MICROSPHERES-MAGNETIC MICROSPHERES

By: Divya Rani Golla

(M.Pharmacy 2nd semester),

DEPARTMENT OF INDUSTRIAL PHARMACY,UNIVERSITY COLLEGE OF

PHARMACEUTICAL SCIENCES, KAKATIYA UNIVERSITY, WARANGAL.

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CONTENTS• Introduction• Polymers used for microspheres preparation• Prerequisites for ideal microparticulate carriers• General methods of preparation• Release pattern of drug• Advantages and disadvantages• Applications• Magnetic microspheres• Characterization• Conclusion• References

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INTRODUCTION

The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body and then maintain the desired drug concentration.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.

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DEFINITION

• 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.

• This is the important approach in delivering therapeutic substance to the target site in sustained and controlled release fashion.

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POLYMERS USED IN THE MICROSPHERE PREPARATION

Synthetic Polymers

• Non-biodegradable

Acrolein

PMMA

Glycidyl methacrylate

Epoxy polymers

• Biodegradable

Lactides and Glycolides copolymers

Polyalkyl cyanoacrylates

Polyanhydrides

Natural Materials• Proteins

Albumins Gelatin Collagen

• Carbohydrates Starch agarose Carrageenan Chitosan

• Chemically modified carbohydrates

Poly (acryl) dextran DEAE cellulose Poly(acryl)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

Bioreabsorbability

Water solubility or dispersibility

Targetability

Polyvalent6/24/2014

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METHODS OF PREPARATIONA. Solvent evaporation method

i. -Single Emulsion techniqueii. -Double emulsion technique

B. Polymerization techniquesiii. Normal polymerization

o Bulk polymerizationo Suspension polymerizationo Emulsion polymerization

iv. Interfacial polymerization

C. Coacervation phase separation techniquesD. Spray drying and spray congealingE. Solvent extraction

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I. Single emulsion technique

Aqueous sol’n/suspension of polymer

Dispersion in organic phaseOil/CHCl3

Chemical Cross linking/heat denaturation

{Gluteraldehyde/formaldehyde/butanol}

Aq.solution/suspension of

polymer

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Aq.Solution of protein/polymer

First emulsion (W/O)

MICROSPHERES

Dispersion in oil/organic phaseHomogenization

Separation, Washing, Drying

Addition of aq. Solution of PVA

Addition to large aq. PhaseDenaturation/hardening

Multiple emulsion

Microspheres in solution

ii. Double emulsion technique

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B. Polymerization Techniques

i. Normal Polymerization

Normal Polymerization is done by bulk, suspension, precipitation, emulsion

and miceller polymerization process.

Monomer + bioactive

material + initiator

Polymerization Polymer block

Mould/Mechanical fragmentation

Microspheres

SCHEMATIC REPRESENTATION FOR BULK POLYMERIZATION

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Drug loading

Monomer Bioactive material Initiator

Dispersion in water and stabilizer

•Vigorous agitation•Heat/radiation

Polymerization

DROPLETS

Separation and drying

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Microspheres

SCHEMATIC REPRESENTATION OF SUSPENSION POLYMERIZATION

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Microspheres

MONOMER AND BIOACTIVE MATERIAL

Aq. Sol’n of NaOH + initiator

+ surfactant above CMC stabilizer

Micellar solution of polymer in aq.medium

Polymerization SeparationWashing & Drying

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SCHEMATIC REPRESENTATION OF EMULSION POLYMERIZATION

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It involves the reaction of various monomers at interface between the two immiscible liquid phases to form a film of polymer.

In this technique two reacting monomers are employed ,one of which is dissolved in the continuous phase while other being dispersed in continuous phase.

The continuous phase is aqueous in nature throughout which the second monomer is emulsified.

The monomers present in either phases diffuse 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.

ii. INTERFACIAL POLYMERIZATION TECHNIQUE

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D. PHASE SEPARATION COASERVATIONE. SPRAY DRYING

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Salt additionNon-solvent additionAddition of incompatible polymerChange in pH

Removal of solventD. Phase separation

E. Spray drying

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F. Solvent Extraction

(This process decreasing hardening time for microspheres)

Polymer in organic solvent

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

Isopropanol)

Organic phase is removed by extraction with water

Microspheres

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Advantages 1. 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.

2. Biodegradable microspheres have the advantage over large polymer implants in that they do not require surgical procedures for implantation and removal.

3. Taste and odor masking.

4. Conversion of oils and other liquids to solids for ease of handling

5. Improvement of flow of powders.

6. They provide protection for unstable drug before and after administration, prior to their availability at the site of action.

7. They enable controlled release of drug.

Ex: narcotic antagonist, steroid hormones.

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Disadvantages 1. Significant initial burst and unpredictable release in certain

cases.

2. The phagocytises of carriers, rapid clearance are common disadvantage.

ROUTES OF ADMINISTRATION

Oral delivery Parenteral delivery

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Release Profile Of Microspheres The release profile from microspheres depends on nature of

the polymer used in the preparation and nature of the active drug.

Drugs could be released through microspheres by any one of the 3 methods :

1. Osmotically driven burst mechanism

2. Pore diffusion mechanism

3. Erosion or degradation of polymer.

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1. Osmotically driven burst mechanism : Water diffuses into the core through biodegradable or non-biodegradable coating, creating sufficient pressure that ruptures the membrane.

2. Pore diffusion method : Here penetrating water front continue to diffuse towards the core.

The dispersed drug/protein dissolves creating a water filled pore network and diffuses out in controlled manner

3. Erosion of polymer : It begins with changes in the micro structure of carrier as water penetrates within it leading to plasticization of matrix. Plasticization leads to cleavage of hydrolytic bonds.

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APPLICATIONS

Vaccine delivery – Improved antigenecity, Antigen release, Stabilization of Antigen.Drug targeting• Ocular: gelation with increased residence time• Intranasal: protein and peptide delivery• Oral

Magnetic microspheresImmunomicrospheresChemoembolizationImagingMicrospongesSurface modified microspheres

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MAGNETIC MICROSPHERES

Definition : Magnetic microspheres are supramolecular particles that are small enough to circulate through capillaries without producing embolic occlusion (<4µm) but are sufficiently susceptible(ferromagnetic) to be captured in micro vessels and dragged in to the adjacent tissues by magnetic field of 0.5 to 0.8 tesla.

Magnetic drug delivery by particulate carriers is a very efficient method of delivering a drug to a localized disease site.

Magnetic microspheres developed to overcome two major problems encountered in drug targeting namely:

I. To decrease RES clearance and

II. Increase target site specificity.

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CONCEPT BEHIND MAGNETIC TARGETING

Drug targeting is a specific form of drug delivery where the drug is directed to its site of action or absorption.

A drug or therapeutic radioisotope is encapsulated in a magnetic compound, injected into patient’s blood stream through large arteries & then stopped with a powerful magnetic field in the target area (systemic and magnetic drug delivery shown in fig).

Depending on the type of drug, it is then slowly released from magnetic carriers and gives a local effect, thus it reduces the loss of drug as freely circulating in body.

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Representation of systemic drug delivery and magnetic taargeting.

Magnetic drug targeting

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When the microspheres are first pushed against the endothelial cells by the magnetic field, an endocytic response was triggered with continuous magnetic influence over certain period of time.

Microspheres migrated from endothelial cells into the interstitial compartment and formed a depot for sustained release over an extended period of time.

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Endothelial cell

Microspheres

• Microspheres

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Magnetic microspheres

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• It is also called as ferric ferrous oxide , Tri iron tetra oxide , and black iron oxide

• A ferromagnetic material when incorporated into microspheres makes them magnetically responsive so that they can be concentrated to the desired site by applying some external magnetic field.

• Iron is strong ferromagnetic material but due to its local tissue irritation and other toxic manifestation it cannot be included into microspheres.

• But such a problem is not seen when magnetite which is chemically ferrous ferric oxide (Fe3O4) biologically compatible and also its ultra fine particle size makes it suitable material.6/24/2014

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little access

Major pathway

Major pathway

little access

Principle of magnetic drug targeting

Drug/Carrier

Target tissue

Target tissue

RES Organs (liver/spleen/bone

marrow)

RES Organs (liver/spleen/bone

marrow)

Phagocytosis

Drug/Carrier

Target tissue

Target tissue

N

S

RES Organs (liver/spleen/bone

marrow)

RES Organs (liver/spleen/bone

marrow)

Phagocytosis

Drug/CarrierMagnetic

Drug/Carrier

Drug/CarrierCirculation

Drug/CarrierCirculation

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SELECTION OF DRUGSIn the selection of drug for the formulation of magnetic

microspheres, following points are to be taken into consideration :

1. The drug is so dangerous or labile that we cannot allow it to circulate freely in the blood stream.

2. The agent is so expensive, that we cannot afford to waste 99.9% of it.

3. Requires a selective, regional effect to meet localized therapeutic objective.

4. Requires an alternative formulation essential to continue treatment in patient whose systemic therapy must be temporarily discontinued due to life threatening toxicity directed at selective organs.

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ADVANTAGES Increased duration of action.

First pass effect can be avoided.

Improved protein and peptide drug delivery.

They enable controlled release of drug.

Ex: narcotic antagonist, steroid hormones.

Reduce toxicity.

Ability to bind and release high concentration of drugs.

Patient compliance is good.

Method of preparations is simple.

Can be injected into the body using hypodermic needle.

Difference occurs maximally in capillary network so efficient delivery of drug to diseased tissue is achieved.

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.

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DISADVANTAGES

1. Major limitation : Drug cannot be targeted to deep-seated organism in the body.

2. Unknown toxicity of magnetic beads.

3. A large fraction(40-60%) of the magnetite, which is entrapped in carriers, is deposited permanently in tissues.

4. It is an expensive, technical approach and requires specialized manufacture and quality control system.

5. It needs specialized magnet for targeting, advanced techniques for monitoring, and trained personnel to perform procedures.

Due to these limitations magnetic drug targeting is likely to be approved only for severe diseases.

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METHOD OF PREPARATION

Magnetically responsive microspheres can be prepared by using albumin as a carrier of drug and magnetite.

Size of microspheres is kept between 1-2 µm, so that they can be injected into blood vessels without problem of thrombo-embolism.

Prepared mainly by two methods:

I. Continuous solvent evaporation (CSE)

II. Phase separation emulsion polymerization(PSEP)

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I. Continuous solvent evaporation method

Drug + Polymer + Magnetite

Dissolved in volatile organic solvent

Forms Homogeneous suspension known as auxiliary solution

Volatile organic solvent evaporated at 22-30° C

Centrifugation

Microspheres

Freeze dried &Stored at 4° C

STIRRING

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Drug + Polymer + Magnetite Vegetable oil

Emulsification by magnetic stirrer

o15,000 rpmo2 minutes

Temp: 100 – 150°C

Add cross linking agent drop wise to above emulsion

WashedFreeze driedStored at 4°C

Stabilization

Drug + Polymer + Magnetite Vegetable oil

Droplets hardening

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II. Phase separation emulsion polymerization

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CHARACTERIZATION It helps to design a suitable carrier for the proteins,

drug and antigen delivery.1. Particle size and shape: Conventional light

microscopy(LM), Scanning electron microscopy(SEM), Confocal laser scanning microscopy(CLSM), Confocal fluorescence microscopy, Laser light scattering and Multisize coulter counter.

2. Electron spectroscopy for chemical analysis(EMCA): Surface chemistry of microspheres , Atomic composition, Surface degradation of biodegradable microspheres.

3. Attenuated total reflectance Fourier transform-infrared spectroscopy(ATR-FTIR): degradation of polymeric matrix of the carrier system and surface composition.

4. Density determination: Multivolume pichnometer.5. Flow properties: Angle of repose, Hausner ratio.

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6. Isoelectric point : Micro electrophoresis apparatus.7. Capture efficiency or drug entrapment capacity :

7. Release studies : in phosphate saline buffer of pH7.4a) Rotating paddle apparatus & b) Dialysis method.Rotating paddle apparatus : sample agitated at

100rpm,samples are taken out at specific time intervals and replaced by same amount of saline.The api is analyzed as per monograph.

Dialysis method: The microspheres are kept in a dialysing bag or tube with membrane, the dialysing media is continuously stirred and samples of dialysate are taken estimated for drug content & Replaced with fresh buffer.

Actual contentTheoretical content

×100% Entrapment =

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8. Angle of contact: wetting property is determined.9. Determination of drug content: UV visible

spectrophotometer.10. Determination of solubility :• Take excess quantity of microspheres in 50ml vials

filled with water.• Shake the vials on a magnetic stirrer.• Filter the solution through whatmann paper no.1

and drug concentration determined at particular λ max value for particular drug.

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MARKETED PRODUCTSTRADE NAME INCI NAME

EA-209 Ethylene/acrylic acid copolymer

Flo- beads SE-3107A(soft beads A)

Ethylene /Methacrylate copolymer

Flo- beads SE-3107B(soft beads B)

Ethylene /Methacrylate copolymer

BPD-800BPD-500BPD-500T

HDl/trimethylol hexyllactyl cross polymer (AND silica)

BPA-500MSP-822

Polymethyl Metharylate

BPA-500X MSP-825MSP-930SUNPMMA-H

Methyl Methacrylate cross polymer

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APPLICATIONS

They have wide application in the field of bio-medicine, bio engineering, biological and biomedical developments.

It is used in enzyme immobilization, cell isolation, protein purification and targeted drugs.

Drug discovery, molecular targeting, and undergoing the pathway of cell cycle regulation.

High throughput DNA isolation. They can be used for stem cell extraction. It is used as chemotherapeutic agent. Magnetic vehicles are used for delivery of therapeutic agent as

they can be targeted to specific location in the body through the application of magnetic field.

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CONCLUSION Over the years, microspheres and magnetic

microspheres have been investigated for targeted drug delivery especially magnetic targeted chemotherapy due to their better tumor targeting. Targeted Drug delivery is an effective method to assist the drug molecule to reach preferably to the desired site. The main advantage of this technique is the reduction in the dose & side effects of the drug.

It is a challenging area for future research in the drug targeting so more researches, long term toxicity study, and characterization will ensure the improvement of magnetic drug delivery system. The future holds lot of promises in magnetic microspheres and by further study this will be developed as novel and efficient approach for targeted drug delivery system

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REFERENCES Vyas S.P, Khar R.K, Targeted & Controlled Drug Delivery novel carrier

systems, CBS Publishers & Distributers, first edition(2002) pp:417-425, 441-444, 460.

Jain N K, Controlled and novel drug delivery, CBS publishers & Distributers, first edition,2002, pp: 236-237.

Alagusundaram.M, Microspheres as a novel drug delivery system, International Journal of ChemTech Research, ISSN : 0974-4290, Vol.1, No.3 , pp 526-534,date : july 2009.

Mukherjee S, Magnetic microspheres a latest approach in novel drug delivery system, Journal of pharmaceutical and scientific innovation, date: 04/01/2012.

Salim Md, Magnetic microspheres as a magnetically targeted drug delivery system, Journal of global pharma technology, ISSN0975-8542.

Satinder kakar, A review on target drug delivery: Magnetic microspheres, Journal of acute disease, date: 30/04/2013.

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