Transcript Slide 1 - pharmaHUB

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
Principles
of
Drug Delivery
Physiology
and
Anatomy
Drug Delivery
Principles
of Controlled
Release
Design
and Regulatory
Issues
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
Drug physico-chemical properties
Body effects and interactions
Improvement of drug effect
Patient comfort and well being
Controlled
Drug Delivery
Drug Delivery – The Market
Fastest growing health sector
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
11.3% and reach $74.5 billion by 2008
The sustained release (oral, injectable and topical) dosage form
market is rising at an AAGR of 9.7% is expected to reach $34.1
billion by 2008
The transmucosal market is expected to grow at an AAGR of 12.8%
and reach $17.7 billion by 2008
The market for targeted delivery systems was $7.3 billion in 2002
and will reach $15.5 billion by 2008
Transdermal systems and implants and IUDs are expected to climb
at AAGRs of 11.1% and 12.4%, respectively
Sales of drugs incorporating drug delivery devices (drug delivery +
controlled release systems) increase 15% annually
Advanced Drug Delivery Systems: New Developments, New Technologies by Shalini Shahani, 2003
Implications of
Physiology and Anatomy
in Drug Delivery
Anatomy vs. Physiology
Anatomy: deals with the structures
(or morphology) of body parts, how
they look and how they are
organized.
Physiology: considers the functions
of these body parts-what do the do
and how.
Organization of the
Human Body
Cells: smallest living units
Approximately 75 trillion cells in a human
adult
Posses many characteristics in common,
but many vary in size, shape, and function
Measured in micrometers
– Red blood cell - about 7.5 m in diameter,
– Human egg cell - about 140 m in diameter
Relevance of Cell Anatomy in Drug
Delivery
Ultimate site of drug
action
– Metabolize drug
– Interact with the cell
to stimulate
production of
proteins or
hormones
– Stimulate elimination
or metabolism of
products
– Eradicate drug
Ultimate site of
transport challenge
– Physicochemical
properties of drugs
– Efflux pumps
MDR
MRP
Cell Membrane, Nucleus, and
Cytoplasm
Cell Membrane: outermost part of the cell
– composed mainly of lipids and proteins
– controls the entrance and exit of substances
Nucleus: directs the activity of the cell
– Nuclear envelope: contains pores that allow certain
dissolved substances (messenger RNA) to move
between the nucleus and the cytoplasm
Cytoplasm: mass of fluid that surrounds
nucleus, where most of the cell activity
occurs
Cytoplasmic Organelles
Endoplasmic
reticulum: Transport
materials within cell,
attachment for
ribosomes, lipid
synthesis
Ribosomes: Protein
synthesis
Vesicles: Store and
transport newly
synthesized molecules
Golgi apparatus:
Package and modify
proteins for transport
and secretion
Mitochondria: Release
energy from food
molecules and
transform energy into
usable form
Lysosomes: Digest
worn cellular parts or
substances that enter
the cell
Other Organelles
Peroxisomes
Centrosomes
Cilia
Flagella
Vesicles
Microfilaments/Microtubules
The Tight Junction
Occludin
Actin and
Myosin Filaments
Mechanism for the Opening of the
Tight Junction
-Ca+2
+Ca+2
+Ca
The Gastrointestinal Tract
esophagus
stomach
liver
large intestine
gallbladder
duodenum
jejunum
ileum
appendix
colon
Anatomical Factors Relevant to
Drug Delivery
pH
Area
Length
Residence time
Metabolic activities
Segment
Area
(m2)
Segment
Length (m)
Area/length Residence
Ratio
time
pH
Oral cavity
100
cm2
-
-
sec to min
6.5
Esophagus
200
cm2
23-25 cm
8
sec
-
Stomach
3.5
0.25
14
90 min
1-2
Duodenum
1.9
0.35
5
30-40 min
4-5.5
Jejunum
184
2.8
66
1.5-2 h
5.5-7
Ileum
276
4.2
66
5-7 h
7-7.5
Colon and
Rectum
1.3
1.5
0.9
1-60 h
7-7.5
Systemic Circulation
Tight
Junction
Polymeric
Carrier
Protein
Proteolytic
Proteolitic
Enzymes
Enzymes
Mucosa
Anatomical Factors Influenced by
External Circumstances
Residence time
Gastric emptying
pH
Metabolic activities
Transport Mechanisms
1
2
3
1 - Paracellular Route
2 - Transcellular Route
3 - Carrier-mediated Route
4 - Transcytosis Route
4
Paracellular
Type of passive transport where hydrophilic
molecules are absorbed through the small
openings between epithelial cells that are
filled with aqueous solution
Comprises 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
Transcellular
Type of passive transport where
hydrophobic molecules are soluble in the
cell membrane
The cell membrane occupies a significant
area of the GI tract
Carrier-mediated
Active or facilitated
transport where the
cell surface contains
specific receptors
These receptors
recognize specific
molecules and
transport them
across the cell
membrane
Can be saturated
Example –vitamin B6
Transcytosis
Active Transport
Mechanism:
– Molecule is recognized in
the surface of the cell
– Membrane ruptures,
forming a vesicle
– Vesicle is transported into
the other side of the cell
– Membrane ruptures again
and the content released
Example –vitamin B12
Metabolic Activity in GI tract
Segment
Enzymes
Oral cavity
Esophagus
Stomach
polysaccharidases
proteases; lipases
Duodenum
polysaccharidases; oligosaccharidases;
proteases; peptidades; lipases
Jejunum
Ileum
oligosaccharidases; peptidades; lipases
oligosaccharidases; peptidades; lipases
Colon and
Rectum
bacterial enzymes
Circumstances Affecting the
Gastrointestinal Tract
Disease
– Diarrhea
– Constipation
– cancer
Psychological state
Accident
Age
Circumstances Affecting the
Gastrointestinal Tract
Body position
Type of drug
Volume ingested
Type of ingested food
Fats
Proteins
Carbohydrates
First Pass Metabolism (FPM)
Portal System
– Portal Vein
Mesenteric Vein
– Superior
– Inferior
– Lienal
Nutrients collected
from the GI tract are
directly transported
to the liver for further
metabolism before
entering
the
systemic circulation
First Pass Metabolism
Liver transforms non-polar drugs into polar
compounds which can be readily
eliminated
Metabolites can be toxic or active
Mechanisms
– Oxidation
– Reduction
– Hydrolysis
– Conjugation
First Pass Metabolism
Factors influencing FPM
– Age
– Diet
– Disease
Different animal species possess different
liver metabolism capabilities
Drugs affected by FPM
Drug Class
Examples
Analgesics
Aspirin, meperidine (Demerol),
pentazocine (Talwin),
propoxyphene (Darvocet)
Antianginal
Nitroglycerin
Antiarrhythmics
Lidocane
Beta-adrenergic blockers
Labetolol, metoprolol (Toprol),
propanolol (Inderal)
Calcium channel blockers
Verapamil (Calan)
Sympathomimetic amines
Isoproterenol (Isuprel)
Tricyclic antidepressants
Desipremine, imipramine
(Tofranil), notriptyline
The Circulatory System
Relevance of the Circulatory
System in Drug Delivery
Transport of drugs to the site of action
Main transport route for immune system
response
– Inflammation
– Foreign body response
Clotting cascade
– Critical factor for implants
Greatest challenge
for implantable systems
Red blood cell
Fibrin
Steps in the formation of a
Thrombus
Control Mechanisms
Blood flow to reduce the localized
concentration of precursors
Rate of several clotting reactions is fast
when catalyzed by a surface
Naturally occurring inhibitors of the
enzymes
Some enzymes activate coagulation
factors but degrade cofactors
Skin and the Integumentary
System
Function of the Skin
Protective cover
– microorganisms, harmful substances,
prevents loss of water
Regulates body temperature
Host of immune system cells
Excrete toxins
Layers of the Skin
Epidermis
Dermis
Subcutaneous layer
Challenges of Transdermal
Drug Delivery
Skin can only by penetrated by small
hydrophobic molecules
– Major resistance comes from stratus corneum
Factors Affecting Transdermal Drug
Delivery
– Site
– Skin condition/disease
– Age
– Metabolism
Immune Response
Foreign Body Response
Immune System
Responsible for
– Protection against foreign antigens
(infection)
– Wound healing
Protection against exogenous materials
(foreign body response)
Detection of internal injury and/or changes in
tissue due to accident or disease
Steps in Body Response to
Implantation
Injury
Acute inflammation
Chronic inflammation
Granulation tissue
Foreign body reaction
Fibrosis
Inflammation
Flow of fluids, proteins and red blood cells
to the site of injury with the purpose of
containing, neutralizing, diluting, walling off
injury
Characterized
– Formation of clot
– Swelling, redness, warming of site
– Neutrophils –phagocyte microorganisms and
foreign material
Acute and Chronic Inflammation
Acute
– Short duration – minutes to days
– Increased swelling
– Migration of white blood cells, neutrophils,
and macrophages
Chronic
– presence of more immune system cells and
growth of new blood vessels and vascular
tissue
Granulation Tissue and Foreign
Body Response
Granulation Tissue
– Body forms granulation tissue to isolate
implant
Foreign Body Response
– Complete formation of a capsule around the
implant
– Presence of most of the immune system cells
Fibrosis
The end of the healing process where the
capsule around the implant is finished
Challenges
– Infection inside the capsule cannot be treated,
therefore implant must be removed
– For a drug delivery device this could be
disastrous
Biocompatibility
Biomaterials
– Is the ability of a material to perform with an
appropriate host response
Medical Devices
– Ability of a device to fulfill its intended function
Respiratory System
Responsible for
– Air filtration
– Transport of carbon
dioxide
Divided into:
– Upper respiratory tract
Organs above the
thorax
– Lower respiratory tract
Organs within the
thorax
Lining of the bronchial
tubes
– Filled with cilia
responsible for moving
irritants and
contaminants out of
the system
Respiratory Tubes
Transport of Gases through the
Respiratory System
Factors Influencing Drug Delivery
Particles over the size of >100 μm are
trapped by the cilia expelled
Factors influenced by external
circumstances
– Breathing rate (psychological state)
– Permeability of gases (disease, age)