Controlled Drug Delivery System

Classification


Activation-modulated Drug Delivery System
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In this group of controlled release drug delivery
system, the release of drug molecules from the
delivery system is activated by some physical,
chemical, or biochemical process and/or by
energy supplied externally.

The rate of drug release is then controlled by
regulating the process applied or energy input.
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Classification : By Physical Means
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3
Activation-
Modulated
DDS
Osmotic pressure
Activated
Osmotic Pressure Activated DDS
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Drug reservoir
( API + osmotic agent)
Delivery Orifice
Semi-permeable
Membrane.
(cellulose esters)
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For the drug delivery system containing a
solution formulation, the intrinsic rate of drug
release is defined by,
Q Pw Am
t hm

For the drug delivery system containing a solid
formulation, the intrinsic rate of drug release is
defined by,
Q Pw Am
t hm


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(
s

e
)

=
(
s

e
) Sd
=
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Where,
Q/t - rate of drug release
P
w
- permiability of semipermiable housing

A
m
-effective S.A. of semipermiable housing
h
m
- thickness of semipermiable housing
(
s
-
e
) Differential osmotic pressure b/w
DDS with osmotic pressure p
s
&
environmental osmotic pressure p
e

Sd Aqueous solubility of drug contained in the

solid formulation.
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Release is controlled at rate determined by,

Water permeability
Surface area of semi-permeable housing
Osmotic pressure gradient

Merits :

A high degree of in vivo- in vitro correlation (IVIVC)
is obtained in osmotic systems.
For oral osmotic systems, drug release is independent
of gastric pH and hydrodynamic conditions.


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Alzet Osmotic Pump
Classification : By Physical Means
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Activation-
Modulated
DDS
Osmotic pressure
Activated
Hydrodynamic
Press. Activated
Hydrodynamic Pressure - Activated DDS
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Rate of drug release is defined by,




Where,
P
f =
fluid permeability
A
m =
effective Surface area
h
m
= thickness of wall with anular opening
(q
s
- q
e
)= differential hydrodynamic pressure
between DDS and environment.

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Q Pf Am
t hm
=
( q
s
- q
e
)
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Release is controlled at rate determined by,

Fluid permeability
Pressure gradient
Surface area of wall with annular opening

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Classification : By Physical Means
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Activation-
Modulated
DDS
Osmotic pressure
Activated
Hydrodynamic
Press. Activated
Vapor
Pressure
Activated
Vapor Pressure Activated DDS
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The rate of drug release is defined by,
Q
=
d
4
(P
s
-P
e
)
t 40.74 ml
Where-
Q/t - rate of drug release
d - Inner diameter of cannula
l - length of cannula
(P
s
-P
e
) - the difference between the vapor
pressure in the vapor chamber &
pressure at the implantation site.
m - viscosity of the drug solution.

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Rate controlled By :
Differential vapor pressure
Formulation viscosity
Size of the delivery cannula

Example,
An implantable infusion pump for constant
infusion of heparin in anticoagulant treatment,
morphine for patients suffering from the intense
pain of terminal cancer.
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Classification : By Physical Means
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17
Activation-
Modulated
DDS
Osmotic pressure
Activated
Hydrodynamic
Press. Activated
Vapor
Pressure
Activated
Mechanically
Activated
Mechanically Activated DDS
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In this type, drug reservoir is in solution form
retained in a container equipped with
mechanically activated pumping system.
A measured dose of the drug formulation is
reproducible delivered in to a body cavity, for ex.
The nose, through the spray head upon manual
activation of the drug delivery pumping system.
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Ex. Metered-dose Inhaler

the volume of solution
delivered is controllable, as
small as 10-100 l & is
independent of the force &
duration of the activation
applied as well as the solution
volume in the container.

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Classification : By Physical Means
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Activation-
Modulated
DDS
Osmotic pressure
Activated
Hydrodynamic
Press. Activated
Vapor
Pressure
Activated
Mechanically
Activated
Magnetically
Activated
Magnetically Activated - DDS
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In this type, drug reservoir is a dispersion of
peptide or protein powders in polymer matrix
from which macromolecular drug can be
delivered only at a relatively slow rate.

Device is fabricated by positioning a tiny magnet
ring in core of hemispherical drug dispersing
polymer matrix.

The external surface is coated with drug
impermeable polymer (ethylene vinyl acetate or
silicone elastomer) except one cavity at the centre
of the flat surface.


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e.g. This delivery device used to deliver protein
drugs such as bovine serum albumin, at a low
basal rate, by a simple diffusion process under
non triggering condition.

As the magnet is activated to vibrate by an
external electromagnetic field, the drug
molecules are delivered at a much higher rate.
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Classification : By Physical Means
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Activation-
Modulated
DDS
Osmotic pressure
Activated
Hydrodynamic
Press. Activated
Vapor
Pressure
Activated
Mechanically
Activated
Magnetically
Activated
Sonophoresis
Activated
Sonophoresis - Activated DDS
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This type of system utilizes ultrasonic energy to
activate or trigger the delivery of drug from
polymeric drug delivery device.

System can be fabricated from nondegradable
polymer (ethylene vinyl acetate) or bioerodiable
polymer (poly[bis(p-carboxyphenoxy) alkane
anhydride].

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Classification : By Physical Means
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Activation-
Modulated
DDS
Osmotic pressure
Activated
Hydrodynamic
Press. Activated
Vapor
Pressure
Activated
Mechanically
Activated
Magnetically
Activated
Sonophoresis
Activated
Ionto-
phoresis
Activated
Iontophoresis - Activated DDS
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Iontophorsis can be defined as the process in
which the flux or rate of absorption of ionic
solutes into or through skin is enhanced by
applying a voltage drop/electrical field across the
skin.
In addition, delivery rate can be controlled by the
intensity of applied electric current or Electro-
chemical potential gradient.

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Iontophoresis facilitated skin permeation rate
of charged molecule (i) consist of 3 components
& is expressed by,
J
i
isp
= J
p
+ J
e
+J
c

J
p
passive skin permeation flux.
J
e
electrical current driven permeation flux
J
c
= convective flow driven skin permeation flux



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Merits :
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Non-invasive technique as a substitute for
chemical enhancers.
Frequency of dosage is reduced.
Provide predictable and extended duration of
action.
Demerits :
Excessive current density leads to pain.
The safe current density varies with electrode
size.
Mol. Wt. of 8000-12000 results in a uncertain
rate of delivery.
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Classification : By Physical Means
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Activation-
Modulated
DDS
Osmotic pressure
Activated
Hydrodynamic
Press. Activated
Vapor
Pressure
Activated
Mechanically
Activated
Magnetically
Activated
Sonophoresis
Activated
Ionto-
phoresis
Activated
Hydration
Activated
Hydration - Activated DDS
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Valrelease Tablets
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Not only hydrophilic polymer but also the
lipophilic polymers, such as silicone elastomer,
can be modified to have swelling properties.

This is achieved by impregnating water-miscible
liquid such as glycerol and/or water soluble salt
such as, sodium chloride, in lipophilic polymer
matrix.


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Classification By : Chemical Means
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Activation-
Modulated
DDS
pH-Activated
DDS
pH-Activated DDS
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This type of chemically activated system permits
targeting the delivery of drug only in the region
with selected pH range.

It fabricated by coating the drug-containing core
with a pH sensitive polymer combination.

For instances, a gastric fluid labile drug is
protected by encapsulating it inside a polymer
membrane that resist the degradative action of
gastric pH, such as combination of ethyl-
cellulose and hydroxymethylcellulose phthalate.

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Classification By : Chemical Means
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Activation-
Modulated
DDS
pH-Activated
DDS
Ion-
Activated
DDS
Ion-Activated DDS
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An ionic or a charged drug can be delivered by
this method & this system are prepared by first
complexing an ionic drug with an ion-exchange
resin containing a suitable counter ion.

Ex. By forming a complex between a cationic
drug with a resin having a So
3
-
group or between
an anionic drug with a resin having a N(CH
3
)
3

group.

The granules of drug-resin complex are first
treated with an impregnating agent & then
coated with a water-insoluble but water-
permeable polymeric membrane.

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This membrane serves as a rate-controlling barrier to
modulate the influx of ions as well as the release of
drug from the system.

Limitations :

The rate of release of the drug is directly proportional
to the concentration of ions at the site of action.

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Classification By : Chemical Means
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Activation-
Modulated
DDS
pH-Activated
DDS
Ion-
Activated
DDS
Hydrolysis-
Activated
DDS
Hydrolysis-Activated DDS
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This type of system depends upon hydrolysis
process to activate the release of drug.
Drug reservoir is either encapsulated in
microcapsules or homogeneously dispersed in
microspheres or nano particles for injection.

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It can also be fabricated as an implantable device.
All these systems prepared from bioerodible or
biodegradable polymers (polyanhydride, o-ester).
It is activated by hydrolysis-induced degradation
of polymer chain & is controlled by rate of
polymer degradation.

Ex. LHRH releasing biodegradable subdermal
implant, which is designed to deliver goserline, a
synthetic LHRH analog for once a month
treatment of prostate carcinoma.

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Classification By : Biochemical Means
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Enzyme - Activated Drug Delivery
System

This type of biochemical system depends on the
enzymatic process to activate the release of drug.

Drug reservoir is either physically entrapped in
microspheres or chemically bound to polymer chains
from biopolymers (albumins or polypeptides).

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The release of drug is activated by enzymatic
hydrolysis of biopolymers (albumins or polypeptides)
by specific enzyme in target tissue.
Ex. Albumin microspheres release 5 fluorouracil
in a controlled manner by protease activated
biodegradation.


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Feedback Regulated Drug Delivery System
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In this group the release of drug molecules from
the delivery system is activated by a triggering
agent.
Rate of drug release is controlled by concen. of
triggering agent.

They are further classified as
A. Bioerosion -regulated drug delivery system
B. Bioresponsive drug delivery system
C. Self-regulating drug delivery system
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A. Bioerosion - Regulated DDS
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.Bioresponsive DDS
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in this type, the drug reservoir is contained in a
device enclosed by bio-responsive membrane
whose drug permeability is controlled by conce.
of biochemical agent.

e.g. glucose-triggered insulin drug delivery
system.


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C. Self-Regulating DDS
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This type of system depends on a reversible &
competitive binding mechanism to activate and to
regulate the release of drug.
Drug reservoir is drug complex encapsulated
within a semi permeable polymeric membrane.
The release of drug from the delivery system is
activated by the membrane permeation of
biochemical agent from the tissue in which the
system is located
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Effect Of System Parameters On CDDS
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Polymer & Solution Solubility

Polymer & Solution Diffusivity

Thickness of polymer diffusion path & hydro-
dynamic layer

Partition Co-efficient

Surface Area

Loading Dose
Polymer Solubility
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For drug to be release, the drug molecules on the
outmost surface must dissociate from its crystal
lattice structure, partition or dissolve in
surrounding medium.

As the solubility of drug particles in rate
controlling membrane and polymer matrix plays
rate-controlling role in release from a polymeric
device. To release at an appropriate rate the drug
should have adequate polymer solubility.

Rate of drug release is directly proportional to
magnitude of polymer solubility.

Solution Solubility
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Aqueous solubility varies from one drug to
another.
Difference in aqueous solubility is depend on the
difference in their chemical structure, types &
physicochemical nature of functional groups &
the variations in their stereo chemical
configurations.
Drug release increases with increase in Solution
solubility of drug.

Partition Coefficient
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Partition co-efficient K of a drug for its
interfacial partitioning from the surface of a drug
delivery device towards an elution medium as
given :
K = C
s
/C
p
Where,
C
s
= conc. Of drug at the solution/polymer
interface
C
p
= solubility of drug in the polymer phase.

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Any variation in either C
s
or C
p
result in increase
or decrease in magnitude of K value.
Rate of drug release increase with increase in
partition coefficient
Polymer Diffusivity
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The diffusion of small molecules in a polymer
structure is a energy activated process in which
the diffusant molecules move to a successive
series of equilibrium positions when a sufficient
amount of energy of activation for diffusion E
d
,
has been acquired by the diffusant & its
surrounding polymer matrix.

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Magnitude of polymer diffusivity is dependant
upon type of functional group and type of stereo
chemical position in diffusant molecule.

The bulkier the functional group attached to
polymer chain lower the polymer diffusivity.

Polymer diffusivity also depends on ,
1) Effect of cross linking (inverse relationship)
2) Effect of crystallinity (inverse relationship)
3) Effect of fillers

Solution Diffusivity

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The diffusion of solute molecules in solution
medium is a result of the random motion of
molecules.
Under concentration gradient molecule diffuse
spontaneously from higher concentration to
lower concentration.
Diffusivity of solute molecule in aqueous
solution usually decreases as its concentration
increases
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Thickness of hydro- dynamic diffusion layer

Surface Area

Loading Dose.
Reference
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Novel Drug Delivery System- Y.W.Chien.
published by Marcel Dekkar, inc., New York
Pg no. 17-36 & 57-111

Controlled And Novel Drug Delivery
N.K.Jain CBS Publishers & Distributors, New
Delhi.

www.pharmainfo.net
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