dr c. v. s. subrahmanyam principal gokaraju rangaraju college of pharmacy hyderabad polymers –...
TRANSCRIPT
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Dr C. V. S. Subrahmanyam
Principal
Gokaraju Rangaraju College of Pharmacy
Hyderabad
Polymers – Controlled Drug Delivery systems
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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
Grcp
CVS
Polymers – Controlled Drug Delivery systems
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ClassificationBinding agents
Acacia, gelatin, sodium alginate
Grcp
CVS
Polymers – Conventional Dosage Forms
Disintegrating agentsStarch, crosscarmellose sodium
PlasticizersPolyethyleneCosolventsPEG 300, PEG 400Thickening agentsXanthin gumCoating agents – nonenteric agentsHPMC, povidone, PEG
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Classification
Cellulose acetate phthalate, HPMC pthalate
Grcp
CVS
Polymers – Conventional Dosage Forms
Bulking agentsMicrocrystalline cellulose (MCC)
Coating agents – enteric agents
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These are release retardantsInsoluble, inert polymers
Grcp
CVS
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
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Not suitable for highly water insoluble drugs
Insoluble, inert polymers
Grcp
CVS
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
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Characteristics- Physiologically inert- Compatible with biological tissue
Grcp
CVS
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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Grcp
CVS
Polymers – BiocompatibilityBioerosion profile
Polyanhydrides with sebacic acidAliphatic acid segment are incorporatedIt increases the bioerosion
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Grcp
CVS
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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Grcp
CVS
Polymers – BiocompatibilityPoly (lactide-glycolide) for sc implantation
Degradability is 50% in 50 days
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Grcp
CVS
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)
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A. Monolithic DevicesDispersion of drug in the
polymerSlab type – polymer controls the release of
drug due to diffusion
Grcp
CVS
Polymers – Diffusion Controlled Devices
i) Solubilized ii) Dispersed
These do not release drug by zero order kineticsThese are simple and convenient
Drug may be:
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B. Reservoir DevicesCore is drug, coat is rate controlling
membraneCoat is microporous, hydrophobic backbone
membrane
Grcp
CVS
Polymers – Diffusion Controlled Devices
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
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C. Solvent Controlled DevicesEg: Osmotically controlled devices
Semipermeable membrane (polymer)
Grcp
CVS
Polymers – Diffusion Controlled Devices
Rigid impermeable flexible barrier (Polymer)Eg: Swelling controlled devices
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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
Grcp
CVS
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
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Type I ErosionWater soluble macromolecules are cross-linked
to form a networkNetwork is insoluble in aqueous environment
Grcp
CVS
Polymers – Chemically Controlled Devices
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
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Type I ErosionCleavage of water soluble polymer backbone
(Type IB)
Grcp
CVS
Polymers – Chemically Controlled Devices
Backbone is cleavedAs cleaving proceeds, the matrix begin to swell
and eventually it will dissolve
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Type I ErosionLimitations
Grcp
CVS
Polymers – Chemically Controlled Devices
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
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Type II ErosionMechanism: Hydrolysis, ionization, protonation
of the pedant groupBackbone of the polymer is intact
Grcp
CVS
Polymers – Chemically Controlled Devices
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
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Type III ErosionMechanism: Hydrolytic cleavage of labile bonds
in the polymer backbone
These are used for systemic administration of
therapeutic agents
Grcp
CVS
Polymers – Chemically Controlled Devices
Sc, im, ip implantation sites
Degradation products must be completelynontoxic
High mol wt (insoluble) polymer
Small watersoluble
molecules
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1) Drug is covalently attached to the polymer
backbone
Hydrolysis of backbone releases the drug
Grcp
CVS
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
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1)Drugs covalently attached to polymerbackbone
Covalent bond gradually breaks (physical)
Grcp
CVS
A chemical reaction is responsible for cleavageEg: Depot system or norethindrone coupled with
water soluble poly (N5-hydroxypropyl-L-
glutamine) by reaction with phosgene
Controlled Devices – Release Mechanisms
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1)Drugs covalently attached to polymerbackbone
After depletion of drug, the polymer should
not remain at the site
Grcp
CVS
Polymer-OH group combine with steroids
produce carbonate linkage
Controlled Devices – Release Mechanisms
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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Grcp
CVS
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 )
Controlled Devices – Release Mechanisms
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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Grcp
CVS
Controlled Devices – Release Mechanisms
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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Grcp
CVS
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
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Slab or monolithic systemDrug diffusion from this monolith is controlled
by diffusion or erosion or a combination of
both
Grcp
CVS
Controlled Devices – Release Mechanisms3) Drug is homogeneously dispersed in
polymermatrix
There are two categories – details follows
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Hydrophilic Bioerodible PolymersBulk erosion takes place – monolithic
systemNature of drugs
Low water soluble substances
Grcp
CVS
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
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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
Grcp
CVS
Polymers – Bioerodible Type
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
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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
Grcp
CVS
Polymers – Bioerodible Type
Degradation occur at amide linkage
Eg: immunoglobulins, catalase etc.
Degradation depends on enzymatic activity
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Hydrolysis occur throughout the bulk of polymer
Hydrophobic Bioerodible Polymers – Bulk Type
Grcp
CVS
Polymers – Bioerodible Type
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
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These are toxicologically innocuous
Hydrophobic Bioerodible Polymers – Bulk Type
Grcp
CVS
Polymers – Bioerodible Type
Examples - DrugsNorethindrone, baboons from poly (lactic acid)
microspheresKinetics of release is determined by diffusion,
Highuchi’s equation
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Early stages: little erosionHydrophobic Bioerodible Polymers – Bulk Type
Grcp
CVS
Polymers – Bioerodible Type
Diffusion is predominantSubsequent stages: rapidly bioerodible
due tocombined effect of diffusion and
erosion
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Outer surface of polymer is effected by hydrolysis
Hydrophobic Polymers – Surface Erosion
Grcp
CVS
Polymers – Bioerodible Type
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
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Mechanism of releaseHydrophobic Polymers – Surface Erosion
Grcp
CVS
Polymers – Bioerodible Type
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
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Eg: Hydrocortisone from n-butyl half ester of
methyl vinyl ether-maleic anhydratecopolymer
Hydrophobic Polymers – Surface Erosion
Grcp
CVS
Polymers – Bioerodible Type
Degradation mechanism is Type IIDegraded product is high mol wt water soluble
polymerFurther degradation is not possibleThese are used for topical applications
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Dispersion of drug in the polymerHydrophobic Polymers – Surface Erosion
Grcp
CVS
Polymers – Bioerodible Type
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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Hydrophobic Polymers – Surface Erosion
Grcp
CVS
Polymers – Bioerodible Type
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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Hydrophobic Polymers – Surface Erosion
Grcp
CVS
Polymers – Bioerodible Type
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
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Poly (ortho esters) - LevonorgestrelHydrophobic Polymers – Surface Erosion
Grcp
CVS
Polymers – Bioerodible Type
Stable in base
Slow at pH 7.4Cleave rapidly at acidic
pHThree units
One unit
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Hydrophobic Polymers – Surface Erosion
Grcp
CVS
Polymers – Bioerodible Type
PolyanhydridesAliphatic and aromatic diacidsThese degrade rapidly in basic medium than in
acidic media
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At higher pH, biodegradation of matrix
Near neutral pH, bioerodible Grcp
CVS
Bioerosion – Regulated Drug Delivery Systems
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Presence of urea
Grcp
CVS
Bioerosion – Regulated Drug Delivery Systems
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Thank you