Martin s Ch 23; - pages 623 631 Saltzman Ch 9; -235 - 280 · Drug release from a CR systems 1. Zero-order release:-Drug release does not vary with time-Relatively constant drug level

Controlled Drug Delivery

Martin’s Ch 23; - pages 623 – 631

Saltzman Ch 9; -235 - 280

Controlled-delivery systems

Are used for:

- Alternative approach to regulate both the duration and

spatial localization of therapeutic agents

Are constructed by:

- The active agent is combined with other (usually

synthetic) components

Involve:

- Combinations of active agents with inert polymers

Controlled-delivery systems

1. Include a component that can be engineered to

regulate an essential characteristic (e.g. duration of

release, rate of release or targeting)

2. Have a duration of action longer than a day

Controlled drug delivery

Issues to consider:

1. Nature of disease and theraphy (acute/chorinic)

2. Drug property

3. Route of drug administration

4. Nature of delivery vehicle

5. Mechanism of drug release

6. Targeting ability

7. biocompability

Controlled Drug delivery systems

Should be:

1. Inert

2. Biocombatible

3. Mechanically strong

4. Convenient for patient

5. Capable of achieving high drug loading

6. Safe from accidental drug release

7. Simple to administer and remove

8. Easy to fabricate

9. Easy to sterilize

Drug release from a CR systems

1. Zero-order release:

- Drug release does not vary with time

- Relatively constant drug level is maintained in plasma over

an extended period of time

2. Variable release:

- Drug is released at variable rates to match with circadian

rhythms or mimic natural biorythms

- Drug concentration is increased episodic, followed by a

“rest” period, when drug level falls below the therapeutic

level

3. Bioresponsive release:

- Drug release is triggered by biological stimulus (pH, T, etc.)

Drug release from a CR systems

1. Zero-order release

2. Variable release

3. Bioresponsive release

Mechanisms of controlled drug delivery

1. Diffusion controlled release mechanisms

2. Dissolution controlled release mechanisms

3. Osmosis controlled release mechanisms

4. Mechanical controlled release mechanisms

1. Diffusion controlled release mechanisms

Diffusion through polymeric membrane or

polymeric/lipid matrix:

a) Rate follows Fick’s law

b) Rate depends on:

- Partition and diffusion coefficients of the drug in

the membrane

- The available surface area

- The membrane thickness

- The drug concentration gradient

c) The release kinetics depends on the shape of

the device:

- Monolith, rate decreases with square root of time

- Micropsheres act as matrix controlled release

1. Diffusion controlled release mechanisms:

DEVICES

a) Reservoir

b) Matrix

c) Drug diffusion from a

homogeneous controlled

drug delivery system

2. Dissolution controlled release mechanisms

Drug release is controlled by dissolution rate of employed

polymer

Devices are either reservoir type or matrix type

Polymer must be either water soluble and/or degrarable

Release is controlled by:

- Tickness and/or

- Dissolution rate of polymer membrane surrounding

the drug core

3. Osmosis controlled release mechanisms

Osmosis controlled or active efflux controlled drug release

-Osmotic p is used to delivery drug with constant rate

Diffusion of water through a semipermeable membrane

from a solution of low low concerntration (hypotonic) to a

solution of high concentration (hypertonic)

=> incerease in the pressure (p) of solution

D p = osmotic p = p required for maintaining

equilibrium with no net movement of water

4. Mechanical controlled release mechanisms

Mechanically driven pumps

Bioresponsive controlled release mechanisms:

- Drug is released in response to changes in the

external environment

O the joy of my soul leaning

pois’d on itself – receiving

identity through materials ,

and loving them

i) Diffusion through membranes

ii) Diffusion through matrix

iii) Hydrogel systems

iv) Degradable systems

v) Particulate systems



Non-degradable, hydrophobic membranes

Reservoir devices, in which a liquid reservoir of drug is

enclosed in a silicone elastomer tube e.g. Norplant, release of

levonorgestrel for 5 years (subcutaneous implantation)

Polymers like EVAc (poly[ethylene(-co-(vinyl acetate)] has

been used to control the delivery of contraceptive hormones

e.g. Progestrasert and lipophilic drugs to eye or skin e.g.

Ocusert and Transderm Nitro

Advantages : long service life nearly constant release rates

i) Diffusion through polymeric membrane

1. Diffusion through Planar Membranes

2. Diffusion through Cylindar Membranes

1. Planar membranes

dcp/dt = Di:p(d2cp/dx2)

Where Di:p = diffusion coefficient for the drug within the polymer material

Cp = concentration of the drug (mg/ml) within the polymer

For a differential control volume in the membrane, Dx,

a mass balance diffusing drug molecule A yields:

1. Planar membranes

At steady state, the drug release from membrane is:

dMt/dt = -ADi:p[(cp,1-cp,s)/L]

And taking into account the partition co-efficients:

Kp:r = [cp/creservoir fluid]equilibrium

Kp:w =[cp/cwater]equilibrium

dMt/dt = -ADi:p[(Kp:rcr – Kp:wcw)/L]

1. Planar membranes

Schematic diagram (Ocusert)

Rate-controlled membranes of poly[ethylene-co-(vinyl

acetate)] enclose a drug reservoir

1. Planar membranes

a) Transdermal

delivery system

b) Planar

controlled-

release system

c) Cylindar

controlled-

release system

Rate limiting

polymer

membranes

1. Planar membranes

Drug release as a function of L of membrane

Each of separate curves represents normalized mass released at particular

value of Di:p/L2(min-1); Di:p = 1x10-8 cm2/s

The cumulative mass

released at y-axis is

scaled by M0= Acp,1L

L= 20 mm

L= 40 mm

L= 60 mm

L= 120 mm

Diffusion coefficients and partition coefficients

for some typical polymer/drug combinations

Diffusion coefficients and partition coefficients

for some typical polymer/drug combinations

2. Cylinder membranes



L = cylinder length

b = cross-sectional radius

b-a = wall thickness

Rate of drug release can be modified by:

a) Changing geometry of the device (b, b/a,or L)

b) Changing drug/polymer combination (=> chages in

K and Di:p)


a) Schematic diagram of

transdermal

testoterone-releasing

system

b) A transdermal patch

(Androderm) releasing

testoterone




dc/dt = Di:pr-1[d/dr r dc/dr)

IF the inside of the cylinder is maintained at a constant

concentration of drug => c = c1 at r = a, and outside the

cylinder is free of drug => c = 0 at r = b, and the cylinder

wall is initially saturated with drug, c = c1 at a<r<b then

the above eq. can be solved to obtain c as a function of

position in the cylinder wall


The total mass of drug released at time t, Mt, is obtained by:

1)Calculating the flux from the surface of the ring via Fick’s

law, Jr(b) = -Di:p(dc/dr)r=b

2)Multiplying the flux by the total surface area available for

release, 2pbL

3)Integrating with respect to time, t

To give: Mt/2pc1L

as a function of time, diffusion coefficient Di:p, flux J and a and b.

And immersion of the cylinder in water gives the steady state:

Mt = (2pc1LDi:pt)/ln(b/a)

2. Cylinder membranesDrug release from a cylinder-reservoir delivery system

The cumulative mass of drug released as a function of time for

cylindar-reservoir devices with a range of physical characteristics.

Overall length of the device, L=2.7 cm, and cross-sectional radius, b=0.5 cm.

a) b/a = 0.5 - 4, with Di:p = 1x10-8 cm2/s and c1 = 20 mg/ml and

b) b) Di:p [cm2/s] is varied (A, B, C, D, E) with b/a = 0.5 and c1 = 20 mg/ml. A = 5x10-7;

B = 1x10-7; C = 5x10-8; D = 1x10-8 and E = 1x10-9



In matrix systems the drug molecules are dissolved or

dispersed throughout a solid polymer phase

Polymer materials are alike in membrane reservoir devices, -

silicone elastomers, EVAc

New slowly dissolving biodegradable polymers

By carefully designing of the material and device, it is

possible to desing delivery systems in which the rate of polymer

degradation and dissolution controls the rate of drug delivery

=> new element for controlling the rate of release of

dispersed or dissolved drugs


1. Matrix delivery systems with Dissolved Drugs

2. Matrix delivery systems for water-soluble

Drugs and Proteins


Drug molecules are dissolved

homogeneously in biocompatible

polymer

Drug molecules are released by

diffusing through polymer to the

surface of the device and further

released into the external

environment

dc/dt = Di:p(d2c/dx2)


Total amount of drug released from matrix can be determined by:

Integration results:

For the early stages (Mt<0.6 M∞, the eq. is closely approximated:

Mt = c0AL - c(x,t)Adx

Where the total amount of drug initially within matrix is M∞ = c0AL

Mt/M∞ = 1- (8/p2)1/(2n+1)2exp[-(Di:p(2n+1)2tp2)/L2]

Mt/M∞ 4(Di:pt/pL2)0.5


Drug release from a planar matrix drug delivery systems as a function of

the rate of diffusion of the dissolved drug in the matrix Di:p


Release of dissolved dexamethasone from an EVAc matrix.

a) As a function of time

b) b) as a function of the square root of time

2. Matrix delivery systems for Water-soluble Drugs and Proteins

Small particles of the drug are dispersed througout a

polymer matrix

Exampleas of release of water-soluble molecules from

polymer films are paint and polyolefins,

and

Variations of these are release of small water-soluble

molecules like dopamine, large molecules like proteins

and DNA

Drug release mechanism appear to be independent of the

size of the dispersed molecule

2. Matrix delivery systems for water-soluble Drugs and Proteins

Matrix systems for proteins

Materials used with proteins are:

- non-degradable

a) hydrophobic polymers; -EVAc, silicone elastomers,

polyuretanes

b) Hydrophilic polymers; -poly(2-hydroxyethyl metacrylate)

Solid particles of proteins are dispersed throughout the polymer

Matrices are immersed in water, and proteins are slowly released

Particle size and molecular controls the release


Particle size

Release of BSA from EVAc matrices


Tortuosity of

protein release

from EVAc

matrices


Molecular weight

Tortuosity measured in EVAc matrices with different Mw fractions


Diffusion coefficient

Effective diffusion

coefficients for

protein release from

EVAc matrices



Water-soluble polymers are cross-linked to materials called

hyrdogels

Hydrogels swell, but do not dissolve in water

The rate of drug diffusion in hydrogels depends on the extent

of cross linking and size the drug

The swelling of these hydrogels is limited osmotic forces and

physical integrity of the polymer network. Polymer network can

be controlled by the porosity of the hydrogel

iii) Hydrogel systemsRole of porosity


Role of cross-linking density of the PVA hydrogel


Role of pH in to the release of oxprenololHCl from

poly[(methyl metacrylate)-co-(methacrylic acid)] beads



Degradiation and disappearance of a biodegradable polymer

matrix occurs in a sequence of steps

Most of the degradation occurs via hydrolysis

Therefore water must enter before degradation

The rate of water penetration depends on the degree of

hydrophobicity and morphology of the polymer matrix

Water penetration occurs via diffusion

Diffusion of the solute into the hydrated phase increases as

predicted by: Free volume theory

The hydrolysis of polyester materials such as pLGA occurs by

following the first order rate kinetics


Changes in a pLGA system

during degradation and drug

release:

a) The uptake of water (filled

squares) and the decrease

in molecular weight (open

squares)

b) The loss of polymer mass

(filled circles) and the

release of drugs (open

circles) for a 18 000

weight-avarage molecular

pLGA 50:50 co-polymer

Idealized patterns of erosion for matrices of biodegradable polymers

In the bulk erosion:

a) The degradation or erosion

events occur more uniformly

throughout the matrix

b) The polymer matrix degrades

heterogeneously

c) Model of erosion in a semi-

crystalline polymer


In most cases the release of drug from matrices of

biodegradable polymers has diffusion kinetics similar to

that of non-degrable matrices

The degradation/erosion of the biodegradable polymers

controls the rate of drug release from the matrix

Often the property of biodegradability is based on water-

soluble polymers combining the advantages of hydrogels

Degradability is obtained by e.g. ester or biodegradable

hydrogel linkages.



Implantable drug delivery systems

Injectable drug delivery systems

- Injected to desired tissue site or blood stream

- Could be microcapsules, microspheres, nanospheres

Ingest able delivery systems


a) Microcapsules

b) Microparticles

a) Surface-modified

nanoparticles, in which

the drug is entrapped

in the solid polymer

core


Responsive delivery systemsMatching the

administration of the

drug with biological

process that is under

treatment

=> Search for

“smart” methods

Figure:

CR activated by cellular

infiltration and enzyme

activity.

Release is initiated by

cellular invasion of the gel

and local secretion of an

enzyme that cleaves the

peptide.

Summary

Polymeric membranes can be used to control the rate of release

Reservoir and transdermal devices are conceptually simple;

=> Rate of drug can be predicted by simple mathematical eq.

Matrix-type delivery systems are simple to make;

=> release is controlled by diffusion of drug through polymer matrix

Mathematical descriptions are complicated

it is difficult to produce a device with constant rate of release

Materials are versatile

Any compound can be formulated into CR matrix

Degradable polymers (hydrolysis) are appealing for clinical medicines

Degradiation is difficult to control

Documents

Martin s Ch 23; - pages 623 631 Saltzman Ch 9; -235 - 280 · Drug release from a CR systems 1. Zero-order release:-Drug release does not vary with time-Relatively constant drug level