Introduction

Mechanisms of controlled release

Intelligent controlled release DDS
Examples
Recent advances
References

Introduction:

Fluctuating plasma level in conventional DF.

Development of CR ,SR, TR Etc.

Targeted delivery

It
has
goal
of
delivering the drug to
specific cell types,
tissues or organs.

Controlled release
Assigned

to release the DRUG at

a PREDETERMINED Rate.

Modulated release
Release

of drug at a variable
rate controlled by
Environmental conditions,
Biofeedback,
Sensor input
External control device.

Sustained release (SR)

In SR Drug release is affected by

External environment.
- Release is slow than
conventional DF.

In CR Release is dependant on the

design of dosage form.

DRUG RELEASE MODULATION

ADVANTAGES

DISADVANTAGES

DRUGS UNSUITABLE FOR CR

Different controlled release systems

Burst like release

Pulsatile release
Zero order (linear) release

Cumulative
release

Diffusion controlled release

Lag followed by
Burst release

Time of release

FACTORS GOVERNING THE DESIGN OF CR

DOSAGE FORMS

Drug related
II. Biological
III. Physiological
IV. Pharmacokinetic
V. Pharmacological
I.

FACTORS GOVERNING THE DESIGN OF CR

DOSAGE FORMS

aqueous solubility

partition coefficient

Drug
Drugrelated
related

protein binding

molecular size

drug stability

FACTORS GOVERNING THE DESIGN OF CR

DOSAGE FORMS

absorption

disease state

distribution

Biological

side effects

elimination

duration of action
margin of safety

FACTORS GOVERNING THE DESIGN OF CR

DOSAGE FORMS

variability on GI
emptying & motility

prolonged drug absorption

Physiological

GI blood flow

FACTORS GOVERNING THE DESIGN OF CR

DOSAGE FORMS

dose dumping

first pass metabolism

Pharmacokinetic

variability of urinary pH
effect on drug elimination

FACTORS GOVERNING THE DESIGN OF CR

DOSAGE FORMS
changes in drug effect
upon multiple dosing

Pharmacological

Sensitivity / tolerance

BASIC PRINCIPLES OF CR
DIFFUSION
SWELLING
BIODEGRADABLE

BIOERODIBLE

or

Schematic depiction of various

classes of controlled release system
Reservoir and monolithic
Matrix
Reservoir

Chemically

Environmental

Matrix

Dissolution

Diffusion

Diffusion and Dissolution

Ion exchange resin

cation

Encapsulation

Controlled
release system

anion

Water penetration controlled

osmotically
Hydrogel

Swelling

Diffusion

Swelling

Chemically controlled
Erodible

Drug linked
polymer

DIFFUSION CONTROLLED SYSTEMS

MONOLITHIC-MATRIX SYSTEMS

Drug
+
polymer

MONOLITHIC-MATRIX SYSTEMS
Materials used as retardants in matrix tablet
formulations :-

MATRIX
CHARACTERISTICS

MATERIAL

Polyethylene
Insoluble, inert
Polyvinyl chloride
matrix
Ethylcellulose
Carnauba wax
Insoluble, Polyethylene glycol
erodable

Castor wax
Methyl cellulose

hydrophilic

Carboxypolymethylene
Sodium alginate
HPMC

RESERVOIR SYSTEMS
Oral system

RESERVOIR SYSTEMS
First layer
Of the drug
crystals

Polymer
phase

Diffusion
layer

DIFFUSION CONTROLLED SYSTEMS

Matrix system
o

Achievement of zero order

is difficult
Suitable for both
degradable & nondegradable systems

Reservoir system

No danger of dose dumping

Not all drugs can be blended
with a given polymeric
matrix

Achievement of zero order

is easy
Degradable
reservoir
systems may be difficult to
design
Rupture
can
result
in
dangerous dose dumping
Drug inactivation by contact
with the polymeric matrix
can be avoided

COMBINED RESERVOIR-MONOLITHIC
SYSTEMS
Phase I outer membrane layers
Phase II reservoir matrix material

Outer membrane layer (phase I)

Dispersed agent in polymer matrix
(phase II)

COMBINED RESERVOIR-MONOLITHIC
SYSTEMS
Monolithic
Matrix (phase
II)

Outer membrane
(phase I)

Initially the release rate of diffusion

through the phase 1 ,as the time progress
,a layer depleted from the active agent is
generated in phase 11 reservoir material
immediately adjacent to the membrane
layer.

Agent
loaded
Matrix
layer

Agent
depleted
Matrix
layer

DISSOLUTION CONTROLLED RELEASE SYSTEMS

Two

classes:
Encapsulation dissolution
control
Matrix dissolution control

Matrix dissolution control

membrane

drug
Membrane controlled

Polymer erosion controlled

DIFFUSION & DISSOLUTION

CONTROLLED SYSTEMS

membrane

Release rate is dependent

on
surface

area
diffusion coefficient of
drug though pore in
coating
conc. of drug in
dissolution media.

drug

WATER PENETRATION CONTROLLED SYSTEMS

rate

control is obtained by
penetration of water into the
system.
classified into 2 parts.
swelling controlled systems
osmotically controlled
systems

SWELLING CONTROLLED SYSTEM

Non-fickian

case II type diffusion

Swollen
matrix

solvent

Swelling zone
Unswollen
polymer matrix

CHEMICALLY CONTROLLED SYSTEMS

delivery systems that change their

chemical structure , when exposed to
biological milieu
This system include biodegradable
polymer that degrade within body as a
result of natural biological process
,eliminating the need to remove the
delivery system after exhausting of
active agent from system

CHEMICALLY CONTROLLED SYSTEMS

The polymer degradation by 2 ways:

Bulk erosion surface erosion

MECHANISM OF POLYMER EROSION

Type IA cleavage of cross links

Type IB disintegration of water soluble polymer backbone

MECHANISM OF POLYMER EROSION

Type II Water insoluble macromolecules are converted into
water soluble compounds by hydrolysis, ionization or
protonation of a pendent group.

hydrolysis
Ionization
protonation
Water insoluble molecules

Water soluble molecules

MECHANISM OF POLYMER EROSION

Type III erosion mechanisim

Hydrolytic
cleavage
Water insoluble molecules

Water soluble molecules

MECHANISM OF DRUG RELEASE

bioactive covalently linked to
polymer backbone , scission of
the bonds connecting the drug to
polymer backbone.

List of biodegradable polymer

Polylactides

(PLA).
Polyglycolides (PGA).
Poly(lactide-co-glycolides)
(PLGA).
Polyanhydrides.
Polyorthoesters.

HYDROGELS
Hydrogels

are water
swollen three dimensional
structures composed of
primarily
hydrophilic
polymers.

HYDROGELS
Classification:-

1) Diffusion controlled release

- reservoir
- matrix

2) Chemically controlled release

- biodegradable polymers
- covalently linked drug & polymer

3) Swelling controlled release

4) Environmentally responsive hydrogel
systems

HYDROGELS
Swelling controlled release

consists of drug dispersion within glassy

polymer matrix. When the system comes in
contact with biofluids, it starts swelling.
Swollen gel
water
Glassy
polymer

Drug release

Environmentally responsive hydrogel

systems

T
pH

pH

The changes in network structure in

response to external environment are
reversible in nature.

Type of hydrogel

Super porous hydrogel

pH sensitive hydrogel
Temperature sensitive hydrogel
Glucose sensitive system
Neutral hydrogel
Oral insulin hydrogel

Super porous hydrogel

Mainly for speedy
swelling
Carried out by
making very fine
particle of dried
hydrogel having
short diffusion path
length

Electronic microscopic fig of super

porous hydrogel

Recent application of super porous

gel in drug delivery

DEVELOPMENT OF GASTRIC
RETENTION DEVICES
Development of fast dissolving tablet
Development per oral peptide delivery
system

ION-EXCHANGE RESIN

Zero order release obtained

kinetics Drug release depends only on

the ionic environment of the resins
containing drug

2 types.- cation exchange resin & anion

exchange resin.

CATION EXCHANGE RESIN :

Synthesized by copolymerization of divinyl

benzene & styrene.
CH

CH

CH2

CH2

SO3H
CH CH2

CH

CH2

CH

CH2

CH

CH2

CH

SO3H

CH
CH2

CH

CH2

CH

CH2

CH

divinyl benzene
SO3H

CH
CH2

CH

CH

styrene

SO3H
CH2

CH

SO3H

CH2

CH

CH

CH
CH2

Anion exchange resin

is
prepared
by
chloromethylation
of
benzene rings of three
dimensional
styrenedivinyl benzene copolymer
network
leading
to
insertion of CH2Cl groups
& forms strong anion
exchange resin.

CH

CH2 CH CH2 CH

Cl- (CH3)3N+CH2

CH

CH2N+(CH3)3Cl-

CH

CH2 CH

CH2

CH2

CH2N+(CH3)3Cl-

CH
CH2

CH

CH

CH2 CH CH2

CH

CH2

CH

CH2N+(CH3)3Cl- CH

CH

CH2N+(CH3)3Cl- CH

CH2

INTELLIGENT CONTROLLED RELEASE DRUG DELIVERY

SYSTEMS:

Provide the bioactive in response

to the physiological need & should
sense the changes & manipulate
the drug release in response to
external
stimuli
like
heat,
ultrasound, magnetic field, pH
and/or
conc.
of
specific
molecules.

:CLASSIFICATION:
pH sensitive
thermosensitive

electically regulated
ultrasonically modulated

pulsatile systems

responsive systems

magnetically modulated
photoresponsive

inflammation responsive
Glucose sensitive

INTELLIGENT
CONTROLLED
RELEASE SYSTEMS
urea responsive

systems utilizing
chelation

systems utilizing
antibodies

systems utilizing
enzymes
glucose responsive

PULSATILE SYSTEMS :-

Magnetically modulated systems :-

No applied
field

Field turn on

Drug release

RESPONSIVE SYSTEMS

Glucose sensitive polymers :-

Glucose in

Glycosylated insulin out

Polymer membrane
Concavalin A

Sepharose 4B beads
glucose
Glycosylated insulin

RESPONSIVE SYSTEMS

Glucose sensitive polymers :-

Polymer A

Polymer B

insulin

glucose

microcapsule
release

SYSTEMS UTILIZING ENZYMES

a) Urea responsive delivery

systems
Urea is converted into NH4HCO3

&
NH4OH by the action of urease that increases the pH.

Hydrogel prepared by immobilizing

urease
In cross-linked bovine serum albumin
N-hyxyl half ester with dispersed drug

SYSTEMS UTILIZING ENZYMES

b) Glucose responsive insulin

delivery : This system utilizes enzyme-glucose
oxidase which converts glucose into
gluconic acid.
Glucose + O2 gluconic acid + H2O
G

G
NR2

NR2

GluOx

NR2

NR2
NR2

NR2

NR2

NR2

GluOx

HNR2

HNR2

GluOx
G

NR2

NR2

HNR2

HNR2

G
NR2

GluOx

NR2

GluOx

HNR2

HNR2

SYSTEMS UTILIZING ENZYMES

b) Glucose responsive insulin delivery :-

GOD

GOD

GOD

GOD

glucose
-

OOC

COO-

insulin

HOOC

COOH

insulin

insulin

Examples:

Insulin

pump,Gluco
watch

An insulin reservoir (like a

regular syringe)
A small battery operated pump
A computer chip for control
Combination with Glucose
sensors

Recent information
Polymer therapeutics
covers natural or synthetic polymers,
which have either inherent therapeutic potential or
carry covalently bonded drugs.
The covalently bonded drugs have to be released at
the desired tissue or cell type. Polymeric therapeutics are
e.g.
polymeric drugs,
polymer-protein conjugates,
polymer-DNA complexes,
polymer-drug conjugates or
polymeric micelles.

Chemo mechanical polymer drug

delivery system

Chemomechanical polymers, developed by

Professor Hans-Jorg Schneider and his team
at the University of Saarland, Germany, have
greatly improved functionality compared to
existing expanding / contracting materials
used to perform biomedical functions, and
could be used in applications such as
actuators, implants, drug release systems and
drug screening.

New polymer enables near zero order drug

release
Cavilink
Highly

TMd

porous polymer micro

bead

Advance technologies in modified release

from dosage form

TIMERx MASRx & COSRx systems

Procise (comprised of a compression coated

core) Drug Delivery Systems Based on
Geometric Configuration

Ringcap Technology tablets

Advance technologies in modified

release from dosage form
Smartrix system multiple layered tab.
Novel Erosion-Controlled Oral Delivery
System
Theriform Technology novel method of
fabrication based on three dimensional
printing, a solid freeform fabrication
technology- implants
Accudep technology layered capsules

Advance technologies in modified release

from dosage form

Threeform technology ,- Meltrex technology

melt extrusion process
Dissocubes ,IDD technology insoluble drug
delivery technology
Zydis oral fast dissolving dosage form.
Orasolv & Durasolv efficient technologies
for production of orally disintegrating
tablets.

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S.P.Vyas, R.K.Khar, Controlled drug delivery- concepts &

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G.S.Banker, Modern Pharmaceutics, 3rd edition, 575
Chien Y.W., Novel fundamentals, developmental concepts,
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Robinson & Lee, controlled drug delivery: fundamentals and
applications, 2nd edition.
Donald L.Wise, Handbook of Pharmaceutical controlled
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Praveen Tyle , drug delivery devices: fundamentals and
applications, Marcel Dekker, 326-363, 376-382.
James Swarbrick, James C. Boylan, Encyclopedia of
Pharmaceutical Technology, Marcel Dekker, III, 282, 297311.

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Leon Lachman, The Theory and Practice of Industrial
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www.glucowatch.com
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