INTRODUCTION ADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM DISADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM REPORTED CASES REGARDING LIMITATIONS AND ADVERSE EFFECTS OF OSMOTIC DRUG DELIVERY SYSTEM PRINCIPLE OF OSMOSIS BASIC COMPONENTS OF OSMOTIC PUMP

1. OSMOTIC DRUG DELIVERY
SYSTEM
By:
Mr. Kailash Vilegave
Asst. Prof,
Shivajirao S. Jhondhle college of Pharmacy
Asangaon .

2. LIST OF CONTENTS
INTRODUCTION
 ADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM
 DISADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM
 REPORTED CASES REGARDING LIMITATIONS AND ADVERSE
EFFECTS OF OSMOTIC DRUG DELIVERY SYSTEM
 PRINCIPLE OF OSMOSIS
 BASIC COMPONENTS OF OSMOTIC PUMP
OSMOTIC PUMPS
 FIRST OSMOTIC PUMP (THREE CHAMBER ROSE-NELSON
OSMOTIC PUMP)
 PHARMETRIX DEVICE
 HIGUCHI LEEPER OSMOTIC PUMPS
 HIGUCHI THEEUWES OSMOTIC PUMP
 ELEMENTARY OSMOTIC PUMP
 MULTICHAMBER OSMOTIC PUMPS
 CONTROLLED PORSITY OSMOTIC PUMPS

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 IMPROVEMENT
IN VITRO EVALUATION
MARKET PRODUCTS
REFERENCES

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

16. Schematic representation of the basic model of
osmotic pressure powered drug delivery systems
PUMP
SEMIPERMEABLE HOUSING
MEMBRANE
Vs Vd
DELIVERY
MOVABLE
ORIFICE
PARTITION
Vs is volume of osmotic agent compartment
Vd is volume of drug compartment

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)

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.

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.

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.

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.

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.

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.

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)

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.

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.

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.

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.

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.

30. FIRST OSMOTIC PUMP (THREE CHAMBER ROSE-
NELSON OSMOTIC PUMP)
Salt Chamber
Water Chamber Drug Chamber
Delivery orifice
Rigid Semi permeable membrane Elastic Diaphragm

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.

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.
Rigid Housing
Drug Chamber
Satd. Sol. Of
MgSO4 contg.
Movable Separator
Solid MgSO4
MgSO4
Semi-permeable
Membrane
Porous Membrane Support

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®.
Fluid to be pumped
Coating contg. Solid
Osmotic compound
SPM Delivery port
Rigid
Semi permeable
Membrane
Osmotic Agent layer Delivery port
Wall of flexible Squeezed
collapsible material Drug Core
Swollen Osmogen layer

34. ALZET OSMOTIC PUMP
 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.

35. ALZET OSMOTIC PUMP ADVANTAGES
 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.

36. Principle 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.

37. ALZET® Osmotic Pumps are available in three sizes

38. ALZET BRAIN INFUSION KITS

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.

40. 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.

41. RELEASE PROFILES
 The mass delivery rate from the pump can be written as:
dm A k Sd
dt z h f e
 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,
Z dm A k Sd
dt z h f

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

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.

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.
Inner microporous Drug chamber
membrane
Delivery orifice
Outer semi permeable COMPOSITE MEMBRANE COATING USED TO
membrane DELIVER MODERATELY SOLUBLE DRUGS

45. 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

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.

47. 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.

48. 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

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, prot
ection 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.

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.
Delivery orifice
Barrier layer
Rate controlling membrane
Push layer
Inner
Compartment
Inner Capsule

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.

53. OROS TRI-LAYER

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.

55. DUROS SYSTEM

56. • Affecting factors
– Compositions of osmotic agent
– Thickness of semipermeable membrane
– Surface area

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.

58. Exit Orifice
Wall
First Drug in diluted soln.
Compartment
Interior Orifice
Second
Compartment
Interior
wall Drug

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 Semi permeable
containing chamber membrane
orifice
Drug containing chamber
Microporous membrane

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.
Aqueous
Environment
Pore Formation and Subsequent
Coating Containing Pore Drug Release
Forming Agents

61. SPECIFICATIONS FOR CONTROLLED
POROSITY OSMOTIC PUMPS
Materials Specifications
Plasticizers and flux regulating 0 to 50, preferably 0.001 to 50
agents 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

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 8 to 500atm typically, with
solution of core 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

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.

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.

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.

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 Tiny orifice opened upon stretches under the
capsule’s osmotic infusion Osmotic pressure
of moisture from the body.
 The delivery orifice opens Elastic Cap
intermittently to achieve a Drug Solution
pulsatile delivery effect.
The orifice forms in the
capsule wall, which is
constructed of an elastic
material. Movable piston
 As the osmotic infusion Separating Barrier
progresses, pressure rises
Semi permeable
within the capsule, causing Osmogen
Membrane
the wall to stretch.
 Elastomers such as styrene-
butadiene copolymer can be
used.

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.

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.

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.

70. Push plates
Second Wall First wall
section section
Push means
Drug
Internal Compartment
A delayed release telescopic capsule release contents after
expansion.

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.

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.

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.

74. Gas generating
couple
Gas
Volume
Amplifier

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.

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.

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.

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.

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.

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.

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.

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

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
Active Agent Core
layer

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.

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.)

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.

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.

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.

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.

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

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

93.  http://www.drugdeliverytech.com/cgi-
bin/articles.cgi?idArticle=15
 http://www.alzet.com/
 http://www.alza.com/
 www.glue.umd.edu/~nsw/enpm808b/he-b.ppt
 www.dissolution.com/vbulletin/ archive/index.php?t-
523.html - 5k
 http://www.drugdeliverytech.com/cgi-
bin/articles.cgi?idArticle=115