Available Online Through RECENT ... · stability enhancement of incompatible aspirin-chlorpheniramine maleate mixture was accomplished by microencapsulating both of them before mixing

Kedar Prasad Meena* et al. /International Journal Of Pharmacy&Technology

IJPT | March-2011 | Vol. 3 | Issue No.1 | 854-893 Page 854

ISSN: 0975-766X Available Online Through Review Article

www.ijptonline.com

RECENT ADVANCES IN MICROSPHERES MANUFACTURING TECHN OLOGY Kedar Prasad Meena* J.S. Dangi , P K Samal and K P Namdeo

SLT Institute of Pharmaceutical Sciences Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G)-495009.

Email:[email protected] Received on 14-02-2011 Accepted on 24-02-2011

ABSTRACT

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. 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. 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. It is the

reliable means to deliver the drug to the target site with specificity, if modified, and to maintain the desired

concentration at the site of interest without untoward effects. Microspheres received much attention not only for

prolonged release, but also for targeting of anticancer drugs to the tumor. 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.

Keywords: Microspheres, controlled release, target site, novel drug delivery.

1. INTRODUCTION









concentration at the site of interest without untoward effects. Microspheres received much attention not only for

prolonged release, but also for targeting of anticancer drugs to the tumour. 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.[1]

Microspheres are discrete spherical particles ranging in average particle size from 1 to 50 microns. Because of

their size and shape, Microspheres offer a ball-bearing effect which will impart finished products with an

elegant silky texture, increased payoff, and enhanced slip. This ball-bearing effect promotes better blendability

on the skin and a more natural finish. Microspheres are also able to scatter light to diminish the look of fine

lines on the skin, while letting enough light through so the look of the skin is natural. This phenomenon is

known as “Soft Focus Effect” or “Optical Blurring.” Some Microspheres are porous and have a high oil

absorption capacity: they can act as carriers to absorb and deliver materials, and can be used for sebum control.

A special use of Microspheres is in mascaras. The non-absorbent grades of silica’s of different diameters have a

volumizing effect, with minimum absorbency.[2] Cellulose Beads are hydrophilic Microspheres made of

cellulose which have a high capacity to absorb moisture. They are also available coloured with inorganic

colorants. Since they can be used in all product forms (powders, anhydrous hot pours, emulsions, etc ...),

Microspheres, whether used individually or in combination, have become indispensable to formulation of state-

of-the-art cosmetic products [3]









concentration at the site of interest without untoward effects.[4] Microspheres received much attention not only

for prolonged release, but also for targeting of anticancer drugs to the tumour. 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.[4]

Overview of Microsphere

As the name implies, microspheres are small, spherical particles. Particle sizes range from 12 to 300 microns in

diameter, and wall thickness can vary from several microns to as low as 0.1 micron. They can be composed of

acrylonitrile, glass, ceramic or phenolic materials. Because they are hollow, the true density of microspheres is

lower than that of other non-soluble additives. The true density of hollow microspheres ranges from 0.60 g/cc to

as low as 0.025 g/cc.[5] .Microspheres are solid spherical particles ranging in size from 1-1000µm. They are

spherical free flowing particles consisting of proteins or synthetic polymers. The microspheres are free flowing

powders consisting of proteins or synthetic polymers, which are biodegradable in nature. There are two types of

microspheres; microcapsules and micromatrices, which are described as, Microcapsules are those in which

entrapped substance is distinctly surrounded by distinct capsule wall and micromatrices in which entrapped

substance is dispersing throughout the microspheres matrix. Solid biodegradable microspheres incorporating a

drug dispersed or dissolved through particle matrix have the potential for the controlled release of drug. They

are made up of polymeric, waxy, or other protective materials, that is, biodegradable synthetic polymers and

modified natural products. Microsphere is a term used for small spherical particles, with diameters in the

micrometer range (typically 1µm to 1000µm (1mm)). , Microspheres: micrometric matrix systems.



Microspheres are matrix systems and essentially spherical in shape, whereas microcapsules may be spherical or

non-spherical in shape. Microcapsules are small particles, which contain an active agent or core material

surrounded by a coating or shell.[6]

Advantages of Microsphere Delivery System

• Protection of unstable, sensitive materials from their environments prior to use.

• Better processability (improving solubility, dispersibility, flowability

• Self-life enhancement by preventing degradative reactions.

• Safe and convenient handling of toxic materials.

• Masking of odor or taste.

• Enzyme and microorganism immobilization.

• Controlled and targeted drug delivery.

• Handling liquids as solids.

• To improve bioavailability

• To improve the stability

• Limiting fluctuation within therapeutic range [7]

Applications of Microspheres

Some of the applications of microencapsulation can be described in detail as given below -

1. 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.

2. 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.

3. It can be used to mask the taste of bitter drugs.

4. 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. [8]

5. It has been used to protect drugs from environmental hazards such as humidity, light, oxygen or heat.

Microsphere does not yet provide a perfect barrier for materials, which degrade in the presence of

oxygen, moisture or heat, however a great degree of protection against these elements can be provided.

For example, vitamin A and K have been shown to be protected from moisture and oxygen through

microsphere.

6. The separations of incompatible substances, for example, pharmaceutical eutectics have been achieved by

encapsulation. This is a case where direct contact of materials brings about liquid formation. The

stability enhancement of incompatible aspirin-chlorpheniramine maleate mixture was accomplished by

microencapsulating both of them before mixing.

7. Microsphere can be used to decrease the volatility. An encapsulated volatile substance can be stored for

longer times without substantial evaporation.[9]

8. Microsphere has also been used to decrease potential danger of handling of toxic or noxious substances.

The toxicity occurred due to handling of fumigants, herbicides, insecticides and pesticides have been

advantageously decreased after microencapsulation.

9. The hygroscopic properties of many core materials may be reduced by microsphere.

10. Many drugs have been microsphere to reduce gastric irritation.

11. Microsphere method has also been proposed to prepare intrauterine contraceptive device.

12. In the fabrication of multilayered tablet formulations for controlled release of medicament contained in

medial layers of tableted particles.[10]

2. PREPARATION METHOD OF MICROSPHERE

Preparation of microspheres should satisfy certain criteria-

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

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

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



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

• Biocompatibility with a controllable biodegradability.[11]

Preparation of microspheres of can be done by suitable methods like:

1. Protein gelation technique.

2. Single Emulsion polymerization technique.

3. Double Emulsion polymerization technique.

4. Multiple emulsion polymerization technique.

5. Solvent evaporation technique.

6. Sonication technique.

7. Spray and freeze drying technique.

8. Emulsification-heat stabilization technique.

9. Quasi-emulsion solvent diffusion method of the spherical crystallization technique.

10. Spray congealing

11. Phase separation coaservation method

12. Polymerisation technique

13. Solvent extraction method[12]

1. Protein gelation technique:

The preparation of Pilocarpine nitrate loaded egg albumin microspheres by thermal denaturation process and

obtained albumin microspheres in the size range of 1-12µm.

Drug loaded microspheres so obtained were evaluated for their size, entrapment efficiency, release rate and

biological response. The entrapment and encapsulation of pilocarpine after process optimization was found to

be 82.63% and 62.5% respectively [13]



Fig-1: Preparation of microspheres by Protein gelation technique.

2. Single Emulsion polymerization technique:

Developed sustained release ethyl cellulose-coated egg albumin microspheres of Diltiazem Hydrochloride to

improve patient compliance. The microsphere were prepared by the w/o emulsion thermal cross-linking method

using different proportion of the polymer to drug ratio[14]

Fig-2: Preparation of microspheres by Single emulsion polymerization technique.



3. Double Emulsion polymerization technique

A double emulsion is usually prepared in two main modes-

Mode 1: One-step emulsification

Mode 2: Two-step emulsification

In one step emulsification mode a strong mechanical agitation is used for the water phase containing a

hydrophilic surfactant and an oil phase containing large amounts of hydrophobic surfactant. Due to this a W/O

emulsion is formed which quickly inverts to form a W/O/W double emulsion.

A two-step procedure is reported where the primary emulsion can be formed as a simple W/O emulsion which

emulsion can be formed as a simple W/O emulsion which is prepared using water and oil solution with a low

HLB (hydrophilic-lipophilic balance) surfactant. In the second step, the primary emulsion (W/O) is re-

emulsified byaqueous solution with a high HLB surfactant to produce a W/O/W double emulsion.[15]

4. Multiple emulsion polymerization technique.

Multiple emulsion method involves formation of (o/w) Primary emulsion (non aqueous drug solution in

polymer solution) and then addition of primary emulsion to external oily phase to form o/w/o emulsion

followed by either addition of cross linking agent (glutaraldehyde) and evaporation of organic solvent.This

method of preparation is ideal for incorporating poorly aqueous soluble drug, thus enhancing its bioavailability.

Sam T et al., carried out the formulation and evaluation of Ketorolac Tromethamine-loaded Albumin

Microspheres for Potential Intramuscular Administration. The microspheres were prepared by multiple

emulsion technique to make the poorly aqueous soluble drug ketorolac tromethamine more bioavailable.[16]



Fig-3: microsphere preparation by multiple emulsion method

5. Solvent evaporation technique.

This process is carried out in a liquid manufacturing vehicle. The albumin microspheres are dispersed in

avolatile 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 microsphere. The

mixture is then heated if necessary to evaporate the solvent. The solvent Evaporation technique to produce

microspheres is applicable to wide variety of core materials. 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. and evaluation of Indomethacin



Microspheres using natural and synthetic polymers as Controlled Release Dosage Forms. And the microspheres

were prepared by solvent evaporation method. The prepared microspheres were pale yellow, free flowing and

spherical in shape. The mean particle size of the microspheres was found in the range of 150 to 400µm. The

drug-loaded microspheres showed 70-86% of entrapment and release was extended.[17]

Fig-4: Basic steps of microsphere by solvent evaporation method.

6. Sonication technique

As the technique name itself is self explanatory, it just involves a simple sonication for certain period of time till

a desired size of albumin microspheres are obtained. The albumin solution of desired concentration is taken

which is sonicated. To this add the drug which will then form intrachain cross-link with cysteine residues of

albumin chains. prepared a stable preparation of air filled human albumin microspheres (Albunex) by sonication

technique. The microspheres ranged in size from 1-10µm with 99% of particles smaller than 10 µm. The mean

size was 5 µm, which is small enough to pass freely through the pulmonary capillary circulation. [18]

7. Spray drying technique

In Spray Drying 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 evaporate instantaneously leading the formation of

the microspheres in a size range 1-100µm. Micro particles are separated from the hot air by means of the

cyclone separator while the trace of solvent is removed by vacuum drying. One of the major advantages of

process is feasibility of operation under aseptic conditions. This process is rapid and leads to the formation of

porous micro particles Developed albumin microspheres of Fluticasone propionate inclusion complexes for



pulmonary delivery by using spray and freeze drying technique. 2-hydroxypropyl-β-cyclodextrin inclusion

complex of Fluticasone propionate was prepared by the spray drying and freeze drying technique in the molar

ratio 1:1. Spray drying came of age during World War II, with the sudden need to reduce the transport weight of

foods and other materials. This surge in interest led to developments in the technology that greatly expanded the

range of products that could be successfully spray dried. It has been used in pharmaceutical technology studies

to produce pharmaceuticals excipient with improved compressibility, such as lactose, to improve flow

properties, to prepare free-flowing granules for tablet production, to improve the drug aqueous solubility and,

consequently, their bioavailability. In addition, a number of formulation processes can be accomplished in one

step in a spray dryer; these include complex formation and micro encapsulation.[19]

Fig-5: Main process stages involved in spray drying process.

Fig-6: Formation of product in spray drying.



Concept of spray drying technique:

The production of particles from the process of spraying has gained much attention in recent years. These

efforts have resulted in spray technology being applied to the manufacture of particles to generate products

ranging from pharmaceutical direct compression excipients and / or granulations to microencapsulated flavors.

The two main spray techniques are spray drying & spray congealing. The action in spray drying is primarily

that of evaporation, whereas in spray congealing it is that of a phase change from a liquid to a solid. The two

processes are similar, except for energy flow. In the case of spray drying, energy is applied to the droplet,

forcing evaporation of the medium resulting in both energy and mass transfer through the droplet. In spray

congealing, energy only is removed from the droplet, forcing the melted to solidify. Spray drying is the most

widely used industrial process involving particle formation and drying. It is highly suited for the continuous

production of dry solids in either powder, granulate or agglomerate form from liquid feedstocks as solutions,

emulsions and pumpable suspensions. Therefore, spray drying is an ideal process where the end-product must

comply with precise quality standards regarding particle size distribution, residual moisture content, bulk

density, and particle shape. [20]

Principle

There are three fundamental steps (figure 1) involved in spray drying

1) Atomization of a liquid feed into fine droplets.

2) Mixing of these spray droplets with a heated gas stream, allowing the liquid to evaporate and leave dried

solids.

3) Dried powder is separated from the gas stream and collected.

Spray drying involves the atomization of a liquid feedstock into a spray of droplets and contacting the droplets

with hot air in a drying chamber.

The sprays are produces by either rotary (wheel) or nozzle atomizers. Evaporation of moisture from the droplets

and formation of dry particles proceed under controlled temperature and airflow conditions. Powder is

discharged continuously from the drying chamber. Operating conditions and dryer design are selected according

to the drying characteristics of the product and powder specification. [21]



8. Emulsification-heat stabilization technique.

The preparation and characterization of albumin microspheres encapsulated with propranolol HCl by emulsion-

heat stabilization technique. Bovine serum albumin microspheres (BSA) containing propranolol HCl were

prepared by emulsification-heat stabilization technique. Briefly, a 5% solution of BSA containing 0.1%

Tween80 was made, to which 4% propranolol HCl was added and used as the aqueous phase. The oil phase

composed of 30 ml maize oil and 10 ml petroleum ether with 1% Span 80 as emulsifier were mixed together

and allowed to stir for 10 min at 1000 rpm. The aqueous phase was added drop wise to the oil phase and stirred

on a magnet stirrer at 1000 rpm for 30 min to form the initial emulsion. This emulsion was then added to 40 ml

of maize oil preheated to 120° C and stirred at 1000 rpm for 15 min to allow the formation and solidification of

microspheres. The microsphere suspension was centrifuged at 3500 rpm for 30 min and the settled microspheres

were washed three times with ether to remove traces of oil on microsphere surfaces. The microspheres were

vacuum dried in a desiccator overnight and storedwere vacuum dried in a desiccator overnight and stored at 4°C

in dark. The microspheres had mean diameters between 1-25 µm of which more than 50 percent were below 5

µm. The encapsulated drug was found to be about 9% w/w of that initially added to microspheres and the

superficial drug was 25% of the total amount of the encapsulated drug. Also albumin microspheres were noted

to possess good bioadhesion in such a way that about 70% of microspheres remained adherent on the surface

mucosa of rat jejunum. The total amount of drug released from microspheres after 12h was 70%.

9. Quasi-emulsion solvent diffusion method of the spherical crystallization technique.

Development and characterization of sustained release microspheres by quasi emulsion solvent diffusion

method. The microspheres were prepared using the quasiemulsion solvent diffusion method of the spherical

crystallization technique. Ketoprofen and Eu RS were dissolved completely in the acetone–dichloromethane

mixture. Then Aerosil was suspended uniformly in the drug– polymer solution under vigorous agitation. The

resultant drug–polymer–Aerosil suspension was poured into the distilled water (150 ml) containing 0.08% of

SDS (i.e. poor solvent) under a moderate agitation (450–750rpm) and thermally controlled at 0–38°C. The

suspension was finely dispersed into quasi-emulsion droplets immediatelyunder agitation, and the drug and

polymers coprecipitated in the emulsion droplets. After agitating the system for 20 min, 150 ml of poor solvent



was added slowly to promote the diffusion of the good solvent from emulsion droplets into poor solvent

resulting in enhancement of the solidification of quasiemulsion droplets. Agitation was extended for another 40

min until the translucent quasi-emulsion droplets turned into opaque microspheres. The solidified microspheres

were recovered by filtration and washed with water, and the resultant products were dried in an oven at 50°C for

6h. The average diameters were about 104-108µm and the drug contents in the microspheres were 62-96%.[22]

10. Spray congealing.

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 cold 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 1-100 µm.[23]

11. 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[24]

12. 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.[25]

13. Solvent extraction.

The contaminants are separated from the solvent either by changing the pressure and temperature, by using a

second solvent to pull the first solvent out of the solvent/contaminant mixture, or by other physical separation

processes. At the completion of this step, concentrated contaminants result. Concentrated contaminants are

removed during the separation process, and the solvent is sent to a holding tank for reuse. The contaminants are

then analyzed to determine their suitability for recycle/reuse, or need for further treatment before disposal.[26]



Fig-7: microsphere preparation by solvent extraction. 3. MATERIALS USED IN MICROSPHERE PREPARATION

They are classified into two types:

1. Synthetic Polymers.

2. Natural polymers.

1. Synthetic polymers are divided into two types.

a. Non-biodegradable polymers

e.g. Poly methyl methacrylate (PMMA) Acrolein,

Glycidyl methacrylate Epoxy polymers

b. Biodegradable polymers

e.g. Lactides,

Glycolides & their co polymers,

Poly alkyl cyano acrylates,

Poly anhydrides

2. Natural polymers obtained from different sources like

proteins,



carbohydrates

and chemically modified

carbohydrates.

Proteins:

Albumin6,

Gelatin7,

and Collagen.

Carbohydrates:

Agarose,

Carrageenan,

Chitosan,

Starch8.

Chemically modified carbohydrates:

Poly dextran,

Poly starch.

Synthetic polymers

Poly alkyl cyano acrylates is a potential drug carrier for parenteral as well as other ophthalmic, oral

preparations. Poly lactic acid is a suitable carrier for sustained release of narcotic antagonist, anti cancer agents

such as cisplatin, cyclo phosphamide, and doxorubicin. Sustained release preparations for anti malarial drug as

well as for many other drugs have been formulated by using of co-polymer of poly lactic acid and poly glycolic

acid. Poly anhydride microspheres (40µm) have been investigated to extend the precorneal residence time for

ocular delivery. Poly adipic anhydride is used to encapsulate timolol maleate for ocular delivery. Poly acrolein

microspheres are functional type of microspheres. They donot require any activation step since the surfacial free

CHO groups over the poly acrolein can react with NH2 group of protein to form Schiff’s base.



Natural polymers

Albumin is a widely distributed natural protein .It is considered as a potential carrier of drug or protiens (for

either their site specific localization or their local application into anatomical discrete sites). It is being widely

used for the targeted drug for the targeted drug delivery to the tumour cells. Gelatin7 microspheres can be used

as efficient carrier system capable of delivering the drug or biological response modifiers such as interferon to

phagocytes. Starch8 belongs to carbohydrate class. It consists of principle glucopyranose unit, which on

hydrolysis yields D-glucose. It being a poly saccharide consists of a large number of free OH groups. By means

of these free OH groups a large number of active ingredients can be incorporated within as well as active on

surface of microspheres. Chitosan13 is a deacylated product of chitin. The effect of chitosan has been

considered because of its charge. It is insoluble at neutral and alkaline Ph values, but forms salts with inorganic

and organic salts. Upon dissolution, the amino groups of chitosan get protonated, and the resultant polymer

becomes positively charged.[27]

4. CURRENT APPROACHES OF MICROSPHERES

4.1 microspheres of acetazolamide by solvent evaporation technique.

Acetazolamide is a carbonic anhydrase inhibitor and it is widely used in the treatment of glaucoma and also

used as diuretics. The drug has a relatively short half life (3-4 hr) and usually administered 3 – 4 times daily in

the form of an immediate release formulation. A sustained release formulation reduces the frequent drug

administration and thus improves patient compliance.

Various proportions of polymers like Eudragit RS and Eudragit RL were dissolved in acetone. Acetazolamide

was powdered and dispersed in polymer solution. This solution was added slowly to a jacketed flask containing

300ml of petroleum ether and light liquid paraffin (40:60 w/w) and 1% w/w span 80 under constant stirring

(400, 500 and 750 RPM). After evaporation of acetone, the microspheres formed were collected by filtration in

vacuum, washed 3-4 times with 50ml of petroleum ether each and dried at room temperature for one day.[28]



4.2 polyacrylamide-co-acrylic acid/hydrogel microspheres prepared by a membrane emulsification

technique.

Poly_acrylamide-co-acrylic acid. Microspheres were prepared following the method reported before w16,17x.

Three kinds of monomer solutions containing different concentrations of acrylamide and acrylic acid were

prepared. Fifteen milliliters of the aqueous monomer solution were dispersed in an oil phase composed of 500

ml of cyclohexane containing 0.06%. 2,29 azobis isobutyronitrile 1.0% . SUNSOFT818H to prepare wro

emulsion by the use of MPG _micro porous glass membrane apparatus Chemical. Hydrophobic MPG

membranes were used, which were treated with octadecyltrichlorosilane _ODS. and trimethylchlorosilane

_TMS.. The average pore sizes of the respective MPG membranes used in this process were 0.33, 0.73, 1.15,

and 1.70 mm. The emulsion prepared was stirred at 365 rpm at 708C under a nitrogen atmosphere and 10 ml of

cyclohexane containing 1.0%.[29]

4.3: Preparation of chitosan microspheres by ionotropic gelation under a high voltage electrostatic field for protein delivery.

Fig-8. Diagram of microspheres preparation. (a) Preparation process and (b) microspheres formation



4.4. Microsphere preparation of PLA for cancer therapy

The preparation of PLA-l microparticles was performed by the classical emulsion solvent-evaporation A 1%,

3% or 8% (w/v, 50 ml) of PVA aqueous solution was prepared by heating and stirring during PVA addition.

The organic phase containing different amounts of PLA-l (0.05; 0.10 or 0.15%) dissolved in chloroform (5 ml)

was then slowly added to the aqueous phase during around five minutes under stirring at about 11,000 rpm

using the Ultra Turrax equipment. The microparticle suspension was subsequently left under magnetic stirring

at a controlled temperature of 25 ◦C for 4 h; thus, all the chloroform had evaporated, the spherical microparticle

were produced. Samples produced were identified as (A) PVA 1% and PLA-l 0.10%, (B) PVA 3%and PLA-l

0.10%, (C) PVA 8% and PLA-l 0.10%, (D) PVA 3% and PLA-l 0.05% and (E) PVA 3%and PLA-l 0.15%. For

the first three samples, we could choose the adequate amount of surfactant and for the other two samples the

suitable amount of polymer was determined. After the determination of these adequate amounts of polymer and

surfactant, the formulation was prepared with nimesulide (7.5 mg) dissolved in the organic phase (sample F).

The separation of the nimesulide microparticles was performed by centrifugation (3000 rpm; 15 min), thus,

washing with water for three times to remove PVA and final sample lyophilization.[30]

4.5. Preparation of narrow or monodisperse poly(ethyleneglycol dimethacrylate) microspheres by

distillation–precipitation polymerization.

The basic polymerization procedure is similar to that described previously for the synthesis of poly- DVB and

poly(DVB-co-CMSt) microspheres by distillation–precipitation polymerization. A typical procedure for the

distillation–precipitation polymerization: EGDMA (2.0 ml, 2.04 g, 14.1 mmol, 2.5 vol% relative to the reaction

medium) and AIBN (0.041 g, 0.24 mmol) 2 wt% relative to the total monomer) were dissolved in 80 ml of

acetonitrile in a dried 100-ml two-necked flask, attaching with a fractionating column, Libieg condenser and a

receiver. The flask was submerged in a heating mantle and the reaction mixture was heated from ambient

temperature till boiling state within 30 min and then the solvent began to be distilled. The initially homogeneous

reaction mixture became milky white after boiling for 10 min. The reaction was ended after 40 ml of

acetonitrile was distilled from the reaction system within 90 min. The boiling point of the reaction mixture was

determined by the thermometer at the top of the fractionating column, which was near the boiling point of



acetonitrile: 82 _C. After the polymerization, the resulting poly- EGDMA microspheres were separated by

vacuum filtration over a G-5 sintered glass filter and washed successively with THF, acetone and ether for three

times. The polymeric particles were dried in vacuum oven under 50 _C till constant weight to afford 1.59 g of

microspheres with 78% yield. The procedures for the other distillation–precipitation polymerizations were

much similar as that for the typical one by altering either the solvent used, or EGDMA concentration, or

initiator concentration, or the EGDMA fraction in the comonomer feed in the case of copolymerization.[31]

4.6. Preparation of chitosan microparticles.

Reacting chitosan with controlled amounts of multivalent anion results in crosslinking between chitosan

molecules. The crosslinking may be achieved in acidic, neutral or basic environments depending on the method

applied. This crosslinking has been extensively used for the preparation of chitosan microspheres.[32]

4.7. Preparation of Biodegradable Microspheres and Matrix Devices Containing Naltrexone.

Emulsification/solvent-evaporation method was used for preparation of naltrexone microspheres. Appropri-ate

amounts of PLA were added to 10 mL methylene chloride to provide concentrations of 2.5%, 3%, 3.5%, and

4% wt/vol; then different amounts of naltrexone were dissolved in the polymer solution to give 1% to 2.5%

wt/vol drug solutions to yield theoretical drug loading of 20%, 30%, 40%, or 50% wt/wt, respec-tively. The

solution was then added drop-wise to a 200-mL aqueous phase solution containing 0.5% wt/vol poly(vinyl

alcohol) (PVA), while the mixture was stirred by an overhead stirrer (Heidolf RZR2100, Kel-hein, Germany) to

form a stable oil/water emulsion system at room temperature (25 ± 2°C). Stirring was continued for up to 5

hours to allow the evaporation of methylene chloride and the formation of solid micro-spheres. Microspheres

were filtered, washed with dis-tilled water, and dried overnight until no weight loss was observed.[33]

4.8. Synthesis of macroporous poly(styrene-divinyl benzene) microspheres by surfactant reverse micelles

swelling method.

A standard recipe is shown in. The mixture ofmonomer, crosslinking agent, HD and Span 80 dissolving initiator

BPO was used as the dispersed phase (monomer phase).Water, where the stabilizer (PVA), surfactant (SDS),

electrolyte (Na2SO4), and inhibitor (HQ) were dissolved, was used as the continuous phase (aqueous phase).

An emulsion was prepared by dispersing the monomer phase into the aqueous phase in a four-neck glass flask



equipped with an anchortype agitator, a condenser, and a nitrogen inlet nozzle. After the emulsion was bubbled

with nitrogen for 1 h, the nozzle was lifted up above the surface of the emulsion and the temperature was

elevated to 75 _C for polymerization. The polymerization was carried out for 20 h under a nitrogen atmosphere.

The polymer particles were washed by water and ethanol four times. The impurities in particles were further

extracted by acetone for 24 h, and then the particles were dried in vacuum at room temperature. The yield of

particles was calculated by the weight of dried polymer microspheres.[34]

4.9. Magnetic microspheres as a magnetically targeted drug delivery system.

Drug targeting is the delivery of drugs to receptors or organs or any other specific part of the body to which one

wishes to deliver the drug exclusively. Magnetic microspheres are successfully utilized for drug targeting but

they show poor site specificity and are rapidly cleared off by RES (reticuloendothelial system) under normal

circumstances. Magnetic microspheres were developed to minimize reticulo-endothelial (RES) clearance and to

increase target site specificity. They can be used to entrap a wide variety of drugs.

Benefits of magnetic microspheres:

1. Magnetic microspheres are site specific and by localization of these microspheres in the target area, the

problem of their rapid clearance by RES is also surmounted.

2. Linear blood velocity in capillaries is 300 times less as compared to arteries, so much smaller magnetic field

is sufficient to retain them in the capillary network of the target area.

3. Avoidance of acute toxicity directed against endothelium and normal parenchyma cell, controlled release

within target tissue for intervals of 30 minutes to 30 hrs. As desired, adaptable to any part of body.

4. In case of tumour targeting, microsphere can internalize by tumour cells due to its much increased phagocytic

activity as compared to normal cells.

5. Problem of drug resistance due to inability of drugs to be transported across the cell membrane can be

surmounted.



Fig-9: Concept of magnetic targeting.

Fig-10: Magnetic drug targeting. Drawbacks of magnetic microspheres 1. By the use of magnetic microspheres in the delivery system, the drug cannot be targeted to deep seated

organs in the body.



2. Magnetic targeting is an expensive technical approach and requires specialized manufacturer and quality

controlled system.

3. It needs specialized magnet for targeting, advanced technique for monitoring, and trained personnel to

perform the procedure[35]

Preparation method

Magnetic microspheres are prepared by mainly two methods namely phase separation emulsion polymerization

(PSEP) and continuous solvent evaporation (CSE) by using mixture of water soluble drugs (for lipophilic drugs,

along with the dispersing agent) and 10 nm magnetite (Fe3O4) particles in an aqueous solvent of matrix

material, which are about 1.0 µm in size, that is small enough to allow them to be injected intravenously.[36]

4.9.1. Tumour targeting via magnetic microspheres

Magnetism can play very important role in cancer treatment. The first clinical cancer therapy trials using

magnetic microspheres were performed by Lubbe et al, in Germany for the treatment of advanced solid tumor

while current preclinical research is investigating use of magnetic particles loaded with different

chemotherapeutic drugs such as mitoxantrone, paclitaxel.

Permanent magnetic field for one hour way found to induces lethal effects on several rodent & human cancers.

Anticancer drugs reversibly bound to magnetic fluids and could be concentrated in locally advanced tumors by

magnetic field that or arranged at tumor surface outside of the subject. Various novel biodegradable magnetic

microspheres are synthesized and their targeting to brain tumor is evaluated in vitro and in animal models. New

cationic magnetic aminodextran microspheres (MADM) have been synthesized. Its potentiality for drug

targeting to brain tumor was studied. These particles were retained in brain tissue over a longer period of time.

4.9.2. Locoregional Cancer Treatment with Magnetic Drug Targeting

The specific delivery of chemotherapeutic agents to their desired targets with a minimum of systemic side

effects is an important, ongoing challenge of chemotherapy. One approach, is the i.v. injection of magnetic

particles [ferrofluids (FFs)] bound to anticancer agents that are then concentrated in the desired area (e.g., the

tumor) by an external magnetic field. Whereas an external magnetic field was focused on the tumor.

Application of FF-MTX is successful in treating experimental squamous cell carcinoma. This “magnetic drug

targeting “offers a unique opportunity to treat malignant tumors locoregionally without systemic toxicity.



Furthermore, it may be possible to use these magnetic particles as a “carrier system” for a variety of anticancer

agents, e.g., radionuclide’s, cancer-specific antibodies, and genes.[37]

4.9.3. Magnetically induced Hyperthermia for treatment of cancer.

Heat treatment of organs or tissues, such that the temperature is increased to 42–46 oC and the viability of

cancerous cells reduces, is known as hyperthermia. It is based on the fact that tumor cells are more sensitive to

temperature than normal cells. In hyperthermia it is essential to establish a heat delivery system, such that the

tumor cells are heated up or inactivated while the surrounding tissues (normal) are unaffected.

4.9.4. Magnetic delivery of chemotherapeutic drugs to liver tumors.

The first clinical cancer therapy trial using magnetic microspheres (MMS) was performed by Lubbe et al. In

Germany for the treatment of advanced solid cancer in 14 patients. Their MMS were small, about 100 nm in

diameter, and filled with 4-epidoxorubicin. The phase I study clearly showed the low toxicity of the method and

the accumulation of the MMS in the target area. However, MRI measurements indicated that more than 50% of

the MMS had ended up in the liver. This was likely due to the particles’ small size and low magnetic

susceptibility which limited the ability to hold them at the target organ. The start-up company FeRx in San

Diego developed irregularly shaped carbon coated iron particles of 0.5–5 m in diameter with very high

magnetic susceptibility and used them in a clinical phase I trial for the treatment of inoperable liver cancer.

They have treated 32 patients to date and are able to super selectively (i.e. well directed) infuse up to 60 mg of

doxorubicin in 600 mg MMS with no treatment related toxicity. [38]

4.9.5. Magnetic targeting of radioactivity.

Magnetic targeting can also be used to deliver the therapeutic radioisotopes. Advantage of these method over

external beam therapy is that the dose can be increased, resulting in improved tumor cell eradication, without

harm to adjacent normal tissues. Magnetic targeted microspheres, which are more magnetically responsive iron

carbon particles, have been radiolabel led in last couple of years with isotopes such as 188Re 90Y, 111In, and 125I

and are currently undergoing animal trials.[39]



4.9.6. Human cholangiocarcinoma xenografts.

Cholangiocarcinoma, a malignant disease, poses a severe hazard to human health. It constitutes 2.32% of biliary

tract disease, and the incidence ratio of male to female is 1.46_1. The incidence of cholangiocarcinoma has

shown a tendency to rise in recent years. Treatment includes mainly operation, and combined chemotherapy and

radiation. But cholangiocarcinoma can be located deep, be anatomically concealed, and difficult to diagnose

early. As a result, the outcome of operation can be unsatisfactory, and the survival rate is very low. Single or

combined application of chemotherapeutic drugs is usually less than 30% successful in the clinic. The targeting

drug with magnetic microspheres to treat human cholangiocarcinoma xenografts. Its can inhibit the growth of

human cholangiocarcinoma xenografts in nude mice. [40]

4.9.7. Magnetic control of pharmacokinetic parameter and Improvement of Drug release.

Magnetite or iron beads in to a drug filled polymer matrix and then showed that they could activate or increase

the release of drug from the polymer by moving a magnet over it or by applying an oscillating magnetic field.

The microenvironment within the polymer seemed to have shaken the matrix or produced ‘micro cracks’ and

thus made the influx of liquid, dissolution and efflux of drug possible thereby achieving magnetically controlled

drug release. Macromolecules such as peptides have been known to release only at a relatively low rate from a

polymer controlled drug delivery system, this low rate of release can be improved by incorporating an

electromagnetism triggering vibration mechanism into the polymeric delivery devices with a hemispheric

design; a zero-order drug release profile is achieved[41]

4.9.8. Magnetic systems for magnetic cell separation.

One important application of magnetic cell separation is the purging of malignant cells from autologous stem

cell products, depletion of T cells, and selection of specific lymphocyte subsets with potential antileukemic

activity. In this way, a cancer patient’s stem cells can be extracted, purified, and then injected again after he has

gone through a harsh cancer. The therapeutic applications of immunomagnetic cell selection are based on

antibodies that bind to cancer cell antigens such as CD10, CD19 or CD20. Two machines for magnetic cell

separation have recently received FDA approval, Cellpro’s “Ceprate SC stem cell collection system” and

Baxter’s “Isolex 300I.” A third system is approved in Europe, Miltenyi’s “ClinicMACS” system. [42]



4.9.9. Combination therapy.

There also exists the combination therapy which would induce hyperthermia treatment followed by

chemotherapy or gene therapy. A combination of chemotherapy or radiation therapy with hyperthermia is found

much more effective than hyperthermia itself. The approach involves use of magnetic microspheres containing

a drug to cause hyperthermia using the standard procedure, followed by the release of encapsulated drug that

will act on the injured cells. It is anticipated that the combined treatment might be very efficient in treating solid

tumor. Ongoing investigations in magnetic hyperthermia are focused on the development of magnetic particles

that are able to self-regulate the temperature they reach. The ideal temperature for hypothermia is 43°C - 45°C,

and particles with a curie temperature in this range have been described by kuznetsov et al[43]

4.10. Preparation of open cellular PMMA microspheres by supercritical carbon dioxide foaming method.

The supercritical experimental setup is schematically shown in Fig. 11 About 2–3 g PMMA micropowder was

placed in a beaker capped with a porous polyethylene thin film and then sealed into the high-pressure stainless

steel vessel (500 ml). After the vessel was preheated to the desired temperature, CO2 gas was introduced into

the vessel to purge it for several minutes. Subsequently, the vessel was pressurized with CO2 using a high-

pressure liquid pump. When the desired pressure was reached, the system was kept at that pressure and

temperature for 2 h. Since the particle size is very small, this time of exposure is sufficient for SC CO2 sorption

into the polymer to reach its thermodynamic solubility. At the end of this period, the vessel was depressurized

by opening valve 10 and venting the CO2 in less than 30 s. The external temperature of the vessel was

maintained constant during the depressurization step. It should be noted that the temperature inside the vessel

decreased as the pressure was rapidly reduced to atmospheric pressure. The temperature was then raised slowly

to the set value (ca. 20 min) and kept at that temperature for about 5 min. After that, the sample was removed

from the vessel and allowed to cool to room temperature.[44]



Fig.11. Schematic illustration of the SC CO2 setup employed: (1) CO2 gas cylinder; (2) condenser; (3) chiller unit; (4) pump; (5) buffer tank; (6) pressure vessel; (7) back pressure valve; (8) temperature indicator; (9) pressure gauge; (10) vent valve; (11) sample; (12) heating jacket; (13) valve.

4.11. An over view: microspheres as a nasal drug delivery system.

All types of microspheres that have been used as nasal drug delivery systems are water-insoluble but absorb

water into the sphere’s matrix, resulting in swelling of the spheres and the formation of a gel. The building

materials in the microspheres have been starch, dextran, albumin and hyaluronic acid, and the bioavailability of

several peptides and proteins has been improved in different animal models. Also, some low-molecular weight

drugs have been successfully delivered in microsphere preparations. The residence time in the cavity is

considerably increased for microspheres compared to solutions. However, this is not the only factor to increase

the absorption of large hydrophilic drugs. The dextran microsphere system was as effective as an absorption

enhancer for insulin as degradable starch microspheres (DSM). The mode of action for improved absorption

found for starch microspheres is also applicable to dextran micro spheres. Microspheres also exert a direct

effect on the mucosa, resulting in the opening of tight junctions between the epithelial cells.[45]

Fig12: Possible routes of transport between the nasal cavity and the brain and CSF



Tab.1: List of prescription nasal product currently present on market

5. CHARACTERIZATION & EVALUATION OF MICROSPHERES

(1) Particle size & size distribution

a. sieving

b. microscopy

c. coulter counter analysis

d. Laser Diffraction analysis

(2) Surface characterization

a. High-resolution microscopy

b. Scanning electron microscopy

c. Scanning tunneling microscopy

3) Surface charge analysis

a. micro electrophoresis

b. Laser doppler anemometry

(4) Density

a. Bulk density

b. Tapped density

(5) Flow properties

a. Angle of reposeÆ

b. Hausner ratio

(6) Drug release profiles



a. In vitro

b. In vivo

(7) Surface area

(8) Porosity

(9) Hardness & friability

(10) Drug content

(11) Drug release profiles.[46]

Evaluation

Some of the evaluation characteristics considered for albumin microspheres are as follows:

1. Interaction study by TLC/ FTIR.

IR spectroscopic studies

The IR spectra of the free drug and the microspheres were recorded. The identical peaks corresponding to the

functional groups and albumin (BSA, Egg albumin, Human serum albumin) features confirm that neither the

polymer nor the method of preparation has affected the drug stability.

Thin layer chromatographic studies

The drug stability in the prepared microspheres can also be tested by the TLC method. The Rf values of the

prepared microspheres can be compared with the Rf value of the pure drug. The values indicate the drug

stability.

2. Surface topography by Scanning Electron Microscopy (SEM)

SEM of the microspheres shows the surface morphology of the microspheres like their shape and size.

3. Particle size distribution of prepared microspheres.

The size of the prepared microspheres can be measured by the optical microscopy method using a calibrated

stage micrometer for randomly selected samples of all the formulations.

4. Drug entrapment capacity.

Efficiency of drug entrapment for each batch can be calculated in terms of percentage drug entrapment (PDE)

as per the following formula:



PDE = x 100

Theoretical drug content can be determined by calculation assuming that the entire drug present in the polymer

solution used gets entrapped in microspheres and no loss occurs at any stage of preparation of microspheres.

5. In vitro release studies.

In-vitro release studies can be performed according to USP XXII type I dissolution apparatus at suitable pH

conditions. The temperature should be maintained at 37±0.5°C and the rotation speed of 100 rpm. Then 5 ml of

sample should be withdrawn at various time intervals and replenished with an equal volume of fresh dissolution

media. The drug content in the sample can be analyzed spectrophotometrically at specific wavelength (nm).[47]

6. Solid state by DSC/XRD.

This test is done by a X-Ray diffractometer to find out the solid state of the drug, polymer and drug-polymer

mixture and also to find out the solid state of the drug in the prepared albumin microspheres

Physicochemical evaluation characterization The characterization of the microparticulate carrier is an

important phenomenon, which helps to design a suitable carrier for the proteins, drug or antigen delivery. These

microspheres have different microstructures. These microstructures determine the release and the stability of the

carrier

(a) Sieve analysis Separation of the microspheres into various size fractions can be determined by using a

mechanical sieve shaker (sieving machine, retsch, germany). A series of five standard stainless steel sieves (20,

30, 45, 60 and 80 mesh) are arranged in the order of decreasing aperture size. Five grams of drug loaded

microspheres are placed on the upper-most sieve. The sieves are shaken for a period of about 10 min, and then

the particles on the screen are weighed

(b) Morphology of microspheres The surface morphologies of microspheres are examined by a scanning

electron microscope (xl 30 sem philips, eindhoven, and the netherlands). The microspheres are mounted onto a

copper cylinder (10 mm in diameter, 10 mm in height) by using a double-sided adhesive tape. The specimens

are coated at a current of 10 ma for 4 min using an ion sputtering device.

(c) Atomic force microscopy (afm) A multimode atomic force microscope from digital instrument is used to

study the surface morphology of the microspheres. The samples are mounted on metal slabs using double-sided



adhesive tapes and observed under microscope that is maintained in a constant-temperature and vibration-free

environment

(d) Particle size Particle size determination approximately 30 mg microparticles is redispersed in 2–3 ml

distilled water, containing 0.1% (m /m) tween 20 for 3 min, using ultrasound and then transferred into the small

volume recirculating unit, operating at 60 ml/ s.

(e) Polymer solubility in the solvents Solution turbidity is a strong indication of solvent power [14]. The cloud

point can be used for the determination of the solubility of the polymer in different organic solvents.

(f) Viscosity of the polymer solutions The absolute viscosity, kinematic viscosity, and the intrinsic viscosity of

the polymer solutions in different solvents can be measured by a u-tube viscometer (viscometer constant at 40

0c is 0.0038 Mm2/s /s) at 25 ± 0.1 0c in a thermostatic bath. The polymer solutions are allowed to stand for 24 h

prior to measurement to ensure complete polymer dissolution.

(g)Density determination The density of the microspheres can be measured by using a multi volume

pychnometer. Accurately weighed sample in a cup is placed into the multi volume pychnometer. Helium is

introduced at a constant pressure in the chamber and allowed to expand. This expansion results in a decrease in

pressure within the chamber. Two consecutive readings of reduction in pressure at different initial pressure are

noted. From two pressure readings the volume and density of the microsphere carrier is determined.

(h)Bulk density The microspheres fabricated are weighed and transferred to a 10-ml glass graduated cylinder.

The cylinder is tapped using an autotrap (quantach- rome, fl, usa) until the microsphere bed volume is

stabilised. The bulk density is estimated by the ratio of microsphere weight to the final volume of the tapped

microsphere bed.

(i) Capture 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 [18]. The percent encapsulation efficiency is calculated using

following equation: % entrapment = actual content/theoretical content x 100

(j) Angle of contact: The angle of contact is measured to determine the wetting property of a micro particulate

carrier. It determines the nature of microspheres in terms of hydrophilicity or hydrophobicity . This



thermodynamic property is specific to solid and affected by the presence of the adsorbed component. The angle

of contact is measured at the solid/air/water interface. The advancing and receding angle of contact are

measured by placing a droplet in a circular cell mounted above objective of inverted microscope. Contact angle

is measured at 200c within a minute of deposition of microspheres

(k) In vitro methods: There is a need for experimental methods which allow the release characteristics and

permeability of a drug through membrane to be determined. For this purpose, a number of in vitro and in vivo

techniques have been reported. In vitro drug release studies have been employed as a quality control procedure

in pharmaceutical production, in product development etc. Sensitive and reproducible release data derived from

physico chemically and hydro dynamically defined conditions are necessary. The influence of technologically

defined conditions and difficulty in simulating in vivo conditions has led to development of a number of in vitro

release methods for buccal formulations; however no standard in vitro method has yet been developed.

Different workers have used apparatus of varying designs and under varying conditions, depending on the shape

and application of the dosage form developed. [48,52]

6. FACTORS INFLUENCING PROPERTIES OF MICROSPHERES.

(A) Dispersed phase



1. Polymers commonly used to form microspheres

2. Choice of solvent

(1) Should be able to dissolve the chosen polymer;

(2) Poorly soluble in the continuous phase;

(3) High volatility and a low boiling point;

(4) Low toxicity.

(5) Alternative components (dispersed phase)

(a) Co-solvent :- organic solvents miscible with water such as methanol and ethanol.

(b) Porosity generator :- increases the degradation rate of polymer and improves drug release rate.

Eg. Incorporating sephadex (cross-linked dextran gel) into insulin–pla microspheres significantly increases

microsphere porosity.

(B) Continuous phase

(a) Surfactant:-

• It reduces the surface tension of continuous phase.

• Avoids the coalescence and agglomeration of drops.

• Stabilizes the emulsion.

• Widely used stabilizers include:

i. Non-ionic: partially hydrolyzed pva , methylcellulose , tween, span

ii. anionic: sodium dodecyl sulphate (sds), sls

iii. cationic: cetyltrimethyl ammonium bromide (ctab).

(b) Alternative component:-

• Antifoaming agent - foaming problem will disturb the formation of microspheres.

• Anti-foams of silicon and non-silicon constituents are used.

(C) Impact of parameters and operating conditions on the properties of microspheres.[49]

Technology limitations in preparing microspheres

• Residual solvents



• Stability

• Non availability of degradable, synthetic polymers

• Encapsulation efficiency

• Limitation of manufacturing process

• Sterilization

Sterilization of microspheres

microspheres that are administered parenterally must be sterile. Sterilization is usually achieved by aseptic

processing. The final product may not be able to undergo terminal sterilization, which may be detrimental to the

delivery system, altering the release pattern or destroying the targeting properties.Sterility assurance is also a

problem for microsphere system: although the exterior can be investigated for sterility by conventional plating

methodology, it is difficult to determine whether the interiors of the microspheres are free from contamination.

A method has been developed whereby the presence of viable organisms in the interior of microspheres systems

can be determined without breaking the microcapsules/microspheres; it involves the detection of the organism

metabolism.[50]

7. MARKETED PRODUCT



8. CONCLUSION

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.Microsphere drug

delivery systems provide tremendous opportunities for designing new controlled and delayed release oral

formulations, thus extending the frontier of future pharmaceutical development. The Microsphere offers a

variety of opportunities such as protection and masking, reduced dissolution rate, facilitation of handling, and

spatial targeting of the active ingredient. This approach facilitates accurate delivery of small quantities of potent

drugs; reduced drug concentrations at sites other than the target organ or tissue; and protection of labile

compounds before and after administration and prior to appearance at the site of action. In future by combining

various other approaches, Microsphere technique will find the vital place in novel drug delivery system.

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Corresponding Author:

Kedar Prasad Meena*

SLT Institute of Pharmaceutical Sciences,

Email:[email protected]

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