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Application of Chemical Engineering Principles to Drug Delivery. Madeline Torres-Lugo, PhD Associate Professor Department of Chemical Engineering University of Puerto Rico Mayagüez Campus. Transport in Biological Systems. Physiology and Anatomy. Principles of Drug Delivery. - PowerPoint PPT Presentation
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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)
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