MICROSPHERES AS DRUG DELIVERY SYSTEM

BY: GAJENDRA GUPTA

GUIDED BY: Dr.K.R.Jadhav

(VICE PRINCIPAL & PROFESSOR OF PHARMACEUTICS)

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DEFINATION Microspheres can be defined as solid, approximately spherical particles

ranging in size from 1 to 1000 μm.

Made up of polymeric, waxy, or other protective materials such as starches, gums, proteins, fats, and waxes and used as drug carrier matrices for drug delivery.

Microcapsules: micrometric reservoir systems

Microspheres: micrometric matrix systems.

Natural polymer can also be used:

Albumin

Gelatin

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.

Drug CorePolymer Coat

= Polymer Matrix

} = Entrapped Drug

MICROCAPSULES MICROSPHERES •Microspheres are essentially spherical in shape, whereas, microcapsules may be spherical or non-spherical in shape.•Microparticles, either microcapsules or microspheres, as the same: ‘microcapsules’.

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Alternative Terms used in place of microspheres: Microbeads

Beads

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They facilitate accurate delivery of small quantities of potent drug and reduced

concentration of drug at site other than the target organ or tissue.

They provide protection for unstable drug before and after administration, prior to

their availability at the site of action.

They provide the ability to manipulate the in vivo action of the drug, pharmacokinetic

profile, tissue distribution and cellular interaction of the drug.

They enable controlled release of drug.

• Ex: narcotic, antagonist, steroid hormones

ADVANTAGE OF MICROSPHERES

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TYPES OF MICROSPHERES Microcapsule: consisting of an encapsulated core particle. Entrapped

substance completely surrounded by a distinct capsule wall.

Micro-matrix: Consisting of homogenous dispersion of active ingredient in particle.

Microcapsule

Micromatrix

Types of Microspheres

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POLYMER USED FOR MICROSPHERES PREPARATIONS

Biodegradable

• Lactides & Glycolides and their copolymers

• Polyanhydrides• Polycynoacrylate

s

Non-biodegradable

• Poly methyl methacrylate

• Acrolein• Epoxy Polymer• Glycidyl

methacrylate

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PROTEIN

Albumin

Gelatiin

Collagen

CARBOHYDRATES

Starch

Agarose

Chitoson

CHEMICALLY MODIFIDED

CARBOHYDRATES

DEAE cellulose

Poly dextran

Poly starch

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PREREQUISITES FOR IDEAL MICROPARTICULATE CARRIERS

Longer duration of action

Control of content release

Increase of therapeutic efficacy

Protection of drug

Reduction of toxicity

Biocompatibility

Sterilizability

Relative stability

Water solubility or dispersibility

Bioresorbability

Targetability

Polyvalent

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• Taste and odour masking

• Conversion of oil and other liquids,

facilitating ease of handling

• Protection of the drug from the environment

• Delay of volatilisation

PARAMETERS THAT CAN BE SATISFACTORILY CONTROLLED

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• 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

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METHODS OF PREPARATIONS

Solvent evaporation method

Single emulsion technique Double emulsion technique

Coacervation phase separation method

Spray drying and spray congealing method

Polymerization method

A. Single Emulsion Technique

Aq solution /suspension of

polymer(natural polymer)

stirring / sonication

Dispersion in Organic phase oil/CHCl3

cross lin

kin

g

Heat denaturation (by adding dispersion To heated oil)

Chemical crosslinking (butanol,HCHO,Glutaraldehyde)

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Microspheres in org.phase

Microspheres in org.phase

Centrifugation, washing, & separation

Microspheres

B. Double Emulsion Technique

Aqueous solution of polymer

dispersion in oil/orgenic phase, vigorous homogenisation(sonication)

Primary emulsion(w/o)

addition of aqueous solution of PVA

W/O/W multiple emulsion

Addition of large aqu. phase

Microspheres in solution

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Separation, washing, drying

MICROSPHERES

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C)Polymerization

A)Normal Polymerization

Normal Polymerization is done by bulk, suspension, precipitation, emulsion and polymerization process.

1. Bulk polymerization:

Microspheres

Moulded/fragmente

d

Polymer (block)

Heated to initiate

polymerization

Initiator accelerate

rate of reaction

Monomer

+ Bioactive material

+ Initiator

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B)Suspension polymerization

Monomer Bioactive material Initiator

Dispersion in water and stebilizer

Droplet

Vigorous Aggitation Polymerization by Heat

Hardened microspheres

Separation & Drying

MICROSP HERES

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c)Emulsion Polymerization

Monomer/ Aq.Solution of NaOH,

Bioactive material Initiator, Surfactant , Stabilizer

Dispersion with vigorous stirring

Micellar sol. Of Polymer in aqueous medium

Polymarization

Microspheres formation

MICROSPHERES

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D)Phase Separation Coacervation

Aq./organic solution of polymer

Drug dispersed or dissolved in the polymer solution

Phase sepration by salt addition, non solvent addition

add. Incompatible polymer,etc

Polymer rich globules

Hardening

Microspheres in aqu./organic phase

separation/drying

MICROSPHERES

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E)Spray Drying

Polymer dissolve in volatile organic solvent(acetone,dichloromethane)

Drug dispersed in polymer solution under

high speed homogenization

Atomized in a stream of hot air

Due to solvent evaporation small droplet or fine mist form

Leads to formation of Microspheres

Microspheres separated from hot air by cyclone separator, Trace of solvent are removed by vacuum drying

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F)Solvent Extraction

Drug is dispersed in organic solvent (water miscible organic solvent such as Isopropanol)

Polymer in organic solvent

Organic phase is removed by extraction with water (This process decreasing hardening time for microspheres)

Hardened microspheres

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G)Precipitation Method

An emulsion is formed, which consists of polar droplets dispersed in a non-polar medium. Solvent may be removed from the droplets by the used of a co-solvent.

The resulting increase in the polymer-drug concentration causes a precipitation forming a suspension of microspheres.

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ROUT OF ADMINISTRATIONOral delivery Parenteral delivery

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MECHANISMS OF DRUG RELEASE1. Degradation controlled monolithic system.

2. Diffusion controlled monolithic system.

3. Diffusion controlled reservoir system.

4. Erodible poly agent system.

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ANALYSIS OF MICROSPHERESElectron Microscopy, Scanning Electron Microscopy and Scanning

Tunneling Microscopy – Surface Characterization of Microspheres

Fourier Transform Raman Spectroscopy or X-ray Photoelectron Spectroscopy –to Determine If Any Contaminants Are Present

Surface Charge Analysis Using Micro-electropshoresis –Interaction of Microspheres Within the Body

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PHYSICOCHEMICAL EVALUATION &

CHARACTERIZATION

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PARTICLE SIZE & SHAPE

The most widely used procedures to visualize micro particles are conventional light microscopy (LM) and scanning electron microscopy (SEM).

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LM provides a control over coating parameters in case of double walled microspheres. The microspheres structures can be visualized before and after coating and the change can be measured microscopically.

SEM allows investigations of the microspheres surfaces and after particles are cross-sectioned, it can also be used for the investigation of double walled systems.

Conflocal fluorescence microscopy is used for the structure characterization of multiple walled microspheres.

Laser light scattering and multi size coulter counter other than instrumental methods, which can be used for the characterization of size, shape and morphology of the microspheres.

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CAPTURE EFFICIENCY

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RELEASE STUDIES It is done by using rotating paddle apparatus and Dialysis method

ANGLE OF REPOSE Determine wetting properties of Microparticulate carriers

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ELECTRON SPECTROSCOPY FOR CHEMICAL ANALYSIS

The surface chemistry of the microspheres can be determined using the electron spectroscopy for chemical analysis (ESCA). ESCA provides a means for the determination of the atomic composition of the surface. The spectra obtained using ECSA can be used to determine the surfacial degradation of the biodegradable microspheres.

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ATTENUATED TOTAL REFLECTANCE FT-IR Used to determine the degradation of the polymeric matrix of the carrier

system.

Surface of microspheres are investigated by ATR.

ATR-FT-IR provides surface composition of microspheres.

IR spectra of surface material

Reflected many times

through the

sample

IR beam is passed through the ATR

cell

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DENSITY DETERMINATION Can be determined by using MULTI VOLUME PYCHNOMETER

Weigh sample in

a cup

Placed in Multi

volume pychnom

eter

Helium is introduced in the chamber

and allowed

to expand

Expansion results

in decrease

in pressure

2 readings are noted

of reduction

in pressure

at different

initial pressure

From 2 reading volume

as well as density is determin

ed

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ISOELECTRIC POINT The micro electrophoresis is an apparatus used to measure the electrophoretic

mobility of microspheres from which the isoelectric point can be determined.

Mean velocity at different Ph values ranging from 3-10 is calculated by measuring the time of particle movement over a distance of 1 mm.

using this data the electrical mobility of the particle can be determined.

The electrophoretic mobility can be related to surface contained charge, ionisable behaviour or ion absorption nature of the microspheres.

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SURFACE CARBOXYLIC ACID Measured by using RADIOACTIVE GLYCINE

C14 glycine ethyl ester

hydrochloride

Microspheres

Radioactive glycine

conjugate EDAC

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RADIOACTIVITY is then measured by using LIQUID SCINTILLATION COUNTER

Carboxylic acid residue can be find out

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IN-VITRO METHODS

Beaker Method• Dosages form is adhere to the bottom of the

beaker containing medium.• Overhead stirrer is used.• Volume of medium-50-500ml• Speed 60-300rpm

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INTERFACIAL DIFFUSION SYSTEM

A. Oral cavity

containing drug in buffer

B. Buccal membrane containing 1-octanol

C. Body fluids

containing 0.2M HCl

D. Protein binding

containing 1-octanol

Before use, the aqueous phase and 1-octanol were saturated with each other.

Samples were withdrawn and returned to compartment A with a syringe.

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MODIFIED KC-CELL

Consist of KC-Cell containing distilled water (50ml) at 370C as dissolution medium

TMDDS was placed in a glass tube fitted with a 10# sieve at the bottom which reciprocate in the medium at 30 strokes per min.

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IN-VIVO METHODS

Animal used: dog, rabbits, rat, cat, hamster, pigs, and sheep

RAT: The oesophagus is ligated to prevent absorption pathways other than oral mucosa

At different time intervals, the blood is withdrawn and analysed

IVIVC CORRELATION

In the analysis of in vitro and in vivo drug correlation, rapid drug absorption may be distinguished from the slower drug absorption by observation of the absorption time for the dosage form. The quicker the absorption of the drug the less is the absorption time required for the absorption of the certain amount of the drug. The time required for the absorption of the same amount of drug from the dosage form is correlated

Dissolution Rate Vs Absorption Rate

If the dissolution rate is the limiting step in the absorption of the drug, and is absorbed completely after dissolution, a linear correlation may be obtained by comparing the percent of the drug absorbed to the percent of the drug dissolved. If the rate limiting step in the bioavailability of the drug is the rate of absorption of the drug, a change in the dissolution rate may not be reflected in a change in the rate and the extent of drug absorption from the dosage form

Percent of Drug Dissolved Vs Percent of Drug

AbsorbedIt is expected that a poorly formulated dosage form releases amount of drug than from a well formulated dosage form, and, hence the amount of drug available for absorption is less for poorly formulated dosage form than from a well formulated dosage form.

% of drug dissolved In-vitro Vs Peak plasma concentration

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APPLICATIONS MICROSPHERES IN VACCINE DELIVERY.

Eg ; Diphtheria toxoid , Tetanus toxoid.

TARGETED DRUG DELIVERY.

Eg ; ocular, eye (cornea).etc

CONTROLLED RELEASE.

Eg ; GI tumors, Bone tumors.

CHEMOEMBOLIZATION.

IMMUNO MICROSPHERES

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Thank you……