dr c. v. s. subrahmanyam

Dr C. V. S. Subrahmanyam

Principal

Gokaraju Rangaraju College of Pharmacy

Hyderabad

Polymers – Controlled Drug Delivery systems

The participant shall be able to:

Objectives of this Session

Describe diffusion controlled devices, using

polymersExplain the chemically controlled devices and

bioerodible polymerDescribe the release mechanisms in terms

of hydrophilic and hydrophobic polymer

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Polymers – Controlled Drug Delivery systems

ClassificationBinding agents

Acacia, gelatin, sodium alginate

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Polymers – Conventional Dosage Forms

Disintegrating agentsStarch, crosscarmellose sodium

PlasticizersPolyethyleneCosolventsPEG 300, PEG 400Thickening agentsXanthin gumCoating agents – nonenteric agentsHPMC, povidone, PEG

Classification

Cellulose acetate phthalate, HPMC pthalate

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Polymers – Conventional Dosage Forms

Bulking agentsMicrocrystalline cellulose (MCC)

Coating agents – enteric agents

These are release retardantsInsoluble, inert polymers

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Polymers – Oral controlled delivery systems

Examples - PolymersPolyethylene, PVC, ethylcellulose

Examples – Dosage formsMatrix tabletsThese do not

disintegrateDirect compression is possibleWet granulation is possible with ethyl alcoholMechanism of releaseLiquid penetration, drug dissolution

anddiffusionChanneling agents promote the

permeationEg: Sorbitol

Not suitable for highly water insoluble drugs

Insoluble, inert polymers

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Polymers – Oral controlled delivery systems

Because release is dissolution rate limiting

Mechanism of releaseNot sensitive to composition of GI

fluidsNot useful for high mg formulationBecause high conc of polymer cannot be

included

Characteristics- Physiologically inert- Compatible with biological tissue

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Polymers – Biocompatibility

- Degrade in the physiologic environment- Toxicologically acceptable metabolitesEg: naturally occurring lactic

acidBioerosion profilePoly bis (o-carbophenoxy) propane (PCPP)

copolymered with sebacic acidThese have hydrolytic instabilityBioerosion is due to crystallinity changes

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Polymers – BiocompatibilityBioerosion profile

Polyanhydrides with sebacic acidAliphatic acid segment are incorporatedIt increases the bioerosion

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Polymers – BiocompatibilityApplications

Peptide antitumor agents are deliveredThese are more important in case of proteinsPeptides themselves can degrade in the

biological environmentThen the polymers must protect these peptide drugs

Implant products

Biodegradable polymers are also required for

sc administration - implantsPoly (lactide-glycolide) for sc implantation

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Polymers – BiocompatibilityPoly (lactide-glycolide) for sc implantation

Degradability is 50% in 50 days

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Polymers – Biocompatibility

Rate of release depends on the biodegradability

of polymers

Intravenous/arterial productsCancer therapy needs these productsExamples - Polymers

Naltrexone (drug) pellets

Polypeptides, polysaccharides, orthoester

Applications

Poly (lactide-glycolide)

A. Monolithic DevicesDispersion of drug in the

polymerSlab type – polymer controls the release of

drug due to diffusion

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Polymers – Diffusion Controlled Devices

i) Solubilized ii) Dispersed

These do not release drug by zero order kineticsThese are simple and convenient

Drug may be:

B. Reservoir DevicesCore is drug, coat is rate controlling

membraneCoat is microporous, hydrophobic backbone

membrane

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Fick’s law is applicableLiquid filled poresZero order kinetics can be achieved

Burst effect is also possibleFabrication is complex, but zero order kinetics

allowed its commercial applications

C. Solvent Controlled DevicesEg: Osmotically controlled devices

Semipermeable membrane (polymer)

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Rigid impermeable flexible barrier (Polymer)Eg: Swelling controlled devices

Release of drug from the polymer is controlled by

a chemical reactionMechanism: Hydrolytic or enzymatic cleavage of

liable bonds, ionization or protonation

Bioerodible polymer are used as implantable

devices

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Polymers – Chemically Controlled Devices

Polymer erosion follows:Conversion of water insoluble material to a

water soluble materials

Device need not be removed from the site of

application

Type I ErosionWater soluble macromolecules are cross-linked

to form a networkNetwork is insoluble in aqueous environment

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Polymer dissolve and swell to the extent that is

allowed by cross-link densityThese cross-links are cleaved (Type IA)

Cleaved parts are water soluble

Type I ErosionCleavage of water soluble polymer backbone

(Type IB)

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Backbone is cleavedAs cleaving proceeds, the matrix begin to swell

and eventually it will dissolve

Type I ErosionLimitations

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1)Matrix swell progressively, dissolution will

limit its useThree dimensional stability is of little

importance2) Cross linked water soluble polymer form

hydrogelsCompletely permeated by waterThen water solubility of drug is important Therefore, low mol wt water soluble drug is

leached rapidlyThen, it is independent of matrix erosion rate

Type II ErosionMechanism: Hydrolysis, ionization, protonation

of the pedant groupBackbone of the polymer is intact

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1)Solubilization does not result, though mol wt

of polymer changesThese type of polymers are used for topical applications, because backbone does

notcleave

High mol wt polymers get eliminated as water

soluble macromolecules

Type III ErosionMechanism: Hydrolytic cleavage of labile bonds

in the polymer backbone

These are used for systemic administration of

therapeutic agents

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Sc, im, ip implantation sites

Degradation products must be completelynontoxic

High mol wt (insoluble) polymer

Small watersoluble

molecules

1) Drug is covalently attached to the polymer

backbone

Hydrolysis of backbone releases the drug

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Controlled Devices – Release Mechanisms

Polymer fragments should not be attached to

the drugReactivity of bond A should be significantly

higher than reactivity of bond BPolymer is a carrier or depot of drugi.e., localised at a certain body site

1)Drugs covalently attached to polymerbackbone

Covalent bond gradually breaks (physical)

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A chemical reaction is responsible for cleavageEg: Depot system or norethindrone coupled with

water soluble poly (N5-hydroxypropyl-L-

glutamine) by reaction with phosgene


1)Drugs covalently attached to polymerbackbone

After depletion of drug, the polymer should

not remain at the site

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Polymer-OH group combine with steroids

produce carbonate linkage


Hydrolysis of carbonate linkage releases the

steroids, release is effective for 144 days

Carrier mode is the unique possibility of carrying

the drug to specific body siteEg: p-Phenylene diamine mustard and immuniglobin (homing group) are

usedagainst mouse lymphomaImmunoglobulin reaches the site

and cleaves to release the drug

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2) Drug contained in a core surrounded by

bioerodible rate controlling membraneSubdermal delivery of contraceptive

steroidsand narcotic anagonist, eg,

naltrexoneEg: Poly (- caprolactone), poly (DL-lactic

acid )


Drug is in the core (Reservoir type)

Surgical removal of drug depleted device is

unnecessary, if polymer is bioerodible

The polymer capsule remain in the tissue for

varying lengths of time, after completion

of therapy

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Degradation is bulk typeHydrolysis of aliphatic poly esters with no

enzymatic contributionDevices erode only after the drug reservoir is

depleted

2) Drug contained in a core surrounded by

bioerodible rate controlling membrane

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Controlled Devices – Release Mechanisms2) Drug contained in a core surrounded

by bioerodible rate controlling

membrane

Rapid fall of viscosity indicates that

the degradation is bulk erosion

Slab or monolithic systemDrug diffusion from this monolith is controlled

by diffusion or erosion or a combination of

both

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Controlled Devices – Release Mechanisms3) Drug is homogeneously dispersed in

polymermatrix

There are two categories – details follows

Hydrophilic Bioerodible PolymersBulk erosion takes place – monolithic

systemNature of drugs

Low water soluble substances

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Polymers – Bioerodible Type

MacromoleculesThese physically entangle in good amounts

anddrug is immobilised

Used as implants for topical, ocular rectal,

utero applications

If drugs are hydrophilic, release is rapid

Toxicity of polymer is low

If polymers are non-digestable, these form a gel layer

Because completely permeated by water

Eg: Hydrogel prepared by copolymerizing vinylpyrrolidone or acrylamide with

N,N’-methylene bis acrylamide

Hydrophilic Bioerodible Polymers – Type I A

Acrylamide microspheres cross-linked with

N, N’ methylene bis acrylamide

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Microspheres cleave by hydrolysis at cross linksHydrophilic Bioerodible Polymers – Type I BEg: Copolymerizing dextran with acrylic acid,

glycidyl ester and N,N’-methylene bis

acrylamideStable at pH 2 to 7As pH increases, hydrolysis increasesDegraded molecules are low mol wt

BSA is entangled in the hydrogel (polyester) by

performing the cross-linking reaction in an

aqueous solution that contains dissolved

macromolecules

Hydrophilic Bioerodible Polymers – Type I B

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Degradation occur at amide linkage

Eg: immunoglobulins, catalase etc.

Degradation depends on enzymatic activity

Hydrolysis occur throughout the bulk of polymer

Hydrophobic Bioerodible Polymers – Bulk Type

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Release is complexDue to diffusion and erosionHence, permeability of drug from the

polymeris not predictable- Matrix can disintegrate before drug

depletion- Large burst in the rate of drug delivery also

takes placeExamples - PolymersCopolymers of glycolic and lactic acidsHistorically these are used as bioerodible

sutures These polymers degrade to metabolic lactic

acid and glycolic acids

These are toxicologically innocuous

Hydrophobic Bioerodible Polymers – Bulk Type

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Examples - DrugsNorethindrone, baboons from poly (lactic acid)

microspheresKinetics of release is determined by diffusion,

Highuchi’s equation

Early stages: little erosionHydrophobic Bioerodible Polymers – Bulk Type

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Diffusion is predominantSubsequent stages: rapidly bioerodible

due tocombined effect of diffusion and

erosion

Outer surface of polymer is effected by hydrolysis

Hydrophobic Polymers – Surface Erosion

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Interior of the matrix remain unchangedRelease is direct consequence of surface erosion Release is predictableDrug release is constant, provided geometry

surface area is constantLife time of device device thicknessRate of release drug loadingExamples - Polymers

Copolymers of methyl vinyl ether and maleic

anhydratePoly (ortho esters)Polyanhydrides

Mechanism of releaseHydrophobic Polymers – Surface Erosion

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Pore diffusion and erosionMore sensitive to digestive fluid compositionWater permeation is promoted by the use of

surfactants or wicking agents (hydrophilic)These also promote

erosionThe polymers promote the direct

compression of ingredientsEg: Sustained release theophylline tablets

Eg: Hydrocortisone from n-butyl half ester of

methyl vinyl ether-maleic anhydratecopolymer


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Degradation mechanism is Type IIDegraded product is high mol wt water soluble

polymerFurther degradation is not possibleThese are used for topical applications

Dispersion of drug in the polymerHydrophobic Polymers – Surface Erosion

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Dissolution of matrix is retarded at a define pHConstant pH environment provide controlled

release

Excellent linearity between drug release

and polymer erosion


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Poly (ortho esters)Degradation is spontaneous (exothermic)Catalysed by traces of acidReaction completes instantaneouslyDegradation products are dense

and cross-linkedHydrolyse at physiologic pH 7.4

As pH is lowered, more labile reaction is

obtainedSide chain is manipulated to change, but backbone does not change


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Manipulation of erosionExcipients in the matrixEg: Contraceptive steroidsNature of excipients (polymer is

hydrophobic)- Slightly acidic salt, eg: Calcium lactate- More hydrophilic polymer- Stabilizer, eg: Magnesium hydroxideAs neutralization continues,

levonorgestralrelease is observed deu to erosion

Poly (ortho esters) - LevonorgestrelHydrophobic Polymers – Surface Erosion

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Stable in base

Slow at pH 7.4Cleave rapidly at acidic

pHThree units

One unit


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PolyanhydridesAliphatic and aromatic diacidsThese degrade rapidly in basic medium than in

acidic media

At higher pH, biodegradation of matrix

Near neutral pH, bioerodible Grcp

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Bioerosion – Regulated Drug Delivery Systems

Presence of urea

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Bioerosion – Regulated Drug Delivery Systems

Thank you

dr c. v. s. subrahmanyam

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