Hemostasis Physiology and Clinical correlations by Dr Faiza.pdf
Osmotic Drug Delivery System
1. OSMOTIC DRUG
DELIVERY SYSTEM
Dr. Gajanan S. Sanap M.Pharm.,Ph.D
Department of Pharmaceutics
Ideal College of Pharmacy and Research
Kalyan 421- 306
2. INDEX
1) Introduction
2) Principle of osmosis
3) Classification of osmotic drug delivery system
4) Factors affecting release of medicament from osmotic DDS
5) Basic components of osmotic system
6) Evaluation
7) Advantages
8) Disadvantages
9) Marketed products
3. 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.
4.
5. Osmotic drug delivery uses the osmotic pressure for controlled delivery of drugs by using osmogens
Osmosis : the net movement of water across a selectively permeable membrane driven by a difference in osmotic pressure across the membrane
Osmotic pressure : the pressure which, if applied to the more concentrated solution, would prevent transport of water across the semi permeable membrane
Osmotic pressure is a colligative property
These systems can be used for both route of administration i.e. oral and parenterals
6. ADVANTAGES OF OSMOTIC DRUG DELIVERY
SYSTEM
The delivery rate of zero-order (which is most
desirable) is achievable with osmotic systems.
Ease of administration
Greater effectiveness in the treatment of chronic
conditions
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 I n coating of osmotic formulations.
Enhance bioavailability
7. Higher release rates are possible with osmotic systems compared with
conventional diffusion-controlled drug delivery systems.
The release rate of osmotic systems is highly predictable and can be
programmed by modulating the release control parameters.
A high degree of in vivo–in vitro correlation (IVIVC) is obtained in
osmotic systems because the factors that are responsible for causing
differences in release profile in vitro and in vivo (e.g., agitation,
variable pH) affect these systems to a much lesser extent.
The release from osmotic systems is minimally affected by the
presence of food in the gastrointestinal tract (GIT). This advantage is
attributed to design of osmotic systems. Environmental contents do
not gain access to the drug until the drug has been delivered out of the
device.
Production scale up is easy.
8. DISADVANTAGES OF OSMOTIC DRUG DELIVERY SYSTEM
Rapid dExpensive
evelopment of tolerance
Chance of toxicity due to dose dumping
Additional patient education and counseling is required.
Hypersensitvity reaction may occur after implantation.
9. OSMOSIS:
• Osmosis refers to the process of movement of solvent from
lower concentration of solute towards higher concentration of
solute across a semipermeable membrane until there is an
equal concentration of fluid on both sides of the membrane.
• Osmotic pressure is a colligative property.
• Difference betwe en diffusion and osmosis:
• In diffusion both the solute and solvent molecules migrate
freely whereas if the solution is confined in a membrane
permeable only to solvent molecules, it is knows osmosis.
• Osmotic pressures of concentrated solutions of soluble
solutes commonly used in controlled formulations are
extermely high because high osmotic pressures are
responsible for high water flow across semi-permeable
membrane.
• Eg: Sodium chloride – 356 atm.
Fructose – 355atm.
10. Principle of Osmosis
• The solvent membrane control delivery of agent from the
osmotic system across the semi permeable membrane,
which in turn drive the agent out. Water influx of osmotic
pump can be describe as,
dv = A LP σ (ΔП – ΔP)
dt h
Where dv = water influx
dt
A = membrane area
h = membrane thickness
P = mechanical permeability
ΔП = osmotic pressure
ΔP = hydrostatic pressure difference between inside and outside the
system
σ = describes the lickages of solute through the membrane.
11. • The general expression for the solute delivery
rate, dM / dt obtained by pumping through the
orifice of the reservoir is given by,
• dM = dV C
dt dt
Where C is concentration of solute if dispersed fluid
12. PRINCIPLE OF OSMOSIS
Abbe Nollet first reported osmotic effect in 1748, but Pfeffer in
1877 had been the pioneer of quant itative 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.
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,
14. 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 eit her side of the membrane.
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.
15. 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
16. 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)
17. 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.
18. BASIC COMPONENTS OF PUMP
Drug
Osmotic agent
Semipermeable agent
Plasticizers
Wicking agent
Solubilising agent
Surfactant
Coating solvent
Flux regulator
Pore forming agent
Hydrophilic and hydrophobic polymers
MATERIAL USED IN FORMULATION OF
OSMOTIC PUMPS.
19. Drugs
Short biological half life
Highly potent drug
Required for prolong treatment
Eg. Nifedipine , virapamil
SEMIPERMEABLE MEMBRANE
Should stable both outside and inside enviourment of device.
Sufficiently rigid and retain its dimensional integrity during the
operational life time of device.
Exhibit sufficient water permeability so as to retain water flux rate in
desired range.
It is used to controlled the amount of water entering to dosage form.
Cellulose acetate is a commonly employed semi permeable polymer
for the preparation of osmotic pumps.
20. SEMIPERMEABLE MEMBRANE FORMING POLYMER
Cellulose polymer
Cellulose acetate(common)
Acetyl content 32% and 38%
Degree of substitution(ds)
Up to 1 - AC - 21%
Ex. Cellulose diacetate
DS=1-2, AC -21-35%
Cellulose triacetate
DS – 2-3 ,AC- 35-44.8%
Other polymers
Agar acetate
Amylose triacetate
Betaglucan acetate
Polyacetals
Polyether coplymer
21. 2) Hydrophilic and Hydrophobic Polymers:
These polymers are used in the formulation development of osmotic
systems for making drug containing matrix core.
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.
Swellable polymers are used for the pumps containing moderately water
soluble drugs since they increase the hydrostatic pressure inside the pump
due to their swelling nature where as non-swellable polymers are use in
case of highly water soluble drugs.
The selection is based on the solubility of the drug as well as the amount
and rate of drug to be released from the pump.
22. 3. WICKING AGENT
Material which has ability to draw water into the porous
network of 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)
polyvinyl pyrrolidone (PVP) bentonite
magnesium aluminium silicate polyester
polyethylene,etc.
A wicking agent is defined as a material with the ability to
draw water into the porous network of a delivery device. A
wicking agent is of either swellable or non-swellable nature.
23. 4) 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.
Osmogens are essential ingredient of the osmotic formulations. They
maintain the osmotic presser in side the tablet of core and thus provide the
controlled release.
Eg: inorganic salts and carbohydrates.
24. 5) Surfactants :
Surfactants are particularly useful when added to wall forming material.
They produce an integral composite that is useful for making the wall of
the device operative.
Eg:polyoxyethelynated glyceryl recinoleate,glyceryl laurate,etc.
6) 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.
The typical solvents include methylene chloride, acetone, methanol,
ethanol, isopropyl alcohol, butyl alcohol, ethyl acetate, cyclohexane,
carbon tetrachloride, water etc. The mixtures of solvents such as
acetone-methanol (80:20), acetone-ethanol (80:20), acetone-water
(90:10), methylene chloride-methanol (79:21),etc.
25. 7) Plasticizers:
Plasticizers increase the workability, flexibility and permeability of the
fluids. Generally from 0.001 to 50 parts of a plasticizer or a mixture of
plasticizers are incorporated in to 100 parts of wall forming materials.
Eg.dialkyl phthalates,alkyl adipates,citrates,benzoates,myristares,etc.
8) 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
multi-particulate osmotic pumps.
These pore-forming agents cause the formation of micro porous
membrane. E.g. sucrose, glucose, fructose, mannose, lactose, sorbitol,
and mannitol .
The microporous wall can be formed in situ by a pore formerby its
leaching during operation of the system. The pores can be formed prior
to operation by gas formation within coating polymer solutions which
result inpores in the final form of the wall.
For example
Alkaline metal salts (NaCl, NaBr, Kcl) , Alkaline earth metals (Cacl2 and
calcium nitrate) , Carbohydrates (glucose, fructose, mannose)
26. 9) Flux Regulators:
• Flux enhancing or flux decreasing agents are added to the
wall forming material in regulating the fluid permeability of
flux throuugh wall.
• Eg:polyhydric alcohols, polybutylene,polypropylene,etc.
it assist in regulating the fluid permeability through
membrane.
add to the wall forming material.
Examples:-
Poly hydric alcohols (poly alkylene glycols)
low molecular weight glycols(poly propylene, poly
butylene and poly amylene)
27. 10. 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)
28. COATING SOLVENTS
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
29. Classification of Osmotic drug
delivery system
1 Implantable Osmotic Drug Delivery System
2 Oral Osmotic Drug Delivery System
30. 1 Implantable Osmotic Drug Delivery System
A. Rose nelson pump
• the first osmotic pump developed in 1955 for the
delivery of drugs to the sheep and cattle gut
• Composed of three chambers
• Water to be loaded prior to use was the drawbacks of
rose nelson osmotic pump
Water
Chamber
Rigid Semi permeable
membrane
Elastic
Diaphragm
Delivery
orifice
Drug
Chamber
Salt
Chamber
31. FIRST OSMOTIC PUMP (THREE CHAMBER
ROSE-NELSON OSMOTIC PUMP)
Drug Chamber
Elastic Diaphragm
Salt Chamber
Rigid Semi permeable membrane
Water Chamber
Delivery orifice
32. Rose Nelson Pump
The pump composed of three chambers: a drug chamber, a salt chamber
holding solid salt, and a water chamber.
A semi permeable membrane separates the salt from water chamber.
The major problem associated with Rose Nelson pumps was that the
osmotic action begin whenever water came in contact with the semi
permeable membrane.
This needed pumps to be stored empty and water to be loaded prior to use.
33. B. Higuchi leeper osmotic pump
• No water chamber
• The activation of device occurs after imbibition of the water
from the surrounding environment
• Employed for veterinary use
• Either swallowed or implanted in body of animal for delivery
of antibiotic or growth hormones to animals
• Pulsatile delivery can be achieved
34. Has rigid housing.
Used for veterinary purpose. 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
35. C. Higuchi Theeuwes Osmotic Pump
• 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®.
• Delivery of DNA by agarose hydrogel implant facilitate genetic
immunization in cattle by using Alzet osmotic pumps
37. • 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 the outer
membrane.
38. 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
39. 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
40. 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.
41. ADVANTAGES
continuous administration of short half-life proteins and peptides.
for chronic dosing of laboratory animals.
Minimize unwanted experimental variables and ensure
reproduciblility
consistent results.
Eliminate the need for nighttime or weekend dosing.
Reduce handling and stress to laboratory animals.
enough for use in mice or very young rats.
Allow for targeted delivery of agents to virtually any tissue.
Cost-effective research tool.
Expose the agent at predictable level.
43. • It is composed of three concentric layers- the drug
reservoir, the osmotic sleeve and the rate controlling
semi–permeable membrane.
• It contains an additional component called flow
moderator is inserted into the body of the osmotic pump
after filling.
• When the system is placed in aqueous environment
water enters the sleeve through semi permeable
membrane, compresses the flexible drug reservoir and
displaces the drug solution through the flow moderator.
44. 2 Oral Osmotic Drug Delivery System
A. Elementary osmotic pump
B. Multi chamber osmotic pump
- expandable
- non expandable
C. Modified osmotic pump
D. Controlled porosity osmotic pump
E. Multiparticulate delayed release system
F. Monnolithic osmtic system
45. A. Elementary osmotic
pump
Semi permeable membrane
Core
Delivery Orifice
• Major method of achieving controlled drug release
• The EOP was developed by Alza undre the name OROS for
controlled release oral drug delivery formulations
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.
46. 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.
47. RELEASE PROFILES
( ) [ ] ( ) def
z
Sk
h
A
dt
dm ⋅−⋅= ππ
( ) [ ] df
z
Sk
h
A
dt
dmZ ⋅⋅⋅== π
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,
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.
48. LIMITATION OF EOP
semi permeable membrane should be 200-300μm
These thick coatings lower the water permeation rate
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.
49. 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
50. 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
51. 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
52. • Fabricated as tablet coated with semipermeable
membrane usually cellulose acetate
• Small orifice is drilled through the membrane coating
• Eliminates separate salt chamber
• Tablet working as a small pump withdrawing water from
external environment
• Ex. Swellable elementary osmotic pump (SEOP): An
effective device for delivery of poorly water-soluble drug
indomethacin
- The results showed that concentration of wetting agent
in the core formulation was a very important parameter in
D24h and release pattern of indomethacin from SEOP system.
Increasing the amount of wetting agent to an optimum
level (60 mg) significantly increased D24h and improved
zero order release pattern of indomethacin
54. B.Multichamber osmotic pump
i. Expandable MCOP
Expandable for solid osmotic system
• PPOP ( push pull osmotic system )
• They contain two or three compartment separated by elastic
diaphragm
• Upper compartment contain drug with or without osmogen
(drug compartment nearly 60 – 80 %) and lower compartment
(Push compartment) contain Osmogen at 20 – 40 %.
• Example ProcardiaXL for Nifedipine
• In vitro and in vivo evaluation of PPOP controlled release
tablet of vinpocetine using numerical deconvolution
technique. (Chemical Abstract, 63- Pharmaceutical Vol. 164., No. 6., August
2010)
55. 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.
56. 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
57. 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
59. Expandable for liquid osmotic system
• A liquid formulation is use for delivering insoluble drugs and
macromolecules.
• Such molecules require external liquid components to assist in
solubilization, dispersion, protection from enzymatic
degradation and promotion of gastrointestinal absorption.
• Thus the L-OROS system was designed for continuous
delivery of liquid drug.
•
60. 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 require 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.
61. 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
62. ii. Non expandable MCOP
Depending on
function of
second chamber
non–expandable
osmotic pump
are divided into,
Drug solution
get diluted in
second chamber
before leaving
device.
Two separate
EOP tablet
formed in
single tablet
63. Drug solution get diluted in second chamber
before leaving device
• Before the drug can exit from the device, it must pass
through a second chamber
• Water is also drawn Osmotically into this chamber due to
osmotic pressure of the second chamber that bears water-
soluble osmogen
• Such is useful when saturated solution of drug irritate GIT
• Reason behind the withdrawl of Osmosin (sodium
indomethacin)
64. Two separate EOP tablet formed in
single tablet
also known as sandwiched osmotic tablet system
65. A more sophisticated version of these devices consists of
two rigid chambers : one chamber contains osmogen and
second chamber contain drug
SPM
Drug
Osmogen
Microporous
membrane
66. 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.
68. 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
69. C. Modified osmotic pump
particles of osmotic agent are coated with an elastic
semipermeable film. These particles are then mixed with
the insoluble drug and compressed in the form of a tablet
70. D. Controlled porosity osmotic
pump
• the delivery orifice is formed by incorporation of a
leachable water-soluble component in the coating material
• Drug release from the whole surface of device rather than
from a single hole which may reduce stomach irritation
problem
71. • The release rate from these types of systems has been reported
to be dependent on :
• the coating thickness (20-500 𝜇m)
• level of soluble components in the coating solubility of the
drug in the tablet core
• osmotic pressure difference across the membrane (8-500 atm)
• independent of the pH and agitation of the release media
• EX. Chitosan-based controlled porosity osmotic pump for
colon-specific delivery system: screening of formulation
variables and in vitro investigation : microbially triggered
colon-targeted osmotic pump (MTCT-OP)
The gelable property at acid condition and colon-specific
biodegradation of chitosan
72. 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
73. SPECIFICATIONS FOR
CONTROLLED POROSITY OSMOTIC
PUMPS
Materials Specifications
Plasticizers and flux regulating
agents
0 to 50, preferably 0.001 to 50 parts
per 100 parts of wall material
Surfactants 0 to 40, preferably 0.001 to 40 parts
per 100 parts of wall material
Wall Thickness 1 to 1000, preferably 20 to 500μm
Micro porous nature 5 to 95% pores between 10Å to
100μm
Pore forming additives 0.1 to 60%, preferably 0.1 to 50%,
by weight, based on the total weight
of pore forming additive and
polymer
pH insensitive pore forming additive
(solid or liquid) preferably 0.1 to
40% by weight
74. SPECIFICATIONS FOR CORE OF
CONTROLLED POROSITY OSMOTIC
PUMPS
Property Specifications
Core loading (size) 0.05ng to 5g or more (include
dosage forms for humans and
animals)
Osmotic pressure developed by a
solution of core
8 to 500atm typically, with
commonly encountered water
soluble drugs and excipients
Core solubility To get continuous, uniform release
of 90% or greater of the initially
loaded core mass solubility, S, to the
core mass density, ρ, that is S/ρ,
must be 0.1 or lower. Typically this
occurs when 10% of the initially
loaded core mass saturates a volume
of external fluid equal to the total
volume of the initial core mass
75. E. Multiparticulate delayed release
system
• In the multiparticulate delayed-release system, pellets
containing drug with or without osmotic agent are coated
with an SPM-like cellulose acetate.
• On contact with an aqueous environment, water
penetrates into the core and forms a saturated solution of
soluble components.
• The osmotic pressure gradient induces a water influx,
resulting in a rapid expansion of the membrane, leading to
the formation of pores.
• The osmotic ingredient and the drug are released through
these pores according to zero order kinetics.
76. F. Monnolithic osmtic
system
• Dispersion of water soluble drug is made in a polymeric
matrix and compressed as tablet.
• Tablet is then coated with semi permeable membrane or
drilled on both side of tablet.
• When MOS comes in contact with aqueous environment, the
water penetrates in the core and forms a saturated solution of
component which will generate osmotic pressure which results
in the rupturing of membrane of polymeric matrix surrounding
the agent. Thus liberating drug to move outside the
environment.
77. • MOS is simple to prepare but the system fails if more then 20
– 30 % volume of active agent is incorporated in device
because above this level significant contribution is from
leaching of substance
• Ketoprofen Monolithic Osmotic Pump Control Release Tablet
made up of PEG 6000, NaCl, CMC-Na and Polyvinyl
pyrrolidone which releases drug at 93.51 % for 24 hrs
(Chemical Abstract, 63- Pharmaceutical Vol. 147., No. 6.,
August 6. 2007. P=1912., 215217m)
78. 4.Factors affecting release of
medicament from Osmotic DDS
A. Solubility
B. Osmotic pressure
C. Delivery orifice
D. Membrane type
79. 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.)
80. 4A. solubility
• Solubility of drug is one of the most important factors since kinetic of
osmotic release is directly related to the drug solubility.
• The fraction of a drug release with zero order kinetic is given by
•
Where F (z): fraction release by zero order
S: drug solubility in g / cm 3
P: density of core tablet.
• Drug with density of unity and solubility less than 0.05 g / cm 3 would
release greater than or equals to 95 % by zero order kinetics
• Drug with density > 0.3 g / cm 3 solubility would demonstrate with higher
release rate > 70 % by zero order.
• Both highly soluble and poorly soluble drugs are not good candidates for
osmotic drug delivery
F (z) = 1 – S
P
81. Solubility modifying approaches
i. Co-compression of drug with excipients
the modification in solubility of CPOP of a highly water-
soluble drug, diltiazem hydrochloride
Co-compression of drugs along with solubility
modulating agents can also be utilized for pulsatile
delivery of drugs
Ex. Demonstrated by salbutamol, highly water soluble drug
ii. Use of encapsulated excipients
Solubility modifier excipient used in form of mini-tablet
coated with rate controlling membrane
82. iii. Use of swellable polymers
for drugs having poor aqueous solubility
Ex. Carbamazapine, theophylline (US patent no. 4,992,278)
vinylpyrrolidone /vinyl acetate copolymer and
polyethylene oxide were used as swelling agent
iv. Use of effervescent mixtures
Another approach to deliver poorly water-soluble drugs
form osmotic drug delivery system
Citric acid and sodium bicarbonate were used as the
effervescent couple for the delivery of acetyl salicylic acid
(US Patent no. 4,036,228)
83. v. Use of cyclodextrin derivatives
CPOP of Testosterone : increase in solubility of drug
from 0.039 mg/ml to 76.5 mg/ml through complexation with
sulfobutyl ether-b-cyclodextrin sodium salt
Comparative study of CPOP of Testosterone with (SBE)- β -CD
and HP- β –CD
vi. Resin modulation approach
Release of a highly water-soluble drug, diltiazem
hydrochloride from a CPOP was modulated effectively using
positively charged anion-exchange resin poly (4-vinyl
pyridine)
Pentaerythritol was used as osmotic agent and citric and
adipic acids were added to maintain a low core pH to assure
that both the drug and resin carry a positive charge.
84. vii. Use of alternative salt form
In case of metoprolol, use of fumarate salt instead of
tartarate salt achieves optimum solubility and provided
extended release up to 24 hr.
viii. Use of crystal habit modifiers
a slightly soluble drug, carbamazepine along with crystal
modifying agents (combination of hydroxymethyl cellulose
and hydroxyethyl cellulose) and other excipients was
formulated. (US patent no. 5,284,662)
85. ix. Use of lyotropic crystals
swell in presence of water
Ex. phosphatidyl choline (lecithin),phosphatidylethanolamine,
phosphatidylserine, phosphatidylglycerol
for osmotic delivery of prazosin lecithin and mixture of
soybean phospholipids was utilized (US patent no. 5,108,756)
x. Use of wicking agents
an approach for poorly water-soluble drugs
Ex. of wicking agent : colloidal silicon dioxide, PVP, sodium
lauryl sulfate
86. 4B Osmotic pressure
• The next release-controlling factor that must be optimized
is the osmotic pressure gradient between inside the
compartment and the external environment
• The simplest and most predictable way to achieve a
constant osmotic pressure is to maintain a saturated
solution of osmotic agent in the compartment
• The release rate of a drug from an osmotic system is
directly proportional to the osmotic pressure of the core
formulation
87.
88. 4C. Delivery orifice
• To achieve an optimal zero order delivery profile, the cross
sectional area of the orifice must be smaller than a
maximum size to minimize drug delivery by diffusion
through the orifice
• Furthermore, the area must be sufficiently large, above a
minimum size to minimize hydrostatic pressure build up in
the system
• The typical orifice size in osmotic pumps ranges from
600µ to 1 mm.
89. Evaluation
• Pore diameter
• Coating thickness
• Hardness
• Friability
• Weight variation
• In vitro evaluation
• In vivo evaluation
90. IN VITRO DELIVERY RATE
MEASUREMENTS
1.Method used by theeuwes and co workers
• osmotic pumps are placed in loosely woven mesh bags of
nylon or polyethylene, and the bags are attached to a rod,
which in turn is attached to a horizontal transfer arm
connected to a vertically reciprocating shaker. The arms
containing several systems are then positioned over test
tubes/containers containing a known amount of release
media
• The release rate (mg/hr) is determined by dividing the
amount of drug in each container by the time (in hours) of
the test interval
91. 2. Conventional USP dissolution apparatus 1 and 2
3. flow-through apparatus
4. In vitro release of
phenylpropanolaminehydrochloride (PPA) from the oral
osmotic pump system and a marketed long-acting product
(spansules) was compared using a calibrated Ghannam-Chien
diffusion system as the dissolution apparatus
92. IN VIVO DELIVERY RATE MEASUREMENT
• Carrid out mainly in dogs
• Theeuwes et al. studied the in vivo release of indomethacin
from OROS pumps in mongrel dogs
• Gastrointestinal transit of an osmotic tablet was measured
by radiolabeling an intact osmotic tablet (placebo osmosin
tablets) and monitoring the movement of the unit in the GI
tract of young and old healthy volunteers using gamma
scintiography (47). The units were observed to move
through the GI tract at about the same rate as the released
contents, arriving at the cecum about 7 hr after dosing
93. In Vitro Evaluation:
1. In vitro Dissolution:
The in vitro release of drug from oral osmotic system has been
evaluated by the conventional USP paddle and basket type apparatus.
US patent described the use of commercial vankel standard dissolution
apparatus.
The dissolution media is generally distilled water as well as stimulated
gastric fluid (for first 2-4 hr) and stimulated intestinal fluids (for
subsequent hours) have been used. The standard specification, which
are followed for the oral controlled drug delivery systems are
equivalently applied for oral osmotic pump.
94. 2 Scanning Electron Microscopy
Coating membranes of formulation obtained before and after complete
dissolution of core contents can be examined for their porous
morphology by scanning electron microscope.
3Effect of pH
To study the effect of pH and to assure a reliable performance of the
developed formulations independent of pH, in vitro release studies can
be conducted in media of different pH.
4 Effect of Agitational Intensity
In order to study the effect of agitational intensity of the release media,
release studies were performed in dissolution apparatus at various
rotational speeds.
95. 5 Effect of Osmotic Pressure
To confirm the major mechanism of drug release, release studies of
the optimized formulation can be conducted in media of different
osmotic pressure. To increase the osmotic pressure of the release
media (pre-equilibrated to 37°C ± 1°C), mannitol (osmotically
effective solute) can be added.
6 Kinetics of Drug Release
the data obtained can be fitted in different models at different time
intervals and by using satistics we can know kinetics of drug release.
Where dv = water influx
dt
A = membrane area
h = membrane thickness
P = mechanical permeability
ΔП = osmotic pressure
ΔP = hydrostatic pressure difference between inside and outside the system
σ = describes the lickages of solute through the membrane.
Where C is concentration of solute if dispersed fluid
The EOP was developed by Alza undre the name OROS for controlled release oral drug delivery formulations
particles of osmotic agent are coated with an
elastic semipermeable film. These particles are then
mixed with the insoluble drug and compressed in the
form of a tablet
