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Lecture 19 Drug Delivery: Controlled Release
What do we mean by controlled release? Control of: 1. delivery rate 2. site of release/activity

Need for Control drug concen.

Traditional drug delivery

toxic level

Therapeutic range

t1 t2

time from administration

longer period of dose efficacy = toxicity risk

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drug concen.

Controlled drug delivery

toxic level

Therapeutic range

time from administration Types of Devices 1. Diffusion Controlled Delivery Devices Monolithic Devices Membrane Controlled Devices Osmotic Pressure Devices Swelling-Controlled Devices

2. Chemically Controlled Approaches Matrix Erosion Combined Erosion/Diffusion Drug Covalently Attached to Polymer Desorption of Adsorbed Drug

3. Electronic/Externally Controlled Devices

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1. Diffusion Controlled Devices a) Monolithic Devices Drug is released by diffusion out of a polymer matrix Release rate depends on initial drug concentration

i)

Case of C0 < Cs (drug concentration C0 is below solubility limit in matrix Cs) Diffusion through matrix limits the release rate

t0

t1

t2

How can we control release rate?

Rate control by choice of matrix: glassy matrix: D~10-10-10-12 cm2/s rubbery matrix: D ~ 10-6-10-7 cm2/s

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Quantifying drug release Governed by Ficks Laws. For 1D: The drug flux J is:
J = D dC dx

C 2C
= D
2 The change in drug concentration with time is: t x

We want to calculate:

dMt/dt = release rate Mt = amount released after time t

Solve Ficks 2nd law with initial & boundary conditions.

Example: For a 1D slab loaded at an initial concentration of C0, with drug concentration in solution resulting in constant surface concentration of Ci. I.C.: C(x,0) = C0
C B.C. 1: x =0
x = 0,t

C0

B.C. 2: C(/2,t) = Ci Solve for C(x,t)

dM t dC ( x, t ) = D Adt dx
x = / 2

Mt
A = cross-sectional area

Ci
0

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The amount of drug released is given by the series solution:

D ( 2n + 1)2 2 Mt 8 = 1 exp t 2 2 2 M n = 0 ( 2 n + 1)

where:

M = amount of drug released at long times (e.g., total amt of drug: M = C0A) = slab thickness

Mt/M 1

0.5

0 time Release rate (from derivative):

dM t D = 2M 2 dt t

1/ 2

short times: ~ t-1/2

2 Dt dM t 8 DM = exp 2 dt 2

long times: exponential decay

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NOTE: dMt/dt and Mt depend on geometry. See handout from Encyclopedia of Controlled Drug Delivery

dMt/dt release rate ~ t-1/2

~ exp(-t) 0 time

ii)

Case of C0 > Cs (drug concentration above solubility limit in matrix) Drug dissolution in polymer matrix limits release rate drug conc.= Cs in matrix
1/ 2

Higuchi model: assumes Ci = 0

Mt = A DCs ( 2C0 Cs ) t

1/ 2 1/ 2 dM t A = 2 t DC C C ( ) s s 0 2 dt

where A = surface area of the slab drug-rich 2nd phase

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For Cs << C0:

dM t A 2 DCs C0 = dt 2 t

1/ 2

How can we control release rate?

b) Membrane Controlled Devices Drug release is controlled by a semi-permeable membrane Diffusion through membrane limits the release rate Advantage: A constant flux device!

Semi-permeable membrane

Neat or concentrated therapeutic agent

Release rate thru membrane described by Ficks 1st law. For 1D:
J= dM t dC = D Adt dx
Typical flux units: g/cm2s

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i) Nonporous semi-permeable membranes Drug diffusion through swollen polymer membrane

dM t DKA = ( C2 C1 ) dt DKA

Conc. inside membrane = C2

Mt =

( C2 C1 ) t

K = membrane partition coefficient (unitless metric of drug solubility in membrane) Which D is referred to?

Conc. outside membrane = C1

dMt/dt
Early release rate independent of time

0 time Is this release profile advantageous?

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ii) Porous semi-permeable membranes Drug diffusion through membrane pores

Requires replacing D by Deff:

Deff
=

D pore

= porosity 0 < < 1 = tortuosity 1

Cross-section of porous semi-permeable membrane c) Osmotic Pressure Devices Osmotic pressure build-up from water in-flux across semi-permeable membrane forces drug release through orifice piston

delivery orifice

semi-permeable membrane osmotic engine (NaCl)

drug reservoir
Ex: DUROS Implant (ALZA) Ti housing, 4mm 45 mm ~ 1 year duration in use for prostate cancer therapy

http://www.alza.com/alza/duros

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Release rate proportional to change in volume of drug reservoir:

10

dM t dV Ak C = C = dt dt

A= membrane area = osmotic pressure differential C = drug concentration in reservoir k= membrane permeability coefficient (~10-6-10-7g/cm/s)

dMt/dt
zero-order release
kinetics

0
time
Controlled Release via Solute Choice for Osmotic Engine () Solute body tissue NaCl KCl sucrose dextrose potassium sulfate Osmotic Pressure (atm) 7 356 245 150 82 39

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d) Swelling Controlled Devices Drug dispersed in a glassy, hydrophilic matrix Swelling in aqueous medium allows drug release

11

glassy polymer matrix with dispersed drug

H2O swelling provides mobility for drug release

Complex release kinetics: modeled by fitting experimental data to power law expression.

Mt = k 't n M
ln(Mt/M)
n=1

ln(k) ln(t)

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2. Chemically Controlled Approaches a) Eroding Monolithic Device Drug is incorporated into a bioerodible or dissolvable polymer matrix

12

t0

t1

t2

i) Surface Erosion Devices

dM
t = ke Ae dt

release rate = strong function of device geometry For a slab:

Ae = instant surface area ke = rxn or dissolution rate const.

2M
const Ae
C0 dM t 2
kM =
e dt C0
zero-order release kinetics

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dMt/dt

13

0 time For other geometries, Ae is a function of time:

dM t = ke Ae (t ) dt
For various geometries, the solution to this expression is:

kt Mt = 1 1 e
M C0
2

Geometry
slab cylinder sphere thickness diameter diameter

n
1 2 3

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Matrix Examples: polyanhydrides poly(sebacic acid anyhydride) poly ortho esters O O

14

(-(CH2)8- C -O-C -)N

DETOSU

ii) Bulk Erosion Devices uniform hydrolysis of bulk matrix polymer hydrolysis rate vs. drug diffusion controls release rate

dM t ~ tn dt
Matrix Example: poly(lactide-co-glycolide) O

n = -1/2 drug diffusion limited

(-O-CH(CH3)-C -)x-r-(-O-CH2-C -)y lactic acid glycolic acid

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iii) Pulsed release systems Mixture of eroding particles with different degradation rates Degradation Profile for Single Eroding Component (schematic) % degrad. 100

15

50

0 time in vivo drug concen. in vivo

time from administration

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Degradation Profile for Mixture of Components (ex., microspheres) % degrad. 100

16

50

0 drug concen. in vivo time in vivo

time from administration Applications Example: one shot vaccines with multiple antigens TT tetanus toxoid DT diptheria toxoid HBSA hepatitis B surface antigen SEB staphylococcal enterotoxoid B
Vaccines stimulate Ab production

How can we achieve different degradation rates?

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Factors influencing degradation: Composition (e.g., PLGA copolymer LA:GA ratio) Geometry

17

iv) Regulated systems Incorporate a component that responds to the in vivo environment Enzyme that catalyzes degradation in presence of a substrate Example: GOD-regulated insulin release Glucose + O2 + H2O Gluconic acid + H2O2
GOD
pH drop promotes acid hydrolysis or swelling of matrix

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b) Polymer-Drug Conjugates

18

Therapeutic agent is covalently or ionically bound to a polymer through a cleavable bond Purposes: increase resistance to proteolysis (protein drugs)
reduce antigenicity/immunogenicity
prolong plasma circulation lifetime
enhance water solubility of hydrophobic agents
reduce toxicity

Example 1: Therapeutic proteins tethered to polyethylene glycol (PEG) protein

Increases intravascular lifetimewhy?

PEG Some clinical systems: PEG-adenosine deaminase (FDA appr. immunodeficiency therapy) PEG-asparaginase (FDA appr. for lymphoblastic leukemia) PEG-hemoglobin PEG-interluekin 2 PEG-alpha interferon PEG-colony stimulating factor

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Example 2: Chemotherapeutic agent attached to water-soluble or hydrolysable backbone

vinyl benzyl fluorouracil

maleic anhydride

(CH

CH2-)n

(CH O=C

CH-)m C=O O

C=O N F O (CH CH2-)n N H O

hydrolysis

(CH O=C

CH-)m C=O OH

H N

O N H

F O

C=O OH

OH

5-fluorouracil

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Example 3: Dendrimer Drug Conjugates (early development) Dendrimers sequentially synthesized, hyperbranched macromolecules

20

1st generation

2nd generation

3rd generation

Two strategies for controlled drug delivery

drug-conjugated chain ends

Drug-filled core (diffusion-controlled)

References Encyclopedia of controlled drug delivery vol. 1, E. Mathiowitz, ed., John Wiley & Sons, NY, 1999. Encyclopedia of controlled drug delivery vol. 2, E. Mathiowitz, ed., John Wiley & Sons, NY, 1999. Biomaterials Science: An introduction to materials in medicine, B.D. Ratner et al., eds., Academic Press, NY 1996.