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Controlled Release
Reservoir-Membrane Systems
1
Overview
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History
Membrane devices with constant release rate
Diffusion cell experiments with first order
release
Burst and lag effects in membrane systems
Diffusion coefficients
Membrane materials
Applications of membrane systems
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Components of membrane systems
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Mechanism: diffusion-controlled
Driving force: ΔC across membrane
Medium: polymer membrane or liquid-filled
pores
Resistance: function of film thickness,
diffusivity of solute in medium
Membrane usually interfaces with biological
site. Biocompatibility may be important.
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History of Membrane Systems
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Folkman and Long (1966 patent)
Folkman studied effect of thyroid hormone on heart
block
Folkman needed non-inflammatory vehicle for
extended release of hormone
Long performed a photographic study of turbulence
induced by artificial Si rubber heart valves
Long noticed that certain dyes permeated Si rubber
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History (continued)
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Folkman and Long tested diffusion of dyes and
drugs across Si tube walls.
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Observed that oil-soluble, low MW (<1000) dyes
permeated membrane
Observed that water-soluble, high MW dyes did not.
This was the beginning of a research EXPLOSION!
First CR device (late 1960s) was use of hormones
for contraception, which has now been widely
studied.
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Theory
C1
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Fick’s First Law
J  D

Cm2
h
C2
Relate Cm1 and Cm2 to surrounding concentrations
K m1 

dCm
 C  Cm1 
 D m2

dx
h


membrane C1<Cm1
the drug
Cm1
“prefers”
the
polymer
C m1
C1
K m2 
Rewrite Flux
Cm 2
C2
 C  C1 
J   DK m  2
 h 
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Body acts as a sink (C2≈0)
C 
J  DK m  1 
h
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Constant rate can be achieved if C1 is kept constant.
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What if C1 is not constant?
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Common situation in diffusion cell
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Drug is depleted from reservoir (1)
Drug accumulates in receiver (2)
membrane
C1
Cm1
Cm2
h
www.permegear.com
C2
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Diffusion cell: Derivation of M1(t)
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Fick’s Law
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dCm
 C2  C1 
J  D
  DK m 
dx
 h 

dt
USS Mass Balance
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V1 dC1 V2 dC2

A dt
A dt
1 1 
d C1  C2 
  AJ   
dt
V1 V2 
J 
Combine USSMB with
Fick’s Law

d C1  C2 
ADK
C  C  1 

l
1
2

V1
1

V2 
Rearrange
d C1  C2 
ADK

C1  C2 
l
1 1 
   dt
V1 V2 
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Diffusion cell
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Integrate with IC: C1-C2= C10-C20
 C1  C2  
ADK
ln  0


0 
C

C
l

2 
 1

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
1 1 
  t
V1 V2 
Apply mass balance
M1  M 2  M
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0
1
Substitute
M 1  C1V1
M 2  C2V2
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Diffusion cell
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Rearrange (see details)
M 10
M1 
V1  V2
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

  ADK V1  V2 t 
  V1 
V2 exp 
lV1V2




Differentiate to find release rate
dM 1  M 10 ADK

dt
lV1
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   ADK V1  V2 t 

exp 
lV1V2

 
First Order Release Rate
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Release profile for diffusion cell
mass of drug in reservoir
(mg)
Drug Release in Diffusion Cell
12
10
8
6
4
2
0
0
2000
4000
6000
8000
10000
tim e (m in)
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Data Analysis
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Diffusion Cell Experiment provides data for C1 vs t
Rearrange equation for M1

  ADK V1  V2 t 
M 1 V1  V2 

 V1  V2 exp 
0
M1
lV1V2


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Taking natural log of both sides results in linearized
eqn
 M 1 V1  V2 

  ADK V1  V2 t 



ln 
 V1   ln( V2 )  
0
M1
lV1V2

1


y  b  mx
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Graphing diffusion cell data
Experiment:
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L=2.5x10-3 cm
V1=V2=3 cm3
A = 2 cm2
K = 1 (water-filled pores)
Analysis
m = -0.000533s-1


m =   ADKlVVV  V  
Solve for D
D=1.0 x 10-6 cm2/s
1
1 2
2
12
10
8
6
4
2
0
0
2000
4000
6000
8000
10000
time (min)
Aqueous Diffusion Coefficient of Drugs
2
log((M1*(V1+V2)/M10-V1)

mass of drug in reservoir
(mg)
Caffeine Release through Microporous Membrane
0
-2 0
-4
5000
10000
15000
20000
-6
25000
30000
35000
y = -0.000533x + 1.098612
-8
-10
-12
-14
-16
time (s)
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Burst and Lag Effects
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Previous analysis was based on steady-state flux
in membrane
J  D
dCm
 C  Cm1 
 D m2

dx
h


membrane
C1
Cm1
Cm2
h
C2
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Burst and Lag
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Lag
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Burst
membrane
membrane
C1
C1
Cm1
Cm2
C2
h
Cm2
Cm1
C2
h
Membrane exposed to reservoir at
t=0
Device stored before use
Initially no drug in membrane
Initial concentration of drug in
membrane = C1
Takes time to build up SS
concentration gradient
Takes time for drug to desorb and
achieve SS concentration gradient
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Lag Time & Burst Effect
Equations for the amount of drug released after SS is attained
in the membrane:
 Lag
SS
M2
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Burst
SS
M2
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ADKC1 
l2 
 t 


l
 6D 
ADKC1 
l2 
 t 


l
 3D 
Equations result from solving transport eqns. (Fick’s 2nd
Law) for USS diffusion with relevant ICs; then taking limit
as t →∞
These equations are for C1=const; C2=0
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Burst and Lag Effects
Lag
ADKC1 
l2 
 t 

M2 
l
 6D 
ADKC1
l
x - intercept  l 2 / 6 D  -tlag
slope of M vs t 
Burst
ADKC1 
l2 
 t 

M2 
l
 3D 
The lag time is the time required for the solute
to appear on the receiver side. It is also the
time required to attain a SS concentration
profile in the membrane
slope of M 2 vs t 
ADKC1
l
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Effect of lag and burst
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Membrane thickness 100 microns
D = 1 x 10 -7 cm2/s
Calculate Lag time and Burst time
Repeat for D = 1 x 10-9 cm2/s
D
tlag
tburst
= 1 x 10 -7 cm2/s
= 2.7 min
= 5.5 min
D
tlag
tburst
= 1 x 10-9 cm2/s
= 277 min
= 555 min
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Diffusivity values for polymers
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Function of MW
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Greater dependence for solute in polymers than
for solute in liquids.
For drugs with <400 MW
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In water: 10-6 cm2/s<D<10-4 cm2/s
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In rubbery polymer: 10-11 cm2/s<D<10-4 cm2/s
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Weak dependence on MW
MW is somewhat important
In glassy polymer: 10-14 cm2/s<D<10-5 cm2/s
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Polymer is very stiff and rigid. Strong dependence on MW
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Diffusion through microporous
membranes
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Molecules move through
liquid-filled pores
Small molecules do not
experience hindered
diffusion
Deff 
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D
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Porosity 0 < ε <1
Tortuosity typically 1 < τ <5
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pathlength is longer than
membrane thickness
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Membrane materials
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Silicone (Silastic – Dow Corning)
EVA – Ethylene Vinyl Acetate
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EVAc- Ethylene Vinyl Acetate copolymer
Entrapped fluids
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Hydrogels and microporous membranes
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Silicone membranes
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Biocompatible and sterilizible
High permeability to many steroids
Low permeability to ionized species
Fick’s law is valid for many compounds
D is on the order of 10-6
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High compared to many polymers
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Applications of Silicone membranes
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5 year contraceptive
Transderm Nitro patch: 0.843 mg/cm2/day
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EVA Membrane Systems
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Advantages over silicone
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Lower permeability to non-polar compounds offers
better rate control
Easier processing and formation of thermoplastic
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Extrusion, injection molding, film casting
Co-polymers can effect big changes in properties
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Flexibility, permeability, strength
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Examples of EVA Systems
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Progestasert
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Progesterone contraceptive by ALZA
Intrauterine device, 65 mcg per day for 400
days
Silicone T-shaped tube with 35 mg drug in
Si oil
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Examples of EVA Systems
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Ocusert
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Pilocarpine glaucoma
treatment system by ALZA
Thin, flexible “contacts” behind
eyelid
Use once a week; replaces
drops 4 times per day
Releases 20 or 40 mcg per
hour
Contains 5-11 mg pilocarpine
Sterilized by irradiation
1.
2.
3.
4.
Clear EVA membrane
Opaque white sealing
ring
Pilocarpine reservoir
Clear EVA membrane
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Oval shape, 6 mm x 13
mm x 0.5 mm
Thin EVA membranes
100 microns thick
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Hydrogel systems
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Hydrophilic monomers that make cross-linked
networks which hold water
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Great ease of synthesis
Wide range of properties
D depends on cross-linking agent and water
content
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Applications of hydrogels membrane
systems
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Fluoride salts in the mough
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Narcotic agonist – cyclazocine
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0.2 – 1.0 mg/day for 6 months
Prevents opiate effect and is used in rehabilitation
Anticancer pouches for direct placement on
tumors
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Applications of microporous membranes
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Microporous Membranes – used in many biomedical applications
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Blood oxygenation, dialysis, wound dressings, drug delivery
Drug Delivery Applications
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Transderm Scop® (scopolamine) —Introduced in 1981 for motion-sickness. Microporous
polypropylene membrane. (Alza-Ciba Geigy)
Transderm-Nitro® (nitroglycerin) — For angina patients. Alternative to the brief effects of sublingual
nitroglycerin and the messiness of nitroglycerin ointment. Microporous EVA membrane. (Alza-Ciba
Geigy)
Catapres-TTS® (clonidine) — Once-a week patch for hypertension replaces up to four daily oral
doses. Uses microporous polypropylene membrane. (Alza-Boehringer/Ingelheim)
Estraderm® (estradiol) —Twice-weekly, convenient estrogen replacement therapy. Avoids first pass
and therefore uses only a fraction of the drug used in the oral therapy. Uses microporous
polypropylene membrane. (Alze-Ciba Geigy)
Duragesic® (fentanyl) —Introduced in 1991 for management of chronic pain via opioid analgesia.
Uses microporous polyethylene membrane. (Alza)
NicoDerm® CQ® (nicotine)—smoking-cessation aid in multiple dosage strengths offering maximum
control of the drug delivery rate. Uses microporous polypropylene membrane. (Alza-GSK)
Testoderm® and Testoderm® —Introduced in 1994 and 1998, respectively, for hormone replacement
therapy in men with a deficiency or absence of testosterone. Microporous EVAc membrane. (AlzaLederle)
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ALZA’s Transderm Scop
Removable strip
Adhesive gel layer with
priming dose
Rate controlling microporous
membrane with highly
permeable liquid in pores
Reservoir with solid drug in
highly permeable matrix
Foil backing, protective and
impermeable
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Controlled release form maintains low conc of drug,
reduces side effects
2.5 cm2 area
200 mcg priming dose
10 mcg/h for 72 h steady state delivery
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Diffusion Cell Equations
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Derivation of M1(t)
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Burst and Lag effects
Ref. Kydonieus, A. Treatise on Controlled Drug Delivery
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