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Osmotiic pump dds
1. OSMOTIC DRUG DELIVERYOSMOTIC DRUG DELIVERY
SYSTEMSYSTEM
By:
Mr. RAGHAVENDRA KUMAR GUNDA M.PHARM
Asst. Prof,
Narasaraopeta Institute of Pharmaceutical Sciences.
Department of Pharmaceutics, NIPS 1
2. LIST OF CONTENTS
INTRODUCTION
ADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEMADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM
DISADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEMDISADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM
REPORTED CASES REGARDING LIMITATIONS ANDREPORTED CASES REGARDING LIMITATIONS AND
ADVERSE EFFECTS OF OSMOTIC DRUG DELIVERY SYSTEMADVERSE EFFECTS OF OSMOTIC DRUG DELIVERY SYSTEM
PRINCIPLE OF OSMOSISPRINCIPLE OF OSMOSIS
BASIC COMPONENTS OF OSMOTIC PUMPBASIC COMPONENTS OF OSMOTIC PUMP
OSMOTIC PUMPSOSMOTIC PUMPS
FIRST OSMOTIC PUMP (THREE CHAMBER ROSE-NELSONFIRST OSMOTIC PUMP (THREE CHAMBER ROSE-NELSON
OSMOTIC PUMP)OSMOTIC PUMP)
PHARMETRIX DEVICEPHARMETRIX DEVICE
HIGUCHI LEEPER OSMOTIC PUMPSHIGUCHI LEEPER OSMOTIC PUMPS
HIGUCHI THEEUWES OSMOTIC PUMPHIGUCHI THEEUWES OSMOTIC PUMP
ELEMENTARY OSMOTIC PUMPELEMENTARY OSMOTIC PUMP
MULTICHAMBER OSMOTIC PUMPSMULTICHAMBER OSMOTIC PUMPS
CONTROLLED PORSITY OSMOTIC PUMPSCONTROLLED PORSITY OSMOTIC PUMPS
Department of Pharmaceutics, NIPS 2
3. ASYMMETRIC MEMBRANE COATED TABLETS
PULSATILE DRUG DELIVERY OSMOTIC PUMPS
DELAYED-DELIVERY OSMOTIC DEVICES
VOLUME AMPLIFIER DELIVERY DEVICE
OSMOTIC DEVICES THAT USE SOLUBILITY MODIFIERS
OSMOTIC DEVICES FOR USE IN ORAL CAVITY
OSMOTIC DEVICE THAT DELIVER DRUG BELOW
SATURATION
MISCELLANEOUS DEVICES
SPECIALIZED COATINGS
PROCESSING AND PERFORMANCE IMPROVEMENTPROCESSING AND PERFORMANCE IMPROVEMENT
IN VITRO EVALUATIONIN VITRO EVALUATION
MARKET PRODUCTSMARKET PRODUCTS
REFERENCESREFERENCES
Department of Pharmaceutics, NIPS 3
4. 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.
Department of Pharmaceutics, NIPS 4
5. 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.
Department of Pharmaceutics, NIPS 5
6. Graph shows nifedipine release from push pull osmotic pump
in artificial gastric and intestinal fluid. The release profile for
both media are similar and not affected by pH.
Department of Pharmaceutics, NIPS 6
7. 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.
Department of Pharmaceutics, NIPS 7
8. Figure shows the cummulative amount of nifidipine released from
push pull osmotic pump (POPP) in vitro and in the GIT tract of dogs
as a function of time.
Department of Pharmaceutics, NIPS 8
9. ADVANTAGES
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.
Department of Pharmaceutics, NIPS 9
10. 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.
Department of Pharmaceutics, NIPS 10
11. REPORTED CASES REGARDING
LIMITATIONS AND ADVERSE EFFECTS OF
OSMOTIC DRUG DELIVERY SYSTEM
During quality control of nifedipine GITS (Gastrointestinal
therapeutic System) tablets, it was observed that several batches show
different release patterns of the drug. It was found that non uniform
coating around the tablet produced different membrane thicknesses,
which was responsible for differences in release pattern among
different patches.
Another case was reported for Osmosin (Indomethacin OROS), which
was first introduced in UK in 1983. A few months after its
introduction frequent incidences of gastointestinal reactions
(hemorrhage and perforation)was observed by the Committee on the
Safety of Medicines, and Osmosin was withdrawn from market.
Department of Pharmaceutics, NIPS 11
12. 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.
Abbe Nollet first reported osmotic effect in 1748, but Pfeffer in 1877 had
been the pioneer of quantitative measurement of osmotic effect.
Pfeffer measured the effect by utilizing a membrane which is selectively
permeable to water but impermeable to sugar. The membrane separated
sugar solution from pure water. Pfeffer observed a flow of water into the
sugar solution that was halted when a pressure p was applied to the sugar
solution. Pfeffer postulated that this pressure, the osmotic pressure π of the
sugar solution is proportinal to the solution concentration and absolute
temperature.
Van’t Hoff established the analogy between the Pfeffer results and the
ideal gas laws by the expression
π = n2RT----------------------(1)
Where n2represents 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.
Department of Pharmaceutics, NIPS 12
13. 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.
Department of Pharmaceutics, NIPS 13
14. 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.
Department of Pharmaceutics, NIPS 14
15. 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.
Department of Pharmaceutics, NIPS 15
16. Schematic representation of the basic model of
osmotic pressure powered drug delivery systems
Vs Vd
PUMP
HOUSING
DELIVERY
ORIFICE
MOVABLE
PARTITION
SEMIPERMEABLE
MEMBRANE
Vs is volume of osmotic agent compartment
Vd is volume of drug compartment
Department of Pharmaceutics, NIPS 16
17. When a single osmotic driving agent is used, the pumping rate of the osmotic
device of (volume per unit time) is defined by
Q/t = Pw Sm [γm (πs- πe)-(ΔPd+ΔPc)] ------------ (4)
Pw is permeability of semi permeable membrane to water;
Sm is effective surface area of the membrane;
γm is osmotic reflection coefficient of the membrane;
πs and πe are the osmotic pressure of saturated solution of osmotic driving
agent and of the environment where device is located, respectively;
ΔPd is elevation of internal pressure generated in the drug formulation
compartment as the result of water influx into osmotic agent compartment;
ΔPc is pressure required to deform drug formulation compartment inward.
If the net osmotic pressure gradient [γm (πs- πe)] is constant and the hydrostatic
pressure (ΔPd+ΔPc) is negligibly small, equation (4) can be simplified to:
Q/t = Pw Sm (πs- πe) -------------- (5)
Department of Pharmaceutics, NIPS 17
18. And a zero order rate of drug release from osmotic
device can be achieved if following conditions are
met:
The amount of osmotic driving agent used is sufficient to
maintain a saturated solution in the osmotic agent compartment
i.e. πs is constant.
The environmental osmotic activity is either constant or
negligibly small i.e. (πs- πe) ≈ constant.
The osmotic reflection coefficient is constant and very close to
unity i.e. γm≈1. That means ideal semi permeable membrane,
selectively permeable to water but not to osmotic drug agent,
should be used.
A sufficiently large delivery orifice and a highly deformable
partition should be used. So, ΔPd =ΔPc≈0.
Department of Pharmaceutics, NIPS 18
19. 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.
Department of Pharmaceutics, NIPS 19
20. 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.
Organic water soluble osmogens:Sorbitol,
Mannitol,etc.
Department of Pharmaceutics, NIPS 20
21. 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.
Department of Pharmaceutics, NIPS 21
22. 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 co-entrapped 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.
Department of Pharmaceutics, NIPS 22
23. 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.
Department of Pharmaceutics, NIPS 23
24. 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)
Department of Pharmaceutics, NIPS 24
25. 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.
Department of Pharmaceutics, NIPS 25
26. 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.
Department of Pharmaceutics, NIPS 26
27. 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.
Department of Pharmaceutics, NIPS 27
28. 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.
Department of Pharmaceutics, NIPS 28
29. 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.
Department of Pharmaceutics, NIPS 29
30. FIRST OSMOTIC PUMP (THREE CHAMBER
ROSE-NELSON OSMOTIC PUMP)
Drug Chamber
Elastic Diaphragm
Salt Chamber
Rigid Semi permeable membrane
Water Chamber
Delivery orifice
Department of Pharmaceutics, NIPS 30
31. 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.
Department of Pharmaceutics, NIPS 31
32. 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.
Porous Membrane Support
MgSO4
Movable Separator
Drug Chamber
Rigid Housing
Satd. Sol. Of
MgSO4 contg.
Solid MgSO4
Semi-permeable
Membrane
Department of Pharmaceutics, NIPS 32
33. 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®
.
Wall of flexible
collapsible material
SPM
Coating contg. Solid
Osmotic compound
Delivery port
Osmotic Agent layer
Rigid
Semi permeable
Membrane
Fluid to be pumped
Delivery port
Swollen Osmogen layer
Squeezed
Drug Core
Department of Pharmaceutics, NIPS 33
34. ALZET®
Osmotic pumps are
miniature, infusion pumps for the
continuous dosing of laboratory
animals as small as mice and
young rats. These minipumps
provide researchers with a
convenient and reliable method
for controlled agent delivery in
vivo.
ALZET OSMOTIC PUMPALZET OSMOTIC PUMP
Department of Pharmaceutics, NIPS 34
35. ALZET OSMOTIC PUMPALZET OSMOTIC PUMP
ADVANTAGESADVANTAGES
Ensure around-the-clock exposure to test agents at predictable
levels.
Permit continuous administration of short half-life proteins and
peptides.
Convenient method for chronic dosing of laboratory animals.
Minimize unwanted experimental variables and ensure reproducible,
consistent results.
Eliminate the need for nighttime or weekend dosing.
Reduce handling and stress to laboratory animals.
Small enough for use in mice or very young rats.
Allow for targeted delivery of agents to virtually any tissue.
Cost-effective research tool.Department of Pharmaceutics, NIPS 35
36. Principle of OperationPrinciple of Operation
ALZET pumps have 3 concentric layers:
Rate-controlling, semi-permeable
membrane
Osmotic layer
Impermeable drug reservoir
ALZET pumps work by osmotic
displacement. Water enters the pump
across the outer, semi-permeable
membrane due to the presence of a high
concentration of sodium chloride in the
osmotic chamber. The entry of water
causes the osmotic chamber to expand,
thereby compressing the flexible
reservoir and delivering the drug solution
through the delivery portal.
Department of Pharmaceutics, NIPS 36
37. ALZETALZET®®
Osmotic Pumps are available in three sizesOsmotic Pumps are available in three sizes
Department of Pharmaceutics, NIPS 37
38. ALZET BRAIN INFUSION KITSALZET BRAIN INFUSION KITS
Department of Pharmaceutics, NIPS 38
39. 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.
Department of Pharmaceutics, NIPS 39
40. ELEMENTARY OSMOTIC PUMP (EOP)
Core containing agent
Delivery Orifice
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. Department of Pharmaceutics, NIPS 40
41. RELEASE PROFILES
The mass delivery rate from the pump can be written as:
Sd is concentration in drug compartment
πf is osmotic pressure of the drug formulation
A is surface area
h is thickness
k is permeability of membrane
πe is osmotic pressure of the environment which is negligible
So zero order release rate can be expressed as,
( ) [ ] ( ) def
z
Sk
h
A
dt
dm ⋅−⋅= ππ
( ) [ ] df
z
Sk
h
A
dt
dmZ ⋅⋅⋅== π
Department of Pharmaceutics, NIPS 41
42. PROBLEM
Area of semi permeable membrane of an elementary osmotic pump
is 2.7 cm2
, thickness is 0.031 cm, permeability coefficient is 2.1*10-6
cm2
/atm*h and the osmotic pressure is 225 atm, calculate the rate of
delivery of the solute under zero-order conditions if the concentration
of saturated solution at 37°C is 290 mg/ cm3
?
dm/dt = (A/h)k(π) Cs
= 2.7 cm2
/ 0.031 cm × 2.1*10-6 cm2
/atm*h × 225 atm × 290 mg/ cm3
= 11.93 mg/h
Department of Pharmaceutics, NIPS 42
43. 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.
Department of Pharmaceutics, NIPS 43
44. 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.
Delivery orifice
Drug chamberInner microporous
membrane
Outer semi permeable
membrane
COMPOSITE MEMBRANE COATING USED TO
DELIVER MODERATELY SOLUBLE DRUGS
Department of Pharmaceutics, NIPS 44
45. DELIVERY OF INSOLUBLE DRUG
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
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Elastic SPM
Rigid SPM
Insoluble Particles
Department of Pharmaceutics, NIPS 45
46. 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.
Department of Pharmaceutics, NIPS 46
47. 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.
OROS ORAL DRUG DELIVERY
TECHNOLOGY
Department of Pharmaceutics, NIPS 47
48. Drug delivery process of two chamber osmotic tablet
Osmotic Drug
Core
SPM
Delivery Orifice Delivery Orifice
Polymer push compartment Expanded push compartment
Before operation During operation
Department of Pharmaceutics, NIPS 48
50. 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.
Department of Pharmaceutics, NIPS 50
51. 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.
Rate controlling membrane
Push layer
Inner Capsule
Delivery orifice
Inner
Compartment
Barrier layer
Department of Pharmaceutics, NIPS 51
52. 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.
Department of Pharmaceutics, NIPS 52
54. 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.
Department of Pharmaceutics, NIPS 54
56. • Affecting factors
– Compositions of osmotic agent
– Thickness of semipermeable membrane
– Surface area
Department of Pharmaceutics, NIPS 56
57. 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 water-
soluble diluents such as sodium
chloride.
Department of Pharmaceutics, NIPS 57
58. Drug
Interior Orifice
Drug in diluted soln.
Wall
Second
Compartment
Interior
wall
First
Compartment
Exit Orifice
Department of Pharmaceutics, NIPS 58
59. 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
Department of Pharmaceutics, NIPS 59
60. 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.
Coating Containing Pore
Forming Agents
Pore Formation and Subsequent
Drug Release
Aqueous
Environment
Department of Pharmaceutics, NIPS 60
61. 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)Department of Pharmaceutics, NIPS 61
62. 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 initialDepartment of Pharmaceutics, NIPS 62
63. 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.
Department of Pharmaceutics, NIPS 63
64. 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.
Department of Pharmaceutics, NIPS 64
65. 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.
Department of Pharmaceutics, NIPS 65
66. 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.
Osmogen Semi permeable
Membrane
Separating Barrier
Elastic Cap
Movable piston
Drug Solution
Tiny orifice opened upon stretches under the
Osmotic pressure
Department of Pharmaceutics, NIPS 66
67. 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.
Department of Pharmaceutics, NIPS 67
68. 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.
Department of Pharmaceutics, NIPS 68
69. 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.
Department of Pharmaceutics, NIPS 69
70. A delayed release telescopic capsule release contents
after expansion.
Second Wall
section
Drug
Internal Compartment
First wall
section
Push plates
Push means
Department of Pharmaceutics, NIPS 70
71. 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.
Department of Pharmaceutics, NIPS 71
72. 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.
Department of Pharmaceutics, NIPS 72
73. 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 gas-
generating couple with the membrane formed of an
expandable material that is permeable to fluid and
impermeable to the couple.
Department of Pharmaceutics, NIPS 73
75. 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.
Department of Pharmaceutics, NIPS 75
76. 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.
Department of Pharmaceutics, NIPS 76
77. 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.
Department of Pharmaceutics, NIPS 77
78. 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.
Department of Pharmaceutics, NIPS 78
79. 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.
Department of Pharmaceutics, NIPS 79
80. 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.
Department of Pharmaceutics, NIPS 80
81. 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.
Department of Pharmaceutics, NIPS 81
82. 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
Department of Pharmaceutics, NIPS 82
83. 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
CoreActive Agent
layer
Department of Pharmaceutics, NIPS 83
84. 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.
Department of Pharmaceutics, NIPS 84
85. 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.)
Department of Pharmaceutics, NIPS 85
86. 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 water-dispersible)
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.
Department of Pharmaceutics, NIPS 86
87. 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.
Department of Pharmaceutics, NIPS 87
88. 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 (COER-24™) 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.
Department of Pharmaceutics, NIPS 88
89. Efidac 24®
(chlorpheniramine) over-the-counter, extended-
release 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 non-
insulin-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. Department of Pharmaceutics, NIPS 89
91. Verma R., Mishra B. and Garg S., Osmotically
controlled oral drug delivery; Drug Development and
Industrial Pharmacy, 26(7), 695-708 (2000)
Kaushal M.and Garg S., “ An Update on Osmotic Drug
Delivery Patents”; Pharmaceutical Technology,
August 2003 38-45.
Theeuwes F.,”Elementary Osmotic Pump”, Journal of
Pharmaceutical Science;64(12):1987-1991(1975).
Theeuwes F., Journal of Pharmaceutical
Science;72:253(1983).
Chein Y., Novel Drug Delivery Systems:398-407
Department of Pharmaceutics, NIPS 91
92. Wong P.,Gupta S. and Stewart B. Modified Release
Drug Delivery Technology: Osmotically controlled
tablets:101-114
Fara J. and and Ray N.; Drug Delivery Devices,
Fundamentals and Applications, :137-175
Santus G., and Baker R., “Osmotic Drug Delivery: A
Review of the Patent Literature,” J. Controlled Release
35, 1–21 (1995).
Swarbrick J. and Boylan J, “Encyclopedia of
Pharmaceutical Technology”, Vol. 3: 297-300
www.fda.gov/ohrms/dockets/ ac/04/slides/2004-
4078S1_13_Khan.ppt
cooklab.rutgers.edu/Intro_Lect_webct.ppt
Department of Pharmaceutics, NIPS 92