Department of Biomedical Engineering

BME 307: Diffusion Lab

Gloria J. Kim, Ph.D.

Department of Biomedical Engineering

Announcements
New Groups for Lab 3!
TBA: NMC lab peer review
Office hours updates
Gloria Kim Thu 1-3pm, E382

Department of Biomedical Engineering

Agenda
Controlled release concepts
Various methods of controlled drug delivery
Lab description

Department of Biomedical Engineering

Department of Biomedical Engineering

Reasons for Interest

Drug re-positioning patenting

Biotherapeutics
Better targeting
Better therapeutic index
TI=Toxic Dose(TD50)/Effective Dose(ED50)

Precise spatial (right place) and temporal

(right time) placement within body

Department of Biomedical Engineering

An Ideal Drug Delivery System

1. Release rate dictated by the needs of the
body over the period of treatment

Constant, zero-order release

Variable (rhythm)

2. Channel the drug to the active site, cell,

tissue, organ (drug targeting)
3. No such DDS exists which perfectly
combines 1 and 2.

Basic Kinetics
rate

dM
t
Zero order kinetics:
= ko
dt
Rate of release is constant
Mt = kot
rate

First order kinetics:

Rate of release is
proportional to the
remaining drug

Square root kinetics:

Rate of release varies as
The square root of time

dMt
= k ( M Mt )
dt
Mt = M[1 exp kt )]
dMt
= kM exp kt
dt
rate

dMt kd
=
dt
t
Mt = 2kd t

Controlled Drug Delivery

Delivery of the drug at a specific rate and/or at a
specific location
Dedicated by the needs of the body or the disease
state
Temporal delivery: control over the rate of drug
release. Generally release is over a long period (days
to weeks or even months)
Spatial delivery: control over location of drug release.
Targeted release or local delivery
Combination of the above
Release rates are only weakly influenced by
environmental conditions pre-determined pattern
for a definite period
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Uses polymers or devices (e.g. pumps etc.)

Sustained Release of Drugs

Mixing active agents (drugs) with excipients and
binders (could be polymers or other molecules)
Slow dissolving coatings
Suspensions
Emulsions
Compressed tablets etc.
These systems release drugs for shorter period of
time (hours to day) and require repeat
administrations
Release rates are strongly influenced by
environmental conditions (temperature, pH)
Some controlled release systems incorporate
sustained release

Controlled Release of Drugs:

Concepts

Plasma Concentration

Bolus dose, repeated administration

Zero order release
Sustained release

Toxicity
Toxic level

MEC
No effect
day

Time
Therapeutic Range

MEC: Minimum effective concentration

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Department of Biomedical Engineering

Diffusion

Mass flow process by which species change their position relative to

their neighbors
Driven by thermal energy and a gradient
Thermal energy thermal vibrations atomic jumps
Concentration / chemical
potential
Gradient

Electric
Magnetic
Stress

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First Law of Diffusion:

Ficks Law
Diffusion: the movement of solute molecules from a higher to
a lower concentration gradient. This molecular movement occurs
by a random walk mechanism in which molecules are continually colliding
with each other while moving on average towards a particular direction
NOTE: concentration gradient doesnt change with time; some how the concentration is always maintained in time

J: diffusive flux, i.e. the mass per unit time of solute movement [g/(m2s)]

C
J = D
x
C/x : concentration gradient in the direction of solute movement
D: proportionality constant defined as the Diffusion constant or Diffusion
coefficient [m2/s]
From a random walk derivation D is related to the root mean square
displacement and time interval (t) by

xrms = 2 Dt

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If a particle takes time T to diffuse L mm. how long will it take to diffuse 2L mm?

Second Law of Diffusion:

Mass Conservation
Accumulation = J x J x + x

= J x J x +
x

J
c

x
x = J x J x +
x
t

J
c
x = x
x
t
from Fick' s first law J = D

c
x

c
c
c c
=

= D
x
x
t
t x x
2c
c
if D f ( x)
= D 2 Fick' s second law
x
t
Accounting Equation
= In Out + Generation - Consumption
= Accumulation
= Final - Initial

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Diffusion Under Different

Conditions
The general form of the diffusion equation remains same, except
the diffusion constant (coefficient D) is calculated or
modified depending on physical and chemical constraints of the
diffusing medium
one has to calculate the effective diffusion coefficient for a
particular system (analytical solutions can be often difficult).
Stokes-Einstein equation:
Diffusion of a spherical particle of radius a in a solution with
viscosity .
This equation is only valid where the diffusing particle is large
compared to surrounding solvent molecules (diffusion in
aqueous medium).

k BT
DA =
6a

kB is Boltzmans constant
T is the temperature in oK
When a is measured from known DA, it is
called the hydrodynamic radius
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Controlled Delivery
Attempts to:
1.

2.
3.

Sustain drug action at a predetermined rate by

maintaining a relatively constant, effective drug
level in the body with concomitant minimization of
undesirable side effects associated with a sawtooth
kinetic pattern
Localize drug action by spatial placement of a
controlled release system (usually rate controlled)
adjacent to or in the diseased tissue or organ
Target drug action by using carriers or chemical
derivatization to deliver drugs to a particular target
cell type
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Department of Biomedical Engineering

Rationale of Controlled
Drug Delivery

Alter PK/PD by:

Design of drug delivery system
Modify drug structure
Modify physiology

Duration of drug action

a design property of the rate controlled dosage form
not a property of the drug molecules inherent kinetic
characteristics.

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Factors Influencing the Design and

Performance of Controlled Release
Dosage forms
1.
2.
3.
4.
5.
6.

Drug properties
Route of drug delivery
Target sites
Acute or chronic therapy
The disease
The patient

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Department of Biomedical Engineering

Polymers in Controlled Drug

Release
Non-degradable polymers
Implants
Oral delivery
Membrane-controlled devices (skin patches)

Degradable polymers
Parenteral, intravenous and mucosal systems
Micro and nanoparticles
Hydrogels
Degradable implants, matrix type
Bulk degradation versus surface degradation
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Polymer-controlled Drug
Release
1. Diffusion-controlled systems:
Reservoir devices
Monolithic (matrix) devices (non-erodible)
2. Solvent-controlled systems:
Osmotically controlled devices
Swelling-controlled devices
3. Chemically-controlled systems:
Drug covalently attached to the polymer backbone
Drug in a core surrounded by a bio-erodible ratecontrolling membrane.
Drug homogeneously dispersed in a bio-erodible
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polymer

Mechanisms of Polymercontrolled Release

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Reservoir Systems
(Diffusion-controlled)

A supersaturated drug reservoir, surrounded by a nondegradable polymer membrane

Could have planar configuration (reservoir between two membranes,
e.g. Ocusert) or reservoir above a polymer membrane (e.g. skin patch)
Could have cylindrical configuration (drug loaded in a tube like device,
e.g. Norplant contraceptive device)
Most commonly used polymers: Silicone elastomers, EVAc
Could achieve nearly constant (zero-order) release rates
Polymer membrane
Skin

Loaded Drug

T=0

T=t

Ocusert
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Department of Biomedical Engineering

Reservoir Systems
Advantages
Zero order (constant) release
Easy to control kinetics by device design parameters

Disadvantages

Non-degradable, must be removed

Impermeable to high molecular weight drugs (low porosities)
Leaks can be dangerous (spilling of supersaturated drug)
Cost of device and surgeries

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Non-erodible Matrix Systems

( Diffusion-controlled)
T=0

T=t

Drug dispersed in polymer

Advantages:
Easy to fabricate
Less severe problem with leaks and cracks
Can be suitable for high molecular weight drugs
Increase loading to make interconnected pores

Disadvantages:
Non-degradable, needs to be removed at end of delivery period
Release rate is not generally zero order
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Bio-erodible Systems
(Chemically-controlled)
T=0

T=t
Drug dispersed in polymer

Drug dispersed in polymer

Released drug

Advantages
Degradable, more patient compliance
Can achieve zero order with surface eroding polymer devices

Disadvantages
Release kinetics is often difficult to control
By-products of degradation may cause biocompatibility problems

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Polymer-drug Conjugates
(Chemically-controlled)
POLYMER BACKBONE

POLYMER BACKBONE
Water or
Enzyme

Drug
T=0

T=t

Primary advantage
Very high drug loading

Primary disadvantage
New Chemical entity

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Swelling-controlled Matrix
(Solvent-controlled, ex:Hydrogels)
T=0

T=t

Drug dissolved in polymer

Advantages

Swollen polymer
from which drug
has been released

Drug dissolved in polymer

Low burst effects

Known or predictable swelling rates
Reformulation of vehicle not necessary for different drugs

Disadvantages
Generally short release periods
Not suitable for all delivery routes or targets
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Polymer-drug Conjugates
Often referred to as Polymer therapeutics
First clear concept was proposed in 1975 by
Ringsdorf
Strategy aimed at direct modification of the drug
molecule with polymers in order to improve biological
activity
Basic idea: Chemical conjugation of specific
polymers to a drug (small molecule, proteins,
peptides, nucleic acids) that can increase their in-vivo
performance and enhance delivery and biological
efficacy
Concept is to modify the drug in such a way that it
acts as a molecule chemically distinct from the
original yet produce a similar or enhanced biological
effect
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Polymer-drug Conjugates
Mostly synthetic polymers are used for conjugation
owing to their controllable structure and properties
Exceptions, natural polysachharides e.g. Dextrans

Usually water soluble (hydrophilic), highly

biocompatible polymers containing reactive functional
groups are used
Polymers can be mono-functional or multifunctional
Most commonly used polymers

Polyethylene glycol (PEG) and derivatives

N-(2-hydroxypropyl) methyl acrylamide (HPMA)
Dextrans and other polysaccharides
Poly(amino acids)
Stimuli-sensitive polymers etc.
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Polymer-drug Conjugates:
Advantages
Modify chemical properties Enhance Solubility
Protection of labile drugs from biochemical degradation Stability
Increased half-life (body residence time) -Stability
Reduction of immunogenicity and toxicity - Safety
Improved targeting (to specific organs and specific cells)
Specificity and bioavailability, Controlled delivery
Improved cellular uptake Bioavailability, Controlled
delivery
Drug conjugation via degradable bonds Controlled
release
Drug conjugation to stimuli responsive polymers
Delivery under specific conditions Controlled release29

Polymer-drug Conjugates:
Advantages
Biochemical and immunologic protection:
Generally attributed to the shielding or masking effect of the
polymer.
In case of PEG, due the high mobility (flexibility) of the PEG
chains and their water binding capability, thermodynamic
effects prevent approach of deleterious macromolecules
(opsonizing proteins, enzymes, immunoglubulins etc.) and
also prevent surface adhesion

Reduction in renal excretion:

Due to the large hydrodynamic volume of the conjugated
drug (increased molecular weight and hydrophilic).
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Polymer-drug Conjugates:
Limitations
Bio-molecule (drug) can lose activity during conjugation
process careful choice of chemistry and reaction sites.
The polymer needs to be eliminated from the body
should not accumulate at organ sites (controlled Mw
distribution)
Polymer can sterically interfere with bioactivity
For multifunctional drugs and polymers, crosslinking can
occur

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Department of Biomedical Engineering

Polymer-drug Conjugates:
Limitations

Purification of un-reacted polymer, bio-molecules and

any reaction products is necessary before in-vivo
application
Sterilization process now involves polymer stability
These are generally viewed by FDA as a new drug
entity (novel chemical composition) even though the
drug molecule itself is well used. Hence need for
comprehensive testing and approval process could
take years and years along with high cost
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Department of Biomedical Engineering

Diffusion Lab (2 weeks)

Altoid-box spectrophotometer
Benchtop spectrophotometer
Hydrogel microspheres loaded with a model
drug

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Department of Biomedical Engineering

Altoid-box Spectrophotometer

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Week 1
Get the Altoid-box spectrophotometer to work
with nScope and MATLAB
Calibrate both spectrophotometers (Week 2 if
necessary)
Make drug-loaded hydrogel microspheres
Hydrogel from: calcium chloride + alginate
Model drug: tartrazine or bovine serum albumin

Determine size distribution and eccentricity

Determine size distribution and eccentricity
Digital/cell phone camera (best image quality possible)
and imageJ

Upload size distribution and eccentricity data

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by Mon (5/9) 3pm on Canvas.

Department of Biomedical Engineering

Week 2
Measure diffusion from the drug-loaded
microspheres
Construct release profiles
Compare Altoid vs. Benchtop
spectrophotometer data

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Department of Biomedical Engineering

Read the lab and review

Beers Law
Accuracy
Precision
Statistical power
Propagation of errors

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