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ByMr. Me gh ra j Su ry aw a nsh i( F i r s t Ye a r M.P ha rm a cy )

2 01 6 - 2 01 7

D e pa r tm e n t o f P ha rm a ce u t i c s R . C . P a te l Ins t i tu t e o f P h arm a c eu t i c a l Ed u ca t io n a nd

Re se arc h ,Sh i rp ur - 4 2 54 0 5

POLYMERIC MICELLES

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CONTENT

INTRODUCTIONMECHANISM OF MICELLIZATIONFACTORS AFFECTING THE CRITICAL MICELLES CONCENTRATIONCHARACTERISTICS OF POLYMERIC MICELLSESTYPES OF POLYMERIC MICELLESTYPES OF POLYMER USEDMETHODS OF PREPARATION CHARACTERIATION OF POLYMERIC MICELLESAPPLICATIONSPATENTED AND MARKETED PREPARATIONCONCLUSIONREFERENCE

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INTRODUCTION

MICELLES:It is lipid molecules that arrange themselves in a spherical form

in aqueous solution.Micelles are Amphiphilic in nature. Made up of polar head and Non-polar chain. AGGRERGATION NO:It is number of molecules present in a micelles when critical

micelle concentartion has been reached.CMC:The concentration of surfactant above which micelles form is

called Critical Micelles Concentration(CMC).

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INTRODUCTION

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POLYMERIC MICELLES:Polymeric Micelles are formed from the association of block

copolymers.Block copolymers micelles have the capacity to increase the

solubility of hydrophobic molecules due to their unique structural composition, which is characterized by a hydrophobic core sterically stabilized by a hydrophilic shell.

The hydrophobic core serves as a reservoir in which the drug molecules can be incorporated by means of chemical, physical or electrostatic interactions, depending on their physicochemical properties.

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MECHANISM OF MICELLIZATION

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Amphiphilic molecule + solvent

Self association of amphiphilic molecules

Polymeric micelles

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MECHANISM OF MICELLIZATION

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Self association of monomer duo to decrease in free energy of system .

This is due to removal of hydrophobic fragments from aqueous surrounding with the formation of micelle with hydrophilic fragment exposed into water.

7FACTORS AFFECTING CRITICAL MICELLES CONCENTRATION

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Structure of Hydrophobic group

Addition of Electrolyate

Effect of Tempertaure up to cloud point

Thermodynamic Aspects

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CHARACTERISTICS OF POLYMERIC MICELLSES

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Polymeric micelles have gathered attention in drug & gene delivery due to :

Biocompatibility.Solubilization of hydrophobic moeities in micellar core.Low Toxicity.Enhanced blood circulation time.Smart or intelligent drug carriers.

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TYPES OF POLYMERIC MICELLES

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Based on intermolecular forces governing the segregation of the core segment from aqueous environment.

ConventionalPolyion complex micellesNon-covalently connected polymeric micellesConventional: Resulting from hydrophilic interaction e.g. Poly(ethylene oxide)-b-poly(propylene oxide)-b-

poly(ethylene oxide

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TYPES OF POLYMERIC MICELLES

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Polyion complex micelles:Resulting from electrostatic interaction between oppositely charged

moieties such as (polyelectrolytes). solution + oppositely charged polymer = polyion complex micelles Features of polyion complex polymeric micelles:Easy self association in aqueous medium.Structural stability.Simple synthetic route.High drug loading capacity.Prolonged circulation in the blood.

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TYPES OF POLYMERIC MICELLES

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Non-covalently connected polymeric micelles:A novel “block-co-polymer-free” technique can also be used for

preparing polymeric micelles. Here, polymeric micelles are obtained via selfassemblage of homopolymer, random co-polymer, graft co-polymer or oligomer for which interpolymer hydrogen bonding complexation serves as the driving force.

Core and shell are non-covalently connected at their homopolymer chain end by specific intermolecular interactions such as H-bonding or metal-ligand interactions in the resultant structures and hence these are termed as non-covalently connected micelles

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TYPES OF POLYMERS USED

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Type of micelleformingco-polymers

Representation ofstructure

Example of polymers

Block copolymers di - blockAAAAAAABBBBBB

Poly(styrene)-b-poly(ethylene oxide)

tri - blockAAAABBBBBAAAA

Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)

Graft copolymers AAAAAAAAAAAAA B B B B B B

N-phthaloylchitosan-g-polycaprolactone

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BLOCK VS RANDOM

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METHODS OF PREPARATION

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Direct Dissolution

Indirect method by using organic solvent

Dialysis Method

Solution Casting Method

Freeze Drying Method

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METHODS OF PREPARATION

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Direct dissolution: Direct dissolution of drug and co-polymer in water. It is simple technique. Drug loading efficiency is low.

Indirect method by using organic solvent: This method applied to amphiphilic co-polymer which is readily

soluble in water.Common organic solvent used in this method, eg. DMSO,

Acetone etc.

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METHODS OF PREPARATION

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Dialysis:Solution of drug and co-polymer in organic solvent are placed in

dialysis bag and the solvent is exchanged with water by immersing the bag into water inducing micelle assembly.

This method is suitable for loading of drug which has poor solubility.

This method suitable for core forming blocks which are long & more hydrophobic.

Dialysis process often take more than 36 hours for efficient drug loading.

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METHODS OF PREPARATION

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METHODS OF PREPARATION

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Solution casting:Volatile organic solvent used to dissolve the co-polymer & drug.After complete evaporation of solvent there is thin film obtained. Drug loaded micelles are obtained by reconstitution of film in

water.

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METHODS OF PREPARATION

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Lyophilization method:

Water + Tert-Butanol mixture is used for dissolving drug as well as co-polymer and then solution is polymerised

Drug loaded polymeric micelles obtained by redispersing the lyophilized product in suitable vehicle

It is simple and cost effective method

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CHARACTERIATION OF POLYMERIC MICELLES

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Critical Micelles Concentration:In aqueous media, amphiphilic polymers can exist in the form of

micelles when the concentration is higher than CMC, and when diluted below this concentration, the micelles may collapse. Hence, CMC is the key parameter for the formation and the static stability of polymeric micelles.

CMC determination: Surface tension measurementChromatography

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CHARACTERIATION OF POLYMERIC MICELLES

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Light scattering DSCViscometryPyrene as fluorscent probe

Size and Shape Determination: After the preparation of the micelles useful information regarding the

polydispersity index of the prepared structures is obtained by examining the micellar solution with quasielastic light scattering technique. Monodisperse micelles produce blue color from light scattering which indicates good micellar preparation, as contrasted with the white color shown by aggregates.

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CHARACTERIATION OF POLYMERIC MICELLES

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Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) techniques have been widely used past many years for the direct visualization, size and shape determination of block copolymer micelles.

In-Vitro Drug Release Behavior: In-vitro drug release behavior from micelles is easily studied by placing

the micellar solution in a dialysis tube.The dialysis bag is immersed into a flask containing release medium, kept

at a constant temperature.At predetermined time intervals, aliquots of the release medium are taken

and replaced by fresh medium.The content of drug released in the medium can be measured by

spectroscopic or other suitable method.

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APPLICATIONS

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Solubilization:Solubilization process leads to enhance solubility poorly water

soluble drug.

This process enhance the bioavalability.

Solubilization capacity was dependent on the hydrophobic block length upto a certain extent (15 units of hydrophobic block), after which the solubilization capacity became independent of the same.

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APPLICATIONS

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DRUG POLYMER COMMENTCamptothecin Pluronic p-105,d-alpha

tocopheryl

PEG-1000 succinate

Increased micellar stability & bioavailability

Docetaxel Polyethylene oxide-b-polystyrene oxide

Increased solubility

Griseofulvin

Paclitaxel

EmBn (E-oxyethylene,B-oxybutylene)

N-octyl-o-sulfate chitosan

Solubilization independent of B block length, when it exceeds about 15B units

Improved bioavailability & reduce cytotoxicity

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APPLICATIONS

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Targeting delivery of drug: It is usually achieved by one of the following approachesAcid sensitive ThermosensitiveStimuli sensitivity internal : pH,enzymes external : temperature,light,ultrasound,magnetic fieldLiganding to micelle surfaceImmunomicelles

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APPLICATIONS

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PATENTED PREPARATION

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Patent No. Polymers Title Observation

US20050019303

Polycaprolactone(PCL) andPolyethylene glycol(PEG)

Biodegradableco-polymer, andpolymeric micellecontaining thesame

The micelles possess good drug andbioactive agent delivery characteristics andare suitable for use in drug delivery orcosmetic applications.

US20060216342

Polyethylene glycolandphosphatidylethanolamine

Micelle deliverysystem loadedwith apharmaceuticalagent

A drug delivery system comprising atargeted form of a polyethyleneglycol(PEG)/lipid-conjugated micelle, which iscapable of stabilizing poorly solublepharmaceutical agents.

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MARKETED PREPARATION

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Product Application Company

Genexol PM Non-small cell lung cancer

Samyang

Estrasorb Estrogen therapy Novavax

Medicelle Cancer treatment Nano Carrier

Flucide Anti-influenza NanoViricides

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CONCLUSION

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Polymeric Micelles are the used as carriers because of their characteristics.

Polymeric micelles have simple method of preparation.Micelles get easily loaded with wide variety of poorly water

soluble drug, resulting in enhanced the bioavalability.Micelles used to targeting the drug delivery.Targeting can also be achieved by attaching specific ligands or

specific antibodies onto their surface.Thus polymeric micelles, as drug carriers, have a bright future.

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REFERENCE

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CVS.Subrahmanynam, “Textbook of Physical Pharmaceutics”, Vallabh Prakashan, Delhi; 2nd edition(2000), pp.327-329.

“Martins Physical Pharmacy and Pharmaceutical Sciences”, Edited by; Patrick J.Sinko, Wolters Kluwer Health, New York, 6th edition, pp.496-497.

V.K.Mourya, Nazma Inamdar, R.B.Nawale, S.S.Kulthe, “Polymeric micelles:General Consideration and their Applications” Indian Journal of Pharmaceutical Education and Research, 2011, pp.128-134.

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REFERENCE

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B. Raja Rajeshwar, Anvesh Gatla, Gaddam Rajesh, N. Arjun, M. Swapna, “Polymeric Micelles: A Nanoscience Technology”, Indo American Journal of Pharmaceutical Research, 2011;1(4), pp.359-360.

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