1

Controlled Release

Reservoir-Membrane Systems

2

Overview

n Historyn Membrane devices with constant release raten Diffusion cell experiments with first order

releasen Burst and lag effects in membrane systemsn Diffusion coefficientsn Membrane materialsn Applications of membrane systems

3

Components of membrane systems

n Mechanism: diffusion-controlledn Driving force: ?C across membranen Medium: polymer membrane or liquid-filled

poresn Resistance: function of film thickness,

diffusivity of solute in mediumn Membrane usually interfaces with biological

site. Biocompatibility may be important.

4

History of Membrane Systems

n Folkman and Long (1966 patent)n Folkman studied effect of thyroid hormone on heart

blockn Folkman needed non-inflammatory vehicle for

extended release of hormonen Long performed a photographic study of turbulence

induced by artificial Si rubber heart valvesn Long noticed that certain dyes permeated Si rubber

5

History (continued)

n Folkman and Long tested diffusion of dyes and drugs across Si tube walls.q Observed that oil-soluble, low MW (<1000) dyes

permeated membraneq Observed that water-soluble, high MW dyes did not.

n This was the beginning of a research EXPLOSION!n First CR device (late 1960s) was use of hormones

for contraception, which has now been widely studied.

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Theory

n Fick’s First Law

n Relate Cm1 and Cm2 to surrounding concentrations

n Rewrite Flux

n Body acts as a sink (C2˜ 0)

n Constant rate can be achieved if C1 is kept constant.

−

−=−=h

CCD

dxdCm

DJ mm 12

−

−==h

CCDKJ m

12

2

22 C

CK m

m =1

11 C

CK m

m =

≅

hC

DKJ m1

membrane

C1

C2h

Cm1

Cm2

C1<Cm1the drug “prefers”the polymer

7

What if C1 is not constant?

n Common situation in diffusion cellq Drug is depleted from reservoir (1)q Drug accumulates in receiver (2)

membrane

C1

C2h

Cm1

Cm2

www.permegear.com

8

Diffusion cell: Derivation of M1(t)

n Fick’s Law

n USS Mass Balance

−

−=−=h

CCDK

dxdCm

DJ m12

( )

+−=

−

=−=

21

21

2211

11VV

AJdt

CCddt

dCA

Vdt

dCAV

J

n Combine USSMB with Fick’s Law

n Rearrange

( ) ( )

+−−=

−

2121

21 11VV

CCl

ADKdt

CCd

( )( ) dt

VVlADK

CCCCd

+−=

−−

2121

21 11

9

Diffusion cell

n Integrate with IC: C1-C2= C10-C2

0

q Apply mass balance

q Substitute

( )( ) t

VVlADK

CCCC

+−=

−−

210021 11

ln21

0121 MMM =+

222

111

VCMVCM

==

10

Diffusion cell

n Rearrange (see details)

n Differentiate to find release rate

n First Order Release Rate

( )

+

+−+

= 121

212

21

01

1 exp VVlV

tVVADKV

VVM

M

( )

+−−=

21

21

1

011 exp

VlVtVVADK

lVADKM

dtdM

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Release profile for diffusion cell

Drug Release in Diffusion Cell

0

2

4

6

8

10

12

0 2000 4000 6000 8000 10000

time (min)

mas

s o

f dru

g in

res

ervo

ir

(mg

)

12

Data Analysis

n Diffusion Cell Experiment provides data for C1 vs t n Rearrange equation for M1

n Taking natural log of both sides results in linearizedeqn

( ) ( )

+−=−

+

21

21210

1

211 expVlV

tVVADKVV

MVVM

( ) ( )

mxby

VlVtVVADK

VVM

VVM

+=

+−+=

−

+

21

212

1

101

211 )ln(ln

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Graphing diffusion cell data

n Experiment:q L=2.5x10-3 cmq V1=V2=3 cm3

q A = 2 cm2

q K = 1 (water-filled pores)

n Analysisn m = -0.000533s-1

n m = n Solve for Dn D=1.0 x 10-6 cm2/s

Caffeine Release through Microporous Membrane

0

2

4

6

8

10

12

0 2000 4000 6000 8000 10000

time (min)

mas

s o

f d

rug

in r

eser

voir

(m

g)

Aqueous Diffusion Coefficient of Drugs

y = -0.000533x + 1.098612

-16-14-12-10

-8

-6-4-202

0 5000 10000 15000 20000 25000 30000 35000

time (s)

log

((M

1*(V

1+V

2)/M

10-V

1)

( )

+−

21

21

VlVVVADK

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Burst and Lag Effects

n Previous analysis was based on steady-state flux in membrane

−

−=−=h

CCD

dxdCm

DJ mm 12

membrane

C1

C2h

Cm1

Cm2

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Burst and Lagn Lag

membrane

C1

C2

h

Cm1

Cm2

Membrane exposed to reservoir at t=0

Initially no drug in membrane

Takes time to build up SS concentration gradient

n Burstmembrane

C1

C2

h

Cm1

Cm2

Device stored before use

Initial concentration of drug in membrane = C1

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:

n Lag

n Burst

n Equations result from solving transport eqns. (Fick’s 2nd Law) for USS diffusion with relevant ICs; then taking limit as t ? 8

n These equations are for C1=const; C2=0

−=

Dl

tl

ADKCM SS

6

21

2

+=

Dl

tl

ADKCM SS

3

21

2

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Burst and Lag Effects

lagtD/ll

ADKC

Dl

tl

ADKCM

-6intercept-x

t vsM of slope

6

Lag

2

1

21

2

=−=

=

−=

lADKC

Dl

tl

ADKCM

12

21

2

t vsM of slope

3

Burst

=

+=

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

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Effect of lag and burst

n Membrane thickness 100 micronsn D = 1 x 10 -7 cm2/sn Calculate Lag time and Burst timen Repeat for D = 1 x 10-9 cm2/s

D = 1 x 10 -7 cm2/s D = 1 x 10-9 cm2/stlag = 2.7 min tlag = 277 mintburst = 5.5 min tburst = 555 min

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Diffusivity values for polymers

n Function of MWq Greater dependence for solute in polymers than

for solute in liquids.q For drugs with <400 MWn In water: 10-6 cm2/s<D<10-4 cm2/s

q Weak dependence on MW

n In rubbery polymer: 10-11 cm2/s<D<10-4 cm2/sq MW is somewhat important

n In glassy polymer: 10-14 cm2/s<D<10-5 cm2/sq Polymer is very stiff and rigid. Strong dependence on MW

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Diffusion through microporousmembranesn Molecules move through

liquid-filled poresn Small molecules do not

experience hindered diffusion

n Porosity 0 < e <1n Tortuosity typically 1 < t <5

q pathlength is longer than membrane thickness

τεD

Deff =

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Membrane materials

n Silicone (Silastic – Dow Corning)n EVA – Ethylene Vinyl Acetateq EVAc- Ethylene Vinyl Acetate copolymer

n Entrapped fluidsq Hydrogels and microporous membranes

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Silicone membranes

n Biocompatible and steriliziblen High permeability to many steroidsn Low permeability to ionized speciesn Fick’s law is valid for many compoundsn D is on the order of 10-6

q High compared to many polymers

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Applications of Silicone membranes

n 5 year contraceptiven Transderm Nitro patch: 0.843 mg/cm2/day

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EVA Membrane Systems

n Advantages over siliconeq Lower permeability to non-polar compounds offers

better rate controlq Easier processing and formation of thermoplasticn Extrusion, injection molding, film casting

q Co-polymers can effect big changes in propertiesn Flexibility, permeability, strength

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Examples of EVA Systemsn Progestasert

q Progesterone contraceptive by ALZAq Intrauterine device, 65 mcg per day for 400

daysq Silicone T-shaped tube with 35 mg drug in

Si oil

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Examples of EVA Systems

n Ocusertq Pilocarpine glaucoma

treatment system by ALZAq Thin, flexible “contacts” behind

eyelidq Use once a week; replaces

drops 4 times per dayq Releases 20 or 40 mcg per

hourq Contains 5-11 mg pilocarpineq Sterilized by irradiation

1. Clear EVA membrane2. Opaque white sealing

ring3. Pilocarpine reservoir4. Clear EVA membrane

q Oval shape, 6 mm x 13 mm x 0.5 mm

q Thin EVA membranes 100 microns thick

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Hydrogel systems

n Hydrophilic monomers that make cross-linked networks which hold waterq Great ease of synthesisq Wide range of propertiesq D depends on cross-linking agent and water

content

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Applications of hydrogels membrane systemsn Fluoride salts in the moughq 0.2 – 1.0 mg/day for 6 months

n Narcotic agonist – cyclazocineq Prevents opiate effect and is used in rehabilitation

n Anticancer pouches for direct placement on tumors

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Applications of microporous membranes

n Microporous Membranes – used in many biomedical applicationsq Blood oxygenation, dialysis, wound dressings, drug delivery

n Drug Delivery Applicationsq Transderm Scop® (scopolamine) —Introduced in 1981 for motion-sickness. Microporous

polypropylene membrane. (Alza-Ciba Geigy)

q 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)

q Catapres-TTS® (clonidine) — Once-a week patch for hypertension replaces up to four daily oral doses. Uses microporous polypropylene membrane. (Alza-Boehringer/Ingelheim)

q 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 microporouspolypropylene membrane. (Alze-Ciba Geigy)

q Duragesic® (fentanyl) —Introduced in 1991 for management of chronic pain via opioid analgesia. Uses microporous polyethylene membrane. (Alza)

q NicoDerm® CQ® (nicotine)—smoking-cessation aid in multiple dosage strengths offering maximum control of the drug delivery rate. Uses microporous polypropylene membrane. (Alza-GSK)

q Testoderm® and Testoderm® —Introduced in 1994 and 1998, respectively, for hormone replacement therapy in men with a deficiency or absence of testosterone. Microporous EVAcmembrane. (Alza-Lederle)

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ALZA’s Transderm ScopRemovable strip

Rate controlling microporousmembrane with highly permeable liquid in pores

Foil backing, protective and impermeable

Adhesive gel layer with priming dose

Reservoir with solid drug in highly permeable matrix

n Controlled release form maintains low conc of drug, reduces side effects

n 2.5 cm2 arean 200 mcg priming dosen 10 mcg/h for 72 h steady state delivery

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Diffusion Cell Equations

n Derivation of M1(t)

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Burst and Lag effects

Ref. Kydonieus, A. Treatise on Controlled Drug Delivery