone (LH-RH) agonist, vaccines,

proteins/peptides and conventional molecules are successfully incorporated into the

microspheres using the method of double emulsion solvent evaporation/ extraction.

Fig 4: Processing scheme for microspheres-preparation by double emulsion technique

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3. Polymerization techniques

The polymerization techniques conventionally used for the preparation of the microspheres

are mainly classified as:

I. Normal polymerization

II. Interfacial polymerization. Both are carried out in liquid phase.

Normal polymerization

It is carried out using different techniques as bulk, suspension, precipitation, emulsion and

micellar polymerization processes. In bulk, a monomer or a mixture of monomers along with

the initiator or catalyst is usually heated to initiate polymerization. Polymer so obtained may

be moulded as microspheres. Drug loading may be done during the process of

polymerization.

Suspension polymerization also referred as bead or pearl polymerization. Here it is carried

out by heating the monomer or mixture of monomers as droplets dispersion in a continuous

aqueous 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. Bulk polymerization has an

advantage of formation of pure polymers.

Interfacial polymerization

It involves the 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.

Fig 5: Polymerization method

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4. Phase separation coacervation technique

This process is based on the principle of decreasing the solubility of the polymer in organic

phase to affect the formation of polymer rich phase called the coacervates. In this method, the

drug particles are dispersed in a solution of the polymer and an incompatible polymer is

added to the system which makes first polymer to phase separate and engulf the drug

particles. Addition of non-solvent results in the solidification of polymer. Poly lactic acid

(PLA) microspheres have been prepared by this method by using butadiene as incompatible

polymer. The process variables are very important since the rate of achieving the coacervates

determines the distribution of the polymer film, the particle size and agglomeration of the

formed particles. The agglomeration must be avoided by stirring the suspension using a

suitable speed stirrer since as the process of microspheres formation begins the formed

polymerize globules start to stick and form the agglomerates. Therefore the process variables

are critical as they control the kinetic of the formed particles since there is no defined state of

equilibrium attainment.

5. Spray drying and spray congealing

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, 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

the small droplets or the fine mist from which the solvent evaporates instantaneously leading

the formation of the microspheres in a size range 1-100µm. 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. The spray drying process is used to encapsulate various penicillins.

Thiamine mononitrate and sulpha ethylthiadizole are encapsulated in a mixture of mono- and

diglycerides of stearic acid and palmitic acid using spray congealing. Very rapid solvent

evaporation, however leads to the formation of porous microparticles.

6. Solvent extraction

Solvent evaporation method is used for the preparation of microparticles, involves removal of

the organic phase by extraction of the organic solvent. The method involves water miscible

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organic solvents such as isopropanol. Organic phase is removed by extraction with water.

This process decreases the hardening time for the microspheres. One variation of the process

involves direct addition of the drug or protein to polymer organic solution. The rate of solvent

removal by extraction method depends on the temperature of water, ratio of emulsion volume

to the water and the solubility profile of the polymer.[3]

Fig 6. Spray drying method for preparation of microsphere.

Solvent Evaporation

The processes are carried out in a liquid manufacturing vehicle. The microcapsule coating is

dispersed in a volatile solvent which is immiscible with the liquid manufacturing vehicle

phase. A core material to be microencapsulated is dissolved or dispersed in the coating

polymer solution. With agitation the core material mixture is dispersed in the liquid

manufacturing vehicle phase to obtain the appropriate size microcapsule. The mixture is then

heated if necessary to evaporate the solvent for the polymer of the core material is disperse in

the polymer solution, polymer shrinks around the core. If the core material is dissolved in the

coating polymer solution, matrix – type microcapsules are formed. The solvent Evaporation

technique is shown in Figure-7. The core materials may be either water soluble or water

insoluble materials. Solvent evaporation involves the formation of an emulsion between

polymer solution and an immiscible continuous phase whether aqueous (o/w) or non-

aqueous.

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Fig 7. Solvent evaporation method for preparation of microsphere.

Wet Inversion Technique

Chitosan solution in acetic acid was dropped into an aqueous solution of counter ion sodium

tripolyposphate through a nozzle. Microspheres formed were allowed to stand for 1hr and

cross linked with 5% ethylene glycol diglysidyl ether. Microspheres were then washed and

freeze dried. Changing the pH of the coagulation medium could modify the pore structure of

CS microspheres.

Complex Coacervation

CS microparticles can also prepare by complex coacervation, Sodium alginate, sodium CMC

and sodium polyacrylic acid can be used for complex coacervation with CS to form

microspheres. These microparticles are formed by interionic interaction between oppositely

charged polymers solutions and KCl & CaCl2 solutions. The obtained capsules were

hardened in the counter ion solution before washing and drying.

Hot Melt Microencapsulation

The polymer is first melted and then mixed with solid particles of the drug that have been

sieved to less than 50µm. The mixture is suspended in a non-miscible solvent (like silicone

oil), continuously stirred, and heated to 5°C above the melting point of the polymer. Once the

emulsion is stabilized, it is cooled until the polymer particles solidify. The resulting

microspheres are washed by decantation with petroleum ether. The primary objective for

developing this method is to develop a microencapsulation process suitable for the water

labile polymers, e.g. polyanhydrides. Microspheres with diameter of 1-1000µm can be

obtained and the size distribution can be easily controlled by altering the stirring rate. The

only disadvantage of this method is moderate temperature to which the drug is exposed.[6]

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CHARACTERIZATION OF MICROSPHERES

Particle size, Shape and Morphology

All the microspheres were evaluated with respect to their size and shape using optical

microscope fitted with an ocular micrometer and a stage micrometer. The particle diameters

of more than 100 microspheres were measured randomly by optical microscope. Scanning

Electron photomicrographs of drug‐loaded microspheres were taken. A small amount of

microspheres was spread on gold stub. Afterwards, the stub containing the sample was placed

in the Scanning electron microscopy (SEM). A Scanning electron photomicrograph was taken

at an acceleration voltage of 20KV.[6]

The most widely used procedures to visualize microparticles are conventional light

microscopy (LM) and scanning electron microscopy (SEM). Both can be used to determine

the shape and outer structure ofmicroparticles.

LM provides a control over coating parameters in case of double walled microspheres. The

microspheres structures can be visualized before and after coating and the change can be

measured microscopically.

SEM provides higher resolution in contrast to the LM. SEM allows investigations of the

microspheres surfaces and after particles are cross-sectioned, it can also be used for the

investigation of double walled systems. Conflocal fluorescence microscopy is used for the

structure characterization of multiple walled microspheres.

Laser light scattering and multi size coulter counter other than instrumental methods, which

can be used for the characterization of size, shape and morphology of the microspheres.[3]

Swelling Index

Swelling index was determined by measuring the extent of swelling of microspheres in the

given buffer. To ensure the complete equilibrium, exactly weighed amount of microspheres

were allowed to swell in given buffer. The excess surface adhered liquid drops were removed

by blotting and the swollen microspheres were weighed by using microbalance. The hydrogel

microspheres then dried in an oven at 60° for 5 h until there was no change in the dried mass

of sample. The swelling index of the microsphere was calculated by using the formula.[6]

Swelling index= (mass of swollen microspheres - mass of dry microspheres/mass of dried

microspheres) 100.

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Entrapment Efficiency

The capture efficiency of the microspheres or the percent entrapment can be determined by

allowing washed microspheres to lyse. The lysate is then subjected to the determination of

active constituents as per monograph requirement. The percent encapsulation efficiency is

calculated using following equation :

% Entrapment = Actual content/Theoretical content x 100.

In Vitro wash-off test

A 1 cm x 1 cm piece of rat stomach mucosa was tied onto a glass slide (3 inch x 1 inch) using

a thread. Microsphere was spread onto the wet, rinsed, tissue specimen and the prepared slide

was hung onto one of the groves of the USP tablet disintegrating test apparatus. The

disintegrating test apparatus was operated such that that the tissue specimen regular up and

down movements in a beaker containing the simulated gastric fluid. At the end of every time

interval, the number of microsphere still adhering on to the tissue was counted and there

adhesive strength was determined.

In Vitro drug release

To carry out In Vitro drug release, accurately weighed 50 mg of loaded microspheres were

dispersed in dissolution fluid in a beaker and maintained at 37±2° C under continuous stirring

at 100 rpm. At selected time intervals 5 ml samples were withdrawn through a hypodermic

syringe fitted with a 0.4µm Millipore filter and replaced with the same volume of pre-warmed

fresh buffer solution to maintain a constant volume of the receptor compartment. The samples

were analyzed spectrophotometrically. The released drug content was determined from the

standard calibration curve of given drug.

In Vitro diffusion studies

In Vitro diffusion studies were performed using in vitro nasal diffusion cell. The receptor

chamber was filled with buffer maintained at 37±2°C. Accurately weighed microspheres

equivalent to 10 mg were spread on sheep nasal mucosa. At selected time intervals 0.5 ml of

diffusion samples were withdrawn through a hypodermic syringe and replaced with the same

volume of pre-warmed fresh buffer solution to maintain a constant volume of the receptor

compartment. The samples were analyzed spectrophotometrically.

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Drug polymer interaction (FTIR) study

IR spectroscopy can be performed by Fourier transformed infrared spectrophotometer. The

pellets of drug and potassium bromide were prepared by compressing the powders at 20 psi

for 10 min on KBr‐press and the spectra were scanned in the wave number range of 4000-

600 cm-1. FTIR study was carried on pure drug, physical mixture, formulations and empty

microspheres.

Stability studies of Microsphere

The preparation was divided into 3 sets and was stored at 4°C (refrigerator), room

temperature and 40°C (thermostatic oven). After 15, 30 and 60 days drug content of all the

formulation was determined spectrophotometrically.[6]

CONCLUSION

The conclusion of this review is that, this review basically impact on the microspheres, its

types, method of preparation and its characterization which is very useful for future studies

and research for advancement of medicinal field. It has been observed that microspheres are

better choice of drug delivery system than many other types of drug delivery system because

it is having the advantage of target specificity and better patient compliance. In future various

other strategies microsphere will find the central place in novel drug delivery, particularly in

diseased cell sorting, diagnostic, gene and genetic materials, safe, targeted and effective in

vivo delivery and supplements as miniature version of diseased organ tissues in the body.

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8. Prasanth VV, Moy AC, Mathew ST, Mathapan R. Microspheres - An Overview. Int. J. of

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Documents

MICROSPHERES A MAGICAL NOVEL DRUG DELIVERY SYSTEM: A … · Drug delivery systems (DDS) that can precisely control the release rates or target drugs to a specific body site have had