MICROSPHERES M pharm Department of Pharmaceutics PDF/PPT

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M pharm
Department of Pharmaceutics

Associate Professor
Department of Pharmaceutics

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Microspheres are defined as solid, spherical particles ranging in size from

1- 1000 µm, made up of polymeric, waxy or other protective materials.

➢ They are spherical free flowing particles consisting of proteins or synthetic

polymers which are biodegradable in nature.

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• Microspheres are manufactured in both solid and hollow form. Hollow

microspheres are used as additives to lower the density of a material.

• Solid biodegradable microspheres incorporating a drug dispersed or

dissolved throughout particle matrix have the potential for controlled

release of the drug.

• These carriers received much attention not only for prolonged release but

also for the targeting anti cancer drugs to the tumour.

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1.Particle size reduction for enhancing solubility of the poorly soluble drug.
2. Provide constant and prolonged therapeutic effect.
3. Decrease dose and toxicity.
4. Protect the drug from enzymatic and photolytic cleavage hence found to be best
for drug delivery
5. Reduce the dosing frequency and thereby improve the patient compliance
6. Better drug utilization will improve the bioavailability and reduce the incidence or
intensity of adverse effects.
7. Protects the GIT from irritant effects of the drug.
8. Biodegradable microspheres have the advantage over large polymer implants
because they do not require surgical procedures for implantation and removal.
9. 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.

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1. The costs of the materials and processing of the controlled release
preparation, are substantially higher than those of standard formulations.

2. The fate of polymer additives such as plasticizers , stabilizers, antioxidants,
fillers, polymer matrix and its effect on the environment.

3. Reproducibility is less.
4. Process conditions like change in temperature, pH, solvent addition, and

evaporation/agitation may influence the stability of core particles to be

5. The environmental impact of the degradation products of the polymer
matrix produced in response to heat, hydrolysis, oxidation, solar radiation
or biological agents.

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• 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

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• This kind of delivery system is very much important which localises the drug to

the disease site.

• In this larger amount of freely circulating drug can be replaced by smaller

amount of magnetically targeted drug.

• Magnetic carriers receive magnetic responses to a magnetic field from

incorporated materials that are used for magnetic microspheres are chitosan ,

dextran etc.

The different types of magnetic microspheres:

a. Therapeutic magnetic microspheres:- used to deliver chemotherapeutic

agent to liver tumors. Drugs like proteins and peptides can also be targeted

through this system.

b. Diagnostic microspheres:- used for imaging liver and also can be used to

distinguish bowel loops from other abdominal structures by forming micron size

particles Ex:supra magnetic iron oxides.
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➢ 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, and the system is found to be

floating on gastric content and increases gastric residence and decreases
fluctuation in plasma concentration.

➢ Moreover it also reduces chances of dose dumping.
➢ It produces prolonged therapeutic effect and therefore reduces dosing

Ex: Drug (ketoprofen)is given in the form of floating microspheres

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• Radio embolization therapy microspheres sized 10-30mm are of larger than the

diameter of the capillaries and gets tapped in capillary bed.

• They are injected in the arteries that leads them to tumour of interest so

these radioactive microspheres deliver high dose to the targeted areas without

damaging the normal surrounding tissues.

• It differs from drug delivery system, as radio activity is not released from

microspheres but acts from within a radioisotope.

• The different kinds of radioactive microspheres are α emitters, β emitters, γ


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The various types of polymers are used for preparation of


e.g:- Albumin microspheres

Gelatin microspheres

Starch microspheres

Dextran microspheres

Carrageenan microspheres

Alginate microspheres

Poly (alkyl cyanoacrylate ) microspheres etc.,

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They are classified into two types:

➢ Synthetic Polymers

➢ Natural polymers

Synthetic polymers are divided into two types.

a) Non-biodegradable polymers:- Poly methyl methacrylate (PMMA), Acrolein,

Glyceryl methacrylate, Epoxy polymers

b) Biodegradable polymers:-Lactides, Glycolides & their co polymers, Poly alkyl

cyanoacrylates, Poly anhydrides

Natural polymers obtained from different sources like proteins, carbohydrates

and chemically modified carbohydrates

• Proteins: Albumin, Gelatin, Collagen

• Carbohydrates: Agarose, Carrageenan, Chitosan, Starch

• Chemically modified carbohydrates: Poly (acryl) dextran, Poly(acryl)starch

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• Bulk polymerization
• Suspension polymerization
• Emulsion polymerization

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Criteria for selection of method of

The ability to incorporate reasonably high concentrations of the

Stability of the preparation after synthesis with a clinically acceptable shelf

Controlled particle size and dispersability in aqueous vehicles
for injection.

Release of active reagent with a good control over a wide time

Susceptibility to chemical modification

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

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Prerequisites for Ideal Microparticulate

• Longer duration of action

• Control release

• Increase of therapeutic efficacy

• Protection of drug

• Reduction of toxicity

• Biocompatibility

• Sterilizability

• Relative stability

• Water solubility or dispersibility

• Targeting

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Spray drying and spray congealing

These methods are based on the drying of mist of the
polymer & drug in the air either by,
• removal of solvent (spray drying)or

• cooling of the solution(spray congealing).


Feasibility of operation in aseptic condition.

Suitable for both bath & bulk mfg.

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Preparation of BSA loaded PLGA

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Suspension polymerization 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

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• Interfacial polymerization essentially precedes involving reaction of various

monomers at the interface between the two immiscible liquid phases to

form a film of polymer that essentially envelops the dispersed phase.

• The monomers present in either phases diffuse rapidly and polymerize

rapidly at the interface.

• Monomer droplet, the formed carrier is of capsular (reservoir)type.

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Specially designed for preparation of reservoir type of the system, also used
for matrix type devices.

Coacervation is induced by subjecting the biphasic system to
conditions which brings coalescence of the polymer by withdrawing the
solvent away from colloidal particles under controlled conditions.

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1)Simple coacervation:

Occurs in presence of only one macromolecule. E.g. water/gelatin

Induced by-

• Non solvent addition

• Salt addition

• Temp. change

• Incompatible polymer addition

2) Complex coacervation:

Two or more macromolecules of opposite charges.
E.g. Solution of positively charged Gelatin with negatively charged Gum

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Solvent extraction:

➢ This method involves removal of the organic phase by extraction of non

aqueous solvent.

➢ It involves water miscible organic solvents like isopropanol .

➢ Organic phase can be removed by extraction with water. This process

decreases the hardening time for the microspheres.

➢ One variation of the process involves direct incorporation of the drug or

protein to polymer organic solution.

➢ Rate of solvent removal by extraction method depends on the temperature of

water, ratio of emulsion volume to the water and solubility profile of polymer.

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Solvent Extraction

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Wax coating & Hot melt technique

In this method, Wax is used to coat the core particles

Ex: Carnauba wax ,Bees wax.


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Air Suspension
• Prof. Dale E. Wurster.
• It consist of dispersing the solid particulate core material in supporting

air stream.

Process variable parameter:-

1) Application rate of coating material.

2) Coating material conc.

3) Core material properties.

➢ An emulsion is formed, which consists of polar droplets dispersed in a

non-polar medium.
➢ Solvent may be removed from the droplets by the use of a co-solvent.
➢ The resulting increase in the polymer-drug concentration causes a

precipitation forming a suspension

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Freeze Drying

• This method involves the freezing of emulsion.

• The continuous-phase solvent is usually organic and is removed by

sublimation at low temperature and pressure.

• Finally, the dispersed-phase solvent of the droplets is removed by

sublimation, leaving polymer-drug particles.

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The BRACE-Process
➢ Ultra Spherical Microspheres

➢ Microspheres with a monodisperse grain size distribution and the smallest

divergence are manufactured by BRACE.

• perfectly spherical Microspheres

• monodisperse grain size, narrow size distribution with diameters

between 50μm and 5000μm

• free flowing, porous, large surface area,soft or rigid

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The BRACE-Process

➢ A liquid is gently pumped through a vibrating nozzle system whereupon

exiting the fluid stream breaks up into uniform droplets.

➢ The surface tension of these droplets moulds them into perfect spheres in

which gelation is induced during a short period of free fall.

➢ Solidification can be induced in a gaseous and/or liquid medium through

cooling, drying, or chemical reaction.

➢ There are no constraints on the type of liquid—molten materials,

solutions, dispersions, sols, or suspensions can be used to manufacture

perfectly spherical microspheres.

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1. Particle size and shape:

The most widely used procedures to visualize microparticles are:

➢ Conventional light microscopy
➢ Scanning electron microscopy (SEM).
➢ Confocal laser scanning microscopy
➢ Confocal fluorescence microscopy
➢ Laser light scattering and multisize coulter counter

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2. Degradation behavior:

The surface chemistry of the microspheres can be determined using the electron

spectroscopy for chemical analysis (ESCA). This method determines the atomic

composition of surface. The spectra of ESCA is used to determine surface

degradation of biodegradable microspheres.

3. Density determination:

The density of the microspheres can be measured by using a multi volume

4. Isoelectric point:

The microelectrophoresis is used to measure the electrophoretic mobility of

microspheres from which the isoelectric point can be determined.

The mean velocity at different pH values ranging from 3-10 is calculated by

measuring time for particle movement over 1mm distance. Using this data

electrical mobility can be determined.

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5.Bulk density measurement: By dipping method.

6.Measurement of glass transition temp (Tg) by DSC: Tg is
measured by DSC for the blank (unloaded) and the prepared loaded

7. Angle of contact:
The angle of contact is measured to determine the wetting property of a
micro particulate carrier.
The angle of repose was calculated by the following equation
tan θ =h/r
where h & r are the height band radius of the heap.

8. Drug entrapment efficiency:
Drug entrapment efficiency it is the percentage of drug that is successfully
entrapped within microspheres, it can be determined by allowing washed
microspheres to lyse. The lysate is then subjected to determination of
active constituents as per monograph. The % encapsulation is calculated
using following equation,
% Entrapment = Actual content/Theoretical content x 100.

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9. Swelling index :
• It is conducted in a phosphate buffer of pH 6.8.
• The diameter is measured periodically by using laser particle size distribution

analyzer until they were decreased by erosion and dissolution.
• The swelling index of the microsphere was calculated by using the formula,
Swelling index= (mass of swollen microspheres – mass of dry microspheres) x100
(mass of dried microspheres)

10. In vitro methods:
Release studies- for different type of microspheres are carried out by using
suitable dissolution media(phosphate buffer pH 7.4), mostly by rotating paddle
apparatus (USP)
• Agitated with 100 rpm, samples were collected at specific time intervals and

replaced by same amount and analyzed.
2. Dialysis method-Carried out in phosphate saline buffer Ph 7.4.

11. Adhesion property:
• Freshly cut piece of pig intestine is used (5 cm long),clean and wash it with

isotonic saline solution.
• Accurate weight of microspheres was placed on mucosal surface, phosphate

buffer of pH 6.8 is warmed at 37 °c was peristaltically pumped at a rate of 5 ml/
min over the tissue.

• The duration of complete washing of microspheres from pig intestine was
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➢ Vaccine delivery – Improved antigenecity, Ag release, Stabilization of Ag.

Eg : Diphtheria toxoid , Tetanus toxoid.

➢ Drug targeting

◦ Ocular: gelation with increased residence time

◦ Intranasal: protein and peptide delivery

◦ Oral

➢ Magnetic microspheres

➢ Immunomicrospheres

➢ Chemoembolization

➢ Imaging

➢ Microsponges

➢ Surface modified microspheres.

➢ Gene delivery
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• Taste and odor masking.
• Conversion of oils and other liquids to solids for ease of handling.
• Protection of drugs against the environment (moisture, light etc.).
• Separation of incompatible materials (other drugs or excipients).
• Improvement of flow of powders.
• Aid in dispersion of water-insoluble substances in aqueous media, and

production of SR, CR, and targeted medications.

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Microencapsulated products currently on the market, such as aspirin,
theophylline & its derivatives, vitamins, antihypertensive, potassium chloride,
progesterone, and contraceptive hormone combinations.

Microencapsulated KCl is used to prevent gastrointestinal complications
associated with potassium chloride.

Microspheres have also found potential applications as injection, or
inhalation products.

Most encapsulation processes are expensive and require significant capital
investment for equipment.

An additional expense is due to the fact that most microencapsulation
processes are patent protected.

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Microcapsules are also extensively used as diagnostics.
Example: temperature-sensitive microcapsules for thermographic
detection of tumors.

In the biotechnology industry microencapsulated microbial cells are being
used for the production of recombinant proteins and peptides.

Encapsulation of microbial cells can also increase the cell-loading capacity
and the rate of production in bioreactors.

A breast tumor line, which was difficult to grow in conventional culture, has
been successfully grown in microcapsules.

Microencapsulated activated charcoal has been used for hemoperfusion.
Paramedical uses of microcapsules include bandages with

microencapsulated anti-infective substances.

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1. Short notes on magnetic microspheres. 5M
2. Enlist the different methods of preparation of microspheres. Explain any

2 methods. 10M x 2
3. Write a note on types of microspheres. 5M
4. Evaluation of microspheres and give its applications. 10M

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➢ S.P.Vyas., R.K.Khar, International Journal for Targeted & Controlled Drug
Delivery Novel Carrier Systems., First Edition :2002.,Reprint :2007 page

➢ N.K.Jain ,Controlled and novel drug delivery edited by reprint 2007

➢ Review article by Kadam N.R and Suvarna

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