Download - Recent updates in synthetic polymers used in drug delivery systems

Recent updates in synthetic Recent updates in synthetic polymers used in drug polymers used in drug

delivery systemsdelivery systems

KUSUM SINGH NEELAM SINGHKUSUM SINGH NEELAM SINGH I.T.S. PHARMACY COLLEGE,GHAZIABAD, INDIAI.T.S. PHARMACY COLLEGE,GHAZIABAD, INDIA

CONTENTSCONTENTS

INTRODUCTIONINTRODUCTION

DEFINITIONDEFINITION

CLASSIFICATIONCLASSIFICATION

PROPERTIES & SELECTION OF SYNTHETIC PROPERTIES & SELECTION OF SYNTHETIC POLYMERSPOLYMERS

SYNTHETIC POLYMERS USED IN DRUG DELIVERY SYNTHETIC POLYMERS USED IN DRUG DELIVERY SYSTEMSSYSTEMS 22

INTRODUCTIONINTRODUCTION

Significant advances have been made in development of Significant advances have been made in development of various drug delivery devices with the help of polymers.various drug delivery devices with the help of polymers.

The earliest DDS first introduced in 1970s were based on The earliest DDS first introduced in 1970s were based on polymers formed from lactic acid.polymers formed from lactic acid.

Today polymeric materials still provides most important Today polymeric materials still provides most important avenues of research primarily because of ease of avenues of research primarily because of ease of processing & ability of researchers to readily control their processing & ability of researchers to readily control their chemical & physical properties via. Molecular system.chemical & physical properties via. Molecular system.

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DEFINITIONDEFINITION

POLYMERSPOLYMERS:-:-

Compounds with high molecular masses formed by Compounds with high molecular masses formed by combination of large number of simple molecules called as combination of large number of simple molecules called as monomers.monomers.

Prepared by addition / condensation polymerization.Prepared by addition / condensation polymerization.

In GreekIn Greek, , PolyPoly means many & means many & merosmeros means units/parts. means units/parts.

Polymers are of 3 types:-Polymers are of 3 types:- Natural, Semisynthetic, Synthetic.Natural, Semisynthetic, Synthetic.

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CLASSIFICATION OF SYNTHETIC POLYMERSCLASSIFICATION OF SYNTHETIC POLYMERS

ON THE BASIS OF STRUCTURE

BRANCHED CHAIN POLYMERSEXAMPLES:-Low Density Polythene

CROSS LINKEDPOLYMERS EXAMPLES:- Bakelite, MF Resin

LINEAR POYMERSEXAMPLES:-

PEG, Polyesters

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CONTD…CONTD…

ON THE BASIS OF DEGRADABILITY OF POLYMERS

BIODEGRADABLEPOLYMERS

NONBIODEGRADABLEPOLYMERS

ENVIRONMENTRESPONSIVEPOLYMERS

ELECTRICALLY & CHEMICALLY CONTROLLED

POLYMERS

THERMOSENSITIVEPOLYMERS

pH-SENSITIVEPOLYMERS

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CLASSCLASS EXAMPLESEXAMPLES

A)A) BIODEGRADABLE POLYMERSBIODEGRADABLE POLYMERS

POLYESTERSPOLYESTERS

POLYANHYDRIDESPOLYANHYDRIDES

POLYAMIDEPOLYAMIDE

PHOSPHOROUSBASEDPHOSPHOROUSBASED

OTHERSOTHERS

PLA, PGA, PHBPLA, PGA, PHB

PCL, PMA, POLYDIOXANONESPCL, PMA, POLYDIOXANONES

POLYSEBACIC ACID, PTAPOLYSEBACIC ACID, PTA

POLYPHOSPHAZENES, POLYPHOSPHAZENES, POLYPHOSPHONATEPOLYPHOSPHONATE

POLYCYANOACRYLATES, POLYCYANOACRYLATES, POLYURETHENES, POLYORTHOESTERSPOLYURETHENES, POLYORTHOESTERS

B)B) NONBIODEGRADABLE NONBIODEGRADABLECELLULOSE DERIVATIVESILICONESACRYLIC POLYMERSOTHERS

CMC, EC, CA, CAPCMC, EC, CA, CAP

PDS, COLLOIDAL SILICAPDS, COLLOIDAL SILICA

PMA, PMMA, PHEMAPMA, PMMA, PHEMA

PVP, EVA. POLYOXAMERPVP, EVA. POLYOXAMER

SYNTHETIC POLYMERSYNTHETIC POLYMER :-

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ON THE BASIS OF MONOMERIC UNITS

CONTD…CONTD…

HOMOPOLYMERS COPOLYMERS

GRAFTEDCOPOLYMERS

ALTERNATINGCOPOLYMERS

BLOCKCOPOLYMERS

RANDOMCOPOLYMERS

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PROPERTIES & SELECTION OFPROPERTIES & SELECTION OFPOLYMERSPOLYMERS

POLYMER IS CHOOSEN ON BASIS OFPOLYMER IS CHOOSEN ON BASIS OF :- :-

Physicochemical propertiesPhysicochemical properties

Need for biochemical characterization.Need for biochemical characterization.

Chemical compositionChemical composition

Micro structural designMicro structural design

Surface properties like lubricity, hydrophilicity, smoothness, Surface properties like lubricity, hydrophilicity, smoothness, surface energysurface energy

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PROPERTIES OF SYNTHETIC POLYMER THAT NEED PROPERTIES OF SYNTHETIC POLYMER THAT NEED TO BE CONSIDERD FOR APPLICATION OF POLYMERS TO BE CONSIDERD FOR APPLICATION OF POLYMERS

TO DRUG DELIVERY SYSTEMSTO DRUG DELIVERY SYSTEMS

SolubilitySolubility

ViscosityViscosity

Polymer- Solvent interactionPolymer- Solvent interaction

CrystallinityCrystallinity

Polymer dissolutionPolymer dissolution

Bioadhesivity of Hydrophilic polymerBioadhesivity of Hydrophilic polymer

Polymer erosion & BiodegradationPolymer erosion & Biodegradation1010

SYNTHETIC POLYMERS USED IN DRUG SYNTHETIC POLYMERS USED IN DRUG DELIVERY DELIVERY SYSTEMSSYSTEMS

SYNTHETIC POLYMERS IN DENDRITIC SYNTHETIC POLYMERS IN DENDRITIC

DRUG DELIVERY SYSTEMSDRUG DELIVERY SYSTEMS DENDRIMERS-DENDRIMERS-

Transport extremely high Transport extremely high

densities of drug molecules.densities of drug molecules.

It is suitable carrier system because:-It is suitable carrier system because:-

Their size & structure can be controlled.Their size & structure can be controlled. Encapsulate small drug molecule to form Polymer micelles.Encapsulate small drug molecule to form Polymer micelles. Serves as “hubs” onto which large number of drug molecules can Serves as “hubs” onto which large number of drug molecules can

attached via covalent bond.attached via covalent bond. 1111

PAMAM DendrimerPAMAM Dendrimer – – Used in gene delivery. It has amineUsed in gene delivery. It has amineTerminal group which binds to DNA by electrostatic charge.Terminal group which binds to DNA by electrostatic charge.

•Prepared either as Divergent /Convergent type.Prepared either as Divergent /Convergent type.•StarburstStarburstTMTM PAMAM dendrimer in intact PAMAM dendrimer in intact (Polyfect(Polyfect(R)(R))) & & fractured form fractured form (Superfect(Superfect®®).).•Fractured form shows better gene expression.Fractured form shows better gene expression.

Polyethyleneimine(PEI)- Polyethyleneimine(PEI)-

• To prepare PEI- gene complex.To prepare PEI- gene complex.• After internalization release of gene complex by endosome occurs due to After internalization release of gene complex by endosome occurs due to protonation of internal 3° Nitrogen by endosomal protonsprotonation of internal 3° Nitrogen by endosomal protons which then results in swelling of endosome & ultimately which then results in swelling of endosome & ultimately releases DNA.releases DNA.

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SYNTHETIC POLYMERSYNTHETIC POLYMER APPLICABILITYAPPLICABILITY

Poly Amino Amine dendrimerPoly Amino Amine dendrimer To deliver 5-Fluro uracil.To deliver 5-Fluro uracil.

For occular drug delivery of For occular drug delivery of Pilocarpine Nitrate.Pilocarpine Nitrate.

Increases solubility of NifedipineIncreases solubility of Nifedipine

Poly aryl ether dendrimerPoly aryl ether dendrimer To deliver MethotrexateTo deliver Methotrexate

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SYNTHETIC POLYMER USED IN MUCOADHESIVE SYNTHETIC POLYMER USED IN MUCOADHESIVE BUCCAL DRUG DELIVERY SYSTEMSBUCCAL DRUG DELIVERY SYSTEMS

Factors to be consideredFactors to be considered :- :- Chain flexibilityChain flexibility Low molecular weightLow molecular weight Ability to form H-bondingAbility to form H-bonding Concentration & swelling of polymers.Concentration & swelling of polymers.

Synthetic Polymers used as Permeation enhancersSynthetic Polymers used as Permeation enhancers:-:-

CLASSCLASS SYNTHETIC POLYMERSSYNTHETIC POLYMERS

SURFACTANTS Polyoxyethylene, Polyoxyethylene-9-lauryl Polyoxyethylene, Polyoxyethylene-9-lauryl ether,Polyoxyethylene-20-cetyl ether ether,Polyoxyethylene-20-cetyl ether

THIOLATED THIOLATED POLYMERSPOLYMERS

Polycarbophil, Polyacrylic acidPolycarbophil, Polyacrylic acid

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BIOADHESIVEBIOADHESIVE PROPERTIESPROPERTIES CHARACTERISTICSCHARACTERISTICSPoly-hydroxylPoly-hydroxyl

ButyrateButyrate

Poly(e-caprolactone)Poly(e-caprolactone)

PolyorthoestersPolyorthoesters

PolyphosphazenesPolyphosphazenes

PolycyanoacrylatesPolycyanoacrylates

Polyvinyl AcetatePolyvinyl Acetate

Polyethyleneoxide-b-Polyethyleneoxide-b-propylene oxidepropylene oxide

BiodegradableBiodegradable

Properties can be changed Properties can be changed by chemical modificationby chemical modification

Surface eroding polymerSurface eroding polymer

Can be tailored with Can be tailored with versatile side chain versatile side chain functioningfunctioning

BiodegradableBiodegradable

BiocompatibleBiocompatible

Amphiphillic surfactantAmphiphillic surfactant

BiocompatibleBiocompatible

Matrix for DDSMatrix for DDS

Cell encapsulationCell encapsulation

Sustained DDS, Sustained DDS, opthalmologyopthalmology

To make films, Hydrogels To make films, Hydrogels in DDSin DDS

Surgical adhesives, glues Surgical adhesives, glues in DDSin DDS

Gels & Blended Gels & Blended membranes in DD & membranes in DD & ImmobilizationImmobilization

Protein deliveryProtein delivery

BIOADHESIVE POLYMERS IN MUCOADHESIVE BIOADHESIVE POLYMERS IN MUCOADHESIVE DRUG DELIVERY SYSTEMSDRUG DELIVERY SYSTEMS

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SYNTHETIC POLYMERS USED IN SUSTAINED SYNTHETIC POLYMERS USED IN SUSTAINED RELEASE DRUG DELIVERY SYSTEMSRELEASE DRUG DELIVERY SYSTEMS

Sustained Release DDS follows 1Sustained Release DDS follows 1stst order release kinetics. order release kinetics.

Increased crosslinking of polymers decreases diffusion rate & thus Increased crosslinking of polymers decreases diffusion rate & thus improves sustained release properties of polymers & decreases improves sustained release properties of polymers & decreases mucoadhesivity.mucoadhesivity.

Synthetic Absorbable Polymers-Synthetic Absorbable Polymers- includeinclude homopolymers like PLA, homopolymers like PLA, PGA, PCL, Polytrimethylene carbonate, Poly(p-dioxanone) & PGA, PCL, Polytrimethylene carbonate, Poly(p-dioxanone) & copolymers like- Poly lactide-co-glycolide, Poly (glycolide-co-copolymers like- Poly lactide-co-glycolide, Poly (glycolide-co-trimethylene carbonate).trimethylene carbonate).

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Poly(Monosteroyl Glycerol-co-Poly(Monosteroyl Glycerol-co-succinate)succinate)

For Sustained release of For Sustained release of Theophylline/ Risperidone from Theophylline/ Risperidone from microparticles in-vitromicroparticles in-vitro

Polyvinyl AcetatePolyvinyl Acetate For sustained release capsules of For sustained release capsules of NifedipineNifedipine

Eudragit RLPM, RSPM & HPMCEudragit RLPM, RSPM & HPMC Sustained release of theophyllineSustained release of theophylline

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SYNTHETIC POLYMER BASED VECTORS IN GENE SYNTHETIC POLYMER BASED VECTORS IN GENE THERAPYTHERAPY

Cationic Polymers Cationic Polymers of high mol. wt. is used.of high mol. wt. is used.

Synthetic Polymers usedSynthetic Polymers used :- :-

PAMAM, Poly(4-Vinyl imidazole), PPL-Poly-L-lysine, PDMAEMA.PAMAM, Poly(4-Vinyl imidazole), PPL-Poly-L-lysine, PDMAEMA.

Poly-L-lysinePoly-L-lysine:-:- Biodegradable, lacks –NH Biodegradable, lacks –NH22 gp. with a pK gp. with a pKa a between 5 & 7 between 5 & 7 allowing no endosmolysis, resulting in low transgene expression.allowing no endosmolysis, resulting in low transgene expression.

This drawback requires inclusion of endosmolytic agent like Fusogenic This drawback requires inclusion of endosmolytic agent like Fusogenic peptide like –peptide like –

Copolymer of Poly-L-lysine with Poly-L-histidine/ L-tryptophan.Copolymer of Poly-L-lysine with Poly-L-histidine/ L-tryptophan.

Polyethyleneimine-Polyethyleneimine- Shows efficient transfecting ability without use of Shows efficient transfecting ability without use of fusogenic agent.fusogenic agent.

PEI offers high charge density due to which it offers increased protection PEI offers high charge density due to which it offers increased protection against serum nucleases.against serum nucleases.

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SYNTHETIC POLYMERS USED IN OPTHALAMIC DRUG SYNTHETIC POLYMERS USED IN OPTHALAMIC DRUG DELIVERY SYSTEMSDELIVERY SYSTEMS

Properties of synthetic Polymers considered for Opthalamic DDS-Properties of synthetic Polymers considered for Opthalamic DDS-

Non-Toxic, Biodegradable, Biocompatible, Optically transparent, Do not Non-Toxic, Biodegradable, Biocompatible, Optically transparent, Do not impede vision, Tolerable, good retention properties, mucoadhesivity.impede vision, Tolerable, good retention properties, mucoadhesivity.

Non-Biodegradable polymeric bioadhesives used as drug delivery Non-Biodegradable polymeric bioadhesives used as drug delivery systems:-systems:-

Copolymers based on Vinylpyrrolidone, Methacrylic acid, Copolymers based on Vinylpyrrolidone, Methacrylic acid,

Polydimethylene- siloxane, Poly (N-isopropyl acrylamide), PAMAM Polydimethylene- siloxane, Poly (N-isopropyl acrylamide), PAMAM dendrimers.dendrimers.

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SYNTHETIC POLYMERSSYNTHETIC POLYMERS APPLICABILITYAPPLICABILITY

Polyhydroxy ethyl - Polyhydroxy ethyl - methacrylatemethacrylate

Used to formulate liposomes loaded with Used to formulate liposomes loaded with Dimyristoyl phosphatidylcholine (DMPC). It Dimyristoyl phosphatidylcholine (DMPC). It is optically transparent & release drug for a is optically transparent & release drug for a period of 8 days.period of 8 days.

Poly (D,L-lactide) Poly (D,L-lactide) Biodegradable polymer used for sustained Biodegradable polymer used for sustained retinal delivery of Celecoxib to inhibit retinal delivery of Celecoxib to inhibit diabetes induced Retinal oxidative demagediabetes induced Retinal oxidative demage

Polyanhydrides, PolyorthoestersPolyanhydrides, Polyorthoesters For sustained release of 5-FUFor sustained release of 5-FU

Poly (Ɛ-caprolactone) rod Poly (Ɛ-caprolactone) rod shaped implantsshaped implants

Tolerated by retinal tissues & used to Tolerated by retinal tissues & used to release corticosteroid triamcinolone release corticosteroid triamcinolone acetide over 4 weeksacetide over 4 weeks

CONTD…CONTD…

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SYNTHETC POLYMERS USED IN TRANSDERMAL SYNTHETC POLYMERS USED IN TRANSDERMAL DRUG DELIVERY SYSTEMDRUG DELIVERY SYSTEM

Polymers are the backbone of TDDS.Polymers are the backbone of TDDS.

TDDS are fabricated as multilayered polymeric laminates or drug- TDDS are fabricated as multilayered polymeric laminates or drug- polymer matrix is sandwiched between two polymeric layers i.e. polymer matrix is sandwiched between two polymeric layers i.e. backing layer & inner polymeric layer which act as adhesive & backing layer & inner polymeric layer which act as adhesive & Rate- controlling membrane.Rate- controlling membrane.

TDDS is formulated either as Matrix form / Reservoir form.TDDS is formulated either as Matrix form / Reservoir form.

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IN TDDS POLYMERS ACTS AS

MATRIX FORMERSBACKING LAYERS

RELEASE LINERS

RATE –CONTROLING MEMBRANE PRESSURE- SENSITIVE

ADHESIVES (PSAs) 2424

1)1) MATRIX FORMERS MATRIX FORMERS Selected on the basis of:-Selected on the basis of:-a)a) Release propertiesRelease propertiesb)b) Adhesion cohesion balanceAdhesion cohesion balancec)c) Physicochemical propertiesPhysicochemical propertiese.g.-Monolithic solid state design is preffered for Passive TDDSe.g.-Monolithic solid state design is preffered for Passive TDDS

Synthetic polymers used-Synthetic polymers used-a)a) Cross linked PEG networkCross linked PEG network• BiocompatibleBiocompatible• Used for protein drug delivery.Used for protein drug delivery.

b) b) Acrylic acid matricesAcrylic acid matrices• Acrylic acid + Plasticizer :- used to make drug- polymer matrix Acrylic acid + Plasticizer :- used to make drug- polymer matrix film. film. • Eudragit RLPM, Eudragit S-100, Eudragit E-100, ethyl acetate Eudragit RLPM, Eudragit S-100, Eudragit E-100, ethyl acetate & MMA& MMA

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c) c) PolyvinylpyrrolidonePolyvinylpyrrolidone Matrix formers with 30% Dibutyl Phthalate to deliver Diltiazem Matrix formers with 30% Dibutyl Phthalate to deliver Diltiazem Hydrochloride & DomethacinHydrochloride & Domethacin

d)d) HPMC HPMC Hydrophillic, swellable polymer used for Oral Controlled DDSHydrophillic, swellable polymer used for Oral Controlled DDS Matrix formers in Propranolol HClMatrix formers in Propranolol HCl For fast release of drug.For fast release of drug.

2) 2) RATE CONTROLLING MEMBRANERATE CONTROLLING MEMBRANEa)a) Ethyl Vinyl AcetateEthyl Vinyl Acetate By altering Vinyl Acetate content membrane permeability can be controlledBy altering Vinyl Acetate content membrane permeability can be controlled

b) b) Silicone RubberSilicone Rubber• BiocompatibleBiocompatible• Highly permeable to steroidsHighly permeable to steroids• Ease of fabricationEase of fabrication• Low microscopic viscosity & used in Controlled Release devices.Low microscopic viscosity & used in Controlled Release devices.

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c) Poly Urethanec) Poly Urethane• Rubbery & increased permeabilityRubbery & increased permeability• Two types:- Polyether urethanes & Polyester UrethanesTwo types:- Polyether urethanes & Polyester Urethanes• Due to more Biodegradability Polyester Urethanes are moreDue to more Biodegradability Polyester Urethanes are more preffered. It is used for Hydrophillic polar drugs.preffered. It is used for Hydrophillic polar drugs.

3)3) PRESSURE SENSITIVE ADHESIVESPRESSURE SENSITIVE ADHESIVES• Characteristic of visco- elastic materialCharacteristic of visco- elastic material

a)a) Poly Iso ButylenePoly Iso Butylene• Formed by cationic polymersFormed by cationic polymers

b) b) Poly AcrylatesPoly Acrylates• Amorphous, gives water clear color in solution & stable towardsAmorphous, gives water clear color in solution & stable towards ageing & have good mechanical properties.ageing & have good mechanical properties.

c)c) SiliconesSilicones• Contains low viscosity Dimethyl siloxane polymer.Contains low viscosity Dimethyl siloxane polymer.• Silicate Resin + PDMS undergoes condensation to form Silicone PSASilicate Resin + PDMS undergoes condensation to form Silicone PSA

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4) 4) BACKING MATERIALSBACKING MATERIALS

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SYNTHETIC POLYMERS USED INSYNTHETIC POLYMERS USED INHYDROGEL DRUG DELIVERY HYDROGEL DRUG DELIVERY SYSTEMSYSTEM

• HYROGELSHYROGELS:- :- • Three dimensional, water swollen systems.Three dimensional, water swollen systems.• Composed of Hydrophilic polymers.Composed of Hydrophilic polymers.• Rendered insoluble due to crosslinking.Rendered insoluble due to crosslinking.

• Synthetic Polymers used in Hydrogel DDSSynthetic Polymers used in Hydrogel DDS

PVA, PE, PEG, PMMA, Polyacrylamide, PEA, PEMA, HEMA, PVPPVA, PE, PEG, PMMA, Polyacrylamide, PEA, PEMA, HEMA, PVP Poly (N-isopropylacrylamide), Poly dimethyl aminoethyl methacrylate,Poly (N-isopropylacrylamide), Poly dimethyl aminoethyl methacrylate, Poly (N- Butyl acrylate), Itaconic acid monoester, HPMA,Poly (N- Butyl acrylate), Itaconic acid monoester, HPMA, Poly Ethylene oxide dimethacrylate (PEODM),Poly Ethylene oxide dimethacrylate (PEODM), Poly (2- dimethylamino) ethyl methacrylate (DEAEMA),Poly (2- dimethylamino) ethyl methacrylate (DEAEMA), Poly (2- diethylamino) ethyl methacrylate (DMAEMA)Poly (2- diethylamino) ethyl methacrylate (DMAEMA)

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SYNTHETIC BIODEGRADABLE SYNTHETIC BIODEGRADABLE POLYMERPOLYMER

PROPERTIES & APPLICABILITYPROPERTIES & APPLICABILITY

A)A) CROSS-LINKED HYDROGELSCROSS-LINKED HYDROGELS Poly (a- amino acids), Poly (g- Poly (a- amino acids), Poly (g-

benzyl-L-glutamate), benzyl-L-glutamate), Polycaprolactone.Polycaprolactone.

INTERPENETRATING INTERPENETRATING HYDROGEL NETWORK HYDROGEL NETWORK like-like-

PCL with HEMAPCL with HEMA

To prepare cross –linked Poly (2- To prepare cross –linked Poly (2- hydroxyethyl-L-glutamine) (PHEG).hydroxyethyl-L-glutamine) (PHEG).

To enhance polymer compatibility.To enhance polymer compatibility.To prevent phase separation.To prevent phase separation.Have hybrid properties.Have hybrid properties.

B) B) NON CROSS-LINKED NON CROSS-LINKED HYDROGELS/ PHYSICAL GELSHYDROGELS/ PHYSICAL GELS PEO- PLA Block copolymerPEO- PLA Block copolymer

PVA & PLGA BlendPVA & PLGA Blend

PEO provides elasticity, hydrophilicityPEO provides elasticity, hydrophilicity PLA provides mechanical strengthPLA provides mechanical strength Water uptake depends on PEO conc.Water uptake depends on PEO conc. HH22O content O content ↑es from 30-80% as PVA ↑es from 30-80% as PVA

content ↑ed FROM 25-95%.content ↑ed FROM 25-95%.

C) GLUCOSE- SENSITIVE C) GLUCOSE- SENSITIVE HYDROGELHYDROGEL Poly (methacrylic acid-g-poly Poly (methacrylic acid-g-poly (ethylene glycol)) , PVP, PHEMA, (ethylene glycol)) , PVP, PHEMA, PDMAEMAPDMAEMA

Forms hydogel membrane which Forms hydogel membrane which immobilizes GO-Enzyme,.immobilizes GO-Enzyme,. This system focuses on INSULIN This system focuses on INSULIN containing “Reservoir”containing “Reservoir”

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SYNTHETIC POLYMERSSYNTHETIC POLYMERS PROPERTIES & APPLICABILITYPROPERTIES & APPLICABILITY

D) D) pH- Sensitive HydrogelspH- Sensitive Hydrogels Cationic polmers- Polyacrylamide, Cationic polmers- Polyacrylamide, PAA, PMMA, PDEAEMA, PDMAEMA.PAA, PMMA, PDEAEMA, PDMAEMA.

Anionic copolymers of PMMA & Anionic copolymers of PMMA & PHEMA.PHEMA. PolyorthoestersPolyorthoesters

have –NHhave –NH22 as ionizable pendant group as ionizable pendant group PDMAEMA & PMMA forms hydrophilic PDMAEMA & PMMA forms hydrophilic hydrogel containing Caffeine. This hydrogel containing Caffeine. This system swells in solsystem swells in soln n with p H<6.6 due with p H<6.6 due to protonation of 3to protonation of 3o o –NH–NH2 2 gp.gp. Have –COOH as Pendant gp.Have –COOH as Pendant gp. Swells at basic/ neutral media.Swells at basic/ neutral media. For Insulin delivery.For Insulin delivery.

E) E) Temperature –sensitive HydrogelTemperature –sensitive Hydrogel Poly (N- isopropyl acrylamide) Poly (N- isopropyl acrylamide) (PNIPAAm).(PNIPAAm).

PEG-PLGA-PEG triblock copolymerPEG-PLGA-PEG triblock copolymer

LCST of gel was 34.4°C .LCST of gel was 34.4°C . Used in “ON-OFF” DDS like for Used in “ON-OFF” DDS like for controlling INSULIN release.controlling INSULIN release. Becomes gel at body Temp., Biodeg. Becomes gel at body Temp., Biodeg. injectable themosensitive hydrogel.injectable themosensitive hydrogel.

F) F) Neutral HydrogelsNeutral Hydrogels PEG & PEOPEG & PEO

PVA, Poly ( N-vinyl-2-pyrrolidone)PVA, Poly ( N-vinyl-2-pyrrolidone)

Provides Stealth properties & Protein Provides Stealth properties & Protein resistance.resistance. Mucoadhesive, to control release rate Mucoadhesive, to control release rate of Theophylline.of Theophylline.

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SYNTHETIC POLYMERSYNTHETIC POLYMER PROPERTIES & APPLICABILITYPROPERTIES & APPLICABILITY

G) G) Polyacrylic acid HydrogelPolyacrylic acid Hydrogel Have bioadhesivity, Have bioadhesivity, superabsorbancy, ability to form superabsorbancy, ability to form extended polymer network through extended polymer network through H-bonding.H-bonding.

H) H) Superporous Hydrogels (SPHs)-Superporous Hydrogels (SPHs)-

1.1. Ist Generation (CSPHs)- formed Ist Generation (CSPHs)- formed of hydrophiic (Acrylamide)/ Ionic of hydrophiic (Acrylamide)/ Ionic (salts of acrylic acid/ (salts of acrylic acid/ sulfopyridine acrylate) sulfopyridine acrylate) monomers.monomers.

2.2. IInd Generation (SPH composites, IInd Generation (SPH composites, SPHCs)-consists of IPNsSPHCs)-consists of IPNs

3.3. IIIrd Generation (SPH Hybrids, IIIrd Generation (SPH Hybrids, SPHHs)- Consists of Integrated SPHHs)- Consists of Integrated IPNs.IPNs.

SPHs are made up of porous SPHs are made up of porous hyrophilic crosslinked polymers which hyrophilic crosslinked polymers which can absorb aqueous fluid upto 100 can absorb aqueous fluid upto 100 times of its weight.times of its weight. Maximum swelling occurs in Maximum swelling occurs in fractions of minutes with SPHs having fractions of minutes with SPHs having Average pores of 200Average pores of 200μμm in size.m in size.

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SYNTHETIC POLYMERS USED IN GASTRORETENTIVE SYNTHETIC POLYMERS USED IN GASTRORETENTIVE DRUG DELIVERY SYSTEMS (GRDDS)DRUG DELIVERY SYSTEMS (GRDDS)

• GRDDS are Oral controlled GRDDS are Oral controlled DDS.DDS.

• Releases drug prior to Releases drug prior to Absorption window.Absorption window.

• Prolongs Drug release rate.Prolongs Drug release rate.

• Ensures optimal BA.Ensures optimal BA.

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• SYNTHETIC POLYMERS USED IN GRDDS-SYNTHETIC POLYMERS USED IN GRDDS-

1)1) FLOATING SYSTEMSFLOATING SYSTEMS• Matrix formers like- Polystyrene, PMMA, Polyacrylates, Matrix formers like- Polystyrene, PMMA, Polyacrylates, Polycarbonates, Polycarbophil & Highly swellable gel- forming Polycarbonates, Polycarbophil & Highly swellable gel- forming hydrocolloid like- HEC, HPMC, HPC, Na CMC.hydrocolloid like- HEC, HPMC, HPC, Na CMC.• They hydrates, swells & maintains density <1 thus, confers They hydrates, swells & maintains density <1 thus, confers buoyancy to dosage form & leads to GRDDS & buoyancy to dosage form & leads to GRDDS & ↓ PDC fluctuations.↓ PDC fluctuations.

2) BIOADHESIVE/ MUCOADHESIVE SYSTEM2) BIOADHESIVE/ MUCOADHESIVE SYSTEM

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33) ) SWELLING SYSTEMSSWELLING SYSTEMS• Polymer should be swellable, hydrophilic, of appt. mol. Wt.Polymer should be swellable, hydrophilic, of appt. mol. Wt.• Swelling depends on degree of crosslinking.Swelling depends on degree of crosslinking.

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SYNTHETIC POLYMERS USED IN CONTROLLED DDSSYNTHETIC POLYMERS USED IN CONTROLLED DDS


Poly (DL- lactide- co- glycolide)Poly (DL- lactide- co- glycolide)

microspheremicrosphereFor Live Rotavirus vaccine, For Live Rotavirus vaccine,

For encapsulating For encapsulating ßß- lactoglo-- lactoglo-

bulin microspheresbulin microspheres

Polyacrylic acidPolyacrylic acid Polyanion excipient to shield Polyanion excipient to shield Transforming Growth Factor (TGF) Transforming Growth Factor (TGF) from inactivation with Alginatesfrom inactivation with Alginates

Poly- Ɛ- caprolactone nanoparticlesPoly- Ɛ- caprolactone nanoparticles For encapsulating Cyclosporine AFor encapsulating Cyclosporine A

Polyester Polyester Tetanus Toxoid (vaccine) Tetanus Toxoid (vaccine) encapsulating microspheres for encapsulating microspheres for single- injection immunizationsingle- injection immunization

• CRDDS follows Zero- order release Kinetics.CRDDS follows Zero- order release Kinetics.• Requires swellable polymers which are capable of forming externalRequires swellable polymers which are capable of forming external gel layer controlling drug release.gel layer controlling drug release.

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SYNTHETIC POLYMERS USED IN CONTROLLED & SYNTHETIC POLYMERS USED IN CONTROLLED & TARGETED DRUG DELIVERY SYSTEMSTARGETED DRUG DELIVERY SYSTEMS

SYNTHETIC POLYMERS USED IN NANOPARTICLE DRUG DELIVERY SYNTHETIC POLYMERS USED IN NANOPARTICLE DRUG DELIVERY SYSTEMSSYSTEMS

Nanoparticles are sub-micron sized colloidal structures.Nanoparticles are sub-micron sized colloidal structures.

Ist Nanoparticles were based on Non-Biodegradable polymers like Ist Nanoparticles were based on Non-Biodegradable polymers like Polyacrylamide, PS, PMMA.Polyacrylamide, PS, PMMA.

Now, Biodegradable polymers like Poly(cyanoacrylates) were used in Now, Biodegradable polymers like Poly(cyanoacrylates) were used in NP.NP.

Synthetic Hydrophobic polymers used in NP-Synthetic Hydrophobic polymers used in NP- PCL, PLA, PLGA, PS.PCL, PLA, PLGA, PS. PMMA, PICA, PBCA, PHCAPMMA, PICA, PBCA, PHCA

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SYNTHETIC POLYMERSYNTHETIC POLYMER PROPERTIES & APPLICABILITYPROPERTIES & APPLICABILITY

1)1) FOR STEALTH NPFOR STEALTH NP POLAXAMERPOLAXAMER- - ABA Block str.ABA Block str. PEO/PEG-PPO/PPG-PEO/PEGPEO/PEG-PPO/PPG-PEO/PEG POLAXAMINESPOLAXAMINES- - Tetrafunctional Tetrafunctional

block copolymer with central block copolymer with central ethylenediamine bridgeethylenediamine bridge

(PEO-PPO)(PEO-PPO)22-X-(PPO-PEO)-X-(PPO-PEO)22

(PEG-PPG)(PEG-PPG)22-X-(PEG-PPG)-X-(PEG-PPG)22

Forms hydrated, hydrophillic steric Forms hydrated, hydrophillic steric barrier on NP surface.barrier on NP surface. To modify PS- NP surface to deliver To modify PS- NP surface to deliver Salmon Calcitonin. Salmon Calcitonin.

2) 2) FOR BIOADHESION OF NPFOR BIOADHESION OF NP Polyacrylic acid (Carbomer/ Polyacrylic acid (Carbomer/ Carbopol)Carbopol)

Swells 1000 times in HSwells 1000 times in H22O & provides O & provides Controlled release.Controlled release.

3) 3) FOR OCCULAR DELIVERYFOR OCCULAR DELIVERY Polyalkyl cyanoacrylatesPolyalkyl cyanoacrylates PCL, Polyester, PVA, HPMCPCL, Polyester, PVA, HPMC

Adheres to conjuctival mucin & Adheres to conjuctival mucin & ↑ ↑ residence time of NP in precorneal area.residence time of NP in precorneal area. To deliver Pilocarpine & BetaxololTo deliver Pilocarpine & Betaxolol

4) 4) FOR BRAIN TARGETINGFOR BRAIN TARGETING Polybutyl cyanoacrylates coated Polybutyl cyanoacrylates coated with Polysorbate- 80with Polysorbate- 80

To deliver Hexapeptide dalargin, To deliver Hexapeptide dalargin, Met- enkephalin Kyotropin, Met- enkephalin Kyotropin, Doxorubicin.Doxorubicin.

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5) 5) FOR LYMPHATIC TARGETINGFOR LYMPHATIC TARGETING Polyalkyl cyanoacrylatesPolyalkyl cyanoacrylates

(PEO-PLys) block copolymer(PEO-PLys) block copolymer

To deliver Insulin for peroral peptide To deliver Insulin for peroral peptide delivery through Peyer’s pathes.delivery through Peyer’s pathes. Conjugated to cis- diaminedichloro- Conjugated to cis- diaminedichloro- Platinum (cDDP) to treat lymph node Platinum (cDDP) to treat lymph node metastases.metastases.

6) 6) FOR TUMOR TARGETINGFOR TUMOR TARGETING PolyalkylcyanoacrylatesPolyalkylcyanoacrylates PolybutylcyanoacrylatesPolybutylcyanoacrylates PolyisobutylcyanoacrylatesPolyisobutylcyanoacrylates N-(2-HPMA)N-(2-HPMA)

To deliver Doxorubicin.To deliver Doxorubicin. To deliver Mitoxantrone, Acyclovir.To deliver Mitoxantrone, Acyclovir. To deliver AdacinomycinTo deliver Adacinomycin Act as lysosmotropic drug carrier for site Act as lysosmotropic drug carrier for site specific delivery of MAb (IgG, Ab B72.3)specific delivery of MAb (IgG, Ab B72.3)

7) 7) ADJUVANT EFFECT FOR ADJUVANT EFFECT FOR VACCINESVACCINES PMMAPMMA For Inluenza Ag & adjuvant to HIV-2 For Inluenza Ag & adjuvant to HIV-2

whole virus vaccine.whole virus vaccine. 4141

SYNTHETIC POLYMERS USED IN SYNTHETIC POLYMERS USED IN MICELLAR DRUG DELIVERY MICELLAR DRUG DELIVERY SYSTEMSYSTEM

• Polymeric Micelles are few tens in nm ,Polymeric Micelles are few tens in nm , crosslinked combination of hydrophilic & hydrophobiccrosslinked combination of hydrophilic & hydrophobic monomers.monomers.

• Forms shell- like structure , hydrophilic portion forms outer shell & Forms shell- like structure , hydrophilic portion forms outer shell & it protects core contents from chemical attacks in aqueous media in it protects core contents from chemical attacks in aqueous media in which they travels.which they travels.

• Drug release occur via polymer degradation.Drug release occur via polymer degradation.

• Have low CMC, slow dissociation rate & long retention of loaded drugHave low CMC, slow dissociation rate & long retention of loaded drug as compared to surfactant micelle.as compared to surfactant micelle. 4242

A)A) pH-sensitive Micelle based on titrable groupspH-sensitive Micelle based on titrable groups• Synthetic block copolymers containing weak basic groupSynthetic block copolymers containing weak basic group:-:-• Poly(2-Vinyl pyridine)-b-PEO, PEO-DMAEMA, PDMAEMA-b-PDAEMA,Poly(2-Vinyl pyridine)-b-PEO, PEO-DMAEMA, PDMAEMA-b-PDAEMA, PEO-b-DMAEMA-b-DEAEMA, DMAEMA-b-Poly[2-(N-morpholino)ethylPEO-b-DMAEMA-b-DEAEMA, DMAEMA-b-Poly[2-(N-morpholino)ethyl methacrylate.methacrylate.

• Copolymers containing weak acidic groupsCopolymers containing weak acidic groups :- :-• Poly[sodium-2-(acrylamido)-2-methyl propanesulfonate-b-polyPoly[sodium-2-(acrylamido)-2-methyl propanesulfonate-b-poly (sodium-6-acryl amido hexanoate) & Poly(sodium-4-styrene (sodium-6-acryl amido hexanoate) & Poly(sodium-4-styrene sulfonate)-b-Poly(sodium-4-vinyl benzoate)sulfonate)-b-Poly(sodium-4-vinyl benzoate)• Forms micelle at pH <5Forms micelle at pH <5• PLLA-b-PEO-b-Polysulfamethoxine- have sulfonamide as acidic gp.PLLA-b-PEO-b-Polysulfamethoxine- have sulfonamide as acidic gp.

• AMPHIPHILIC STAR POLYMERAMPHIPHILIC STAR POLYMER• Prepared from Ethyl methacrylate,Prepared from Ethyl methacrylate, PEG-MA, t-butyl MAPEG-MA, t-butyl MA• For delivery of hydrophobic drug For delivery of hydrophobic drug like Progesterone.like Progesterone.

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B) B) pH-sensitive Polyelectrolyte complexespH-sensitive Polyelectrolyte complexes• Formed by electrostatic interaction of two oppositely charged Block Formed by electrostatic interaction of two oppositely charged Block copolymer.copolymer.• ExamplesExamples:-:-• [PEO-b-Poly(L-lysine)] & [PEO-b-Poly(Aspartic acid)][PEO-b-Poly(L-lysine)] & [PEO-b-Poly(Aspartic acid)]• (PEO-b-PMANa) & Poly (N-ethyl-4-vinyl pyridinium bromide)(PEO-b-PMANa) & Poly (N-ethyl-4-vinyl pyridinium bromide)• Cationic block copolymer forms complex with Polyanionic biomolecules likeCationic block copolymer forms complex with Polyanionic biomolecules like DNA & ODNs like PEO-b-Polyspermine which make complex with ODNs.DNA & ODNs like PEO-b-Polyspermine which make complex with ODNs.• PEO-b-PPO triblock combination for Doxorubicin delivery.PEO-b-PPO triblock combination for Doxorubicin delivery.

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POLYMER VESCICLESPOLYMER VESCICLES

Microscopic sac that encloses a volume with molecularly thin Microscopic sac that encloses a volume with molecularly thin membrane. The membrane are self- directing assemblies of membrane. The membrane are self- directing assemblies of amphiphilic molecues with dual hydrophobic- hydrophobic amphiphilic molecues with dual hydrophobic- hydrophobic characters.characters.


Non-ionic Polyethylene-oxide- Poly Non-ionic Polyethylene-oxide- Poly butadienebutadiene

To form vesicles in aqueous solutionTo form vesicles in aqueous solution

PMOXA- PDMS- PMOXAPMOXA- PDMS- PMOXA Water soluble & midblock is Water soluble & midblock is hydrophilichydrophilic

(PEO- Polyethylethylene(PEO- Polyethylethylene To form polymerosomes in aqueous To form polymerosomes in aqueous solution for encapsulating solution for encapsulating DoxorubicinDoxorubicin 4646

SYNTHETIC POLYMERS USED INSYNTHETIC POLYMERS USED IN LIPOSOME DRUG DELIVERY SYSTEMSLIPOSOME DRUG DELIVERY SYSTEMS

• Polymer properties to be consideredPolymer properties to be considered :- :-• Low immunogenic.Low immunogenic.• structural versatility.structural versatility.• Improves liposomal stability.Improves liposomal stability.• Easy to associate with liposome surface.Easy to associate with liposome surface.

A) A) pH-Sensitive Polymer –Liposome systempH-Sensitive Polymer –Liposome system• pH-sensitive synthetic polymers used:-pH-sensitive synthetic polymers used:-• Poly-L-lysine & Poly (His)Poly-L-lysine & Poly (His) – – • Positively charged at low Ph Positively charged at low Ph • Interact with negatively charged membranes & promotes fusogenic Interact with negatively charged membranes & promotes fusogenic properties.properties.

• PAMAMPAMAM – Shows pH-dependent membrane destabilization & thus used for – Shows pH-dependent membrane destabilization & thus used for cytoplasmic gene delivery.cytoplasmic gene delivery.

• N-isopropylacrylamideN-isopropylacrylamide--•Provide Temp-responsive properties.Provide Temp-responsive properties.

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• STEALTH LIPOSOMESSTEALTH LIPOSOMES

• POLYETHYLENE GLYCOLPOLYETHYLENE GLYCOL – –• Hydrophilic, FlexibleHydrophilic, Flexible• ↑ ↑ Repulsive forces at surface & thus Repulsive forces at surface & thus ↓ ↓ interaction & plasma protein interaction & plasma protein adsorption.adsorption.

• POLOXAMERPOLOXAMER- - • Amphipathic polymer with ABA Block structure.Amphipathic polymer with ABA Block structure.• PEO-PPO-PEGPEO-PPO-PEG

• POLOXAMINES-POLOXAMINES-• Tetrafunctional Block copolymer with four PEO-PPO Blocks joined togetherTetrafunctional Block copolymer with four PEO-PPO Blocks joined together by central Ethylene diamine bridge.by central Ethylene diamine bridge.• [(PEO-PPO)[(PEO-PPO)22- X- (PPO-PEO)- X- (PPO-PEO)22]]• [(PEG-PPG)[(PEG-PPG)22- X- (PEG-PPG)- X- (PEG-PPG)22]]

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REFERENCESREFERENCES

Remington, “The Science & Practice of Pharmacy”Remington, “The Science & Practice of Pharmacy” Volume- Volume- ІІ , B.I. Publications Pvt. Ltd, Lippincott Williams & , B.I. Publications Pvt. Ltd, Lippincott Williams &

Wilkins company.Wilkins company.

Lachman Leon, Lieberman HA, Kanig J.L, “The Theory & Lachman Leon, Lieberman HA, Kanig J.L, “The Theory & Practice of Industrial Pharmacy”, 3Practice of Industrial Pharmacy”, 3rdrd edition, Varghese edition, Varghese Publication.Publication.

Banker G.S., Rhodes C.T., “Modern Pharmaceutics”, 4Banker G.S., Rhodes C.T., “Modern Pharmaceutics”, 4thth edition Revised, Informa Health care.edition Revised, Informa Health care.

Vyas S.P., Khar R.K., “Targeted & Controlled Drug Delivery” Vyas S.P., Khar R.K., “Targeted & Controlled Drug Delivery” CBS Publishers & DistributorsCBS Publishers & Distributors

Jain N.K., “Pharmaceutical Product Development”, Jain N.K., “Pharmaceutical Product Development”, 11stst edition, Cbs Publishers & Distributors. edition, Cbs Publishers & Distributors.

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•Wiseman N, Xiao.H, Cherie. O, “Retention acid system of cationic Wiseman N, Xiao.H, Cherie. O, “Retention acid system of cationic microparticles & anionic polymers experiments & pilot machine microparticles & anionic polymers experiments & pilot machine trials”, Tappi Journal, Volume 83trials”, Tappi Journal, Volume 83

• Hoshino Y, Urakani T, Kodama Takashi, Oku Naota, Shea J.K, “ Hoshino Y, Urakani T, Kodama Takashi, Oku Naota, Shea J.K, “ Design of Design of SyntheticSynthetic Polymer NP that capture & neutralize a toxic Polymer NP that capture & neutralize a toxic peptide”, Wiley Interscience.peptide”, Wiley Interscience.

• Heller J, “The use of Polymer is construction of Controlled Release Heller J, “The use of Polymer is construction of Controlled Release Devices”,National Institute on Drug Abuse Research monograph Devices”,National Institute on Drug Abuse Research monograph series.series.

• Girish Y, Punitha S, “Polymers in mucoadhesive buccal DDS –A Girish Y, Punitha S, “Polymers in mucoadhesive buccal DDS –A Review”, Int. J. Res. Pharm. Sci. Vol- 1, Issue-2, 170-186, 2010.Review”, Int. J. Res. Pharm. Sci. Vol- 1, Issue-2, 170-186, 2010.

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•Jain N.K., “Progress in Controlled & Novel Drug Delivery systems”, Jain N.K., “Progress in Controlled & Novel Drug Delivery systems”, 1st edition, CBS Publishers & Distributors 1st edition, CBS Publishers & Distributors

•Jauhar S.P., “ Modern’s Chemistry”, Modern PublishersJauhar S.P., “ Modern’s Chemistry”, Modern Publishers

• Kandavilli S, Nair V, Panchagnula R, “Polymers in Transdermal Kandavilli S, Nair V, Panchagnula R, “Polymers in Transdermal Drug Delivery Systems”, Pharm. Tech. J.Drug Delivery Systems”, Pharm. Tech. J.

• Kshirsagar NA, “Drug Delivery System”, Journal of Pharmacology.Kshirsagar NA, “Drug Delivery System”, Journal of Pharmacology.

• Twaites B, Heras C, Alexander C, “Synthetic Polymers as Drugs & Twaites B, Heras C, Alexander C, “Synthetic Polymers as Drugs & Therapeutics”, Journal of material chemistry. Therapeutics”, Journal of material chemistry.

•Duncan R, “Designing Polymer conjugates as lysosmotropic Duncan R, “Designing Polymer conjugates as lysosmotropic nanomedicines”, Biochemical society Transaction (2007) Vol 35, nanomedicines”, Biochemical society Transaction (2007) Vol 35, Part 1Part 1

• Elvira C, Gallardo A, Roman J.S., Cifuentes A, “ Covalent Polymer Elvira C, Gallardo A, Roman J.S., Cifuentes A, “ Covalent Polymer Drug Conjugates”, MDPIDrug Conjugates”, MDPI

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