Principles of Drug DeliveryPrinciples of Drug Delivery

Drug DeliveryDrug Delivery

DefinitionDefinition– The appropriate administration of drugs through The appropriate administration of drugs through

various routes in the body for the purpose of various routes in the body for the purpose of improving healthimproving health

– It is highly interdisciplinaryIt is highly interdisciplinary– It is not a young fieldIt is not a young field– It has recently evolved to take into considerationIt has recently evolved to take into consideration

Drug physico-chemical propertiesDrug physico-chemical properties

Body effects and interactionsBody effects and interactions

Improvement of drug effect Improvement of drug effect

Patient comfort and well beingPatient comfort and well being

Controlled Drug Delivery

ConventionalConventional ControlledControlled

Drug DeliveryDrug Delivery

SustainedSustained

ExtendedExtended

Site-specificSite-specific

PulsatilePulsatile

EnteralEnteral

ParenteralParenteral

OtherOther

Oral AdministrationOral Administration

AdvantagesAdvantages– Patient: Convenience, Patient: Convenience,

not invasive, higher not invasive, higher compliancecompliance

– Manufacture: well Manufacture: well established processes, established processes, available infrastructureavailable infrastructure

DisadvantagesDisadvantages– Unconscious patients Unconscious patients

cannot take dosecannot take dose– Low solubilityLow solubility– Low permeabilityLow permeability– Degradation by GI Degradation by GI

enzymes or floraenzymes or flora– First pass metabolismFirst pass metabolism– Food interactionsFood interactions– Irregular absorptionIrregular absorption

Oral AdministrationOral Administration

Traditional oral Traditional oral delivery systemsdelivery systems– TabletsTablets– CapsulesCapsules– Soft gelatin capsulesSoft gelatin capsules– SuspensionsSuspensions– ElixirsElixirs

Buccal/SublingualBuccal/Sublingual

AdvantagesAdvantages– By-pass First pass By-pass First pass

metabolism metabolism – Rapid absorptionRapid absorption– Low enzymatic activityLow enzymatic activity

Disadvantages Disadvantages – Discomfort during Discomfort during

dissolutiondissolution– Probability of swallowing- Probability of swallowing-

lost of effectlost of effect– Small dosesSmall doses

Traditional delivery Traditional delivery system/devicessystem/devices– TabletsTablets– Chewing gumChewing gum

Example from Industry: Generex Example from Industry: Generex BiotechnologyBiotechnology

Oral-Lyn: liquid formulation of human Oral-Lyn: liquid formulation of human insulin administered to buccal mucosa by insulin administered to buccal mucosa by aerosolizationaerosolization– Drug carried in lipid micellesDrug carried in lipid micelles

RectalRectal

AdvantagesAdvantages– By-pass first pass By-pass first pass

metabolismmetabolism– Useful for childrenUseful for children

DisadvantagesDisadvantages– Absorption depends Absorption depends

on disease stateon disease state– Degradation by Degradation by

bacterial florabacterial flora– UncomfortableUncomfortable

Traditional delivery Traditional delivery system/devicessystem/devices– SuppositorySuppository– EnemaEnema

Example from Industry: Valeant Example from Industry: Valeant PharmaceuticalsPharmaceuticals

Diastat AcuDial: diazepam rectal gelDiastat AcuDial: diazepam rectal gel

Intravenous (IV)Intravenous (IV)

AdvantagesAdvantages– Drug 100% bioavailableDrug 100% bioavailable– Rapid responseRapid response– Total control of blood Total control of blood

concentrationconcentration– Maximize incorporation Maximize incorporation

of degradable drugsof degradable drugs– By-pass FPMBy-pass FPM

DisadvantagesDisadvantages– InvasiveInvasive– Trained personnelTrained personnel– Possible toxicity due to Possible toxicity due to

incorrect dosingincorrect dosing– sterilitysterility

Traditional delivery Traditional delivery system/devicessystem/devices– Injection-bolusInjection-bolus– IV bag - infusionIV bag - infusion

SubcutaneousSubcutaneous

AdvantagesAdvantages– Patient self-Patient self-

administration administration – Slow, complete Slow, complete

absorptionabsorption– By-pass FPMBy-pass FPM

DisadvantagesDisadvantages– Invasive Invasive – Irritation, Irritation,

inflammationinflammation– Maximum dose Maximum dose

volume - 2mLvolume - 2mL

IntramuscularIntramuscular

AdvantagesAdvantages– Patient can Patient can

administer the drug administer the drug himselfhimself

– Larger volume than Larger volume than subcutaneoussubcutaneous

– By-pass first pass By-pass first pass metabolismmetabolism

DisadvantagesDisadvantages– Invasive – patient Invasive – patient

disconfortdisconfort– Irritation, Irritation,

inflamationinflamation– May require some May require some

trainingtraining

InhalersInhalers

AdvantagesAdvantages– By-pass FPMBy-pass FPM– Gases are rapidly Gases are rapidly

absorbedabsorbed

DisadvantagesDisadvantages– Solids and liquids Solids and liquids

can be absorbed if can be absorbed if size is below 0.5umsize is below 0.5um

Example from Industry: Nektar Example from Industry: Nektar TherapeuticsTherapeutics

Pulmonary delivery of Pulmonary delivery of Insulin Insulin – Amorphous aerosol Amorphous aerosol

particles with ~1particles with ~1μμm m diametersdiameters

solubilized drug molecules

aerosol particle

capillary cell

lung cell

insulin moleculesGlass stabilizer

TransdermalTransdermal

AdvantagesAdvantages– Local effectLocal effect– Ease of Ease of

administrationadministration

DisadvantagesDisadvantages– Low absorption for Low absorption for

some drugssome drugs– May cause allergic May cause allergic

reactionsreactions

RequirementsRequirements– Low dosage <10 Low dosage <10

mg/mLmg/mL– MW< 1,000MW< 1,000

Factors Influencing the Selection Factors Influencing the Selection of the Delivery Routeof the Delivery Route

Drug physico-chemical propertiesDrug physico-chemical properties– Drug molecular size (molecular weight)Drug molecular size (molecular weight)– Half-lifeHalf-life– Chemical stabilityChemical stability– Loss of biological activity in aqueous Loss of biological activity in aqueous

solutionsolutionProteinsProteins

– Denaturation, degradationDenaturation, degradation

Example from Industry: 3M Example from Industry: 3M CompanyCompany

MMicrostructured icrostructured TTransdermal ransdermal SSystem: ystem: MTSMTS– Microneedle systemMicroneedle system– Drug-in-adhesive technology platformDrug-in-adhesive technology platform

(a) 3M microneedle system and (b) histological section of microneedles in

guinea pig skin

Factors Influencing the Selection Factors Influencing the Selection of the Delivery Routeof the Delivery Route

– Solubility in aqueous solution Solubility in aqueous solution (hydrophobicity/hydrophilicity)(hydrophobicity/hydrophilicity)

pHpH

pKa - ionizationpKa - ionization

TemperatureTemperature

ConcentrationConcentration

CrystalinityCrystalinity

Particle sizeParticle size

State of hydrationState of hydration

Factors Influencing the Selection Factors Influencing the Selection of the Delivery Routeof the Delivery Route

Drug biological interactionsDrug biological interactions– Sensitive to FPMSensitive to FPM– Low membrane permeabiltiyLow membrane permeabiltiy

Efflux pumps (MRP, MDR) – cancer drugsEfflux pumps (MRP, MDR) – cancer drugsHydrophilicityHydrophilicityHigh-density chargeHigh-density charge

– Enzymatic degradationEnzymatic degradation– Bacterial degradationBacterial degradation– Half-lifeHalf-life– Side effectsSide effects

IrritationIrritation

Factors Influencing the Selection Factors Influencing the Selection of the Delivery Routeof the Delivery Route

Desired pharmacological effectDesired pharmacological effect– LocalLocal

topical, vaginaltopical, vaginal

– SystemicSystemicoral, buccal, IV, SC, IM, rectal, nasaloral, buccal, IV, SC, IM, rectal, nasal

– Immediate response Immediate response IV, SC, IM, nasalIV, SC, IM, nasal

– Dose sizeDose size– Drug molecular sizeDrug molecular size

Manufacture of Classical Oral Manufacture of Classical Oral Delivery SystemsDelivery Systems

FormulationFormulation – combination of active – combination of active ingredients with the appropriate excipientsingredients with the appropriate excipients

ExcipientsExcipients – inactive ingredients – inactive ingredients employed for the purpose of dilution, employed for the purpose of dilution, protection, stability, controlled release, protection, stability, controlled release, taste, fillers, coloring, disintegration, etctaste, fillers, coloring, disintegration, etc

BlendingBlendingBlendingBlending

GranulationGranulationGranulationGranulation

MillingMillingMillingMilling

CompressionCompressionCompressionCompression

CoatingCoatingCoatingCoating

LabelingLabelingLabelingLabeling

PackingPackingPackingPacking

WetWetWetWet DryDryDryDry

Manufacture Process Manufacture Process for Tabletsfor Tablets

and Capsulesand Capsules

Pharmacokinetics and Pharmacokinetics and PharmacodynamicsPharmacodynamics

PharmacokineticsPharmacokinetics PharmacodynamicsPharmacodynamics

Design Design of dosage regimenof dosage regimen

•Where?Where?•How much?How much?•How often?How often?•How long?How long?

PlasmaPlasmaConcentrationConcentration

Effects

Plasma refers to the clear supernatant fluid that results from blood after the cellular components have been removed

Plasma ConcentrationPlasma ConcentrationP

las

ma

co

nc

en

trat

ion

(m

g/m

L)

Time (min)

Therapeutic window

Toxicity

No therapeutic effect

Time (min)

Pla

sm

a c

on

ce

ntr

atio

n (

mg

/mL

)

Unsuccessfultherapy

Successfultherapy

Magnitude of Drug ResponseMagnitude of Drug Response

Depends upon concentration achieved at Depends upon concentration achieved at the site of actionthe site of action– DosageDosage– Extent of absorptionExtent of absorption– Distribution to the siteDistribution to the site– Rate/extent of eliminationRate/extent of elimination

From the Site of Delivery to Elimination…From the Site of Delivery to Elimination…steps in drug delivery, absorption, distribution and eliminationsteps in drug delivery, absorption, distribution and elimination

Drug DeliveryDrug Delivery– Selection of drug delivery routeSelection of drug delivery route

Knowledge of physicochemical propertiesKnowledge of physicochemical properties

– Design of dosing regimenDesign of dosing regimen

AbsorptionAbsorption– Knowledge of PK and PDKnowledge of PK and PD

First pass effectFirst pass effect

MDR or MRPMDR or MRP

From the Site of Delivery to Elimination…From the Site of Delivery to Elimination…steps in drug delivery, absorption, distribution and eliminationsteps in drug delivery, absorption, distribution and elimination

DistributionDistribution– Drugs must reach the site of actionDrugs must reach the site of action

TissueTissue

PlasmaPlasma

EliminationEliminationMetabolismMetabolism

– Liver, kidneys, cellsLiver, kidneys, cells

ExcretionExcretion– KidneysKidneys– Feces Feces

Depends upon drug binding capabilities

Oral Oral AdministrationAdministration

Intravenous Intravenous InjectionInjection

IntramuscularIntramuscularInjectionInjection

SubcutaneousSubcutaneousInjectionInjection

GastrointestinalGastrointestinalTractTract

CirculatoryCirculatorySystemSystem

TissuesTissues MetabolicMetabolicSitesSites

Exc

reti

on

Exc

reti

on

Absorption of drugs could vary within Absorption of drugs could vary within different administration routesdifferent administration routes

500 mg dose 500 mg dose givengiven– intramuscularlyintramuscularly– orallyorally

**to the same subject on**to the same subject on

separate occasionsseparate occasions

Biological barriers Biological barriers greatly affect the greatly affect the extent of drug extent of drug absorptionabsorption

Absorption of drugs could vary within the same Absorption of drugs could vary within the same administration routeadministration route

Important ConceptsImportant Concepts

Volume of distributionVolume of distribution– apparent volume into apparent volume into

which a drug which a drug distributes in the body distributes in the body at equilibriumat equilibrium

– direct measure of the direct measure of the extent of distributionextent of distribution

– V = amount of drug in V = amount of drug in the body/Plasma drug the body/Plasma drug concentrationconcentration

C

AV

Mathematical Modeling of Drug Mathematical Modeling of Drug DispositionDisposition

Single compartmentSingle compartment

Single compartment with absorptionSingle compartment with absorption

Two compartmentsTwo compartments

Two compartments with absorptionTwo compartments with absorption

Physiological ModelsPhysiological Models

Single Compartment ModelSingle Compartment Model

Assumptions:Assumptions:– Body one compartment characterized by a Body one compartment characterized by a

volume of distribution (Vvolume of distribution (Vdd) )

– Drug is confined to the plasma (small V)Drug is confined to the plasma (small V)

C, Vd

absorption

eliminationk, C

t

C/C0

One-Compartment Model with One-Compartment Model with AbsorptionAbsorption

Low absorption occursLow absorption occursAbsorption is the rate-Absorption is the rate-limiting steplimiting stepSlow absorption may Slow absorption may represent drug entry represent drug entry through GI tract or through GI tract or leakage into circulation leakage into circulation after SC injectionafter SC injectionDrugs require multiple Drugs require multiple doses to maintain drug doses to maintain drug concentration within concentration within therapeutic windowtherapeutic window

t

M/D0

t

M/D0

Two-Compartment ModelTwo-Compartment Model

Drug rapidly Drug rapidly injectedinjectedDrug distributed Drug distributed instantaneously instantaneously throughout one throughout one compartment and compartment and slowly throughout slowly throughout second second compartmentcompartmentDescribes drug Describes drug concentration in concentration in plasma injected plasma injected IVIV

C1, V1

C2, V2

k2, C2

k12 k21

k1, C1

Compartment 1Compartment 1

Compartment 2

Compartment 2

t t

Concentration after ingestion Concentration with slow absorption

C/C0C/C0

Physiological ModelsPhysiological Models

Determination of the Efficacy of Determination of the Efficacy of the Delivery Routethe Delivery Route

Bioavailability (F)Bioavailability (F)– Fraction of the drug that reached the systemic Fraction of the drug that reached the systemic

circulationcirculation– According to the FDA, Food, Drug, and Cosmetic According to the FDA, Food, Drug, and Cosmetic

ActAct““The rate and extent to which an active ingredient The rate and extent to which an active ingredient or active moiety is absorbed from a drug product or active moiety is absorbed from a drug product and becomes available at the site of action. For and becomes available at the site of action. For drugs that are not intended to be absorbed in the drugs that are not intended to be absorbed in the bloodstream, bioavailability may be assessed by bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and measurements intended to reflect the rate and extent to which the active ingredient or active extent to which the active ingredient or active moiety becomes available at the site of action.”moiety becomes available at the site of action.”

Factors Influencing BioavailabiltyFactors Influencing Bioavailabilty

Delivery routeDelivery route

The site of measurementThe site of measurement

Type of animal employedType of animal employed

Physiological state of the animal/humanPhysiological state of the animal/human– DiseaseDisease– Anesthesia Anesthesia

Implications of PK and PD in Implications of PK and PD in Drug DeliveryDrug Delivery

The PK and PD of a drug may be affected The PK and PD of a drug may be affected when administered via different routeswhen administered via different routes– ExamplesExamples

Proteins – oral vs. intramuscularProteins – oral vs. intramuscularMorphine – oral vs. intramuscularMorphine – oral vs. intramuscular

The PK and PD of a drug delineates its The PK and PD of a drug delineates its therapeutic windowtherapeutic window– Degree of absorptionDegree of absorption– Degree of elimination and/or metabolismDegree of elimination and/or metabolism

ExampleExample– Tetracycline (infection) – given 6 to 8 hoursTetracycline (infection) – given 6 to 8 hours– Digoxin (cardiac failure)– given dailyDigoxin (cardiac failure)– given daily

Where to Find PD and PK Where to Find PD and PK InformationInformation

United States PharmacopeiaUnited States Pharmacopeia– www.usp.orgwww.usp.org– It is also paper publishedIt is also paper published– Provides standards, chemical properties, and Provides standards, chemical properties, and

protocols to perform pharmacological protocols to perform pharmacological experimentsexperiments

Federal Drug Administration – if it has Federal Drug Administration – if it has already being approvedalready being approved– www.fda.orgwww.fda.org