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Controlled Release

Introduction and Background

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Topics

n Definitionsn Classifications of CR Systemsq Rate control, physical form

n Design considerationsn Routes of administrationn Review of mass transfer

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Definition of Controlled Release

n A system that:q Delivers an agent at a controlled rate for an

extended timeq Might localize drug action by spatial placement

near where it is neededq Might target drug action by using techniques to

deliver drug to a particular cell type

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Controlled Release Agents

n In nature (?)q Oxygenation of bloodq Transport of nutrients

and waste through cell membranes

q Transport and evaporation of water (sweat) to control body temperature

n Engineered systems (?)q Drugsq Biocidesq Fragrances

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Controlled Release vs. Sustained Release

n Controlled drug deliveryq Well-characterized and reproducible dosage formq Controls entry to the body according to the

specifications of the required drug delivery profilen rate and duration of delivery are designed to achieve

desired concentration

n Sustained Releaseq Release of drug is extended in timeq Rate and duration are not designed to achieve a

particular profile.

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Controlled Release vs. Conventional

n Conventionalq Periodic administrationq Non-specific

administrationq High systemic

concentrations can be toxic, causing side effects or damage to organs

q Low concentrations can be ineffective

Time

Sys

tem

ic D

rug C

once

ntrat

ion

ConventionalControlled Release

Effective

Ineffective

Toxic

n CR q Drug Concentration rises

quickly to effective level. q Effective concentration is

maintained for extended time

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Disadvantages of Conventional Delivery

n Inconvenientn Difficult to monitorn Careful calculation necessary to prevent

overdosingn Large amounts of drug can be “lost” when

they don’t get to the target organn Drug goes to non-target cells and can cause

damagen Expensive (using more drug than necessary)

(Brainstorm)

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Advantages of Controlled Release

n Reproducible rate, prolonged deliveryn Less frequent administration

q Better patient complianceq Increased convenience

n Reduced side effects because effective C is maintained

n Targeting can eliminate damage to non-target organs

n Less drug usedn Re-patenting without new drug development

(Brainstorm)

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Challenges to Controlled Release

n Cost of formulation – preparation and processing

n Fate of controlled release system if not biodegradable

n Biocompatibilityn Fate of polymer additives, e.g., plasticizers,

stabilizers, antioxidants, fillers

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Polymer Systems for Controlled Release

n Classified byq Type of deviceq Rate controlling mechanism

Solvent activationOsmotic pump or polymer swelling

Osmotic Pumps

(Hybrids)

Chemical reaction – erosion or cleavage

Reservoir/Membrane

DiffusionThrough a matrix or membrane

Matrix

MechanismsTypes

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Matrix Systems

n Drug is physically blended with the polymerq Dissolved or dispersed

n This is the simplest and cheapest device

At t=0

Polymer matrix contains uniformly dissolved or dispersed drug

At time t

Drug is being released by some rate-controlling mechanism

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Reservoir Systems

n With or without a rate-controlling membranen Geometric Formq Microbead – thin polymer coating around

particles or dropletsq Microtube – polymeric hollow fiber

Microbeads Microtube

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The Osmotic Pump

Rigid semipermeablemembrane

Osmotic agent

Flexible impermeable wall

Reservoircontainingdrug

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Rate Control: Diffusion

Drug dissolvedor dispersed

in polymer

Adapted from Langer, Science, 249, 1990

Polymer film (membrane)

Drug

Time 0 Time t

Time 0Time t

Membrane System

Drug surrounded by polymer film or membrane

Matrix System

Drug is distributed uniformly throughout polymer

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Diffusion Systems

Contac® 12 Hour Cold Capsules

Nocoderm® Patch

Ocusert®

(Pilocarpine for Glaucoma)

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Rate Control: Chemical Reaction

water or enzyme

Cleavage of drugfrom polymer

backbone

Adapted from Langer, Science, 249, 1990

Time tTime 0 drug

polymer backbone polymer backbone

Degradation of polymer

Drug dissolved or dispersed in

polymer

Time 0 Time t

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Biodegradable Systems

n Implants for release of anticancer drugsn Lupron Depot®

q Injectable microspheresq Once per month injectonq Prostrate cancer, fertility treatment, early puberty

n Malaria vaccine

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Rate Control: Solvent Activation

Drug dissolved

in polymer

Time 0

Time t

Swollen Polymer from which drug has been released

Swelling allows drug to migrate more easily

Adapted from Langer, Science, 249, 1990

Time 0 Time t

Osmotic pressure causeswater to penetrate,forming pores and releasing drug

Pores permit release

Drug dispersed

in polymer

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Design Considerations

n Basic componentsq Active agentq Polymer

n Polymer design considerations (?)q Physical propertiesn Glass transition temperaturen Diffusion characteristics

q Compatibility with activeq Stability – must not decompose in storageq Biocompatibility of polymer and degradation productsq Ease of formulation and fabricationq Mechanical properties are stable when drug is addedq Cost

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Design considerations

n Agentq Physicochemical propertiesn Stabilityn Solubilityn Partitioningn Chargen Protein binding propensity

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Design Considerations

n Route of deliveryn Target sites

q Desired site for efficacyq Sites to avoid to minimize side effects

n Type of therapy q Acute or chronic – rate and durationn e.g., 1 yr contraceptive implant vs. antibiotic for acute infection

n Patient conditionq Cognative ability and memoryq Physical condition – ambulatory, bedridden, etc.

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Routes of Administration for CR

n Parenteral – outside GI tractq Usually refers to

injectablesn Subcutaneousn Intramuscularn Intraperitonealn Intravenous

n Advantagesq Bypasses some routes of

metabolic clearance

n Disadvantages (?)q Painfulq Inconvenient

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Routes of Administration

n Oralq Most common routen Easy to formulate and manufacturen Patient compliance is generally goodn Inexpensive dosage form

q Tricky due to environment of GI tractn pH degradationn Enzymatic degradationn Intestinal motility – affects residence time

q Single patient and patient-to-patient variationsn Absorption limitations in stomach

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Routes of Administration

n Buccal/ Sublingualq Thin mucous membraneq Rich blood supplyq Mild pH ~6.0

n Nasalq Easy administrationq Rapid absorptionq Bypasses certain

clearance routes

n Rectalq No pH or enzymatic

degradation as in oral (+)q More effective than

buccal or sublingual for some drugs (+)

q Limited absorption (-)

n Pulmonaryq Large S.A. for absorption

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Routes of Administration

n Transdermalq Accessible organ, large surface areaq Avoid first pass metabolismq Avoid GI incompatibility of drugsq Good patient complianceq Transport across skin can be a challenge

n Ocularq Localized delivery for eye disordersq Good absorption for many drugsq Loss of drug in tears