MICROSPHERES

INTRODUCTION
• Microspheres are solid spherical particles made up of polymeric
substances, in which the drug is dispersed through out the
microsphere matrix, its size ranges from 1-1000μm.
• Microcapsules are small particles that contain drug or core
material surrounded by a shell or coating of polymer.
There are two types
 HISTORY
• The concept of packing microscopic
quantities of material with in

microspheres dates to 1930’s the

work of Bungenberg de Jong and
coworkers on the entrapment of
substance with coacervates.
• Use of micropsheres in industry
started in 1960`s.
 ADVANTAGES OF MICROSPHERES
1. They facilitate accurate delivery of small quantities of potent drug
and reduced concentration of drug at site other than the target organ
or tissue.
2. They provide protection for unstable drug before and after
administration, prior to their availability at the site of action.
3. They provide the ability to manipulate the in vivo action of the
drug, pharmacokinetic profile, tissue distribution and cellular
interaction of the drug.
4. They enable controlled release of drug. Ex: narcotic, antagonist,
steroid hormones.
5. Particle size reduction for enhancing solubility of the poorly
soluble drug.
6. Provide constant and prolonged therapeutic effect.
7. Provide constant drug concentration in blood there by increasing
patent compliance.
9. Reduce the dosing frequency and thereby improve the patient
compliance
10.Better drug utilization will improve the bioavailability and reduce
the incidence or intensity of adverse effects.
11. Protects the GIT from irritant effects of the drug.
12.Biodegradable microspheres have the advantage over large
polymer implants in that they do not require surgical procedures
for implantation and removal.
13.Controlled release delivery biodegradable microspheres are used
to control drug release rates there by decreasing toxic side effects,
and eliminating the inconvenience of repeated injections.
14.Decrease dose and toxicity.
 DISADVANTAGES
1. The costs of the materials and processing of the controlled release
2. preparation, are substantially higher than those of standard
formulations.
3. The fate of polymer matrix and its effect on the environment.
4. The fate of polymer additives such as plasticizers , stabilizers,
antioxidants and fillers.
5. Reproducibility is less.
6. Process conditions like change in temperature, pH, solvent
addition, and evaporation/agitation may influence the stability of
core particles to be encapsulated.
7. The environmental impact of the degradation products of the
polymer matrix produced in response to heat, hydrolysis,
oxidation, solar radiation or biological agents.
 IDEAL CHARACTERISTICS of microspheres:
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.
 Susceptibility to chemical modification
 Potential use of microspheres in the pharmaceutical
industry
• Taste and odour masking
• Conversion of oil and other liquids, facilitating ease of handling
• Protection of the drug from the environment
• Delay of volatilisation
• Freedom from incompatibilities between drug and excipients,
especially the buffers
• Improvement of flow properties
• Dispersion of water insoluble substance in aqueous media
• Production of sustained release, controlled release and targeted
medication
 MICROSPHERE MANUFACTURE
Most important physicochemical characteristics that may
be controlled in microsphere manufacture are:

• Particle size and distribution

• Polymer molecular weight
• Ratio of drug to polymer
• Total mass of drug and polymer
 MICROSPHERES PREPERATION METHODS

1) SINGLE EMULSION TECHNIQUE

2) DOUBLE EMULSION TECHNIQUE
3) POLYMERISATION TECHNIQUE
A) Normal
Polymerisation
Bulk polymerisation
Suspension polymerisation
Emulsion polymerisation
B) Interfacial Polymerisation
1) COACERVATION PHASE SEPERATION
2) SPRAY DRYING & SPRAY CONGEALING
3) SOLVENT EXTRACTION
HEAT
 SUSPENSION POLYMERIZATION
 This is also referred as bead or pearl polymerization.
 It is carried out by heating the monomer or composition of
monomers as droplets dispersion in a continuous aqueous phase.
 Droplets may also contain an initiator and other additives
 INTERFACIAL POLYMERIZATION TECHNIQUE
This involves the reaction of various monomers at interface between
the two immiscible liquid phases to form a film of polymer.
Oil+ Monomer-A Water + Monomer-B

O/W Emulsion

• The monomers present in either phases diffuse rapidly and

polymerize rapidly at the interface.
• If the polymer is soluble in droplet it will lead to the formation of
the monolithic type of carrier.
• If the polymer is insoluble in monomer droplet, the formed carrier
is of capsular.
 ADV & DISADV:
 Bulk polymerization forms pure polymer.
 In Bulk polymerization Heat of reaction affects
thermolabile drugs.
 Emulsion & suspension polymerization suitable for
thermolabile drugs.
 In Emulsion & suspension polymerization polymer
associates with unreacted monomer/ additives.
 Interfacial polymerization causes toxicity with
unreacted monomer.
 High permeability of film, fragile & non-biodegradable
microspheres.
 Drug degradation during polymerization
 COACERVATION PHASE SEPERATION TECHNIQUE
• Specially designed for preparing reservoir type to encapsulate water soluble
drugs (proteins & peptides).
• For hydrophobic drugs (steroids) matrix type are designed.
Principle: solubility of polymer is decreased in organic phase to form polymer rich
phase called coacervates.

Addition of salt,
non-solvent,
incompatible
polymer,
pH change
 SPRAY DRYING & SPRAY CONGEALING
Depending on the removal of solvent or cooling the solution are
named as “drying” and “congealing”, respectively.
Polymer dissolve in volatile organic solvent(acetone,DCM)

Drug dispersed in polymer solution under

high speed homogenization

Atomized in a stream of hot air

Solvent evaporation form small droplets

Leads to formation of Microspheres

Microspheres separated from hot air by cyclone separator,

Trace of solvent are removed by vacuum drying

Adv: Aseptic condition operation, Bulk manufacturing.

% Drug content = (amount of encapsulated drug
amount of added drug) *100
Surface carboxylic acid & amino acid residue:
Measured by using RADIOACTIVE GLYCINE.
C14 glycine ethyl ester hydrochloride + Microspheres  Radioactive
glycine conjugate
C14 acetic acid + Microspheres  Radioactive acid conjugate
Condensing agent – EDAC (1-ethyl-3(3-dimethyl aminopropyl)
carbidiimide)
Radioactivity is measured by using LIQUID SCINTILLATION COUNTER
 APPLICATIONS
1. Vaccine delivery :
Improved antigenecity, Antigen controlled release, Stabilization of
Antigen. Ex: Diphtheria toxoid , Tetanus toxoid
2. Stability:
Microspheres are co-encapsulated with buffer salts, stabilizers.
Ex: triblock co-polymer (A-block = PLA/ PLAGA, B-block = PEO).
3. Antigen release:
Release of antigen in microspheres is influenced by structure, micro-
morphology, nature and type of polymer.
The release my follow burst mechanism, pore diffusion, erosion or
combination.
4. Microspheres and immune system:
Microsphere interaction with macrophages depends on particle size.
Microspheres < 10µ  Antigen presenting cell  Activate B&T cells.
Microspheres > 10µ  degrade/ release antigen  Antigen
presenting cell.
5. Targeting using microparticulate carriers:
a. Ocular:
rapid conversion of microparticulate suspension to gel leads to
longer retention time in eye.
b. Intranasal:
bioadhesive microspheres are used for delivery of proteins &
peptides.
c. Oral:
• multiple unit systems spreads over large area, avoid risk of dose
dumping.
• Oral route is suitable for soluble antigens.
• Anti-infective agents of poor aqueous solubility are
Incorporated in to pH sensitive microparticles.
• Attachment to ulcerated colonic tissue depends on size.
(10µ<1µ<0.1µ)
6. Immuno-microsphere (MAB`s mediated targeting):
MAB`s are extremely specific molecules used to target selected sites.
MAB`s are directly attached by covalent coupling to the free aldehyde,
amino, hydroxy groups on microsphere surface.
MAB`s are attached to microsphere by following methods
1. Non-specific adsorption: (Vander waals-London forces)
MAB`s + Hydrophobic microspheres  hydrophilic  cell targeting.
2. Specific adsorption:
Microsphere + ligand + MAB  Immuno-microsphere.
Ligands = avidin-biotin, Proteins-A form Staphylococcus aureus.
3. Direct coupling:
Free functional groups on microspheres surface under go direct
coupling. Ex: Polyacroline microspheres (free carboxyl groups) +
MAB`s
4. Coupling via reagents:
Suitable when microspheres do not have free functional groups/
functional groups that do not bind. Carbodiimide method,
cyanogen bromide method, glutaraldehyde method, dextran
bridge method. etc.,
7. Chemoembolization:
This is endovascular therapy, which involves selective arterial
embolization (blocking) of tumour together with local delivery of drug
loaded microspheres.
Blockade of arterioles and capillary bed of tumour has 2 benefits.
1. Increases time of absorption of drug at tumour site.
2.Blockage of blood supply causes ischemia & tumour regression.
microspheres of size > 40 µ are injected intra-arterially for
chemoembolization.
Ex: degradable starch microspheres are used for liver metastates.
8. Microsponges- topical porous microspheres:
• Microsponges are porous microspheres having interconnected
voids of particle size range 5-300µ.
• Depending up on size pore length may range up to 10µ and pore
volume 1ml/g.
• These can entrap wide range of active ingredients such as
emollients, fragrances, essential oils, sunscreens and anti
infectives and used as topical carrier system.
• Microsponges can be formulated as creams, lotions, powders.
9. Surface modified microspheres:
• This achieves targeting to discrete organs and to avoid rapid
clearance form the body by phagocytosis.
Ex: Poloxamer on surface of polystyrene/ PMMA microspheres 
more hydrophilic  reduced macrophage uptake.
• PEG coated protein microspheres show decreased
immunogenecity.
• Surface modifiers = antibodies, proteins, polysaccharides,
chelating compounds, synthetic soluble polymers.
Magnetite