Concept and system design for rate controlled dds

CONCEPT AND SYSTEM DESIGN FOR
RATE-CONTROLLED DDS

PRESENTED BY :
GANDHI SONAM MUKESHCHANDRA
Dept. of Industrial Pharmacy

CONTENTS

 Introduction.
 Defination.
 Advantages.
 Disadvantages.
 Delivery rates.
 Pharmacokinetic consideration.
 Modes of drug release.
 Controlled release therapeutic system.
 Mechanism of control release.

INTRODUCTION
CONTROLLED RELEASE DRUG DELIVERY SYSTEM:

 Controlled drug delivery system has been introduced to overcome
the drawback of fluctuating drugs levels associated with
conventional dosage forms.

 Introduced to be an ideal drug delivery system.

 Development of novel & potent drug delivering system.

 Development of new, better & safe drug with larger therapeutic
index.

 Effective & safer use of existing drugs through concept &
techniques of controlled delivery system.

DEFINATION

Controlled drug delivery system is the
one which delivers the drug at a predetermined
rate, locally or systematically for a specified
period of time.

ADVANTAGES

» Reduction in dosing frequency.
» Reduced fluctuations in circulatory drug
levels.
» Avoidance of night time dosing.
» Increase the patient compliance.
» More uniform effect.
» Decrease side effect like reduced GI irritation.

DISADVANTAGES

» High cost .

» Poor in-vitro & in-vivo correlation.

» Dose dumping.

» Reduced potential for dose adjustment.

» Increases the first pass effect.

 CONTROLLED DRUG DELIVERY SYSTEM:
Controlled drug delivery systems is the one
which delivers the drug at a predetermined rate , locally or
systematically for a specified period of time.
 SUSTAINED DELIVERY SYSTEM:
Sustained delivery systems means the release of active agent is slower than
conventional formulation, but is significantly effected by an external environment.
Ex: enteric coated tablets.

 IMMEDIATE RELEASE DDS :
Release drug immediately in blood to achieve therapeutic effective level.

PLASMA DRUG CONCENTRATION PROFILE:

» HOW TO ACHIVE CONTOLLED- RELEASE DRUG
ADMINISTRATION:-
The therapeutic efficacy of a drug, under clinical
conditions is not simply function of it’s intrinsic
pharmacological activity of equal importance in the path of
drug molecule must taken from the site of administration
to sites of action.
» Various conditions the drug molecules encounter along the
path of distribution may alter either the effectiveness of the
drug or affect the amount of the drug reaching the site of
pharmacologic action.

Concept and system design for rate controlled dds

» As illustrated in the flow diagram all of these intermediate
steps can be grouped & Classified in to three main
branches.

1. Pharmaceutics

2. Biopharmaceutics /Pharmacokinetics

3. Pharmacodynamic/Clinical Pharmacology

DELIVERY RATES
» Most of the release profiles from delivery systems are
categorized in to three main types.
1. zero order release

» In the simplest release pattern called zero order release.
» In zero order release, the delivery rate remains constant.
» The release rate from these devices is given as,

dMt/dt = k
Where,
k is constant, t is time & Mt representing the mass of
active agent released.

2. First order release:
» The release rate is directly proportional to the amount of
active ingredient loaded in device. Mathematically, this
may be represented as:-

dMt/dt=k (Mo-Mt)
Where,
Mo=mass of active moiety in the device.

» This indicated that the release rates declines exponentially
with time & with depletion of active ingredient the release
rate approaches zero.

3. Square-root of time or t-1/2 release:

» Release of drug is linear with the reciprocal of the square
root of times.
» Following equation represents such release profile,

dMt /dt=k/t1/2

» In classes of control release device ,one of these pattern are
used.

absorptio actio
n n

Conventional dosage

action

Control release dosage

Modes of Drug Release

Basically there are three basic modes of drug delivery:-
1) Targeted delivery.
2) Controlled release.
3) Modulated release.

1. Targeted delivery:
It refers to the systemic administration of a
drug carrier with the goal of delivering the drug to specific
cell , tissue or organs .

2. Controlled release:-
It refers to the use of a delivery device with
objective of the releasing the drug in patient body at
predetermined rate .

3. Modulated release:-
It implies use of a drug delivery device that
release the drug at a variable rate, controlled by
environmental condition , biofeedback , sensor input or an
external control device.

Controlled release therapeutic system

It may be passive preprogrammed or active preprogrammed or active self
programmed.

 Passive preprogrammed: -
Category in which the release rate is predetermined & is no influenced
or altered by the external biological environment.

 Active preprogrammed system:-
It include most metered insulin pumps whose release rate can be
regulated by source external to the body.

 Active self-programmed therapeutic system:-
Modulated release rate according to information gathered by the
sensor with changing biological environment like change in blood sugar
level in diabetes.

Controlled release polymeric system can be
classified acc. to the mechanism

Primary control release is achieved by diffusion,
degradation and swelling followed by diffusion.

» Diffusion.
» Swelling.
» Degradation (biodegradation/ bioerodable) system.

CLASIFICATION OF CONTROLLED
RELEASE SYSTEM

I. Rate programmed DDS

II. Activation modulated DDS

III. Feedback regulated DDS

IV. Site-targating DDS

I. Rate preprogrammed DDS:
A) Diffusion controlled or polymer matrix diffusion
controlled DDS
Reservoir system.
Monolithic matrix delivery system.
B) Polymer membrane permeation controlled drug delivery
system
Encapsulation dissolution control .
Matrix dissolution control.
C) Micro reservoir partition controlled drug delivery

II. Activation modulated CCDS:
A) Physical means:
 Osmotic pressure activated DDS
 Hydrodynamic pressure activated DDS
 Vapour pressure activated DDS
 Mechanically activated DDS
 Sonophoresis activated DDS
 Iontophoresis activated DDS
 Hydration activated DDS
B) chemical means:
 pH activated DDS.
 Ion activated DDS.
 Hydrolysis activated DDS.
C) Biochemical means.
 Enzyme activated DDS
 Biochemical activated DDS

I) RATE PROGRAMMED DDS:

» The release of drug molecules from the delivery
system has been preprogrammed at specific rate
profiles.

» This was accomplished by system design, which
controls the molecular diffusion of drug molecules in
and across the barrier medium within or surrounding
the delivery system.

A) Diffusion controlled or polymer-matrix diffusion
controlled DDS:

» These systems are broadly divided into two categories.

1. Reservoir systems.
2. Monolithic systems

1. Reservoir system:
» In membrane controlled reservoir system the
therapeutic agent is contained in a core surrounded
by a thin polymer membrane and the active agent is
released to the surrounding environment by diffusion
process through the rate limiting membrane for the
reservoir type of system.
» These systems consist of a reservoir either solid drug
,dilute solution or highly concentrated drug solution
within a polymer matrix.

Eg:-

Implantable dosage/oral system

Transdermal system

2) Monolithic- matrix delivery system:
In monolithic matrix delivery system the therapeutic
agent is dispersed in polymer matrix and drug release is
controlled by its diffusion from the matrix into the
surrounding environment.

» To formulate such system polymer and active agent are
mixed to form a homogenous system.

» With the passage of time and continuous drug release, the
delivery rate normally decreases in these type of systems.

The basic mechanism of drug release from these two
systems are fundamentally different
Matrix system Reservoir system

• Suitable for both non degradable and • Degradable reservoir system may be
difficult design.
degradable system.

• Achievement of ‘zero order’ release is • Achievement of zero order release is
difficult. easy.

• No danger of dose dumping in case of • Danger of dose dumping .
rapture.
• Very easy to fabricate in wide range of
• very easy to fabricate in a wide range size and shape.
of size and shape .

• Water soluble drugs have a tendency
to burst from the system.

B) Polymer membrane permeation CDDS

1. Encapsulation dissolution control.
2. Matrix dissolution control.

» In this type of system, drug formulation is partially or
totally encapsulated within a drug reservoir compartment.
it is drug release surface is covered by a rate controlling
polymer member having a specific permeability.

» The drug reservoir may exist in solid, suspension or
solution form.

1. Encapsulation dissolution control
» These systems involve coating of individual particle of
drug with a slow dissolution material.
» The coated particles can be compressed directly into tablets
or placed in capsules.

2. Matrix dissolution control:
» In this approach drug is dispersed in a slow dissolving
matrix consist of polymers.

» The rate of penetration of dissolution fluid into the matrix
determines the drug dissolution and subsequent release.

C) Micro Reservoir Partition Controlled DDS:
(dissolution and diffusion controlled release system)

 In such systems, the drug core is enclosed in a partially
soluble membrane. pores are thus created due to
dissolution of parts of the membrane which
permit entry of aqueous medium into the core and hence
drug dissolution.
 Allow diffusion of dissolved drug out of the system.

» The rate of drug release dq/ dt from this DDS is defined by,

II) Activation modulated CDDS:
» In this group of CRDDS, the release of drug molecules
from the delivery system is activated by some physical,
chemical method.

» Biochemical process facilitated by the energy supplied
externally.

1) OSMOTIC PRESSURE ACTIVATED DDS:
» Depends upon osmotic pressure to activate release.

» Rate of release controlled by osmotic gradient.

» Can also be controlled by water permeability, effective
surface area of semi permeable housing.

» E.g. Alzet osmotic pump.

2) HYDRODYNAMIC PRESSURE ACTIVATED DDS:

» It can be fabricated by enclosing a collapsible,
impermeable container which contains a liquid drug
formulation to form drug reservoir compartment.

» A composite laminate of an absorbent layer and a
swellable, hydrophilic polymer layer is sandwiched
between the drug reservoir compartment and housing.

» In the GIT laminate absorbs the GI fluid through the
annular opening at the lower end of housing and
becomes increasingly swollen , which generate
hydrodynamic pressure in the system.

» The hydrodynamic pressure thus created forces the
drugs reservoir component to reduce in volume and
causes the liquid drug formulation to release through
the delivery orifice.

3) VAPOUR PRESSUR ACTIVATED DDS:
» Depends upon vapour pressure.

» Pumping compartment contain fluorocarbon fluid
which vaporized at body temp at implantation site and
create vapour pressure.

» Pressure moves partition upwards and this force causes
the delivery of drug solution.

4) MECHANICALLY ACTIVATED DDS:

 In this system, the drug reservoir solution formulation
retained in a container equipped with a mechanically
activated pumping system.
 A typical example of this type of system is
development of a metered dose nebulizer for intranasal
administration.
 The drug reservoir is contained in a container
equipped with a mechanically activated pumping
system.
 The volume of delivered solution is controllable as
small as 10-100 l.

5) MAGNETICLLY ACTIVATED DDS:
In this type of DDS the drug reservoir is
dispersion of peptide or polymer matrix from which
macromolecular drug can delivered only at a relatively slow
rate . This low rate of delivery can be improved by
incorporation of electromagnetically triggered vibration
mechanism into the polymer delivery device.

6) SONOPHORESIS ADDS:

 In that ultrasonic energy used to activate the delivery of
drug from a polymeric drug delivery device.

 This system is fabricated from either a non-degradable or
bio-degradable polymer.

 The enhanced release was also observed in non erodible
system exposed to ultrasound where the release rate is
diffusion controlled.

7) IONTOPHORESIS ACTIVATED DDS:
» It is defined as the permeation of ionized drug molecule
across biological membrane under the influence of electric
current.
» This type of DDS uses electric current to activate and to
modulate the diffusion of the charged drug molecule across
a biological membrane.
» The iontophoresis facilitate skin permeation rate of a
charged molecule it consist of three components and is
expressed by, Jiisp= Jp +Je
+Jc

8) HYDRATION ACTIVATED DDS (Swelling
controlled system)
» This type of ACDDS depends on the hydration induced
swelling process to activate the drug.

» In this system the drug reservoir is homogeneously
dispersed in a swellable polymer matrix fabricated from a
hydrophilic polymers.

» The release of drug is controlled by the rate of swelling of
polymer.

9) pH ACTIVATED DDS:

• Delivery of drug only in
region of specific PH ranges.
• Drug containing core
fabricated with PH sensitive
polymer combination.
• E.g. in GIT coating
membrane resist action of
gastric fluid & protect
gastric degradation.

10. ION ACTIVATED DDS:
» Ionic or charged drug can only be delivered by this
system.
» System preparation: complexing ionic drugs.
» ( complex of cationic or anionic + resin having
N(CH3)3 groups= system)
» ( Granules of system impregnate the agent (e.g.
polyethylene glycol 4000) that reduce rate of swelling
and then coated by water insoluble membrane.
(ethylene cellulose).
» Membrane works as rate controlling barrier to
modulate influx of ions as well as release of drug from
system.

11) HYDROLYSIS ACTIVATED DDS:

» Depends on hydrolysis to activate the release.

» Can be fabricated as implantable device.

» System prepared from bio-degradable polymers only.

e.g poly (lactic-glycolic), poly (anhydride)

» Release of drug achieved by hydrolysis induced
degradation of polymer chain.

» Rate of release controlled by rate of polymer degradation.

12) ENZYME ACTIVATED DDS:

» Need enzymatic processes to activate release of drug.

» System activates by the enzymatic hydrolysis of bio
polymers by specific enzyme in tissue.

» E.g development of albumin micro sphere that release 5-
flurouracil in controlled manner by protease activated
biodegradation.

III. Feedback regulated DDS:
» Release of drug activates by triggering agent in the body
and also regulated by its concentration via some feedback
mechanism.

» Some feedback regulated systems:

1. Bio-erosion - regulated DDS

2. Bio-responsive - regulated DDS

3. Self regulating DDS

1. Bioerosion regulated DDS:

» Feedback regulated DDS concept applied.

» Consist of drug dispersed bio- erodible polymer ( poly-
vinyl methyl ether)

» Coated with immobilized urease.

» In neutral PH polymer erodes very slowly.

» In presence of urease, urea is converted into ammonia ;
present at surface of system

• Causes increase in PH and rapid degradation of polymer
matrix and also release of drug molecules.

2. Bio responsive DDS:

» Feedback regulated concept.

» Device having drug reservoir enclosed by bio-responsive
polymeric membrane.

» The drug permeability controlled by biochemical agent in
tissue where system is located.

» E.g. glucose-triggered insulin delivery system.

In this system the
amount of drug delivered
is bioresponsive to the
concentration of the
biochemical agent.
The drug reservoir
is enclosed in a polmeric
matrix.

3. Self regulating DDS:
» Depends on reversible and competitive mechanism to
activate and to regulate the release of drug.

» Drug reservoir is drug complex , encapsulated within
semi permeable polymeric membrane.

» Release of drug from delivery system activated by
membrane permeation of biochemical agent from the
tissue in which the system is located.

» This system depends on reversible and competitive
binding mechanism to activate and regulate the release of
drug
» The release of drug depends on the concentratin of the
biochemical agent in the tissue,
» Eg: insulin-sugar-lectin complex.

Effect of System Parameters on CDDS:

» Various parameters which affect the overall controlled
drug release profile are:

1. Polymer solubility.
2. Solution solubility.
3. Partition coefficient.
4. Polymer diffusivity.
5. Solution diffusivity.
6. Drug loading dose
7. Surface area.

Concept and system design for rate controlled dds

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Concept and system design for rate controlled dds