principles of drug delivery
DESCRIPTION
Principles of Drug Delivery. Drug Delivery. Definition The appropriate administration of drugs through various routes in the body for the purpose of improving health It is highly interdisciplinary It is not a young field It has recently evolved to take into consideration - PowerPoint PPT PresentationTRANSCRIPT
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