Transcript osmotic drug delivery system

OSMOTIC DRUG DELIVERY
SYSTEM
INTRODUCTION
Osmotic drug delivery uses the osmotic pressure of drug or other
solutes (osmogens or osmagents) for controlled delivery of drugs.
Osmotic drug delivery has come a long way since Australian
physiologists Rose and Nelson developed an implantable pump in
1955.
ADVANTAGES OF OSMOTIC DRUG
DELIVERY SYSTEM
The delivery rate of zero-order (which is most
desirable) is achievable with osmotic systems.
Delivery may be delayed or pulsed, if desired.
For oral osmotic systems, drug release is
independent of gastric pH and hydrodynamic
conditions which is mainly attributed to the
unique properties of semipermeable membrane
(SPM) employed in coating of osmotic
formulations.
ADVANTAGES
Higher release rates are possible with osmotic systems
compared with conventional diffusion-controlled drug
delivery systems.
The release rate of osmotic systems is highly predictable
and can be programmed by modulating the release control
parameters.
A high degree of in vivo–in vitro correlation (IVIVC) is
obtained in osmotic systems because the factors that are
responsible for causing differences in release profile in vitro
and in vivo (e.g., agitation, variable pH) affect these
systems to a much lesser extent.
The release from osmotic systems is minimally affected by
the presence of food in the gastrointestinal tract (GIT). This
advantage is attributed to design of osmotic systems.
Environmental contents do not gain access to the drug until
the drug has been delivered out of the device.
Production scale up is easy.
DISADVANTAGES OF OSMOTIC DRUG
DELIVERY SYSTEM
Toxicity due to dose dumping.
Rapid development of tolerance.
Additional patient education and counseling is
required.
Hypersensitvity reaction may occur after implantation.
PRINCIPLE OF OSMOSIS
Osmosis refers to the process of movement of solvent
from lower concentration of solute towards higher
concentration of solute across a semi permeable
membrane.
Pfeffer measured the effect by utilizing a membrane
which is selectively permeable to water but impermeable
to sugar.
Van’t Hoff established the analogy between the Pfeffer
results and the ideal gas laws by the expression
π = n2RT----------------------(1)
Where n2 represents the molar concentration of sugar (or
other solute) in the solution, R depicts the gas constant,
and T the absolute temperatue.
This equation holds true for perfect semipermeable
membranes and low solute concentrations.
Another method of obtaining a good approximation of
osmotic pressure is by utilizing vapour pressure
measurements and by using expression:
π = RT ln (Po/P)/v -------- (2)
Where Po represents the vapour pressure of the pure
solvent, P is the vapour pressure of the solution and v is
the molar volume of the solvent. As vapour pressure can
be measured with less effort than osmotic pressure this
expression is frequently used.
Osmotic pressure for soluble solutes is extremely high.
This high osmotic pressure is responsible for high water
flow across semipermeable membrane.
The rate of water flow dictated by osmotic pressure can be
given by following equation,
dV/dt = A θ Δπ/l ----------------------- (3)
Where dV/dt represents the water flow across the
membrane area A and thickness l with permeability θ.
 Δπ depicts the difference in osmotic pressure between
the two solutions on either side of the membrane.
NOTE- This equation is strictly applicable for perfect
semipermeable membrane, which is completely
impermeable to solutes.
• A number of osmotic pressure powered drug
delivery system has been developed. The
principle of their operation can be described by
a basic model as outlined in following figure.
Schematic representation of the basic model of
osmotic pressure powered drug delivery systems
PUMP
HOUSING
SEMIPERMEABLE
MEMBRANE
Vs
Vd
MOVABLE
PARTITION
Vs is volume of osmotic agent compartment
Vd is volume of drug compartment
DELIVERY
ORIFICE
BASIC COMPONENTS OF OSMOTIC
PUMP
DRUG
Drug itself may act as an osmogen and shows good aqueous
solubility (e.g., potassium chloride pumps).
But if the drug does not possess an osmogenic property,
osmogenic salt and other sugars can be incorporated in the
formulation.
OSMOGEN / OSMAGENT / OSMOTIC
DRIVING AGENT
For the selection of osmogen, the two most
critical properties to be considered are osmotic
activity and aqueous solubility.
Osmotic agents are classified as,
Inorganic water soluble osmogens:Magnesium sulphate, Sodium chloride, Sodium
sulpahte, Potassium chloride, Sodium bicarbonate,etc.
Organic polymeric osmogens:Na CMC, HPMC, HEMC, etc.
Mannitol,etc.
Organic water soluble osmogens:Sorbitol,
SEMIPERMEABLE MEMBRANE
Semipermeable membrane must possess certain
performance criteia:
It must have sufficient wet strength and water
permeability.
It should be selectively permeable to water and
biocompatible.
Cellulose
acetate
is
a
commonly
employed
semipermeable membrane for the preparation of osmotic
pumps.
Some other polymers such as agar acetate, amylose
triacetate, betaglucan acetate, poly (vinylmethyl) ether
copolymers, poly (orthoesters), poly acetals, poly (glycolic
acid) and poly (lactic acid) derivatives.
The unique feature of semipermeable membrane utilized
for an osmotic pump is that it permits only the passage of
water into the unit, thereby effectively isolating the
dissolution process from the gut environment.
HYDROPHILIC AND HYDROBHOBIC
POLYMERS
These polymers are used in the formulation
development of osmotic systems containing matrix
core.
The selection of polymer is based on the solubility of
drug as well as the amount and rate of drug to be
released from the pump.
The highly water soluble compounds can be coentrapped in hydrophobic matrices and moderately
water soluble compounds can be co-entrapped in
hydrophilic matrices to obtain more controlled release.
Examples of hydrophilic polymers are Hydroxy ethyl
cellulose, carboxy methyl cellulose, hydroxyl propyl
methyl cellulose, etc.
Examples of hydrophobic polymers are ethyl cellulose,
wax materials, etc.
WICKING AGENTS
It is defined as a material with the ability to draw
water into the porous network of a delivery device.
The function of the wicking agent is to draw water to
surfaces inside the core of the tablet, thereby creating
channels or a network of increased surface area.
Examples: colloidon silicon dioxide, kaolin, titanium
dioxide, alumina, niacinamide,sodium lauryl sulphate
(SLS), low molecular weight polyvinyl pyrrolidone
(PVP), bentonite, magnesium aluminium silicate,
polyester and polyethylene,etc.
SOLUBILIZING AGENTS
Non swellable solubilizing agents are classified into
three groups:
Agents that inhibits crystal formation of the drugs or
otherwise act by complexation of drug (e.g., PVP,
PEG, and cyclodextrins)
A high HLB micelle forming surfactant, particularly
anionic surfactants (e.g., Tween 20, 60, 80, poly oxy
ethylene or polyethylene containing surfactants and
other long chain anionic surfactants such as SLS).
Citrate esters and their combinations with anionic
surfactants (e.g., alkyl esters particularly triethyl
citrate)
SURFACTANTS
They are added to wall forming agents.
The surfactants act by regulating the surface energy of
materials to improve their blending in to the composite
and maintain their integrity in the environment of use
during the drug release period.
Examples: polyoxyethylenated glyceryl recinoleate,
polyoxyethylenated castor oil having ethylene oxide,
glyceryl laurates, etc.
COATING SOLVENTS
Solvents suitable for making polymeric solution that is
used for manufacturing the wall of the osmotic device
include inert inorganic and organic solvents.
Examples: methylene chloride, acetone, methanol,
ethanol, isopropyl alcohol, ethyl acetate, cyclohexane,
etc.
PLASTICIZERS
Permeability of membranes can be increased by adding
plasticizer, which increases the water diffusion
coefficient.
Examples: dialkyl pthalates, trioctyl phosphates, alkyl
adipates, triethyl citrate and other citrates, propionates,
glycolates, glycerolates, myristates, benzoates,
sulphonamides and halogenated phenyls.
FLUX REGULATORS
Flux regulating agents or flux enhancing agent or flux
decreasing agent are added to the wall forming
material; it assist in regulating the fluid permeability
through membrane.
Poly hydric alcohols such as poly alkylene glycols and
low molecular weight glycols such as poly propylene,
poly butylene and poly amylene,etc. can be added as
flux regulators.
PORE FORMING AGENTS
These agents are particularly used in the pumps
developed for poorly water soluble drug and in the
development of controlled porosity or multiparticulate
osmotic pumps.
The pore formers can be inorganic or organic and solid
or liquid in nature.
For example
Alkaline metal salts such as sodium chloride, sodium
bromide, potassium chloride, etc.
Alkaline earth metals such as calcium chloride and
calcium nitrate
Carbohydrates such as glucose, fructose, mannose,etc.
Classification
Oral osmotic tablet
Single
osmotic pump
Elemantary
osmotic pump
(EOP)
Controlled
porosity
osmotic pump
Osmotic
bursting
osmotic pump
Multi-chamber
osmotic pump
Push pull
osmotic pump
(PPOP)
Oral osmotic
capsules
OROS- CT
Implantable
osmotic system
DUROS
osmotic
pump
L- OROS
Sandwich
osmotic
tablets (SOTS)
Pelleted delayed
release
ALZET
osmotic
pump
Assymetric
membrane capsule
Telescopic capsule
for delayed release
22
FIRST OSMOTIC PUMP (THREE CHAMBER ROSENELSON OSMOTIC PUMP)
Salt Chamber
Water Chamber
Drug Chamber
Delivery orifice
Rigid Semi permeable membrane
Elastic Diaphragm
PHARMETRIX DEVICE
This device is composed of impermeable
membrane placed between the semi permeable
membrane and the water chamber.
These allows the storage of the pump in fully water
loaded condition. The pump is activated when seal
is broken. Water is then drawn by a wick to the
membrane surface and pumping action begins.
This modification allows improved storage of the
device, which on demand can be easily activated.
HIGUCHI LEEPER OSMOTIC PUMPS
It has no water chamber, and the activation of the device occurs after
imbibition of the water from surrounding environment.
It has a rigid housing.
Widely employed for veterinary use. It is either swallowed or implanted in
body of an animal for delivery of antibiotics or growth hormones to animal.
Modification: A layer of low melting waxy solid, is used in place of movable
separator to separate drug and osmotic chamber.
Rigid Housing
Drug Chamber
Satd. Sol. Of
MgSO4 contg.
Solid MgSO4
Movable Separator
MgSO4
Semi-permeable
Membrane
Porous Membrane Support
HIGUCHI THEEUWES OSMOTIC PUMP
 In this device, the rigid housing is consisted of a semi permeable membrane. The drug is
loaded in the device only prior to its application, which extends advantage for storage of the
device for longer duration.
 The release of the drug from the device is governed by the salt used in the salt chamber and
the permeability characteristics of outer membrane.
 Diffusional loss of the drug from the device is minimized by making the delivery port in shape
of a long thin tube.
 Small osmotic pumps of this form are available under the trade name Alzet ®.
Fluid to be pumped
Coating contg. Solid
Osmotic compound
SPM
Delivery port
Rigid
Semi permeable
Membrane
Osmotic Agent layer
Wall of flexible
collapsible material
Squeezed
Drug Core
Swollen Osmogen layer
Delivery port
ELEMENTARY OSMOTIC PUMP
Rose Nelson pump was further simplified in the
form of elementary osmotic pump(by
Theeuwes,1975) which made osmotic delivery
as a major method of achieving controlled drug
release.
ELEMENTARY OSMOTIC PUMP (EOP)
Delivery Orifice
Core containing agent
Semi permeable
membrane
It essentially contains an active agent having a suitable osmotic pressure.
It is fabricated as a tablet coated with semi permeable membrane, usually
cellulose acetate.
A small orifice is drilled through the membrane coating. This pump eliminates
the separate salt chamber unlike others. When this coated tablet is exposed to
an aqueous environment, the osmotic pressure of the soluble drug inside the
tablet draws water through the semi permeable coating and a saturated
aqueous solution of drug is formed inside the device.
The membrane is non-extensible and the increase in volume due to imbibition
of water raises the hydrostatic pressure inside the tablet, eventually leading to
flow of saturated solution of active agent out of the device through the small
orifice.
The process continues at a constant rate till the entire solid drug inside the
tablet is eliminated leaving only solution filled shell. This residual dissolved
drug is delivered at a slower rate to attain equilibrium between external and
internal drug solution.
LIMITATION OF EOP
Generally in osmotic pumps the semi permeable membrane
should be 200-300μm thick to withstand pressure with in
the device.
These thick coatings lower the water permeation rate,
particularly for moderate and poorly soluble drugs.
In general we can predict that these thick coating devices
are suitable for highly water soluble drugs.
This problem can be overcome by using coating materials
with high water permeabilities. For example, addition of
plasticizers and water soluble additive to the cellulose
acetate membranes, which increased the permeability of
membrane up to ten fold.
MODIFICATIONS IN ELEMENTARY
OSMOTIC PUMP
• The first layer is made up of thick micro porous film that provides the
strength required to withstand the internal pressure, while second layer is
composed of thin semi permeable membrane that produces the osmotic flux.
• The support layer is formed by:
• Cellulose acetate coating containing 40 to 60% of pore forming agent
such as sorbitol.
Inner microporous
membrane
Drug chamber
Delivery orifice
Outer semi permeable
membrane
COMPOSITE MEMBRANE COATING USED TO
DELIVER MODERATELY SOLUBLE DRUGS
DELIVERY OF INSOLUBLE DRUG
Rigid SPM
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Elastic SPM
Insoluble Particles
• Coating osmotic agent with elastic semi permeable film
• Mixing of above particles with the insoluble drug
• Resultant mixture is coated with the rigid semi permeable
membrane
MULTICHAMBER OSMOTIC PUMPS
• Multiple chamber osmotic pumps can be divided
into two major classes
a) Tablets with a second expandable osmotic
chamber
b) Tablets with a non-expanding second chamber
a) Tablets with a second expandable osmotic
chamber
• In the tablets with a second expandable osmotic
chamber, the water is simultaneously drawn into
both the chambers in proportion to their
respective osmotic gradients, eventually causing
an increase in volume of the chamber and
subsequently forcing the drug out from the drug
chamber.
• The matrix should have sufficient osmotic pressure
to draw water through the membrane into the
drug chamber. Under hydrated conditions matrices
should have to be fluid enough to be pushed easily
through a small hole by the little pressure
generated by the elastic diaphragm.
OROS ORAL DRUG DELIVERY TECHNOLOGY
• OROS® technology employs osmosis to provide precise,
controlled drug delivery for up to 24 hours and can be used
with a range of compounds, including poorly soluble or
highly soluble drugs.
Before operation
During operation
Delivery Orifice
Delivery Orifice
Osmotic Drug
Core
SPM
Polymer push compartment
Expanded push compartment
Drug delivery process of two chamber osmotic tablet
LIQUID OSMOTIC SYSTEM (L-OROS)
• A liquid formulation is
particularly well suited for
delivering insoluble drugs and
macromolecules such as
polysaccharide and
polypeptides.
• Such molecules requie external
liquid components to assist in
solubilization, dispersion,
protection from enzymatic
degradation and promotion of
gastrointestinal absorption.
• Thus the L-OROS system was
designed to provide continuous
delivery of liquid drug
formulation and improve
bioavailability of drugs.
• Another type of L-OROS system consists of a hard gelatin
capsule containing a liquid drug layer, a barrier layer and
a push layer surrounded by a semipermeable membrane.
The L-OROS hardcap system was designed to
accommodate more viscous suspensions with higher drug
loading than would be possible using softcap design.
Delivery orifice
Barrier layer
Rate controlling membrane
Push layer
Inner
Compartment
Inner Capsule
LIQUID DRUG DELIVERY OTHER THAN L-OROS
USE OF POROUS PARTICLES
• The controlled release of liquid active
agent formulations is provided by
dispersing porous particles that
contain the liquid active agent
formulation in osmotic push-layer
dosage forms.
• The liquid active agent formulations
may be absorbed into the interior
pores of the material in significant
amounts and delivered to the site of
administration in the liquid state.
• Microcrystalline cellulose, porous
sodium carboxymethyl cellulose,
porous soya bean fiber and silicon
dioxide—all of which have high
surface area and good absorption
properties— and can be used
indosage form described here in.
OROS TRI-LAYER
DUROS®
• DUROS® implants are designed to bring the benefit of continuous
therapy for up to one year. The non-biodegradable, osmotically
driven system is intended to enable delivery of small drugs,
peptides, proteins, DNA and other bioactive macromolecules for
systemic or tissue-specific therapy.
• Viadur® (leuprolide acetate implant), the first marketed product to
incorporate DUROS®, is indicated for the palliative treatment of
advanced prostate cancer.
ADVANTAGES
• Can deliver highly concentrated and viscous formulations.
• Improved patient compliance
• Titanium protects the drug from enzymatic degradation.
• The system can be engineered to deliver a drug at a desired
dosing rate with high degree of precision.
DUROS SYSTEM
• Affecting factors
– Compositions of osmotic agent
– Thickness of semipermeable membrane
– Surface area
b) DEVICES WITH A NON-EXPANDING
SECOND CHAMBER:
• This group can be subdivided into
two subgroups depending upon the
function of the second chamber.
• In one group the second chamber
serves for the dilution of the drug
solution leaving the device. This is
important in cases where drugs
causes irritation of GIT.
• Before the drug can exit from the
device, it must pass through a
second chamber. Water is also
drawn osmotically into this chamber
either due to osmotic pressure of
the drug solution or because the
second chamber that bears watersoluble diluents such as sodium
chloride.
Exit Orifice
Wall
Drug in diluted soln.
First
Compartment
Interior Orifice
Second
Compartment
Interior
wall
Drug
• The second group of non-expanding multichamber devices essentially
contains two separate simple OROS tablets formed into a single tablet.
Two chambers contain two separate drugs both are delivered
simultaneously. This system is also known as sandwiched osmotic
tablet system (SOTS).
• A more sophisticated version of this device consists of two rigid
chambers, one contains biologically inert osmotic agent such as sugar
or NaCl, and the second chamber contains the drug. When exposed to
aqueous environment, water is drawn into both chambers across the
semi permeable membrane. The solution of osmotic agent then passes
into the drug chamber through the connecting hole where it mixes
with the drug solution before escaping through the micro porous
membrane that forms part of the wall around the drug chamber.
Relatively insoluble drugs can be delivered using this device.
Osmotic agent
containing chamber
Semi permeable
membrane
orifice
Drug containing chamber
Microporous membrane
CONTROLLED PORSITY OSMOTIC
PUMPS
They are not having any aperture for release of drugs. The
drug release is achieved by the pores, which are formed in the
semi permeable wall in situ during the operation.
The semi permeable coating membrane contains water-soluble
pore forming agents. This membrane after formation of pores
becomes permeable for both water and solutes.
Aqueous
Environment
Coating Containing Pore
Forming Agents
Pore Formation and Subsequent
Drug Release
SPECIFICATIONS FOR CONTROLLED
POROSITY OSMOTIC PUMPS
Materials
Specifications
Plasticizers and flux regulating
agents
0 to 50, preferably 0.001 to 50
parts per 100 parts of wall
material
Surfactants
0 to 40, preferably 0.001 to 40
parts per 100 parts of wall
material
Wall Thickness
1 to 1000, preferably 20 to 500μm
Micro porous nature
5 to 95% pores between 10Å to
100μm
Pore forming additives
0.1 to 60%, preferably 0.1 to
50%, by weight, based on the
total weight of pore forming
additive and polymer
pH insensitive pore forming
additive (solid or liquid) preferably
0.1 to 40% by weight
SPECIFICATIONS FOR CORE OF
CONTROLLED POROSITY OSMOTIC PUMPS
Property
Specifications
Core loading (size)
0.05ng to 5g or more (include
dosage forms for humans and
animals)
Osmotic pressure developed by a
solution of core
8 to 500atm typically, with
commonly encountered water
soluble drugs and excipients
Core solubility
To get continuous, uniform
release of 90% or greater of the
initially loaded core mass
solubility, S, to the core mass
density, ρ, that is S/ρ, must be
0.1 or lower. Typically this occurs
when 10% of the initially loaded
core mass saturates a volume of
external fluid equal to the total
volume of the initial core mass
ASYMMETRIC MEMBRANE COATED
TABLETS
Here, the coatings have an asymmetric structure, similar to
asymmetric membranes made for reverse osmosis or ultra
filtration, in that the coating consists of a porous substrate
with a thin outer membrane.
Asymmetric tablet coating possesses some unique
characteristics, which are more useful in development of
osmotic devices they are as follows:
High water fluxes can be achieved.
The permeability of the coating to water can be adjusted by
controlling the membrane structure.
The porosity of the membrane can be controlled to
minimize the time lag before drug delivery begins and
allowing the drug to be released from large number of
delivery ports.
PULSATILE DRUG DELIVERY
• Delivering a drug in one or more pulses is sometimes beneficial, from
the required pharmacological action point of view.
• Mechanical and drug solubility–modifying techniques have been
implemented to achieve the pulsed delivery of drugs with an osmotic
system.
SOLUBILITY MODULATION FOR
PULSED RELEASE
The composition described in the patents comprised the drug
salbutamol sulfate and modulating agent sodium chloride.
Pulsed delivery is based on drug solubility. Salbutamol’s solubility
is 275 mg/mL in water and 16 mg/mL in a saturated solution of
sodium chloride. Sodium chloride’s solubility is 321 mg/mL in water
and 320 mg/mL in a saturated solution. These values show that
the solubility of the drug is a function of the modulator
concentration, whereas the modulator’s solubility is largely
independent of the drug concentration.
The tablet is similar to elementary osmotic pump, with a mixture
of salbutamol and sodium chloride in the tablet core.
The release profile of the device is constant for salbutamol until
the sodium chloride becomes exhausted, afterwards the remaining
drug is delivered as a large pulse.
This rlease pattern is exploited for nocturnal asthma in which
pulsatile delivery of salbutamol is desirable.
PULSATILE DELIVERY BASED ON AN
EXPANDABLE ORIFICE.
• The system is in the form
of a capsule from which
the drug is delivered by
the capsule’s osmotic
infusion of moisture from
the body.
• The delivery orifice opens
intermittently to achieve a
pulsatile delivery effect.
The orifice forms in the
capsule wall, which is
constructed of an elastic
material.
• As the osmotic infusion
progresses, pressure rises
within the capsule, causing
the wall to stretch.
• Elastomers such as
styrene-butadiene
copolymer can be used.
Tiny orifice opened upon stretches under the
Osmotic pressure
Elastic Cap
Drug Solution
Movable piston
Osmogen
Separating Barrier
Semi permeable
Membrane
PORT SYSTEM
•The Port® System (Port
Systems, LLC) consists of a
gelatin capsule coated with a
semipermeable membrane (eg,
cellulose acetate) housing an
insoluble plug (eg, lipidic) and an
osmotically active agent along
with the drug formulation.
•When in contact with the
aqueous medium, water diffuses
across the semipermeable
membrane, resulting in increased
inner pressure that ejects the
plug after a lag time. The lag
time is controlled by coating
thickness. The system showed
good correlation in lag times of
in-vitro and in-vivo experiments
in humans.
DELAYED-DELIVERY OSMOTIC
DEVICES
Because of their semipermeable walls, osmotic
devices inherently show a lag time before drug
delivery begins. Although this characteristic is
usually cited as a disadvantage, it can be used
advantageously.
The delayed release of certain drugs (e.g., drugs for
early morning asthma or arthritis) may be
beneficial. The following slides describes other
means to further delay drug release.
TELESCOPIC CAPSULES FOR
DELAYED
RELEASE
The
dispenser comprises
a housing that has first- and second-wall sections in
a slideable telescoping arrangement.
The housing maintains integrity in its environment of use.
 The device consists of two chambers; the first contains the drug and an exit
port, and the second contains an osmotic engine. A layer of wax-like material
separates the two sections.
To assemble the delivery device, the desired active agent is placed into one
of the sections by manual- or automated-fill mechanisms.
The bilayer tablet with the osmotic engine is placed into a completed cap part
of the capsule with the convex osmotic layer pointed into the closed end of
the cap and the barrier layer exposed toward the cap opening. The open end
of the filled vessel is fitted inside the open end of the cap, and the two pieces
are compressed together until the cap, osmotic bilayer tablet, and vessel fit
together tightly.
As fluid is imbibed through the housing of the dispensing device, the osmotic
engine expands and exerts pressure on the slideable connected first and
second wall sections.
During the delay period, the volume of the reservoir containing the active
agent is kept constant; therefore, a negligible pressure gradient exists
between the environment of use and the interior of the reservoir. As a result,
the net flow of environmental fluid driven by the pressure to enter the
reservoir is minimal, and consequently no agent is delivered for the period.
Push plates
Second Wall
section
First wall
section
Push means
Drug
Internal Compartment
A delayed release telescopic capsule release contents after
expansion.
DELAYED-RELEASE DELIVERY BASED
ON MULTIPLE COATINGS
The osmotically driven pump can be miniaturized to a size suited for
swallowing or implanting. The pump may be used to administer a drug in a
fluid form after an initial activation period during which essentially no drug is
administered.
 The basic components of the pump are semi permeable membrane (SPM)
that encapsulates an osmotically effective solute and drug and a discharge
port through which the drug is dispensed. A micro porous outer cover
surrounds the SPM and protects it from an external aqueous environment.
 A water-swellable composition is positioned between the end of the SPM and
the outer cover.
 As the pump is placed in an aqueous environment, water from the
environment passes through the micro porous portion of the outer cover into
the water swellable composition. The water swellable composition absorbs
water, expands, and in piston-like fashion displaces the outer cover, thereby
exposing the SPM to the aqueous environment and activating the osmotic
pump.
The time required for the water-swellable composition to absorb water,
expand, and displace the outer cover provides an initial activation period
during which essentially no drug is delivered by the pump.
By suitably adjusting the membrane composition and structure, a
predetermined activation period in the range of 3–18 h is achieved.
ENTERIC AND COLON TARGETED
OSMOTIC DOSAGE FORMS
Use of osmotic systems for the pH triggered burst of the
active agent is disclosed.
The devices are designed for oral administration, either in
the form of tablets or capsules.
If used in tablets, the core consists of the drug, osmagent,
diluents, and superdisintegrants. The tablets are coated first
by SPM walls of insufficient thickness and then overcoated
with the pH-triggered coating solution.
The pH-triggered solution contains polymers such as
cellulose acetate phthalate, pH-sensitive Eudragit grades,
and insoluble polymers. The patent claims that using only
pH-sensitive materials to achieve site-specific delivery is
difficult because the drug often leaks out of the dosage form
before it reaches the release site or desired delivery time.
VOLUME AMPLIFIER DELIVERY
DEVICE
One of the limitations with osmotic devices, is the
incomplete release of the drug.
Here we will see the use of volume amplifiers to deliver the
entire drug contained in the system.
The device consists of a core, an SPM, and a delivery orifice.
In addition to the drug and the osmagent, the compartment
contains a volume amplifier to increase the amount of agent
delivered from the system.
The amplifier consists of a membrane surrounding a gasgenerating couple with the membrane formed of an
expandable material that is permeable to fluid and
impermeable to the couple.
Gas generating
couple
Gas
Volume
Amplifier
EFFERVESCENT ACTIVITY-BASED
SYSTEMS
• The osmotic device comprises a semi permeable wall that
surrounds a compartment housing a drug that exhibits limited
solubility under neutral and acid conditions and a compound
capable of releasing carbon dioxide in the presence of an acid.
• As fluid is imbibed through the wall into the compartment at a rate
determined by the wall’s permeability and the osmotic pressure
gradient across the wall, a basic solution containing drug and
compound is formed, which is delivered from the compartment
through the passageway.
• The released compound reacts with the acid in the environment at
the device–environment interface and evolves carbon dioxide,
thereby providing an effervescent suspension that delivers the
drug to the environment in a finely dispersed form over time. Thus
the agent is delivered in a form that is rapidly absorbed and does
not block the orifice of the delivery device.
• Drugs that can be delivered by such a system are those
that exhibit a propensity for rapid precipitation in an
environment that has a pH less than 7 (e.g., the
stomach). A few examples are the anti-inflammatory
arylcarboxylicacids such as indomethacin, aspirin,
diclofenac, fenoprofen, flufenamic acid and prioxicam.
• The osmotic device without the compound releases the
drug in the presence of an artificial gastric fluid
containing hydrochloric acid; however, the drug
precipitates onto the wall of the device and the exit
port of the passageway and is therefore not observed
in the fluid of the environment. This problem is rectified
with the use of an effervescent system.
OSMOTIC DEVICES THAT USE
SOLUBILITY MODIFIERS
For slightly soluble drug carbamazepine
System consists of a core, crystal habit modifier
and osmotic driving agent.
Crystal habit modifying agent is useful only when
drug exists in more than one crystalline form and
when desired form of the drug is not the most
stable form.
Crystal modifying agent modifies the solubility of
the drug.
 The change in solubility should be significant.
For slightly soluble drug
The core consists of a drug with limited
solubility in water or physiological
environments, a nonswelling solubilizing agent
to enhance the solubility of the drug, and an
osmagent.
In addition, a nonswelling wicking agent is
dispersed throughout the composition. A
delivery system for nifedipine used colloidal
silicon dioxide, polyvinylpyrrolidone, and
sodium lauryl sulfate as nonswelling wicking
agents.
For sparingly soluble drug
The core consists of an active ingredient that is sparingly
soluble in water, a hydrophilic polymeric swelling agent
composed of a mixture of a vinylpyrrolidone–vinyl acetate
copolymer with an ethylene oxide homopolymer, and a
water-soluble substance for inducing osmosis.
This mixture has the surprising advantage that pressure
produced during swelling does not cause the system to
rupture and that the swelling speed is uniform, which allows
almost constant amounts of active ingredient to be released
from the system. Theophylline, aspirin, carbamazepine and
nifedipine have been delivered by this system.
Use of Vitamin E tocopheryl polyethylene glycol
succinate (TPGS)
Vitamin E tocopheryl polyethylene glycol succinate
(TPGS)–drug compositions to obviate the need for
surfactants or nonevaporated cosolvents. The
advantage of using a TPGS–drug solid solution is that
insoluble drugs can be considered soluble for the
purpose of getting the drug out of the osmotic device.
Cyclosporine has been cited as an example in patent.
OSMOTIC DEVICES FOR USE IN ORAL
CAVITY
Unique advantage of nicotine delivery by an oral
osmotic device.
• The system consists of a nicotine salt and an optional
alkaline salt, which is capable of reacting with the nicotine
salt in the presence of water to form a nicotine base. The
conversion of nicotine salt to a nicotine base may take place
within or outside the device and in the patient’s mouth. The
nicotine base or salt is delivered from the compartment
through a passageway in the wall.
• The advantage is that nicotine salt exhibits good stability
and a long shelf life, and the nicotine base exhibits excellent
absorption through oral mucosal membranes.
OSMOTIC DEVICE THAT DELIVER DRUG
BELOW SATURATION
• These types of delivery devices are
useful for dispensing drugs that are
irritants to mucosal and GIT tissue
such as potassium chloride, aspirin,
and indomethacin.
• The system comprises a first wall of a
semi permeable material that
surrounds a compartment containing
a drug formulation and has a
passageway through the wall for
releasing agent from the
compartment. A second wall is
positioned away from the first wall
and is constructed of a micro porous
or hydrogel material. Because of the
distance between the two walls, a
distribution zone interposed between
the first and second walls exists
MISCELLANEOUS DEVICES
• The device has a centrally located expandable core that is completely
surrounded by an active substance-containing layer, which is completely
surrounded by a membrane.
• The core consists of an expandable hydrophilic polymer and an optional
osmagent. The composition immediately surrounding the core
comprises an active substance, an osmagent, and an osmopolymer. The
membrane is micro porous in nature and may have a delivery orifice.
• The device is capable of delivering insoluble, slightly soluble, sparingly
soluble, and very soluble active substances to the environment.
Exit Orifice
Microporous membrane
Active Agent
layer
Core
SPECIALIZED COATINGS
• The wall in this case is formed of a semipermeable hydrophobic
membrane that has pores in the wall. The pores are substantially
filled with a gas phase. The hydrophobic membrane is permeable to
water in the vapor phase and is impermeable to an aqueous medium
at pressures less than 100 Pa. The drug is released by osmotic
pumping or osmotic bursting upon the imbibition of sufficient water
vapor into the device core.
• These devices minimize incompatibilities between the drug and the
ions (such as hydrogen or hydroxyl) or other dissolved or suspended
materials in the aqueous medium because contact between the drug
and the aqueous medium does not occur until after the drug is
released, which results from the SPM’s selective permeability for
water vapor.
FACTORS AFFECTING THE PERFORMANCE
OF OSMOTIC DRUG DELIVERY SYSTEM
Physico-chemical properties of the drug
• Solubility
• Solid or liquid
• Viscosity (Liquids)
• Rheological properties
Properties of osmotic agent
• Osmotic pressure difference generated by the agent which
ultimately will decide the water influx and in turn the delivery of
active.
Membrane type and characteristics
• Wet strength
• Water permeability
Size of delivery orifice
Characteristics of the polymer used (e.g. Hydration,
Swelling etc.)
PROCESSING AND PERFORMANCE
IMPROVEMENT
•
•
•
•
Improvement of adhesion between core and semipermeable
membrane.
The tablet core containing the drug and other required components is
evenly coated with a discrete layer of a water-soluble (or waterdispersible) and water-permeable non osmotically active solid
polymeric binder to a level of less than10%.
The SPM is then coated on the tablet.
Enhancing the startup and performance of osmotic drug
delivery systems.
The osmotic delivery system should include a liquid or gel additive
that surrounds the osmotic agent to enhance startup and lubricate the
osmotic agent.
The liquid or gel additive is an incompressible lubricating fluid that fills
any air gaps between the osmotic agent and the walls of a chamber
and substantially reduces startup delays.
IN VITRO EVALUATION
• The in vitro release of drugs from oral osmotic systems
has been evaluated by the conventional USP paddle
and basket type apparatus.
• The dissolution medium is generally distilled water as
well as simulated gastric fluid (for first 2-4 h) and
intestinal fluids (for subsequent hours) have been used.
• The standard specifications, which are followed for the
oral controlled drug delivery systems are equivalently
applicable for oral osmotic pumps.
• In vivo evaluation of oral osmotic systems has been
carried out mostly in dogs. Monkeys can also be used
but in most of the studies the dogs are preferred.
MARKET PRODUCTS
• Products Incorporating ALZA's OROS® Technology
Alpress™ LP (prazosin) once-daily extended-release tablet sold in
France for the treatment of hypertension.
Cardura® XL (doxazosin mesylate) sold in Germany for the
treatment of hypertension.
Concerta® (methylphenidate HCl) CII once-daily extended-release
tablet for the treatment of Attention Deficit Hyperactivity Disorder
(ADHD) in patients age six and older.
Covera-HS® (verapamil) a Controlled Onset Extended Release (COER24™) system for the management of hypertension and angina pectoris.
Ditropan XL® (oxybutynin chloride) extended-release tablet for the
once-a-day treatment of overactive bladder characterized by symptoms
of urge urinary incontinence, urgency and frequency.
DynaCirc CR® (isradipine) once-daily, extended-release tablet for the
treatment of hypertension.
Efidac 24® (chlorpheniramine) over-the-counter, extendedrelease tablet providing 24-hour relief from allergy symptoms and
nasal congestion.
Glucotrol XL® (glipizide) extended-release tablet used as an
adjunct to diet for the control of hyperglycemia in patients with noninsulin-dependent diabetes.
Sudafed® 24 Hour (pseudoephedrine) over-the-counter nasal
decongestant for 24-hour relief of colds, sinusitis, hay fever and other
respiratory allergies.
Procardia XL® (nifedipine) extended-release tablet for the
treatment of angina and hypertension.
Volmax® (albuterol) extended-release tablet for relief of
bronchospasm in patients with reversible obstructive airway disease.
Products Incorporating ALZA's DUROS® Implant
Technology
Viadur® (leuprolide acetate implant) delivers leuprolide
continuously for 12 months as a palliative treatment for advanced
prostate cancer.
THANK YOU
-PHARMA STREET