Application of Chemical Application of Chemical Engineering Principles to Engineering Principles to

Drug DeliveryDrug DeliveryMadeline Torres-Lugo, PhDMadeline Torres-Lugo, PhD

Associate ProfessorAssociate ProfessorDepartment of Chemical EngineeringDepartment of Chemical EngineeringUniversity of Puerto Rico Mayagüez University of Puerto Rico Mayagüez

CampusCampus

PhysiologyPhysiologyandand

AnatomyAnatomy

Transport Transport in Biologicalin Biological

SystemsSystems

Principles Principles ofof

Drug DeliveryDrug Delivery

PrinciplesPrinciplesof Controlledof Controlled

ReleaseRelease

Design Design and Regulatoryand Regulatory

IssuesIssues

Drug DeliveryDrug 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

Drug Delivery – The MarketDrug Delivery – The Market

Fastest growing health sectorFastest growing health sectorThe U.S. market for drug delivery systems in 2002 was $38.8 billion, The U.S. market for drug delivery systems in 2002 was $38.8 billion, and is expected to rise at an average annual growth rate (AAGR) of and is expected to rise at an average annual growth rate (AAGR) of 11.3% and reach $74.5 billion by 200811.3% and reach $74.5 billion by 2008The sustained release (oral, injectable and topical) dosage form The sustained release (oral, injectable and topical) dosage form market is rising at an AAGR of 9.7% is expected to reach $34.1 market is rising at an AAGR of 9.7% is expected to reach $34.1 billion by 2008 billion by 2008 The transmucosal market is expected to grow at an AAGR of 12.8% The transmucosal market is expected to grow at an AAGR of 12.8% and reach $17.7 billion by 2008and reach $17.7 billion by 2008The market for targeted delivery systems was $7.3 billion in 2002 The market for targeted delivery systems was $7.3 billion in 2002 and will reach $15.5 billion by 2008 and will reach $15.5 billion by 2008 Transdermal systems and implants and IUDs are expected to climb Transdermal systems and implants and IUDs are expected to climb at AAGRs of 11.1% and 12.4%, respectivelyat AAGRs of 11.1% and 12.4%, respectivelySales of drugs incorporating drug delivery devices (drug delivery + Sales of drugs incorporating drug delivery devices (drug delivery + controlled release systems) increase 15% annuallycontrolled release systems) increase 15% annually

Advanced Drug Delivery Systems: New Developments, New Technologies by Shalini Shahani, 2003

Implications of Implications of Physiology and AnatomyPhysiology and Anatomy

in Drug Deliveryin Drug Delivery

Anatomy vs. PhysiologyAnatomy vs. Physiology

Anatomy:Anatomy: deals with the structures deals with the structures (or morphology) of body parts, how (or morphology) of body parts, how they look and how they are they look and how they are organized. organized.

Physiology:Physiology: considers the functions considers the functions of these body parts-what do the do of these body parts-what do the do and how. and how.

Organization of the Organization of the Human Body Human Body

Approximately 75 trillion cells in a human Approximately 75 trillion cells in a human adultadult

Posses many characteristics in common, Posses many characteristics in common, but many vary in size, shape, and functionbut many vary in size, shape, and function

Measured in micrometers Measured in micrometers – Red blood cell - about 7.5 Red blood cell - about 7.5 m in diameter, m in diameter, – Human egg cell - about 140 Human egg cell - about 140 m in diameterm in diameter

Cells: smallest living unitsCells: smallest living units

Relevance of Cell Anatomy in Drug Relevance of Cell Anatomy in Drug DeliveryDelivery

Ultimate site of drug Ultimate site of drug action action – Metabolize drugMetabolize drug– Interact with the cell Interact with the cell

to stimulate to stimulate production of production of proteins or proteins or hormoneshormones

– Stimulate elimination Stimulate elimination or metabolism of or metabolism of productsproducts

– Eradicate drugEradicate drug

Ultimate site of Ultimate site of transport challengetransport challenge– Physicochemical Physicochemical

properties of drugsproperties of drugs– Efflux pumpsEfflux pumps

MDRMDR

MRPMRP

Cell Membrane, Nucleus, and Cell Membrane, Nucleus, and CytoplasmCytoplasm

Cell Membrane:Cell Membrane: outermost part of the cell outermost part of the cell– composed mainly of lipids and proteins composed mainly of lipids and proteins – controls the entrance and exit of substances controls the entrance and exit of substances Nucleus:Nucleus: directs the activity of the cell directs the activity of the cell– Nuclear envelope:Nuclear envelope: contains pores that allow certain contains pores that allow certain

dissolved substances (messenger RNA) to move dissolved substances (messenger RNA) to move between the nucleus and the cytoplasm between the nucleus and the cytoplasm

Cytoplasm: mass of fluid that surrounds Cytoplasm: mass of fluid that surrounds nucleus, where most of the cell activity nucleus, where most of the cell activity occursoccurs

Cytoplasmic OrganellesCytoplasmic Organelles

Endoplasmic Endoplasmic reticulum: reticulum: Transport Transport materials within cell, materials within cell, attachment for attachment for ribosomes, lipid ribosomes, lipid synthesis synthesis Ribosomes: Ribosomes: Protein Protein synthesis synthesis Vesicles: Vesicles: Store and Store and transport newly transport newly synthesized moleculessynthesized molecules

Golgi apparatus: Golgi apparatus: Package and modify Package and modify proteins for transport proteins for transport and secretionand secretionMitochondria: Mitochondria: Release Release energy from food energy from food molecules and molecules and transform energy into transform energy into usable formusable formLysosomes: Lysosomes: Digest Digest worn cellular parts or worn cellular parts or substances that enter substances that enter the cellthe cell

Other OrganellesOther Organelles

PeroxisomesPeroxisomes

CentrosomesCentrosomes

CiliaCilia

FlagellaFlagella

VesiclesVesicles

Microfilaments/MicrotubulesMicrofilaments/Microtubules

The Tight JunctionThe Tight Junction

Actin andMyosin Filaments

Occludin

Mechanism for the Opening of the Mechanism for the Opening of the Tight JunctionTight Junction

-Ca+2 +Ca+2-Ca+2 +Ca+2

The Gastrointestinal TractThe Gastrointestinal Tract

esophagus

stomach

large intestine

jejunumduodenum

ileum

colonappendix

gallbladder

liver

Anatomical Factors Relevant to Anatomical Factors Relevant to Drug DeliveryDrug Delivery

pHpH

AreaArea

Length Length

Residence timeResidence time

Metabolic activitiesMetabolic activities

SegmentSegment AreaArea

(m(m22))

Segment Segment Length (m)Length (m)

Area/length Area/length RatioRatio

Residence Residence timetime

pHpH

Oral cavityOral cavity 100 100 cmcm22

-- -- sec to minsec to min 6.56.5

EsophagusEsophagus 200200

cmcm22

23-25 cm23-25 cm 88 secsec --

StomachStomach 3.53.5 0.250.25 1414 90 min90 min 1-21-2

DuodenumDuodenum 1.91.9 0.350.35 55 30-40 min30-40 min 4-5.54-5.5

JejunumJejunum 184184 2.82.8 6666 1.5-2 h1.5-2 h 5.5-75.5-7

IleumIleum 276276 4.24.2 6666 5-7 h5-7 h 7-7.57-7.5

Colon and Colon and RectumRectum

1.31.3 1.51.5 0.90.9 1-60 h1-60 h 7-7.57-7.5

Systemic Circulation

Polymeric Carrier

TightJunction

Mucosa

Protein

ProteoliticEnzymesProteolyticEnzymes

Anatomical Factors Influenced by Anatomical Factors Influenced by External CircumstancesExternal Circumstances

Residence time Residence time

Gastric emptyingGastric emptying

pHpH

Metabolic activitiesMetabolic activities

Transport MechanismsTransport Mechanisms1 2 3 4

1 - Paracellular Route2 - Transcellular Route3 - Carrier-mediated Route4 - Transcytosis Route

ParacellularParacellular

Type of passive transport where hydrophilic molecules are absorbed through the small openings between epithelial cells that are filled with aqueous solutionComprises the 0.01% of the total surface area of the epithelium Intercellular spaces vary according to their location in the GI tract– Duodenum – 0.8 nm– Colon – 0.3 nm

TranscellularTranscellular

Type of passive transport where Type of passive transport where hydrophobic molecules are soluble in the hydrophobic molecules are soluble in the cell membranecell membrane

The cell membrane occupies a significant The cell membrane occupies a significant area of the GI tractarea of the GI tract

Carrier-mediatedCarrier-mediated

Active or facilitated Active or facilitated transport where the transport where the cell surface contains cell surface contains specific receptorsspecific receptorsThese receptors These receptors recognize specific recognize specific molecules and molecules and transport them transport them across the cell across the cell membranemembraneCan be saturatedCan be saturated

Example –vitamin BExample –vitamin B66

TranscytosisTranscytosis

Active TransportActive TransportMechanism:Mechanism:– Molecule is recognized in Molecule is recognized in

the surface of the cellthe surface of the cell– Membrane ruptures, Membrane ruptures,

forming a vesicleforming a vesicle– Vesicle is transported into Vesicle is transported into

the other side of the cellthe other side of the cell– Membrane ruptures again Membrane ruptures again

and the content released and the content released

Example –vitamin B12Example –vitamin B12

Metabolic Activity in GI tractMetabolic Activity in GI tract

SegmentSegment EnzymesEnzymesOral cavityOral cavity polysaccharidasespolysaccharidases

EsophagusEsophagus --

StomachStomach proteases; lipasesproteases; lipases

DuodenumDuodenum polysaccharidases; oligosaccharidases; polysaccharidases; oligosaccharidases; proteases; peptidades; lipasesproteases; peptidades; lipases

JejunumJejunum oligosaccharidases; peptidades; lipasesoligosaccharidases; peptidades; lipases

IleumIleum oligosaccharidases; peptidades; lipasesoligosaccharidases; peptidades; lipases

Colon and Colon and RectumRectum

bacterial enzymesbacterial enzymes

Circumstances Affecting the Circumstances Affecting the Gastrointestinal TractGastrointestinal Tract

DiseaseDisease– DiarrheaDiarrhea– ConstipationConstipation– cancercancer

Psychological statePsychological state

AccidentAccident

AgeAge

Body positionBody position

Type of drugType of drug

Volume ingestedVolume ingested

Type of ingested foodType of ingested foodFatsFats

ProteinsProteins

CarbohydratesCarbohydrates

Circumstances Affecting the Circumstances Affecting the Gastrointestinal TractGastrointestinal Tract

First Pass Metabolism (FPM)First Pass Metabolism (FPM)

Portal SystemPortal System– Portal VeinPortal Vein

Mesenteric VeinMesenteric Vein– SuperiorSuperior– InferiorInferior– LienalLienal

Nutrients collected Nutrients collected from the GI tract are from the GI tract are directly transported directly transported to the liver for further to the liver for further metabolism before metabolism before entering the entering the systemic circulationsystemic circulation

First Pass MetabolismFirst Pass Metabolism

Liver transforms non-polar drugs into polar Liver transforms non-polar drugs into polar compounds which can be readily compounds which can be readily eliminatedeliminatedMetabolites can be toxic or activeMetabolites can be toxic or activeMechanismsMechanisms– OxidationOxidation– ReductionReduction– HydrolysisHydrolysis– ConjugationConjugation

First Pass MetabolismFirst Pass Metabolism

Factors influencing FPMFactors influencing FPM– AgeAge– DietDiet– DiseaseDisease

Different animal species possess different Different animal species possess different liver metabolism capabilitiesliver metabolism capabilities

Drugs affected by FPMDrugs affected by FPM

Drug ClassDrug Class ExamplesExamples

AnalgesicsAnalgesics Aspirin, meperidine (Demerol), Aspirin, meperidine (Demerol), pentazocine (Talwin), pentazocine (Talwin), propoxyphene (Darvocet)propoxyphene (Darvocet)

AntianginalAntianginal NitroglycerinNitroglycerin

AntiarrhythmicsAntiarrhythmics LidocaneLidocane

Beta-adrenergic blockersBeta-adrenergic blockers Labetolol, metoprolol (Toprol), Labetolol, metoprolol (Toprol), propanolol (Inderal)propanolol (Inderal)

Calcium channel blockersCalcium channel blockers Verapamil (Calan)Verapamil (Calan)

Sympathomimetic aminesSympathomimetic amines Isoproterenol (Isuprel)Isoproterenol (Isuprel)

Tricyclic antidepressants Tricyclic antidepressants Desipremine, imipramine Desipremine, imipramine (Tofranil), notriptyline(Tofranil), notriptyline

The Circulatory SystemThe Circulatory System

Relevance of the Circulatory Relevance of the Circulatory System in Drug DeliverySystem in Drug Delivery

Transport of drugs to the site of actionTransport of drugs to the site of action

Main transport route for immune system Main transport route for immune system response response – InflammationInflammation– Foreign body responseForeign body response

Clotting cascade Clotting cascade – Critical factor for implantsCritical factor for implants

Greatest challenge for implantable systems

Fibrin

Red blood cell

Steps in the formation of a Steps in the formation of a ThrombusThrombus

Control MechanismsControl Mechanisms

Blood flow to reduce the localized Blood flow to reduce the localized concentration of precursorsconcentration of precursors

Rate of several clotting reactions is fast Rate of several clotting reactions is fast when catalyzed by a surfacewhen catalyzed by a surface

Naturally occurring inhibitors of the Naturally occurring inhibitors of the enzymesenzymes

Some enzymes activate coagulation Some enzymes activate coagulation factors but degrade cofactorsfactors but degrade cofactors

Skin and the Integumentary Skin and the Integumentary SystemSystem

Function of the SkinFunction of the Skin

Protective coverProtective cover– microorganisms, harmful substances, microorganisms, harmful substances,

prevents loss of waterprevents loss of water

Regulates body temperatureRegulates body temperature

Host of immune system cellsHost of immune system cells

Excrete toxinsExcrete toxins

Layers of the SkinLayers of the Skin

EpidermisEpidermis

DermisDermis

Subcutaneous layerSubcutaneous layer

Challenges of Transdermal Challenges of Transdermal Drug DeliveryDrug Delivery

Skin can only by penetrated by small Skin can only by penetrated by small hydrophobic molecules hydrophobic molecules – Major resistance comes from stratus corneumMajor resistance comes from stratus corneum

Factors Affecting Transdermal Drug Factors Affecting Transdermal Drug DeliveryDelivery– SiteSite– Skin condition/diseaseSkin condition/disease– AgeAge– MetabolismMetabolism

Immune ResponseImmune ResponseForeign Body ResponseForeign Body Response

Immune SystemImmune System

Responsible forResponsible for– Protection against foreign antigens Protection against foreign antigens

(infection)(infection)– Wound healingWound healing

Protection against exogenous materials Protection against exogenous materials (foreign body response)(foreign body response)

Detection of internal injury and/or changes in Detection of internal injury and/or changes in tissue due to accident or diseasetissue due to accident or disease

Steps in Body Response to Steps in Body Response to ImplantationImplantation

InjuryInjury

Acute inflammationAcute inflammation

Chronic inflammationChronic inflammation

Granulation tissueGranulation tissue

Foreign body reactionForeign body reaction

FibrosisFibrosis

InflammationInflammation

Flow of fluids, proteins and red blood cells Flow of fluids, proteins and red blood cells to the site of injury with the purpose of to the site of injury with the purpose of containing, neutralizing, diluting, walling off containing, neutralizing, diluting, walling off injuryinjuryCharacterized Characterized – Formation of clotFormation of clot– Swelling, redness, warming of siteSwelling, redness, warming of site– Neutrophils –phagocyte microorganisms and Neutrophils –phagocyte microorganisms and

foreign materialforeign material

Acute and Chronic InflammationAcute and Chronic Inflammation

AcuteAcute– Short duration – minutes to daysShort duration – minutes to days– Increased swellingIncreased swelling– Migration of white blood cells, neutrophils, Migration of white blood cells, neutrophils,

and macrophagesand macrophages

ChronicChronic– presence of more immune system cells and presence of more immune system cells and

growth of new blood vessels and vascular growth of new blood vessels and vascular tissuetissue

Granulation Tissue and Foreign Granulation Tissue and Foreign Body ResponseBody Response

Granulation TissueGranulation Tissue– Body forms granulation tissue to isolate Body forms granulation tissue to isolate

implantimplant

Foreign Body ResponseForeign Body Response– Complete formation of a capsule around the Complete formation of a capsule around the

implantimplant– Presence of most of the immune system cellsPresence of most of the immune system cells

FibrosisFibrosis

The end of the healing process where the The end of the healing process where the capsule around the implant is finishedcapsule around the implant is finished

ChallengesChallenges– Infection inside the capsule cannot be treated, Infection inside the capsule cannot be treated,

therefore implant must be removedtherefore implant must be removed– For a drug delivery device this could be For a drug delivery device this could be

disastrousdisastrous

BiocompatibilityBiocompatibility

BiomaterialsBiomaterials– Is the ability of a material to perform with an Is the ability of a material to perform with an

appropriate host responseappropriate host response

Medical DevicesMedical Devices– Ability of a device to fulfill its intended functionAbility of a device to fulfill its intended function

Respiratory SystemRespiratory System

Responsible forResponsible for– Air filtrationAir filtration– Transport of carbon Transport of carbon

dioxidedioxide

Divided into:Divided into:– Upper respiratory tractUpper respiratory tract

Organs above the Organs above the thoraxthorax

– Lower respiratory tractLower respiratory tractOrgans within the Organs within the thoraxthorax

Lining of the bronchial Lining of the bronchial tubestubes– Filled with cilia Filled with cilia

responsible for moving responsible for moving irritants and irritants and contaminants out of contaminants out of the systemthe system

Respiratory TubesRespiratory Tubes

Transport of Gases through the Transport of Gases through the Respiratory SystemRespiratory System

Factors Influencing Drug DeliveryFactors Influencing Drug Delivery

Particles over the size of Particles over the size of >100 >100 μμmm are are trapped by the cilia expelledtrapped by the cilia expelled

Factors influenced by external Factors influenced by external circumstancescircumstances– Breathing rate (psychological state)Breathing rate (psychological state)– Permeability of gases (disease, age)Permeability of gases (disease, age)