Drug and Gene Delivery

Edith Mathiowitz

Release kinetics Data interpretation ( Drug molecular weight could

be any size, not just proteins)

Controlled release of drugs, proteins, genes

could be applied by incorporating them as dissolved
or dispersed form.
Kinetic models or expressions describe time-dependent
behavior of the drug released

Release kinetics Data interpretation

Mathematical modeling could be use for:
Predicting drug release rats from and diffusion
behavior through polymers.
Elucidating the physical mechanism of drug transport
by comparing release data to mathematical
modeling.
Lack of systemic analysis and classifications is
responsible for the use of inappropriate models

DIFFUSION-CONTROLLED
SYSTEMS

Diffusion in Drug Delivery Systems

Most delivery systems (except or swelling controlled)
could be described by the two Ficks law of diffusion.

Diffusion in Drug Delivery Systems

Assumptions made in describing drug diffusion

through polymers by equations 1 and 2.

1. One-dimensional diffusion is appropriate for treatment

of drug release from thin, planar systems, application to
thick slabs or short cylinders is incorrect.
2. The drug diffusion coefficient Dip is assumed to be
independent of drug concentration.
3. Ji is the drug flux with respect to the mass average
velocity v of the system.

Solution of equations 1 or 2 provides the following

information about drug release through polymers:
Determination of concentration profiles from the normalized
drug concentration, c/c0 versus dimensionless position, x/, as a
function of dimensionless Fourier time, Dipt/2.
c0 is a reference drug concentration,
is the slab thickness.
Drug release rates, dMt/A dt, can be determined by
differentiating the previous expressions with respect to position
and evaluating the derivative at the water- or dissolutionmedium interface. Here, A is the diffusion cross-sectional area.

Diffusion in Drug Delivery Systems

Diffusion in Drug Delivery Systems

Semiemipirical equations

Diffusion in Drug Delivery Systems

Semiemipirical equations
The importance of this analysis is easily understood
(Fig. 1) because most mathematical solutions of
equation 2 for Fickian drug diffusion give release
kinetics described by equation 5 with n = 0.5.
Consequently, the release rate is proportional to t 1/ 2.

Mt
n
= kt
M

Release Kinetics from DiffusionControlled Systems

A special case when n=1 can be obtained when
describing drug release from membrane type diffusioncontrolled systems.
geometrical shapes of matrix systems e.g.,
hemispheres,
swelling controlled release systems.

This type of release kinetics is known as zero-order

release kinetics
characterized by constant drug-release rates

Diffusion in Drug Delivery Systems

Semiemipirical equations

Mt
= kt n
M

Release Kinetics from Diffusion-Controlled Systems

Drug diffusion through the polymer is achieved by
molecular diffusion due to concentration gradients.
These systems may be classified as Porous or nonporous.
Porous controlled-release systems contain pores that are
large enough that diffusion of the drug is accomplished
through water that has filled the pores of the polymer
These pores are usually of size greater than
200-500 A0

Release Kinetics from Diffusion-Controlled Systems

Noporous systems
Contain meshes of molecular (drug) dimensions.
Molecular diffusion occurs effectively through the whole polymer
The drug diffusion coefficient refers to the polymer phase.

Release Kinetics from Diffusion-Controlled Systems

Polymer parameters controlling the drug diffusion
coefficient:
degree of crystallinity
size of crystallites,
degree of cross-linking,
degree of swelling,
molecular weight of the polymer.

Many swollen, porous polymer systems retain the main

characteristics of the porous structure so that drug
diffusion occurs simultaneously through water-filled
pores and through the swollen polymer per se.

Release Kinetics from Diffusion-Controlled Systems

Study of controlled release requires the study of
diffusion, or transport through a particular medium.
Transport mechanisms:
Ordinary diffusion.
The gradient that produces this diffusion behavior is due to a
concentration gradient.
Should be referred to as chemical potential gradient rather than
concentration gradient.

Release Kinetics from Diffusion-Controlled Systems

We use one dimension, but the actual system are three
dimensions.
The true type of release is a result of a gradient of activity, where
the activity has incorporated in it the true non ideal behavior of
the drug or solutes that is being released at the same time.
The non ideal is expressed in terms of activity coefficient.
(Activity coefficient) X (Mole fraction) = activity that leads to
gradient

Release Kinetics from Diffusion-Controlled Systems

Drug diffusion in rubbery polymers

10-6 to 10-7 cm/sec

Drug diffusion in glassy polymers

10-10 to 10-12 cm/sec

Release Kinetics from Diffusion-Controlled Systems

Convection:
Pores of polymers are large.
Flux of drug due to drug being carried with the solvent

Carrier-mediated transport:
Transport of molecules that have reacted and transported fast

Release Kinetics from Diffusion-Controlled Systems

Release Kinetics from Diffusion-Controlled Systems

Reservoir (Membrane) Systems

Reservoir (Membrane) Systems

Reservoir (Membrane) Systems

Reservoir (Membrane) Systems

Reservoir (Membrane) Systems

General Conclusions for Diffusion-Controlled, Reservoir Systems

1.

Zero-order release kinetics with these systems is obtained only when the release
experiment is done under perfect sink conditions

2.

In all other situations the kinetics should be expected to be time-dependent

3.

Depending on the method of release, the kinetics could be such that the rate
drops exponentially or even as t-1/2.

Porous Reservoir Systems

Porous Reservoir Systems

MATRIX DEVISES

Matrix (Monolithic) System

The drug is incorporated in the polymer phase
as dissolved or in dispersed form.
The solubility of the drug in the polymer
becomes a controlling factor
When the initial drug loading is below the
solubility limit, release is achieved by simple
molecular diffusion through the polymer.
When the drug loading is above the
solubility limit, dissolution of the drug in the
polymer becomes the limiting factor

MATRIX DEVICES
Porous Systems:
Those with pores of diameter larger than 100 diffusion of drug occurs
through water-filled pores.
Non-Porous Systems:
Those with molecular-size pores (smaller than 100) diffusion of drug occurs
through polymer.
Dispersed Systems:
Drug is loaded at concentration levels above the solubility concentration of the
drug in the polymer.
Dissolved Systems:
Drug is loaded at concentration levels below the solubility concentration of the
drug in the polymer.

4 CASES

1) Dissolved Drug: Diffusion through the polymer.

2) Dispersed Drug: Diffusion through the polymer.
3) Dispersed Drug: Diffusion through the channels.
4) Dissolved Drug: Diffusion through the channels.

CASE 1: Dissolved Drug: Diffusion

Through the Polymer
I)

Loading < Solubility

II)

Rate-limiting step is diffusion through

polymer.

III)

Can be made by simply soaking system in drug

solution.

This is a desorption problem.

Matrix (Monolithic) SystemsDissolved Drug, Nonporous Systems

Matrix (Monolithic) Systems Dissolved Drug, Nonporous

Systems

Matrix (Monolithic) Systems Dissolved Drug, Nonporous

Systems

Matrix (Monolithic) Systems

Dissolved Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dissolved Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dissolved Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dissolved Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dissolved Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dissolved Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dissolved Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dissolved Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dissolved Drug, Nonporous Systems

CASE 1: Dissolved Drug: Diffusion Through the Polymer

I)

Loading < Solubility

II)

Rate-limiting step is diffusion through

polymer.

III)

Can be made by simply soaking system in drug

solution.

This is a desorption problem.

A reasonable conclusion from this analysis is that it is not possible to achieve zeroorder release of drugs using matrix systems and simple geometrical shapes
(films, cylinders, spheres).
There are at lease three exceptions:
I.

Matrix Systems of Hemispherical Type

[R. S. Langer et al., in Controlled Release of Bioactive
Materials, R. Baker, ed., 177, Academic Press, N.Y. 1980].
II. Porous matrix Systems Where Drug-Dissolution is the Controlling Step
[N.A. Peppas et al., Biomaterials, 3, 27 (1982)]
[S.K. Chandrasekaran & D.R. Paul, J. Pharm. Sci., 71, 1399
(1982)].
These Will Be Discussed Later
III. Swelling-Controlled Release Systems

Case 2: Dispersed Drug: Diffusion Through Polymer

I)

Loading >> Solubility

II)

Rate limiting step, diffusion through polymer

III)

Can be made by solvent casting or compression molding

Higuchi Model, Assumptions

1]

Drug is uniformly suspended

2]

Drug is in a fine state, particle size << l

3]

No swelling or shrinkage

4]

Interface between dissolved drug region and

dispersed drug region moves
into the interior as a front

Matrix (Monolithic) Systems

Dispersed Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dispersed Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dispersed Drug, Nonporous Systems

Matrix (Monolithic) Systems

Dispersed Drug, Nonporous Systems

Dispersed drug nonporous systems

Porous Matrix Systems

Porous Matrix Systems

Modeling of the drug-release kinetics of porous
matrix systems is still at a rather primitive stage
Points to be considered
If the polymer phase is hydrophobic, swelling is
negligible, and the problem can be treated as a constant
volume diffusion problem.
If the polymer phase is hydrophilic, two modeling
routes may be considered.

Porous Matrix Systems

If the pores are large enough to be "channels"
for diffusion (pore diameter greater than 150
A),
diffusion occurs predominantly through these
water-filled pores and the effective diffusion
coefficient, Deff, of equation 21 must be used.
If the pores are smaller than 100 A, then the
diffusion coefficient, Dip, through the swollen
polymer can be used without corrections for
porosity and tortuosity.

Porous Matrix Systems

Phenomena related to drug partition in the
pore walls and hindered diffusion due to the
relative size of the drug with respect to the
pores can be addressed by including the
parameters Kp and Kr in the diffusion
coefficient through water and using the
effective diffusion coefficient, Deff, described
by equation 23.
Phenomena related to elastically changing
pore walls must be taken into consideration.

Matrix (Monolithic) Systems

Porous matrix Systems

Swelling controlled systems

Swelling-controlled release systems: difficult to model
Complex macromolecular changes occurs in the polymer
during release.
These systems consist of water-soluble drugs that are
initially dispersed in solvent-free glassy polymers.
If a slab is placed in contact with water, diffusion of
water into the polymer will be observed
This depends on the thermodynamic interactions between
the polymer and the solvent.
This dynamic swelling phenomenon may lead to
considerable volume expansion of the original slab.

Swelling controlled systems

Two fronts (interfaces) are characteristic of the swelling
behavior:
The swelling interface that separates the rubbery (swollen)
state from the glassy state and that moves inward with velocity
v
The polymer interface that separates the rubbery state from
water and moves outward

Swelling controlled systems

Swelling of glassy polymers is accompanied by macromolecular
relaxation, which become important at the swelling interface.
This relaxation, affects the drug diffusion through the polymer, so
that Fickian or non-Fickian diffusion may be observed.

Swelling controlled systems

Mathematical modeling of this type of diffusion behavior belongs
to a category of mathematical problems known as Stefan, StefanNeumann, or moving-boundary problems.
The Fickian diffusion equation 2 is solved with concentrationdependent or concentration-independent

Models for These Situations

I.

Monte-Carlo simulations and computer models which

recreate the random generation of pores as drug release
occurs.
[R. Siegel & R. Langer, in press].
These models will be discussed by R. Langer in the Matrix Section

II.

Dissolution-controlled models
[N.A. Peppas et al., Biomaterials, 3, 27 (1982)]
[N.A. Peppas, J. Biomed. Mater. Res., 17, 1079 (1083)]
{S.K. Chandrasekaran & D.R. Paul, J. Pharm. Sci., 74, 1399
(1982)]

Swelling controlled systems

A common procedure for analyzing experimental data of
drug release from swelling-controlled release systems is
by fitting them to equation 5
Determining the exponent n.
The value of this exponent is characteristic of the Fickian
or non-Fickian diffusion behavior of swelling-controlled
release systems.
It is possible to derive sufficient conditions for obtaining
zero-order release from swelling-controlled release
systems

Swelling controlled systems

Chemically controlled systems

Osmotic Systems

Dissolution- controlled Systems