Transcript Controlled Release Oral Drug Delivery System Dr. Basavaraj K. Nanjwade M. Pharm., Ph.

Controlled Release Oral
Drug Delivery System
Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D.
Dept of Pharmaceutics
KLE University College of Pharmacy
Belgaum-590010, karnataka, India
Cell No: 00919742431000
E-mail: [email protected]
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Contents
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Overview of Digestive system
Introduction
Advantages
Disadvantages
Dissolution
Diffusion
Combination of Dissolution & Diffusion
Osmotic pressure controlled system
Hydrodynamically balanced systems
pH controlled
Ion exchange controlled systems
References
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Concept
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Controlled drug delivery is one which delivers
the drug at a predetermined rate, for locally or
systemically, for a specified period of time.
Continuous oral delivery of drugs at
predictable
& reproducible kinetics for
predetermined period throughout the course of
GIT.
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Controlled Release System
Matrix
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Plasma concentration time profile
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Challenges in Oral Drug Delivery
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Development of drug delivery system
Delivering a drug at therapeutically effective
rate to desirable site.
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Modulation of GI transit time
Transportation of drug to target site.
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Minimization of first pass elimination
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Advantages
 Total dose is low.
 Reduced GI side effects.
 Reduced dosing frequency.
 Better patient acceptance and compliance.
 Less fluctuation at plasma drug levels.
 More uniform drug effect
 Improved efficacy/safety ratio.
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Disadvantages
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Dose dumping.
Reduced potential for accurate dose
adjustment.
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Need of additional patient education.
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Stability problem.
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Mechanism aspects of Oral drug
delivery formulation
1.Dissolution : 1. Matrix
2. Encapsulation
2.Diffusion :
1. Matrix
2. Reservoir
3.Combination of both dissolution & diffusion.
4.Osmotic pressure controlled system
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Dissolution Definition
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Solid substances solubilizes in a given solvent.
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Mass transfer from solid to liquid.
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Rate determining step: Diffusion from solid to
liquid.
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Several theories to explain dissolution –
Diffusion layer theory (imp)
Surface renewal theory
Limited solvation theory.
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Noyes Whitney Equation
dc/dt = kD.A (Cs – C )
dc/dt = D/h A. (Cs – C)
dc/dt = Dissolution rate.
k= Dissolution rate constant (1st order).
D = Diffusion coefficient/diffusivity
Cs = Saturation/ maximum drug solubility.
C =Con. Of drug in bulk solution.
Cs-C=concentration gradient.
h =Thickness of diffusion layer.
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Matrix Type
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Also called as Monolith dissolution
controlled system.
Controlled dissolution by:
1.Altering porosity of tablet.
2.Decreasing its wettebility.
3.Dissolving at slower rate.
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First order drug release.
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Drug release determined by
dissolution rate of polymer.
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Eg. Dimetane extencaps, Dimetapp
extentabs.
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Soluble drug
Slowly
dissolving
matrix
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Matrix devices
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In this system the solid drug dispersed in
to the insoluble matrix.
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Encapsulation
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Called as Coating dissolution
controlled system.
Soluble drug
Dissolution rate of coat depends
upon stability & thickness of
coating.
Masks
colour,odour,taste,minimising
GI irritation.
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One of the microencapsulation
method is used.
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Eg. Ornade spansules,
Chlortrimeton Repetabs
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Slowly
dissolving
or erodible
coat
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Diffusion
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Major process for absorption.
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No energy required.
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Drug molecules diffuse from a region of higher
concentration to lower concentration until equilibrium is
attainded.
Directly proportional to the concentration gradient
across the membrane.
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Matrix Diffusion Types
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Rigid Matrix Diffusion
Materials used are insoluble plastics such as PVP & fatty
acids.
Swellable Matrix Diffusion
1. Also called as Glassy hydrogels.Popular for sustaining
the release of highly water soluble drugs.
2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum,Tragacanth.
Semisynthetic -HPMC,CMC,Xanthum gum.
Synthetic -Polyacrilamides.
Examples: Glucotrol XL, Procardia XL
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Matrix system
Rate controlling
step:
Diffusion of dissolved
drug in matrix.
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Advantage and Disadvantage of
Matrix and Reservoir system
Matrix system
1.
Suitable for both nondegradable and degradable
system.
2.
No danger of ‘dose
dumping’ in case of
rupture.
Reservoir system
1.
Degradable reservoir
systems may be difficult to
design.
2.
Rupture can result in
dangerous ‘dose dumping’
3.
3.
Achievement of ‘zero
order’ release is difficult
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Achievement of ‘zero
order’ release is easy.
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Methods to develop the Reservoir devices
a) Press coating (slowly soluble films and coating)
b) Air suspension techniques
• The microencapsulation process is commonly used procedure
to drug particle incorporated in to tablet or capsule.
• In most cases drug is incorporated in coating film as well as in
the microcapsule.
• The care should be taken during placement into tablet or
capsule dosage forms to minimize fragmentation or fusion of
the particle both effects will alter release characteristics.
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Factor effecting constant drug release
•
Polymer ratio in the coating
The increase the polymer ratio decrease in drug release due to
leaching effect.
•
Film thickness
The drug release rate from an insoluble membrane is expected to
increase as the membrane thickness decreases.
•
Hardness of microcapsule
The hardness of microcapsule increase, prolong the time of drug
release.
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Higuchi Equation
Q = DE/T (2A.E Cs)Cs.t)1/2
Where ,
Q=amt of drug release per unit surface area at time t.
D=diffusion coefficient of drug in the release medium.
E=porosity of matrix.
Cs=solubility of drug in release medium.
T=tortuosity of matrix.
A=concentration of drug present in matrix per unit
volume.
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Reservoir System
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Also called as Laminated matrix device.
Hollow system containing an inner core surrounded
in water insoluble membrane.
Polymer can be applied by coating or micro
encapsulation.
Rate controlling mechanism - partitioning into
membrane with subsequent release into surrounding
fluid by diffusion.
Commonly used polymers - HPC, ethyl cellulose &
polyvinyl acetate.
Examples: Nico-400, Nitro-Bid
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Reservoir System
Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.
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Dissolution & Diffusion
Controlled Release system
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Drug encased in a partially soluble
membrane.
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Pores are created due to dissolution
of parts of membrane.
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It permits entry of aqueous medium
into core & drug dissolution.
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Diffusion of dissolved drug out of
system.
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Eg. Ethyl cellulose & PVP mixture
dissolves in water & create pores of
insoluble ethyl cellulose membrane.
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Insoluble
membrane
Entry of
dissolution
fluid
Drug
diffusion
Pore created by
dissolution of
soluble fraction of
membrane
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Osmotic Pressure Controlled
Drug Delivery System
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Introduction
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The oral drug delivery has been popular most widely
utilized route of administration among all the routes that
have been explored for the systemic delivery of drugs.
The bioavailability of drug from these formulations may
vary significantly, depending on factors such as physicochemical properties of the drug, presence of excipients etc.
The drug release can be modulated by different ways but
the most of novel drug delivery systems are prepared using
matrix, reservoir or osmotic principle.
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Introduction
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Osmotic pressure is used as driving force for these
systems to release the drug in controlled manner.
Osmotic drug delivery technique is the most interesting
and widely acceptable among all other technologies used
for the same.
These systems can be used for both route of
administration i.e. oral and parenterals. Oral osmotic
systems are known as gastro-intestinal therapeutic
systems (GITS).
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Principle
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Here osmotic pressure is used as the power/source or energy to
activate and control the release of drug from the device. In this
system, the drug reservoir contains the drug either in the form of
solid or as solution, which is enclosed within a semipermiable
housing having controlled water permeability. The drug is activated
to release in solution form at a constant rate through a special
delivery orifice.

The rate of drug release is modulated by controlling the gradient of
osmotic pressure.(i.e. differences in osmotic pressure b/w the drug
delivery system and the external environment)
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Oral controlled release:
Osmotic tablet technology
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Once- or twice-daily dosing regimens for crystalline and enhancedbioavailability drugs is often desired and needed to maximize
therapeutic effect, patient safety, and compliance.
Bend Research has developed two proprietary tablet technologies
that provide drug release in a predictable, reliable manner. Both
dosage forms are driven by osmotic/hydrostatic pressure and
provide steady-state, zero-order release that is generally
independent of GI pH and agitation.
These attributes minimize patient-to-patient variability and allow
accurate prediction of in vivo performance from in vitro dissolution
testing. A wide range of release rates is possible.
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Osmotic swellable-core
technology
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A
bi-layer
tablet
containing an insoluble,
semipermeable coating
with a delivery orifice
Preferred API and dose:
poorly water soluble, or
bioavailability-enhanced
forms ; low to moderate
dose.
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Osmotic asymmetric membrane
technology
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A single-layer tablet containing an
insoluble,
asymmetric
microporous
coating produced by controlled phase
separation
Preferred API and dose: water soluble;
low to high dose.
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Oral osmotic pumps
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Controlled porosity osmotic pump
Osmotic bursting osmotic pump
Osmotic pump for insoluble drugs
Delayed Delivery Osmotic
device
Telescopic capsule
Oros CT (Colon
Targeting)
Sandwiched oral
therapeutic system
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Elementary osmotic pump
It is simplest possible form of osmotic pump as it does
not require special equipment and technology. It can
be mass –produced economically using ordinary
tabletting and coating machine and a facility to drill an
orifice.
The elementary osmotic pump consists of an osmotic
core containing drug, which is coated with a
semipermiable membrane, usually cellulose acetate,
with a delivery orifice.
The core may or may not contain an osmotic agent depending
on the osmotic activity of the drug. When exposed to aqueous
environment, the core imbibes water osmotically at a
controlled rate through the semipermiable membrane,
forming a saturated drug solution inside the system. The
membrane being non-extensible, internal volume of the
pump remains constant.
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Elementary osmotic pump
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Elementary osmotic pump
The system delivers, via the orifice, in
any time interval, a volume of saturated
solution of drug equal to volume of water
uptake. This process is continues at a
constant rate until all solid drug inside the
tablet has been dissolved and only a
solution filled shell remains.
The residual dissolved drug
continues to be delivered, but at a
declining rate, until the osmotic
pressure inside and outside the
pump is equal.
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Acutrim tablet
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It is an oral osmotic pressure controlled G.I. DDS. this systems are
fabricated by encapsulating an osmotic drug core containing an
osmotically active drug or a combination of an osmotically inactive
drug with an osmotically active salt like Nacl, within a
semipermiable membrane made from cellulose acetate polymer.
A delivery orifice with a controlled diameter is drilled, using a laser
beam, through the coating membrane for controlling the drug release.
The polymer membrane is not only semipermiable in nature but is
also rigid & capable of maintaining the structural integrity of the G.I.
DDS during the course of drug release. It is permeable to the influx of
water in G.I.T. but impermeable to drug solutes.
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Acutrim tablet
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It is a solid tablet of
water soluble and
osmotically active
phenylpropanolamine
(PPA) HCl enclosed
within a semipermiable
membrane made from
cellulose triacetate. The
surface of the
semipermiable membrane
is further coated with a
thin layer of PPA dose for
immediate release.
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In the GIT, the GI fluid
dissolves the immediately
releasable PPA layer,which
provides an initial dose of
PPA, and its water
component then penetrates
through the semipermiable
membrane at a rate
determined by PwAm/hm to
dissolve the controlled
release dose of PPA. Under
the osmotic pressure
differential created (πs-πe),
the PPA solution is
delivered continuously at a
controlled ratethrough an
orifice predrilled by a laser
beam.
It is designed to
provide a controlled
delivery of PPA over
a duration of 16hr for
appetite suppression
in a weight control
program. The same
delivery system has
also been utilized for
the oral controlled
delivery of
Indomethacin.
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Modifications
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The external surface of the semipermiable membrane can be coated with a
layer of bioerodable polymer like enteric coating, it regulate the penetration of
GI fluid through the semipermiable membrane & target the delivery of a drug
to the lower region of the GIT.
The coating membrane of the DDS can be constructed from a laminate of two
or more semipermiable membranes with differential permeabilities.
The osmotic pressure controlled GI delivery system can be further modified to
constitute two compartments separated by a movable partition. The
osmotically active compartment absorbs water from GI fluid to creat an
osmotic pressure that acts on the partition forces it to move upward and to
reduce the volume of the drug reservoir compartment and to release the drug
formulation through the delivery orifice .
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Modifications
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Modifications

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This system has been applied to the development of a
GI-delivery system for the oral controlled delivery of
Nifedipine .
Further more, a two compartment GI-delivery system
has been applied to the simultaneously GI-controlled
delivery of two drugs, such as Oxprenolol sebacinate
and Hydralazine HCl, from separate compartment,
simultaneously and independently at different
delivery rates.
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Push pull osmotic pump
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Push pull osmotic pump is a modified EOP. through, which it is possible to
deliver both poorly water-soluble and highly water soluble drugs at a constant
rate.
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This system resembles a standard bilayer coated tablet. One layer (depict as the
upper layer) contains drug in a formulation of polymeric, osmotic agent and
other tablet excipients.
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This polymeric osmotic agent has the ability to form a suspension of drug in
situ. When this tablet later imbibes water, the other layer contains osmotic and
colouring agents, polymer and tablet excipients. These layer are formed and
bonded together by tablet compression to form a single bilayer core. The tablet
core is then coated with semipermeable membrane.
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Push pull osmotic pump
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Push pull osmotic pump
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After the coating has been applied, a small hole is drilled through
the membrane by a laser or mechanical drill on the drug layer
side of the tablet.
When the system is placed in aqueous environment water is
attracted into the tablet by an osmotic agent in both the layers.
The osmotic attraction in the drug layer pulls water into the
compartment to form in situ a suspension of drug.
The osmotic agent in the non-drug layer simultaneously attract
water into that compartment, causing it to expand volumetrically
and the expansion of non drug layer pushes the drug suspension
out of the delivery orifice.
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Osmotic pump with nonexpanding second chamber

The second category of multi-chamber devices comprises system
containing a non-expanding second chamber. This group can be
divided into two sub groups, depending on the function of second
chamber.

In one category of these devices, the second chamber is used to
dilute the drug solution leaving the devices. This is useful because
in some cases if the drug leaves the oral osmotic devices in a
saturated solution, irritation of GI tract is a risk.
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Osmotic pump with nonexpanding second chamber
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Example: - The problem that lead to withdrawal of
osmosin, the device consist of a normal drug
containing porous tablet from which drug is released as
a saturated solution. However before the drug can
escape from the device it must pass through a second
chamber.
Water is also drawn osmotically into this chamber
either because of osmotic pressure of drug solution or
because the second chamber contain, water soluble
diluents such as NaCl.
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Osmotic pump with nonexpanding second chamber

This type of devices consist of two rigid chamber, the first
chamber contains a biologically inert osmotic agent, such as sugar
or a simple salt like sodium chloride, the second chamber contains
the drug. In use water is drawn into both the chamber through the
surrounding semi permeable membrane.

The solution of osmotic agent formed in the first chamber then
passes through the connecting hole to the drug chamber where it
mixes with the drug solution before exiting through the micro
porous membrane that form a part of wall surrounding the
chamber. The device could be used to deliver relatively insoluble
drugs.
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Osmotic bursting pump
 This system is similar to an EOP except delivery orifice is
absent and size may be smaller. When it is placed in an aqueous
environment, water is imbibed and hydraulic pressure is built up
inside until the wall rupture and the content are released to the
environment.
 Varying the thickness as well as the area the semipermeable
membrane can control release of drug. This system is useful to
provide pulsated release.
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Controlled Porosity Osmotic
Pumps
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In this type two layers of membrane are applied on pumps .

The inner is microporous membrane, which is made up of
cellulosic material containing some pore forming agents. A
semipermeable membrane cover this layer.

When the system is placed in an aqueous environment the
soluble components of first layer of coating dissolve, resulting
in a microporous , which provides greater flux of water into the
system.
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Pumps for insoluble drugs
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In this system particles of osmotic agents are coated with an
elastic semipermeable membrane.
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These coated particles are then mixed with the relatively
insoluble drug and tableted and coated with the rigid
semipermeable membrane in usual way.

When this system is placed in an aqueous environment, water is
drawn through the two membranes in-turn into the osmotic
agent particles, which swell and hydrostatic force delivers the
insoluble drug out of the pump.
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Sandwiched osmotic tablets

It is composed of polymeric push layer sandwiched
between two drug layers with two delivery orifices.

When placed in the aqueous environment the middle
push layer containing the swelling agents swells and the
drug is released from the two orifices situated on
opposite sides of the tablet and thus SOTS can be
suitable for drugs prone to cause local irritation of the
gastric mucosa.
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Sandwiched osmotic tablets
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Osmotic Pressure Controlled
System
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Osmotic Pressure Controlled
System
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Advantages

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Osmotic drug delivery system for oral and parenteral use offer
distinct and practical advantage over other means of delivery. The
following advantages contributed to the popularity of osmotic drug
delivery system.
They typically give a zero order release profile after an initial lag.
Deliveries may be delayed or pulsed if desired.
Drug release is independent of gastric pH and hydrodynamic
condition.
They are well characterized and understood.
The release mechanisms are not dependent on drug.
A high degree of in-vitro and in vivo correlation .
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Advantages & Disadvantages

The rationale for this approach is that the presence of water in
GIT is relatively constant, at least in terms of the amount
required for activation and controlling osmotically base
technologies.
Disadvantages
 Costly .
 If the coating process is not well controlled there is a risk of
film defects, which results in dose dumping.
 Size hole is critical .
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Marketed products
Product name
Active
Design
Acutrim
Phenylpropanola
mine
Elementary pump 75 mg
Alpress LP
Prazosin
Push-pull
2.5-5 mg
Cardura XL
Doxazosin
Push-pull
4.8 mg
Ditropan XL
Oxybutinine
chloride
Push-pull
5, 10 mg
Efidac 24
Pseudoephedrine
Elementary pump 60 mg , 180 mg
Glucotrol XL
Glipizide
Push-pull
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Dose
5, 10 mg
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Introduction



This system is either capsule or tablet form is designed to prolong GI
residence time in an area of the GIT to maximize drug reaching its
absorption site in solution state & hence ready for absorption.
Hydrodynamically balanced system are also known as floating drug
delivery system. HBS have a bulk density lower than gastric fluid &
hence remain floating in the stomach.
This is a hydration activated drug delivery system depends on the
hydration induced swelling process to activate the release of drug. In
this system the reservior is homogenously dispersed in a swellable
polymer matrix fabricated from a hydrophilic polymer.
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Principle
• In GIT the laminate absorb GI fluids & become
increasingly swollen , which generate hydrodynamic
pressure in the system,the hydrodynamic pressure thus
created forces the drug reservior compartment to reduce in
volume and causes the liquid drug formulation to release
through the delivery orifice at a rate defined by :-
• Q / t=Pf Am/ hm ( qs - qe)
• Where, Pf = Fluid permeability, Am = Effective surface
area , hm= Thickness of wall with annular openings,
( qs - qe)= Difference in the hydrodynamic pressure
between the drug delivery system( qs ) & the environment
(qe).
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Principle

Hydrodynamic pressure activated drug delivery system
can be fabricated by enclosing a collapsible,
impermeable container, which contains a liquid drug
formulation to form a drug reservoir compartment inside
a rigid shape retaining housing a composite laminate of
an absorbent layer and a swellable, hydrophilic polymer
layer is sandwiched between the drug reservoir
compartment and the housing.
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Principle
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



Rate controlling factors:
Fluid permeability ,
Effective area of wall with openings ,
Hydrodynamic pressure gradient.
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Formulation
and
development
of
Hydrodynamically balanced system (HBS)
or Floating drug delivery system(FDDS)
Selection of drug
candidate:
1.Drugs which are
predominantly absorbed from
upper part of GIT.
2. drugs which are acting locally
on stomach.
3. drugs those are poorly soluble
at alkaline pH.
4.drugs that degrade in the colon.
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Three major requirements for
FDDS formulation:
1. It must form a cohesive gel
barrier.
2.Specific gravity lower than
gastric content(1.004-1.010).
3. Release content slowly to
serve as a reservoir.
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FORMULATION
20-75% w/w of one or more gel forming hydrocolloid are
incorporated into the formulation and then compressing
these granules into a tablet (or encapsulating into
capsules).
e.g., Hydroxy ethyl cellulose,
Hydroxy propyl cellulose,
Hydroxy propyl methyl cellulose &
Sodium carboxy methyl cellulose.
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Classification of FDDS
Types of FDDS
depending on the use
of 2 formulation
variables
EFFERVESCENT
FLOATING
DOSAGE
FORMS
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NONEFFERVESCENT
FLOATING
DOSAGE FORMS
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EFFERVESCENT FLOATING
DOSAGE FORMS




These floating drug delivery system employ matrices from swellable polymers like
Methocel or Chitosan & effervescent components such as Sodium bicarbonate &
Tartaric or Citric acid or matrices having chambers of liquid components that
gasify at body temperature.
The matrices are prepared in such a manner that when they come in contact with
stomach fluid , CO2 is generated, & retained entrapped in hydrocolloid gel.
This leads to an upward flow of the dosage form and maintains it in a floating
condition.
A single layered tablet can be prepared by initially mixing the CO2 generating
component in tablet matrix. A bilayered tablet may be compressed in which gas
liberating component is present in hydrocolloid layer and the drug is compressed
in other layer of sustain release
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Multiple type of floating dosage
system




Multiple type of floating dosage system composed of effervescent layers and
swellable membrane layers coated on sustained release pills.
The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid
was divided into 2 sublayers to avoid direct contact between the 2 agents. These
sublayers were surrounded by a swellable polymer membrane containing polyvinyl
acetate and purified shellac.
When this system was immersed in the buffer at 37ºC, it settled down and the solution
permeated into the effervescent layer through the outer swellable membrane. CO2 was
generated by the neutralization reaction between the 2 effervescent agents, producing
swollen pills (like balloons) with a density less than 1.0 g/mL.
It was found that the system had good floating ability independent of pH and
viscosity and the drug (para-amino benzoic acid) released in a sustained
manner(Figure ,A and B).
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Multiple type of floating dosage
system
Figure . (A) Multiple-unit oral floating drug delivery system. (B)
Working principle of effervescent floating drug delivery system.
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Triple-layer tablet floating
dosage system

Swellable asymmetric triple-layer tablet with floating ability to prolong the
gastric residence time of triple drug regimen (tetracycline, metronidazole,
and clarithromycin) in Helicobacter pylori–associated peptic ulcers using
hydroxy propyl methyl cellulose (HPMC) and poly ethylene oxide (PEO) as
the rate-controlling polymeric membrane excipients.

The design of the delivery system was based on the swellable asymmetric
triple-layer tablet approach. HPMC and PEO were the major rate-controlling
polymeric excipients.

Tetracycline and metronidazole were incorporated into the core layer of the
triple-layer matrix for controlled delivery, while bismuth salt was included in
one of the outer layers for instant release.
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Triple-layer tablet floating
dosage system

The floatation was accomplished by incorporating a gas-generating layer
consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with
the polymers.

The in vitro results revealed that the sustained delivery of tetracycline and
metronidazole over 6 to 8 hours could be achieved while the tablet remained
afloat.

The floating feature aided in prolonging the gastric residence time of this
system to maintain high-localized concentration of tetracycline and
metronidazole.
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Triple-layer tablet floating
dosage system
Figure- Schematic presentation of working of a triple-layer system. (A) Initial
configuration of triple-layer tablet. (B) On contact with the dissolution medium the
bismuth layer rapidly dissolves and matrix starts swelling. (C) Tablet swells and erodes.
(D) and (E) Tablet erodes completely.
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NON -EFFERVESCENT
FLOATING DOSAGE FORMS
FORMULATION:
It includes;
 Gel forming or swellable cellulose type of
hydrocolloids & polysaccharides.
 Matrix forming polymers (polycarbonate,
polyacrylate, polymethacrylate & polystyrene).
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MECHANISM

Gel forming hydrocolloids swells in contact with gastric fluid after oral
administration and maintains a relative integrity of shape and a bulk density of
less than unity within gastric environment. The air thus trapped by the swollen
polymer imparts buoyancy to the dosage form.

The gel barrier controls the rate of solvent penetration into the device & the rate
of drug release from the device.

It maintains a bulk density of less than 1 and thus remains buoyant in the
gastric fluid inside the stomach for up to 6 hrs; conventional dosage forms
disintegrate completely within 60 min and are emptied totally from the stomach
shortly afterward.
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Advantages of HDDS
1. Improved drug absorption.
2. Controlled delivery of drugs.
3. Delivery of drugs for local
action in stomach.
4. Minimizing the mucosal
irritation due to drugs, by drug
releasing slowly at controlled
rate
5. Site specific drug delivery.
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6. Treatment of gastro intestinal
disorders such as gastroesophageal reflux.
7. Simple and conventional
equipments required for
manufacture.
8. Ease of administration and
better patient compliance.
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Disadvantages of HDDS
1. Gastric retention is influenced
by many factors such as gastric
motility, pH and presence of
food. These factors are never
constant and hence the buoyancy
can not be predicted.
2. Require sufficiently high level
of fluids in the stomach.
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3. Not suitable for drugs with
stability or solubility problems in
stomach.
4. Drugs with irritant effect on
gastric mucosa are not suitable.
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Marketed products
PRODUCT
ACTIVE INGREDIENT
MADOPAR
LEVODOPA & BENSERZIDE
VALRELEASE
DIAZEPAM
TOPALKAN
ALUMINIUM MAGNESIUM
ANTACID
ALMAGATE FLAT COAT
ANTACID
LIQUID GAVISON
ALGINIC ACID & NaHCO3
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CONCLUSION




HBS system can remain in the stomach for longer period hence can release
the drug over a prolong period of time.
These systems are particularly advantageous for drugs that are specifically
absorbed from stomach or proximal part of small intestine ( e.g., Riboflavin &
Furosemide).
Drugs that have poor bioavailability because of site specific absorption from
the upper part of GIT are potential candidates to be formulated as floating
drug delivery systems, thereby maximizing their absorption.
FDDS also serves as an excellent drug delivery system for the eradication of
Helicobacter pylori, which can cause chronic gastritis & peptic ulcers.
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pH controlled GI delivery
systems

This type of GI delivery system is designed for
the controlled release of acidic or basic drugs in
GIT, at a rate independent of the variation in GI
pH.
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Formulation

This system is prepared by first blending acidic or basic
drug with one or more buffering agents,
Eg. Pri, sec, ter salt of citric acid.

Then granulating with excipients, to form small granules
and then coating the granules with GI fluid permeable
film-forming polymer.
Eg. Cellulose derivatives.
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Mechanism

Polymer coating controls the permeation of GI fluid.

The GI fluid permeating into the device is adjusted by
the buffering agents to an appropriate constant pH.

This is the pH where drugs dissolve and is delivered
through the membrane at the constant rate, regardless
of the location of device in the alimentary canal.
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pH controlled GI Drug Delivery
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pH responsive hydrogels

This system have been targeted for per-oral controlled
drug delivery, taste masking of bitter drugs and
intravascular drug release during elevated blood pH in
certain CVS defects.

It includes the ionic polymers, for eg. Polyacrylamide,
poly acrylic acid, poly methacrylic acid, etc.
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Mechanism

In aqueous media of appropriate pH and ionic
strength, pendant groups, ionised and
developed fixed charges on the fixed charges
generating electrostatic repulsive forces
responsible for pH dependent swelling or
deswelling of the hydrogel, thereby controlling
the drug release.
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Drug release pattern




This system is designed in a monobasic or pulsatile
pattern.
Peroral controlled drug delivery requires uniform drug
delivery with increase in drug pH, gradient in different
segments of GI Lumen.
Eg. Albumin cross-linked 1-vinyl-2-pyrrolidinone
hydrogels were studied for their swelling behaviour at
different values.
Swelling increases above pH 7, thus correlating with
the maximal transit time of the drug delivery system
through the intestine.
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Drug release pattern

Pulsatile pattern of drug release is required in the
diseased state exhibiting a rhythmic pattern.

For localised delivery of heparin and streptokinase
based on poly( N-isopropyl acrylamide-comethacrylic acid) hydrogel, were assessed for their
swelling behaviour in response to pulses in
temperature and pH.
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pH- Activated Drug Delivery System

This system permits targeting the delivery of a drug only in the region with a
selected pH range.

Drugs administered orally would encounter a spectrum of pH ranging from 7
in the mouth, 1 - 4 in the stomach and 5 - 7 in the intestine.


Since most drugs are weak acids or weak bases, their release is pH dendent.
However, buffers can be added to the formulation to help maintain a constant
pH, like salts of citric acid, tartaric acid, phosphoric acid are commonly used.
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pH- Activated Drug Delivery
System

pH Activated Drug Delivery System is fabricated by coating the drugcontaining core with a pH–sensitive polymer combination.

For example, a gastric fluid labile drug is protected by encapsulating it inside
a polymer membrane that resists the degradative action of gastric pH, such as
the combination of Ethyl cellulose and Hydroxylmethylcellulose phthalate.
In the stomach, coating membrane resists the action of gastric fluid (pH<3) &
the drug molecule is thus protected from acid degradation.
After gastric emptying the Dosage form reaches the small intestine and comes
in contact with intestinal fluid (pH>7.5) which activates the erosion of polymer
- Hydroxylmethylcellulose phthalate from the coating membrane.
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pH- Activated Drug Delivery
System
This leaves a microporous membrane of intestinal
fluid insoluble polymer of Ethylcellulose, which
controls the release of drug from the core tablet.
The drug solute is thus delivered at a controlled
manner in the intestine.
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pH- Activated Drug Delivery
System
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Ion Exchange Resinates As
Controlled Release Drug
Delivery Systems
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Introduction



It is an attractive method for Sustained
Release drug delivery systems.
Drug release characteristics depend upon the
ionic environment of the resin containing drug.
Therefore, it is less susceptible to environment
conditions such as enzyme content and pH at
the absorption site.
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Introduction


This approach requires the presence of ions in
solution, and therefore it would not be applicable
to the skin, or other areas with limiting
quantities of eluting ions.
Where as the Subcutaneous and Intramuscular
routes have pool of available ions, and therefore,
would be better suited for this approach.
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Principle
Resins are water-insoluble materials containing anionic or
cationic groups in repeating units on the resin chain.
A Cation Exchange Resin generally has Sulphonic and
Carboxylic functional groups as an integral part of the resin and
an equivalent amount of cationic drug molecules.
An Anion Exchange Resin generally has quaternary ammonium
groups and polyalkylamine functional groups as an integral part
of the resin and an equivalent amount of anionic drug
molecules.
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Types of Ion Exchange Resins
Resin type
Chemical constitution
Strongly acidic cation
exchanger
Sulphonic acid group attached to a
styrene and divinylbenzene copolymer
R – SO3 - H +
Weakly acidic cation
exchanger
Carboxylic acid group attached to an
acrylic and divinylbenzene copolymer
R – COO - Na +
Strongly basic anion
exchanger
Quaternary ammonium group attached
to a styrene and divinylbenzene
copolymer
R –N (CH3)3+ Cl
Weakly basic anion
exchanger
Polyalkylamine group attached to a
styrene and divinylbenzene copolymer
R –NH (R)2+ Cl
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Structure
-
-
96
Types of Ion Exchange Resins
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Mechanism
H+
Cation exchange resin:
+ Resin – SO3 - Drug +
Resin – SO3 - H + + Drug +
Anion exchange resin:
Cl - + Resin – N (CH3)3+ Drug Resin – N (CH3)3 + Cl - + Drug-
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Drugs Suitable for Resinate Preparation
1.
Drugs should have acidic and basic groups in their chemical
structure.
2.
Biological half life should be between 2-6 hrs, drugs with t1/2 <
1 hr or > 8 hrs are difficult to formulate.
3.
The drug is to be absorbed from all regions of GI tract.
4.
Drugs should be stable sufficiently in the gastric juice.
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Some Important Properties of
Ion-Exchange Resins

Particle Size and form :
The rate of ion exchange reactions depend on the size of the resin particles.

Decreasing the size of resin particle significantly decreases the time
required for the reaction to reach equilibrium with the surrounding medium.

Most of the ion exchange resins are available in the form of spherical
beads. When the beads are immersed in water, they imbibe a limited amount
of water to form a homogenous gel like structure.

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Some Important Properties of
Ion-Exchange Resins

Ion exchange resins have hydrocarbon network to which ionizable sulphonic
acid groups are attached. The hydrogen ions are completely dissociated in the
imbibed water and are free to diffuse through out the entire resin bead and
hence can be exchanged for an equivalent amount ions of like charge.

Porosity : Porosity is defined as the ratio of the volume of the material to its
mass. The limiting size of ions which can penetrate into a resin matrix
depends strongly on the porosity.

Swelling :The swelling behavior of the resin has a marked effect on the
release characteristics of drug resinates. The amount of swelling is inversely
proportional to the degree of divinylbenzene crosslinking present in the resin.
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Some Important Properties of
Ion-Exchange Resins


Ion exchange capacity:
It is expressed in the terms of milliequivalents per gram of ion exchange
resin.
eg. The exchange capacity of a cation exchange resin is usually found in the
laboratory by determining the number of milligram equivalents of sodium
ion which are absorbed by 1 gram of the dry resin in the hydrogen form.
The Resin ion exchanger should be Stable, Pure and free from toxicity.
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General Preparation Of Drug Resinates
Loading of drugs is done by two ways :Column Process: A highly concentrated drug solution
is eluted through a bed or column of the resin until
equilibrium is established.
Batch Process: The resin particles are stirred with a
large volume of concentrated drug solution.
The drug resin is then washed to remove the contaminating ions
and dried to form particles or beads.
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General Preparation Of Drug
Resinates

The release rate can be further controlled by coating the drug resin complex using
microencapsulation .

Coated and uncoated drug resin complexes can be mixed in certain ratios and can be
filled into capsules with excipients or suspended in a palatable flavored vehicle
containing suitable suspending agents.

The release of drug from uncoated resin beads is expected to begin immediately while
release from the coated form would be delayed giving sustained effect.

The drug containing resin granules are first treated with an impregnating polymer such
as PEG 6000 to retard the rate of swelling in water and further coated with a water
permeable polymer such as Ethyl Cellulose to control the rate of release.
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General Preparation Of Drug
Resinates
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Applications

Adsorbents of Toxins

As Antacids

As Bile Acid binding agents

In treatment of Liver diseases

In Renal insufficiency

In Ophthalmology for glaucoma
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Therapeutic applications
1. Cholestyramine  It is a quaternary ammonium anion
exchange resin with basic groups attached to a
stryne – divinyl benzene copolymer.
 Used for the reduction of elevated serum
cholestrol
levels
in
patients
with
hypercholestrolemia.
2. Colestipol
Similar anion exchange resin, used as a
hypolipidemic drug. It increases the catabolic rate
of low density lipoproteins and decreases
cholestrol level.
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Therapeutic applications
3. Sod. Polystrene
It is a sulphonic cation exchange resin used
in the treatment of hyperkalemia and renal
failure.
4. Phenteramine
A sympathomimetic amine used for the short
term management of hypotension has also been
formulated as ion exchange resins.
5.Dextromethorphan It is used as an Antitussive that raises the
threshold of cough center in the CNS and
suppresses cough.
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References




N K, Jain, Advanced in Controlled Drug Delivery
System, pg no.290 -302
Yie w.chein, Novel Drug Delivery System, edition 2,
vol-3,pg no.30 – 32
Joseph R. Robinson, Controlled drug delivery
Fundamentals and Applications, pg no. 412 - 414
www.google.com
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Thank you
E-mail: [email protected]
Cell No: 00919742431000
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