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59| P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 6(3): May-June 2017

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.96***

ICV 6.16***

Pharmaceutical Sciences REVIEW ARTICLE …………!!!

MICROSPHERES AS DRUG CARRIERS FOR CONTROLLED DRUG

DELIVERY

Shilpa Kumaria*

, Seema Sainia, Naresh Singh Gill

b

aDepartment of Pharmaceutics, Rayat Institute of Pharmacy, Railmajra, SBS Nagar

bDepartment of Pharmaceutical Chemistry, Rayat Institute of Pharmacy, Railmajra, SBS

Nagar.

KEYWORDS:

Microspheres, Prolonged

Release, Bioadhesive,

Solvent, Technique,

Delivery, Novel.

For Correspondence:

Shilpa Kumari*

Address:

Department of

Pharmaceutics, Rayat

Institute of Pharmacy,

Railmajra, SBS Nagar.

ABSTRACT

Microspheres are multiparticulate drug delivery systems which are

prepared to obtain prolong or controlled drug delivery to improve

bioavailability, stability and to target the drug to specific site at a

predetermined rate. They are characteristically free flowing powders

having particle size ranging from 1-1000 μm. They have various types

like Bioadhesive microspheres, Magnetic microspheres, Floating

microspheres, Radioactive microspheres, Polymeric microspheres,

Biodegradable polymeric microspheres. They are prepared by methods

like Spray Drying, Solvent Evaporation, Single emulsion technique,

Double emulsion technique, Phase separation coacervation technique,

Spray drying and spray congealing, Solvent extraction, Quassi emulsion

solvent diffusion. In future by combining various other strategies,

microspheres will find the central place in novel drug delivery,

particularly in diseased cell sorting, diagnostics, gene & genetic

materials, safe, targeted and effective in vivo delivery and supplements as

miniature versions of diseased organ and tissues in the body.

60 | P a g e International Standard Serial Number (ISSN): 2319-8141


INTRODUCTION

1. Controlled drug delivery system:

A controlled drug delivery system is usually designed to deliver the drug at particular rate. Safe and

effective blood levels are maintained for a period as long as the system continues to delivery the

drug. This predetermined rate of drug release is based on the desired therapeutic concentration and

the drug’s pharmacokinetics. The basic rationale for controlled drug delivery is to alter the

pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug

delivery system or by modifying the molecular structure and or physiological parameters 1.This

system plays a vital role in controlling the pharmacological effect of drug as it can influence the

pharmacokinetic profile of the drug, the rate of drug release, the site and duration of action and

subsequently the side effect profile. An optimal drug delivery system ensures that the active drug is

available at the site of action for the correct time and duration. The concentration at appropriate site

should be above the minimal effective concentration (MEC) and below the minimal toxic

concentration (MTC). This concentration interval is known as the therapeutic range. Achieving the

desired concentration of drug is dependent on the frequency of dosing, the drug clearance rate, and

the route of administration. The CRDDS can reduce the undesired fluctuation of drug level, thus

diminishing side effects while improving the therapeutic outcome of the drug 2.

Figure1: Plasma drug con. Profile from conventional multiple dosing and an ideal controlled

delivery formulation3.

1.2 Advantages of controlled drug delivery:

Maintenance of drug levels within a desired range.

Delivery of “difficult” drugs: slow release of water-soluble drugs, fast release of low

solubility drugs.

Less dosing and increased patient compliance.

Eliminate over or under dosing.

Prevention of side effects.



Reduction in Health care cost.

Improved efficiency in treatment.

Reduction in adverse side effects and improvement in tolerability 4.

1.3 Mechanism of Controlled Drug Release Systems:

The controlled release formulations can be divided into different categories based on the

mechanism of drug release.

Diffusion Controlled System:

Basically diffusion process shows the movement of drug molecules from a region of a higher

concentration to one of lower concentration. The flux of the drug J (in amount / area -time), across

a membrane in the direction of decreasing concentration is given by Fick’s law.

J= - D dc/dx ……….Eq.1

Where, D = diffusion coefficient in area/ time, dc/dx = change of concentration 'c' with distance 'x'

Diffusion systems are characterized by release rate of drug is dependent on its diffusion through

inert water insoluble membrane barrier. There are basically two types of diffusion devices5.

a) Reservoir Type:

In the system, a water insoluble polymeric material encloses a core of drug, which controls release

rate. Drug will partition into the membrane and exchange with the fluid surrounding the particle or

tablet.

Figure 2: Schematic Representation of Reservoir Diffusion Controlled Drug Delivery Device

The rate of drug released (dm/dt) can be calculated using the following equation

Dm/dt = ADK∆C/ ℓ ……….Eq.2

Where, A = Area, D = Diffusion coefficient, K = Partition coefficient of the drug between the drug

core and the membrane, ℓ = Diffusion path length, ΔC= Concentration difference across the

membrane 6, 7

.



b) Matrix Type:

A solid drug is homogenously dispersed in an insoluble matrix and the rate of release of drug is

dependent on the rate of drug diffusion and not on the rate of solid dissolution 8, 9

.

Figure 3: Schematic Representation of Monolithic (matrix) Diffusion Controlled Drug Delivery

Device

Dissolution Controlled Systems:

Drugs having high aqueous solubility and dissolution rate, shows challenge in controlling their

dissolution rate. Dissolution-controlled release can be obtained by slowing the dissolution rate of a

drug in the GI medium, incorporating the drug in an insoluble polymer and coating drug particles or

granules with polymeric materials of varying thickness. The rate limiting step for dissolution of a

drug is the diffusion across the aqueous boundary layer. The solubility of the drug provides the

source of energy for drug release, which is countered by the stagnant-fluid diffusional boundary

layer. The rate of dissolution (dm/dt) can be approximated by:

dm/dt = ADS/h …………Eq.3

Where, S = Aqueous solubility of the drug, A = Surface area of the dissolving particle or tablet.

D = Diffusivity of the drug and h = Thickness of the boundary layer 10, 11

a) Encapsulation Dissolution Controlled Systems:

The drug particles are coated or encapsulated by microencapsulation techniques with slowly

dissolving materials like cellulose, poly ethylene glycols, polymethacrylates, waxes etc. the

dissolution rate of coat depends upon the solubility and thickness of the coating. Those with the

thinnest layers will provide the initial dose. The maintenance of drug levels at late times will be

achieved from those with thicker coating 12

.

Figure 4: Encapsulation Dissolution Controlled Systems



b) Matrix Dissolution Controlled Systems:

In matrix systems the drug is homogeneously dispersed throughout a rate controlling medium. The

drug release is often first order from such matrices 13

.

Dissolution and Diffusion Controlled Release Systems

The drug core is enclosed in a partially soluble membrane. Pores are thus created due to dissolution

of parts of the membrane which permit entry of aqueous medium into the core and hence drug

dissolution and diffusion of dissolved drug out of the system14, 15, 16

.

Figure 5: Dissolution and Diffusion Controlled Release System

Water Penetration Controlled Systems:

In water penetration controlled delivery systems, rate control is obtained by the penetration

of water into the system17

. They are:

Swelling Controlled Systems

Osmotically Controlled Release Systems.

Methods using lon Exchange:

This system is designed to provide the controlled release of an ionic or ionizable drug 18

. The drug is

released by exchanging with appropriately charged ions in the GIT. The drug is then diffuse out of the

resin 19

.

Resin+ - drug- + X- resin+ - X- + drug- ………….Eq.4

Where X- is ions in the GIT, They are mainly of 2 types cation exchange and anion exchange resin.

Chemically Controlled Release Systems:

Chemically controlled release systems are the systems that change their chemical structure, when

exposed to biological fluid20

.

pH– Independent Formulations:

As we know that the most of drugs are either weak acids or weak bases, the release from sustained

release formulations is pH dependent. However, buffers such as salts of amino acids, citric acid,

phthalic acid phosphoric acid or tartaric acid can be added to the formulation, to help to maintain a

constant pH thereby rendering pH independent drug release 21

.



Hydrogels:

Hydrogels are water swollen three dimensional structures composed of primarily hydrophilic

polymers. They are insoluble because of chemical or physical cross-links. Hydrogels provide

desirable protection of labile drugs, peptides and proteins 22, 23

.

Altered Density Formulations:

Several approaches have been developed to prolong the residence time of drug delivery system in

the gastrointestinal tract like High density approach and Low density approach 24

.

2. Microspheres:

Microspheres are characteristically free flowing powders consisting of proteins or synthetic

polymers which are biodegradable in nature and ideally having a particle size less than 200 μm and

with diameters 1 μm to 1000 μm25

. Microspheres are sometimes referred to as microparticles.

Microspheres can be manufactured from various natural and synthetic materials. Glass

microspheres, polymer microspheres and ceramic microspheres are commercially available 26

. They

can be delivered through various routes like oral, nasal, colonal, parentally, opthalmic and

transdermal etc27

.

2.1 Advantages of microspheres:

Particle size reduction for enhancing solubility of the poorly soluble drug.

Provide constant and prolonged therapeutic effect.

Provide constant drug concentration in blood thereby increasing patient compliance.

Decrease dose and toxicity.

Protect the drug from enzymatic and photolytic cleavage hence found to be best for drug delivery of

protein.

Reduce the dosing frequency and thereby improve the patient compliance.

Better drug utilization will improve the bioavailability and reduce the incidence or intensity of

adverse effects.

Microsphere morphology allows a controllable variability in degradation and drug release.

Convert liquid to solid form & to mask the bitter taste.

Protects the GIT from irritant effects of the drug.

Biodegradable microspheres have the advantage over large polymer implants in that they do not

require surgical procedures for implantation and removal.

Controlled release delivery biodegradable microspheres are used to control drug release rates

thereby decreasing toxic side effects, and eliminating the inconvenience of repeated injections 28

.



2.2 Types of microspheres:

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 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.

Magnetic Microspheres

This kind of delivery system is very much important which 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 that are used for magnetic microspheres are chitosan, dextran etc.

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.

Polymeric Microspheres

The different types of polymeric microspheres can be classified as follows and they are

biodegradable polymeric microspheres and synthetic polymeric microspheres.

i. Biodegradable Polymeric Microspheres:

Natural polymers such as starch are used with the concept that they are biodegradable,

biocompatible, and also bioadhesive in nature. Biodegradable polymers prolong the residence time

when come in contact with mucous membrane due to its high degree of swelling property with

aqueous medium and results in gel formation. The rate and extent of drug release is controlled by

concentration of polymer and the release pattern in a sustained manner.

ii. Synthetic Polymeric Microspheres:

The interest of synthetic polymeric microspheres are widely used in clinical application, moreover

that also used as bulking agent, fillers, embolic particles drug delivery vehicles etc and proved to

be safe and biocompatible29

.

2.3 Material used in preparation of microspheres:

A number of different substances, both biodegradable as well as non-biodegradable have been

investigated for the preparation of microspheres. These materials include the polymers which are

classified into two categories:



1. Synthetic polymers

2. Natural polymers.

1. Synthetic polymers: They are employed as carrier materials and are divided into two

types:-

A) Non-biodegradable polymers: for ex- Poly methyl methacrylate, Glycidyl methacrylate,

Epoxy polymers.

B) Biodegradable polymers: for ex- Lactides and Glycolides and their copolymers, Poly alkyl

cyano acrylates, Poly anhydrides.

2. Natural polymers: They are obtained from different sources like proteins, carbohydrates,

and chemically modified carbohydrates.

A) Proteins- Albumin, Gelatin, Collagen.

B) Carbohydrates- Agarose, Gelatin, Starch, Chitosan, Carrageenan.

C) Chemically modified carbohydrates- Poly (acryl) dextran, starch, DEAE cellulose 30

.

2.4 Method for preparation of microspheres:

Techniques used for preparation of microspheres

Solvent evaporation technique -:

Solvent evaporation technique is one of the oldest and widely used methods for preparation of

microsphere. When drug loading is low, this method is used for preparation of microsphere. 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 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 core materials may be either water soluble or water insoluble materials. Solvent

evaporation involves the formation emulsion between polymer solution and an immiscible

continuous phase whether aqueous (o/w) or non-aqueous 31

.

Single emulsion techniques -:

There are several natural polymers for ex- carbohydrates and proteins that act as microparticulate

carriers and are prepared by single emulsion technique. In which the natural polymers are dissolved

or dispersed in the non-aqueous medium e.g. oil. In next step, cross linking is carried out by either

of two following methods 32

.



1. Cross linking by heat:

Cross linking by heat is carried out by adding the dispersion, to previously heated oil. Heat

denaturation is however, not suitable for the thermolabile drugs 33

.

2. Chemical cross linking:

Chemical cross liking is done with the help of agents such as glutraldehyde, formaldehyde,

terephthaloyl chloride etc. This method suffers from disadvantage of excessive exposure of active

ingredients to chemicals if added at the time of preparation, chitosan solution (in acetic acid) by

adding to liquid paraffin containing a surfactant resulting in the formation of w/o emulsion 34

.

Microspheres preparation by single emulsion technique shown in fig.6

Figure 6: Processing scheme for microspheres preparation by single emulsion technique

Double emulsion technique -:

Involves the formation of the multiple emulsions or the double emulsion of type w/o/w and is best

suited to the water-soluble drugs, peptides, proteins and the vaccines. 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 then

subjected to the homogenization or the sonication before addition to the aqueous solution of the

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

then subjected to the solvent removal either by solvent evaporation or by solvent extraction process.

In the latter case, the emulsion is added to the large quantity of water (with or without surfactant)

into which organic phase diffuses out 35

.



Figure 7: Processing scheme for microspheres-preparation by double emulsion technique

Polymerization -: The polymerization techniques used for the preparation of the

microspheres are mainly classified as:

Normal polymerization

Interfacial polymerization

1. Normal polymerization

A) 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 initiator is added to the reaction

mixture to facilitate or accelerate the rate of the reaction. The polymer so obtained may be molded

or fragmented as microspheres. For loading of drug, adsorptive drug loading or adding drug during

the process of polymerization may be adopted.

B) Suspension polymerization:

It is carried out by heating the monomer or mixture of monomers with active principles (drugs) as

droplets dispersion in a continuous aqueous phase. The droplets may also contain an initiator and

other additives.

C) Emulsion polymerization:

However, differs from the suspension polymerization as due to presence of the initiator in the

aqueous phase, which later on diffuses to the surface of the micelles or the emulsion globules.

2. Interfacial Polymerization -:

In Interfacial polymerization 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 aqueous in nature through which the second monomer is emulsified.

The monomers present in either phase diffuse rapidly and polymerize rapidly at the interface. Two

conditions arise depending upon the solubility of formed polymer in the emulsion droplet. If the

polymer is soluble in the droplet it will lead to the formation of the monolithic type of the carrier on



the hand if the polymer is insoluble in the monomer droplet, the formed carrier is of capsular

(reservoir) type 36

.

Phase separation coacervation technique -:

In this process the solubility of polymer is decreased in the organic phase to affect the formation of

the polymer rich phase known as coacervates. It is used for the preparation of reservoir type system

encapsulated water soluble drug such as proteins, peptides37

. The phase separation coacervation

method shown in the fig.8.

Figure 8: Coacervation phase separation method

Spray drying technique -:

In spray drying process, core material is dispersed in coating solution, in which the coating

substance is dissolved and in which the polymer is insoluble, followed by atomisation of the

mixture into air stream.

Principle: Three steps involved during spray drying process are:

Atomisation-It involves conversion of a liquid feed into fine droplet.

Mixing-Mixing is carried out by passing hot air stream through spray droplets, which causes

evaporation of liquid and leaving behind dried particles.

Dry- Dried powder is separated from the air stream and collected.

Spray Congealing Technique

Spray congealing technique is similar as that of spray drying technique; the difference between

two techniques is only that the dispersion of core material is done in a melted coating substance

not in a coating solution followed by atomisation into air stream. Substance such as fatty acid,

polymer, waxes, sugars which are solid at room temperature, but can be melted at certain



temperature can be used in spray congealing technique 38

.

Figure 9: Spray drying and spray congealing

Solvent extraction:

For the formation of the emulsion between polymer solution and an immiscible continuous phase in

aqueous (o/w) as well as non-aqueous phase (w/o) 39.

2.5 Application of microspheres:

Prolonged release dosage forms. The microsphere drug can be administered, as microsphere

is perhaps most useful for the preparation of tablets, capsules or parenteral dosage forms.

Microsphere can be used to prepare enteric-coated dosage forms, so that the medicament

will be selectively absorbed in the intestine rather than the stomach.

From the mechanical point of view, microsphere has been used to aid in the addition of oily

medicines to tableted dosage forms. This has been used to overcome problems inherent in

producing tablets from otherwise tacky granulations. This was accomplished through

improved flow properties. For example, the non-flowable multicomponent solid mixture of

niacin, riboflavin, and thiamine hydrochloride and iron phosphate may be encapsulated and

made directly into tablets.

It has been used to protect drugs from environmental hazards such as humidity, light,

oxygen or heat.

Release of proteins, hormones and peptides over extended period of time.

Gene therapy with DNA plasmids and also delivery of insulin.

Vaccine delivery for treatment of diseases like hepatitis, influenza, pertussis, ricin toxoid,

diphtheria, birth control.

Passive targeting of leaky tumour vessels, active targeting of tumour cells, antigens, by

intra-arterial/intravenous application.

Tumour targeting with doxorubicin and also treatments of leishmaniasis.

Magnetic microspheres can be used for stem cell extraction and bone marrow purging.



Used in isolation of antibodies, cell separation and toxin extraction by affinity

chromatography.

Used for various diagnostic tests for infectious diseases like bacterial, viral, and fungal.

Can be used for radio embolisation of liver and spleen tumours.

Used for radio synvectomy of arthritis joint, local radiotherapy, interactivity treatment.

Imaging of liver, spleen, bone marrow, lung and even imaging of thrombus in deep vein

thrombosis can be done.

Determining the imaging of particular sites using radio labeled microspheres40, 41, 42

.

2.6 Variables influencing drug release pattern of microspheres:

There are following factors which directly/indirectly affect the drug release characteristics of the

microspheres:

Concentration of the polymer in dispersed phase:

Polymer concentration in aqueous phase indirectly affects the time and drug release. As the

polymer concentration in aqueous phase increases, size of microspheres is increased which results

increase in time and slower drug release from microspheres.

Drug: Polymer Ratio (DPR):

Drug release from microspheres is affected by the ratio of the drug to the polymer as increasing in

the first causes faster drug release. By increasing the amount of drug loading, a point will be

reached when the solid drug particles upon dissolution will begin to form continuous pores or

channels within the matrix. Under these circumstances, the path of release for drug molecules will

be diffusion within the channels formed from areas where drug has previously leached out from the

matrix. In other words, as the amount of drug content is increased the matrix will become more

porous as drug is leached out from the polymer and thus faster release rate occurs. At lower drug-

polymer ratios, the mean particle size of the micropellets was less than that at higher drug-polymer

ratios. Therefore, the drug release from micropellets prepared at lower drug- polymer ratios was

faster than that of micropellets prepared at higher drug polymer ratios because of the small size of

the micropellets, which provided a large surface area for faster drug release.

Selection of solvent system for the dispersed phase:

Selection of solvent system based on the volatility of solvent, solubility of polymer and type of

method of preparation used for preparation of microspheres. Solvent should have high volatility and

high polymer solubility.



Effect of Temperature:

Microspheres prepared at 60℃ showed faster drug release than the microspheres prepared at 10 ℃.

This can be attributed to the decrease in viscosity of the oily phase as the temperature increases,

which in turn decrease the microspheres.

Effect of stirring speed:

The drug release rate was increasing on increasing the stirring rate. Drug release was higher in the

case of microspheres prepared at a higher stirring rate but at low stirring rate the release rate was

slow. This can be attributing that smaller size microspheres have a larger surface area exposed to

dissolution medium, giving rise to faster drug release43

.

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