detailed presentation regarding novel drug delivery, that is osmotic drug delivery

1. OSMOTIC PRESSURE
CONTROLLED PUMPS
- AASHU GUPTA

2. WHAT SHOULD BE CHOSEN ????
CONVENTIONAL DRUG THERAPY
OR
CONTROLLED RELEASE DRUG THERAPY

3. PROBLEMS WITH CONVENTIONAL
DRUG THERAPY
 If the dosing interval is not proper according to the
biological half life of the drug, then large peak
&valleys are formed in the drug blood level.Thus, the
drugs with short biological half lives require frequent
dosing to maintain constant blood level.
 The drug level may not be within the defined
therapeutic range, hence problems associated in certain
diseased conditions where early effect is not obtained.
 Patient non compliance due to mutiple dosing can lead
to failure in the therapy.

4. SPECIFICATIONS WITH CONTROLLED
RELEASE DRUG THERAPY
 SUSTAINED DRUG ACTION - by maintaining relatively
constant & effective drug level in the body ith minimization of
the side effects.
 LOCALIZED DRUG ACTION - by placing the controlled
release system adjacent to the diseased tissue or the organ.
 TARGETED DRUG ACTION - by using carriers or
chemical derivatives to deliver drug to particular target cell type.
 PROVIDE A THERAPEUTICALLY BASED DRUG
RELEASE SYSTEM - rate & amount of the drug release is
according to the therapeutic needs of the body.

5. • Controlled release dosage form are actually designed to
release drug in-vivo according to predictable rate that can
be verified by in-vitro measurement.
• Potential development and new approaches to oral
controlled release dosage form includes -
1. Hydrodynamic pressure controlled system
2. Intragastric floating tablet
3. Transmucosal tablet
4. Microporous membrane coated tablet
• Osmotic drug delivery has come a long way since
Australian physiologists Rose and Nelson developed an
implantable pump in 1955. Osmotic drug delivery uses the
osmotic pressure for controlled delivery of drugs by using
osmogens (for upto10 – 16 hrs). It is the most upcoming &
popular controlled release system which can be used
nowadays.

6. CLASSIFICATION OF CONTROLLED
DDS
1. Rate-programmed drug delivery systems
 Polymer membrane permeation-controlled drug delivery systems
 Polymer matrix diffusion-controlled drug delivery systems
 Microreservoir partition- controlled drug delivery systems
2. Activation-modulated drug delivery systems-
 Osmotic Pressure- activated drug delivery systems
 Hydrodynamic pressure- activated drug delivery systems
 Vapor pressure- activated drug delivery systems
 Mechanically activated drug delivery systems
 Magnetically activated drug delivery systems
 Sonophoresis –activated drug delivery systems
 Iontophoresis-activated drug delivery systems
 Hydration-activated drug delivery systems

7.  pH–activated drug delivery systems
 Ion-activated drug delivery systems
 Hydrolysis-activated drug delivery systems
 Enzyme-activated drug delivery systems
 Bio chemical-activated drug delivery system
3. Feedback- regulated drug delivery systems
 Bioerosion- regulated drug delivery system
 Bio responsive drug delivery systems
 Self-regulating drug delivery systems
4. Site targeting drug delivery systems

8. OSMOTICALLY
CONTROLLED
DRUG
DELIVERY
SYSTEM

9. TOPICS COVERED
1. INTRODUCTION TO OSMOTIC DRUG DELIVERY
SYSTEM
2. ADVANTAGES
3. DISADVANTAGES
4. NEED OF FORMULATING ODDS
5. MECHANISM OF ODDS
6. PARAMETERS AFFECTING ODDS
7. FORMULATION OF ODDS
8. PREPARATION OF ODDS
9. CLASSIFICATION & DETAIL OF EACH OSMOTIC PUMP
10.NEWER TECHNOLOGY IN ODDS
11.EVALUATION
12.MARKET FORMULATIONS

10. WHAT IS OSMOTIC PRESSURE???
 Osmotic pressure is a most important colligative property
according to pharma point of view. Colligative property means
that the concentration of solution is independent of the solute
property.
 Osmotic pressure of a solution is the external pressure that must
be applied to the solution in order to prevent it being diluted by
the entry of solvent via a process known as Osmosis. Such
membrane is only permeable to solvent molecule. Because only
solvent can pass through the semi permeable membrane, the
driving force for the osmosis arises from the inequity of the
chemical potentials of the solvent on opposing side of the
membrane.
 It is used in the pharma field in the -
1. in the ajustment of the tonicity
2. in the development of the osmotic drug delivery
3. in oral drug deliveries

11. INTRODUCTION TO OSMOTICALLY
CONTROLLED DRUG DELIVERY SYSTEM
 Osmotically controlled drug delivery system, deliver the drug in a large
extent and the delivery nature is independent of the physiological
factors of the gastrointestinal tract and these systems can be utilized for
systemic as well as targeted delivery of drugs. Osmotically controlled
oral drug delivery systems utilize osmotic pressure for controlled
delivery of active agents .
 Among the controlled release devices, osmotically controlled hold a
stable place because of its reliability to deliver the API at predetermined
zero order rate for prolonged period of time so these are used as the
standard dosage forms for the constant delivery of contents.
 Osmotic Pump Controlled Release Preparation is a novel drug delivery
system with eternally drug delivery rate as characteristic and controlled
with the osmotic pressure difference between inside and outside of the
semipermeable membrane as drug delivery power.

12.  Recently, osmotic tablets have been developed in which once the tablet
comes in contact with the aqueous environment, the water-soluble
component dissolves, and an osmotic pumping system results. Subsequently,
water diffuses into the core through the microporous membrane, setting up
an osmoticgradient and thereby controlling the release of drug.
 The first osmotic effect was reported by Abbe Nollet in 1748. Later in 1877,
Pfeffer performed an experiment using semi-permeable membrane to
separate sugar solution from pure water. He showed that the osmotic
pressure of the sugar solution is directly proportional to the solution
concentration and the absolute temperature. In 1886, Vant Hoff identified an
underlying proportionality between osmotic pressure, concentration and
temperature. He revealed that osmotic pressure is proportional to
concentration and temperature and the relationship can be described by
following equation –
π = n2RT
where, π = osmotic coefficient
n2 = molar concentration of solute in the solution
R = gas constant
T = Absolute temperature

13. ADVANTAGES
OF OSMOTIC
DDS
ZERO ORDER
DELIVERY
POSSIBLE
DRUG RELEASE
INDEPENDENT
OF GASTRIC pH ,
MOTILITY &
PRESENCE OF
FOOD
DELIVERY
MAY BE
DELAYED
OR PULSED
HIGHER
RELEASE
RATES
NO EFFECT
OF ANY
AGITATION
RELATED
PROBLEMS
HIGH
DEGREE OF
IVIVC
PRODUCTION
SCALE UP IS
EASY
RELEASE
RATE IS
PREDICTABLE

14. DISADVANTAGES
OF OSMOTIC DDS
RAPID
DEVELOPMENT
OF TOLERANCE
CHANCES OF
TOXICITY DUE
TO DOSE
DUMPING
HYPERSENSI-
TIVITY
REACTION
CAN OCCUR
VARIATION IN
COMPOSITION OF
MEMBRANE
CAUSES ERROR.
THICKNESS OF
MEMBRANE &
ITS SURFACE
AREAAFFECTS
THE RESULT.
INTEGRITY &
CONSISTENCY
DIFFICULT TO
MAINTAIN
EXPENSIVE
RELEASE CAN
BE VARIED
DUE TO THE
SIZE OF HOLE

15. Osmotic Pump Systems for the Poorly Water-soluble Drugs
Although push-pull osmotic pump executes an approximately constant
release for the poorly water-soluble drugs, its applications are highly
limited by the complexity of preparation. Therefore, a relative simple
push-pull osmotic pump system is developed based on the application of
polymers. In this system, special polymers (such as Arabic gum, PEO) are
employed as the osmagent instead of salt. When the water is imbibed by
the osmotic pressure, the polymers swell up, change into a suspension
containing drugs, and then are extruded through the orifice along with the
drug.
CONTINUE….

16. WHY DO WE GO FOR THIS DRUG
DELIVERY ???
1. In order to reduce the dose
2. To decreases dose related side effect
3. To minimizes rate of administration
4. To provide controlled release and
5. To increase patient compliance

17. MECHANISM OF OSMOTIC DDS
 Core contain water soluble osmotically active agent and blended with water soluble
or insoluble drug, additives and coating has been carried out which functions as
semi permeable membrane.
 Since barrier is only permeable to water, initial penetration of water dissolves the
critical part of the core, resulting in development of an osmotic pressure difference
across the membrane.
 The device delivers a saturated volume equal to the volume of water uptake through
the membrane. Initial lag time (per hour) during which delivery rate increases to its
maximum value, drug release is zero order, until all solid material is dissolved.

18. PARAMETERS AFFECTING THE
OSMOTIC DDS
 Orifice size
 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
buildup in the system. Otherwise, the hydrostatic pressure can deform the
membrane and affect the zero-order delivery rate. Therefore, the cross-
sectional area of the orifice should be maintained between the minimum
and maximum values.
 Methods to create a delivery orifice in the osmotic tablet coating
are:
1. Mechanical drill
2. Laser drill - This technology is well established for producing sub-
millimeter size hole in tablets. Normally, CO2 laser beam (with output
wavelength of 10.6μ) is used for drilling purpose, which offers excellent
reliability characteristics at low costs.

19. 3. Indentation: that is not covered during the coating process: Indentation is made is
core tablets by using modified punches having needle on upper punch. This
indentation is not covered during coating process which acts as a path for drug release
in osmotic system.
4. Use of leachable substances in the semipermeable coating
 SOLUBILITY
• The release rate depends on the solubility of the solute inside the drug delivery system.
Therefore, drugs should have sufficient solubility to be delivered by osmotic delivery. In the
case of lowsolubility compounds, several alternate strategies may be employed. Broadly, the
approaches can be divided into two categories. First, swellable polymers can be added that
result in the delivery of poorly soluble drugs in the form of a suspension .Second, the drug
solubility can be modified employing different methods such as co compression of the drug
with other excipients,which improve the solubility. For example, cyclodextrin can be
included in the formulation to enhance drug solubility . Additionally, alternative salt forms
of the drug can be employed to modulate solubility to a reasonable level. In one case, the
solubility of oxprenolol is decreased by preparing its succinate salt so that a reduced
saturation concentration is maintained.

20. • 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
F (z) = 1 –
𝑺
𝑷
where F (z) = fraction release by zero order
S = drug solubility in g / cm3
P = density of core tablet.
• Drug with density of unity and solubility less than 0.05 g / cm3 would release
greater than or equals to 95 % by zero order kinetics. Drug with density > 0.3 g /
cm3 solubility would demonstrate with higher release rate > 70 % by zero order.
 SEMI-PERMEABLE MEMBRANE
• Since the semipermeable membrane is permeable to water and not to ions, the release rate is
essentially independent of the pH of the environment. Additionally, the drug dissolution
process takes place inside the delivery system, completely separated from the environment.
Drug release from osmotic system is largly independent of pH and agitational intensity of
GIT.
• Example are: Cellulose Ester, Cellulose Triacetate, Cellulose Propionate, Cellulose
Acetate Butyrate, Ester, Ethyl Cellulose and Eudragits.

21. • Among above Cellulose Acetate Butyrate is most commanly used as –
1. High water permeability,
2. Permeability can be adjusted by varying the degree of acetylation of polymer
and also by increasing plastisizer concentration,
3. Flux enhancer and,
4. Superior drying property so advantageneous to thermolabile drugs.
• However asymmetric membrane capsule are new type of coating which
can be fully utilized for osmotic drug delivery system and offers significant
advantage over membrane coating used in conventional Osmotic DDS which
devoid of coating defects and they are having higher rate of water influx which
allow the release of drug with lower or no osmotic pressure or lower solubility.
SPM WVTR
(g/100m2/24hr/mmthick)
PVA 100
Methyl cellulose 70
Cellulose acetate 40-75
Ethyl cellulose 75
Ethylene vinyl acetate 1-3
Cellophane >1.2

22.  OSMOTIC PRESSURE
• The osmotic pressure π directly affects the release rate. To achieve a zero-
order release rate, it is essential to keep π constant by maintaining a saturated
solute solution. Many times, the osmotic pressure generated by the saturated
drug solution may not be sufficient to achieve the required driving force. In
this case, other osmotic agents are added that enhance osmotic pressure. For
example, addition of bicarbonate salt not only provides the necessary osmotic
gradient but also prevents clogging of the orifice by precipitated drug by
producing an effervescent action in acidic media.
• Rate of drug release from an Osmotic system is directly proportional to
osmotic Pressure of the core formulation. In order to achieve optimized and
constant Osmotic Pressure in compartment Osmotic agent must be added to
tablet.
𝒅𝑴
𝒅𝒕
=
𝑨𝒌𝝅𝑪
𝒉
• Thus, osmogens needed to be added either as a single component or in a
combined form.
• These can be either organic or inorganic or a combination of both.

23. Osmotic pressures of saturated solution of commonly used
osmogents
COMPOUNDS OF MIXTURE OSMOTIC PRESSURE ( atm
)
Lactose-fructose 500
Dextrose-fructose 450
Sucrose-fructose 430
Mannitol-fructose 415
Sodium chloride 356
Fructose 335
Lactose-dextrose 225
Mannitol-dextrose 225
Dextrose-sucrose 190
Mannitol-sucrose 170
Sucrose 150
Mannitol-lactose 130
Sodium phosphate tribasic 36
Sodium phosphate dibasic 31

24. FORMULATION OF OSMOTIC DDS
 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.
Various drug candidates such as Diltiazem HCl, Carbamazepine, Metoprolol,
Oxprenolol, Nifedipine, Glipizide etc are formulated as osmotic delivery.
 SEMI-PERMEABLE MEMBRANE - An important part of the osmotic drug
delivery system is the semipermeable membrane housing. Therefore, the polymeric
membrane selection is key to the osmotic delivery formulation. The membrane
should possess certain characteristics, such as impermeability to the passage of drug
and other ingredients present in the compartments. The membrane should be inert
and maintain its dimensional integrity to provide a constant osmotic driving force
during drug delivery. Any polymer that is permeable to water but impermeable to
solute can be used as a coating material in osmotic devices. e.g. Cellulose esters like
cellulose acetate, cellulose acetate butyrate, cellulose triacetate and ethyl cellulose
and Eudragits. Polymers are agar acetate, amylase triacetate,betaglucan, acetate,
poly (vinylmethyl)ether copolymers, poly(orthoessters)poly acetals and selectively
permeable poly(glycolic acid) and poly (lactic acid)derivatives can be used as
semipermeable film forming materials.

25. • OSMOGENT - Osmotic agents maintain a concentration gradient across the membrane.
They also generate a driving force for the uptake of water and assist in maintaining drug
uniformity in the hydrated formulation. Osmotic components usually are ionic compounds
consisting of either inorganic salts or hydrophilic polymers. Osmotic agents can be any salt
such as sodium chloride, potassium chloride, or sulfates of sodium or potassium and
lithium. Additionally, sugars such as glucose, sorbitol, or sucrose or inorganic salts of
carbohydrates can act as osmotic agents. The polymers may be formulated along with
poly(cellulose), osmotic solutes, or colorants such as ferric oxide. Swellable polymers such
as poly(alkylene oxide), poly(ethylene oxide), and poly (alkalicarboxymethylcellulose) are
also included in the push layer of certain osmotic systems. Further, hydrogels such as
Carbopol (acidic carboxypolymer),Cyanamer (polyacrylamides), and Aqua-Keeps (acrylate
polymer polysaccharides composed of condensed glucose units such as diester cross-linked
polygluran) may be used.
• HYDROPHILIC & HYDROPHOBIC POLYMERS -These polymers are used in the
formulation development of osmotic system for making drug containg matrix
convection.The highly water soluble compounds can be coentrappedcoentrapped in
hydrophobic matrices and moderately water soluble compounds can be co-entrapped
hydrophilic matrices to obtain more controlled release.The non-swellable polymers are used
in caseof highly water-soluble drugs. Ionic hydrogels such as sodium carboxymethyl
cellouse are preferably used because of their osmogenic nature. Hydrophilic polymers such
as hydroxy ethyl cellulose ,carboxy methylcellulose, hydroxy propyl MC, high m.wt poly
(vinyl pynolidone) and hydrophobic polymers such as EC and wax materials used for this
purpose.

26. • WICKING AGENTS - 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. They are characterized by having the ability to undergo physisorption
with water. The function of the wicking agent is to carry water to surfaces inside the core of
the tablet, there by creating channels or a network of increased surface area. Materials,
which suitably for act as wicking agents include colloidal silicon dioxide, kaolin, titanium
dioxide, etc.
• SOLUBILIZING AGENTS - These are classified under three groups-
1. Agents that inhibit crystal formation of the drugs or otherwise act by complexation with
the drugs. Eg PVP, poly (ethylene glycol)(PEG 8000) and alpha, beta
gammacyclodextrins.
2. A high HLB micelle- forming surfactant, particularly anionic surfactants (eg tween 20, 60
and 80 , poly oxy ethylene or polyethylene containing surfactants and other long chain
anionic surfactants such as SLS).
3. Citrate esters and their combinations with anionic surfactants. eg alkyl esters particularly
tri ethyl citrate.
• SURFACTANTS - They are added to wall forming agents. They 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.

27. • 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
that do not adversely harm the core, wall and other materials. The typical solvents include
methylene chloride, acetone, methanol, ethanol, isopropyl alcohal, butyl alcohal, 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), methylene chloride-methanol-water (75:22:3) etc. can be used.
• PLASTICIZERS - Different types and amount of plasticizers used in coating membrane
also have a significant importance in the formulation of osmotic systems. They can change
visco-elastic behavior of polymers and these changes may affect the permeability of the
polymeric films. Some of the plasticizers used are Polyethylene glycols, Ethylene glycol
monoacetate; and diacetate- for low permeability films.
• FLUX REGULATORS - Delivery systems can be designed to regulate the permeability
of the fluid by incorporating fluxregulating agents in the layer. Hydrophilic substances
such as polyethethylene glycols (300 to 6000 Da), polyhydric alcohols, polyalkylene
glycols, and the like improve the flux, whereas hydrophobic materials such as phthalates
substituted with an alkyl or alkoxy (e.g., diethyl phthalate or dimethoxy ethylphthalate)
tend to decrease the flux. Insoluble salts or insoluble oxides, which are substantially water-
impermeable materials, also can be used for this purpose.

28. • 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. Like
alkaline metal salts such as sodium chloride, sodium bromide, potassium
chloride, etc. or alkaline earth metals such as calcium chloride and
calcium nitrate & Carbohydrates such as glucose, fructose, mannose, etc.
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. These poreforming agents cause the
formation of microporous membrane. The microporous wall may be
formed in situ by a pore-former by its leaching during the operation of
the system. 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, potassium sulphate,
potassium phosphate etc., alkaline earth metals such as calcium chloride
and calcium nitrate, carbohydrates such as sucrose, glucose, fructose,
mannose, lactose, sorbitol, mannitol and, diols and polyols such as poly
hyric alcohols and polyvinyl pyrrolidone can be used as pore forming
agents.

29. PREPARATION OF OSMOTIC DDS
• One method is to utilize an osmotic mechanism to provide pre-programmed,
controlled drug delivery to the gastro intestinal tract. The technology comprises
a polymer membrane with one or more laserdrilled holes surrounding a core
containing the drug or drugs, with or without osmotic or other agents.
• Another oral technology uses a multiple dose system containing a large
number of micro particles, on the order of 5,000 to 40,000 micro particles per
capsule or tablet,depending on the specific formulation.Microparticle operates
as a miniature delivery system, releasing the drug at an adjustable rate and over
an extended period of time by means of osmotic pressure.
• A third technology was developed as simple monolithic matrix systems. These
approaches use conventional tableting technologies to form swellable, erodible
matrix tablets, caplets, or capsules that can potentially yield first-order drug
release profiles up to 24 hours.
• In addition, any combination of soluble, highly soluble, insoluble, low drug
dose, high drug load, and combinations can be easily formulated with these
technologies.

30. CLASSIFICATION OF OSMOTIC
DDS
 These can be particularly divided into two types –
1. IMPLANTABLE OSMOTIC PUMPS
2. ORAL OSMOTIC PUMPS
IMPLANTABLE
OSMOTIC PUMP
ROSE NELSON
PUMP
HIGUCHI-
LEEPER PUMP
MINI OSMOTIC
PUMP
HIGUCHI-
THEEUWES
PUMP

31. ORAL OSMOTIC
PUMPS
ELEMEN-
TARY
CONTROLLED
POROSITY
MULTICHA-
MBER
MODI-
FIED
MULTI -
PARTICUL
ATE
RELEASE
MONO-
LITHIC
NON
EXPANDABLE
EXPANDABLE
FOR SOLID FOR LIQUID
BILAYER TRILAYER

32. IMPLANTABLE PUMPS
ROSE-NELSON PUMP - In, 1955, two Australian physiologists
reported the first osmotic pump. They were interested in delivery of drug to the gut of
sheep and cattle. The pump consisted of three chambers a drug chamber with an
orifice, a salt chamber with elastic diaphragm containing excess solid salt, and a water
chamber. A semipermiable membrane separates the drug and water chamber. The
difference in osmotic pressure across the membrane moves water from the water
chamber in to the salt chamber. The volume of chamber increases because of this
water flow, which distends the latex diaphragm separating the salt and drug chambers,
thereby pumping drug out of the device.

33.  HIGUCHI – THEEUWES PUMP - In the early 1970s,
Higuchi and Theeuwes developed another, even simpler variant of the Rose-Nelson
pump. As with the Higuchi- Leeper pump, water to activate the osmotic action of the
pump is obtained from the surrounding environment. In the Higuchi-Theeuwes device,
however, the rigid housing is dispensed with and the membrane acts as the outer casing
of the pump. This membrane is quite sturdy and is strong enough to withstand the
pumping pressure developed inside the device. The device is loaded with the desired
drug prior to use. When the device is placed in an aqueous environment, release of the
drug follows a time course set by the salt used in the salt chamber and the permeability
of the outer membrane casing. Most of the Higuchi-Theeuwes pumps use a dispersion
of solid salt in a suitable carrier for the salt chamber of the device. Small osmotic
pumps of this form are available under the trade name Alzet®.Delivery of DNA by
agarose hydrogel implant facilitates genetic immunization in cattle by using Alzet
osmotic pumps.

34. HIGUCHI-LEEPER PUMP - Higuchi Leeper pump is widely
swallowed or implanted in the body of animal for delivery of antibiotic or growth hormones.
Higuchi Leeper pump consist of rigid housing and semi permeable membrane. A layer of low
melting waxy solid, such as microcrystalline paraffin wax is used in place of elastic
diaphragm to separate the drug and osmotic chamber. Recent modification in Higuchi-Leeper
pump accommodated pulsatile drug delivery. The pulsatile release was achieved by the
production of a critical pressure at which the delivery orifice opens and releases the
drug.Pulsatile delivery could be achieved by using Higuchi Leeper pump; such modifications
are described and illustrated in Figure. The Pulsatile release of drug is achieved by drilling
the orifice in elastic material that stretches under the osmotic pressure. Pulse release of drug
is obtained after attaining a certain critical pressure, which causes the orifice to open. The
pressure then reduces to cause orifice closing and the cycle repeats to provide drug delivery
in a pulsatile fashion. The orifice should be small enough to be substantially closed when the
threshold level of osmotic pressure is not present.

35. MINI OSMOTIC PUMP - Implantable Mini osmotic pump is
composed of three concentric layers-the drug reservoir, the osmotic sleeves and the rate
controlling semi permeable membrane. The additional component called flow moderator is
inserted into the body of the osmotic. The inner most compartment of drug reservoir which is
surrounded by an osmotic sleeve, a cylinder containing high concentration of osmotic agent.
The osmotic sleeve is covered by a semi permeable membrane 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. These
pumps are available with variety of delivery rates between 0.25 to 10ml per hour and delivery
duration between one day and four weeks.
ALZET® MINI OSMOTIC
PUMP

36. ORAL PUMPS
 ELEMENTARY OSMOTIC PUMP - Elementary
osmotic pump was invented by Theeuwes in 1974 and 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. Small orifice is drilled through the
membrane coating. When this coated tablet is exposed to an aqueous environment,
the osmotic pressure of the soluble drug inside the tablet draws water through the
semipermeable 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 inhibition
of water raises the hydrostatic pressure inside the tablet, eventually leading to flow of
saturated solution of active agent out of the device through a small orifice. The pump
initially releases the drug at a rate given by equation -
dMt/dt = (dV/dt). Cs
where, dV/dt depicts the water flow into the tablet
Cs is the solubility of the agent inside the tablet.

37. • ADVANTAGES –
1. The system can contain the agent in solid form at loading higher than 90% of the total
volume, and the agent can be delivered at rates several orders of magnitude higher
than can be achieved by solution diffusion through polymeric membranes.
2. The delivery rate, the fraction of total content is delivered at zero order, and the
system's delivery portal size can be calculated for delivery of a single compound.
3. Normally EOP deliver 60 – 80 % of its content at constant rate.
4. It has short lag time of 30 – 60 minute.
• DISADVANTAGES –
1. SPM should be 200-300μm thick to withstand pressure.
2. Thick coatings lowers the water permeation rate.
3. Applicable mostly for water soluble drugs.

38. MODIFIED OSMOTIC PUMP –
FOR MODERATELY SOLUBLE DRUGS -Semi permeable membrane must be
200-300 microns thick to withstand the pressure generated within the device. These thick
membranes lowers water permeation rate, which is not desirable for moderately soluble
drugs. This problem can be overcome by using coating materials with high water
permeability. For example, addition of plasticizers and water soluble additive to
the cellulose acetate membranes, this increased the permeability of membrane up
to ten fold. Composite structured semi permeable membrane is used for moderately soluble
drugs. 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.
• ADVANTAGE – overcomes the major disadvantage of the elementary pump as it can
be used only for the water sioluble drugs.

39. FOR INSOLUBE DRUGS - Osmotic agents are coated with an elastic semi permeable
membrane film in fluid bed coater and this particle are then mixed with insoluble drugs and
compressed to form tablet which is coated with SPM and orifice is created in membrane. After
coming in contact with aqueous environment, water is drawn through the two membranes into
the osmotic agent particle which swells and hydrostatically pushes the insoluble drug via the
orifice.
• ADVANTAGE – Majiority of the pharmaceutical drugs are hydrophobic in nature ,
hence these types of pump can be used.
Value Proposition of these pumps -
•Controlled release maintains appropriate therapeutic level of active agent for several days
•pH sensitive membrane with coitus trigger
•Improved drug administration for the patient
•Greater drug release efficiency and delivery duration
•Ideal for delivery of contraceptives
•Potential neutralizer for other infectious diseases such as HIV which one could contract
during sexual intercourse

40.  CONTROLLED POROSITY PUMP -A controlled
porosity osmotic pump-based drug delivery system Unlike the elementary osmotic pump
(EOP) which consists of an osmotic core with the drug surrounded by a semipermeable
membrane drilled with a delivery orifice, controlled porosity of the membrane is
accomplished by the use of different channeling agents in the coating. The CPOP contains
water soluble additives in coating membrane, which after coming in contact with water;
dissolve resulting in an in-situ formation of a microporous membrane. Then the resulting
membrane is substantially permeable to both water and dissolved solutes and the
mechanism of drug release from these system was found to be primarily osmotic, with
simple diffusion playing a minor role. Drug delivery from asymmetric membrane capsule
is principally controlled by the osmotic pressure of the core formation. In-situ formed
delivery orifice in the asymmetric membrane in mainly responsible for the solubilization
in the core for a drug with poor water solubility. It is laser or micro driven orifice. When
Controlled Porosity Osmotic Pump is placed in aqueous environment the water soluble
component of coating dissolves and forms micropores in membrane and water diffuses
inside the core through microporous membrane, setting up an osmotic gradint and thereby
controlling the release of drug. The rate of release from controlled porosity osmotic pump
is dependent on-
1) Level of soluble component in coating
2) Coating thickness
3) Osmotic pressure across the membrane
4) Solubility of drug in tablet core

41. Drug release from the whole surface of device rather than from a single hole which may
reduce stomach irritation problem. Hole is produce by the coating procedure hence
complicated laser drilling is not
required. Citric acid is use as pore forming agent in Chitosan based colon specific pumps.
MUTIPARTICULATE DELAYED RELEASE SYSTEM –
Pellets containing drug with or without osmotic agent are coated with semi permeable
membrane which on contact with aqueous environment results in penetration of water in
core and forms a saturated solution of soluble component. The osmotic pressure difference
results in rapid expansion of membrane, which leads to the formation of pores. For
controlled release drug is located at first orifice and for fast release drug layer located
adjacent to second orifice. Push layer is located in between controlled and fast release
layer.

42. 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 waxlike 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.

43.  MONOLITHIC OSMOTIC PUMPS - 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.
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 form 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.

44.  MULTI CHAMBER OSMOTIC PUMP - Although
EOP is simple to design and well suited for drug with intermediate water solubility there are
many drugs with either poor or high water solubility. This problem has led to development
of MOP. There are two type of MOP –
1. EXPANDABLE –
a. FOR SOLIDS - Push pull osmotic pump is a modified EOP. Through, which it is
possible to deliver both poorly water-soluble and highly water soluble drugs at a constant
rate. This system resembles a standard bilayer coated tablet. One layer (depict as the upper
layer) contains drug in a formulation of polymeric, osmotic agent and other tablet excipients.
This polymeric osmotic agent has the ability to form a suspension of drug in situ. When this
tablet later imbibes water, the other layer contains osmotic and colouring agents, polymer and
tablet excipients. These layers are formed and bonded together by tablet compression to form
a single bilayer core. The tablet core is then coated with semi permeable membrane. After the
coating has been applied, a small hole is drilled through the membrane by a laser or
mechanical drill on the drug layer side of the tablet. When the system is placed in aqueous
environment water is attracted into the tablet by an osmotic agent in both the layers. The
osmotic attraction in the drug layer pulls water into the compartment to form in situ a
suspension of drug. The osmotic agent in the non-drug layer simultaneously attract water into
that compartment, causing it to expand volumetrically and the expansion of non drug layer
pushes the drug suspension out of the delivery orifice.

45. b. FOR LIQUIDS - OROS-CT is used as a once or twice a day formulation for targeted
delivery of drugs to the colon. The OROS-CT can be a single osmotic agent or it can be
comprised of as many as five to six push pull osmotic unit filled in a hard gelatin capsule. After
coming in contact with the gastric fluids, gelatin capsule dissolved and the enteric coating
prevents entry of fluids from stomach to the system as the system enters into the small intestine
the enteric coating dissolves and water is imbibed into the core thereby causing the push
compartment to swell. At the same time flowable gel is formed in the drug compartment, which
is pushed out of the orifice at a rate, which is precisely controlled, by the rate of water transport
across the semi permeable membrane. One type of L-Oros system consists of a soft gelatin
capsule (softcap™) surrounded by a barrier layer, an osmotic push layer, and a semipermeable
membrane. As with other Oros system, drug is released through a delivery orifice in the
semipermeable membrane. Another type of L-Oros system consists of a hard gelatin capsule
(Hardcap™) containing a liquid drug layer, a barrier layer, and a push layer surrounded by a
semipermeable membrane.

46. SoftCap™ HardCap™
2. NON-EXPANDABLE - Non expandable osmotic pump maintains the volume
throughout the period of operation means the rigid one. Depending on function of second
chamber non-expandable osmotic pump are divided into two subtypes –
• Drug solution gets diluted in second chamber before leaving device. Such is useful
when saturated solution of drug irritate GIT.
• Two separate EOP tablet formed in single tablet. Here one chamber contains osmogen
and second chamber contain drug. When such system comes in contact with aqueous
environment, solution of osmotic agent formed in first chamber is delivered to drug
chamber via the concentric hole, where it mixes with drug solution before coming out of
the micro porous membrane that forms the pores of SPM surrounding the drug chamber
useful for insoluble drug delivery.

48. NEWER TECHNOLOGY IN ODDS
 Osmodex® Technology - The Osmodex® family of proprietary technologies
combines laser drilled tablet technology with variety of single active and
multiple active drug delivery devices. Osmodex® systems simplify dosing and
aid in patient compliance.It includes –
1. Osmodex® ID delivery for insoluble drugs - This platform provides flexible
delivery options for insoluble drugs. It can accommodate first order, zero order
or delayed release options while assuring full release over the targeted
timeframe. This technology has been used to solve multiple challenging
insoluble drug delivery problems (Example – Osmotica Nifedipine Extended
release Tablets).
2. Osmodex® SD delivery for soluble drugs - This platform technology can be
used to resolve delivery challenges of soluble low-bioavailability drugs or
drugs requiring targeted delivery.
3. Osmodex® Double CR combination - This dual controlled release platform
allows delivery of two drugs from a single osmotic tablet where each drug
release pattern can be independently tailored to the desired release profile.

49. 4. Osmodex® Triple combination tablet -This delivery system incorporates
compressed druglayers around an osmotic core. This combination provides the
benefits of immediate release and controlled release delivery, along with the unique
benefits of an osmotic controlled release to achieve three different release rates in
the same tablet
• Duros Technology - DUROS pharmaceutical systems are miniature
osmotic implants that deliver drugs for 3 months to 1 year with precise zero-order
delivery kinetics. The technology is suited for potent drugs and can deliver up to 500 mg
of drug from a single implant with a 1- cc drug reservoir. Formulation technology has
been developed that maximizes drug payload, stabilizes drugs chemically and physically
for extended periods at body temperature, and involves the use of aqueous and non-
aqueous vehicles. Advanced applications of the DUROS technology are in clinical and
preclinical testing and include the CHRONOGESIC system, delivering sufentanil
systemically for chronic pain. The DUROS technology is a miniature drugdispensing
system that operates like a miniature syringe and releases minute quantities of
concentrated drug formulations in a continuous, consistent flow over months or years.
The system is implanted under the skin and can be as small as 4 mm OD X 44 mm L or
smaller. The drug formulation is contained in the drug reservoir compartment. The drug
formulation may be either a solution or suspension. Duros system was chosen for their
biocompatibility and suitability for implant use. The drug-contacting materials are also
screened for compatibility with the drug and the specific drug formulation excipients.

50. Duros Advanced Applications of Duros Technology -
1. CHRONOGESIC™(sufentanil) Pain Therapy System - Chronic pain, defined
as pain lasting 6 months or longer, is a significant problem associated with chronic
diseases, including cancer and various neurological and skeletal disorders. To The
CHRONOGESIC system is implanted in the inside of the upper arm using a
specially designed sterile implanter The Implanter is a trocar-like device that
facilitates precise, efficient subcutaneous placement of the CHRONOGESIC
implant.
2. Targeted Drug Delivery with Catheterized Osmotic Pumps - Catheters of
different designs can be attached to the exit port of an osmotic pump for targeted
drug delivery. A number of organs and tissues have been evaluated as target sites
in various animal models using ALZET Osmotic Pumps, which have been the
devices of choice in numerous scientific research activities involving laboratory
animals. Catheters should be flexible, compatible with targeted tissues/organs, and
non-reactive with and nonabsorptive toward drug solutions. The most commonly
used materials for catheters include silicone elastomers and polyolefin polymers,
such as low-density polyethylene. Pharmacological agents for targeted delivery
include various small-molecularweight drugs as well as peptides and proteins. The
most common catheter material for site-specific drug delivery using ALZET with
a catheter has been a low-density polyethylene tubing.

51. 3. Specific Drug Delivery Using Duros with a Precision Miniature Catheter – To
deliver drug to a specific target site, DURECT is developing proprietary
miniaturized catheter technology that can be attached to the DUROS system to
direct the flow of drug directly to the target organ or tissue. Site-specific delivery
enables a therapeutic concentration of a drug to be present at the desired target
without exposing the entire body of the patient to a similar dose. The precision,
miniature size, and performance characteristics of the DUROS system will allow for
continuous site-specific delivery to a variety of precise locations within the body.
4. DUROS Intratumoral Delivery of Antineoplastic Agents Into The Brainstem -
Local or site-specific delivery of chemotherapeutic agents increases drug
concentration at the tumor target, decreases systemic exposure and toxicities, and
increases the duration of exposure of the tumor to the drug. Experimental and
clinical studies have demonstrated statistically significant increases in survival
associated with local therapy for brain tumors. Drugs have been delivered via
controlledrelease biodegradable matrices and infusion pumps.The brainstem
continuously monitors and regulates cardiovascular, respiratory, and other
autonomic functions, and hence, attempts to target chemotherapy directly into this
brain area has always been met with extreme caution. One approach being tested, to
maximize the effectiveness of chemotherapeutic agents in this sensitive brain region,
is insertion of a catheter into the pons of the brainstem for intratumoral
chemotherapy.

52. EVALUATION OF OSMOTIC ODDS
1. Characterization of dosage form
2. Effect of osmotic agents
3. Swelling properties
4. Membrane stability and thickness
5. Orifice diameter and drug release
6. Weight variation
7. Hardness
8. Friability
9. 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

53. 11. In vivo evaluation –In vivo evaluation of oral osmotic systems has been
carried out mostly in dogs. As the environment in the intestinal tract of the dog
is very similar to that of human beings terms of both pH and motility, dogs have
been used widely for in vivo delivery rate measurement of drugs from
osmotically controlled oral drug delivery systems and also to establish in vitro
in vivo correlation. Monkeys can also be used but in most of the studies the
dogs are preferred.
12. Effect of pH - These are done to see the effect of pH on developed
formulations, so a in-vitro study is carried out in different medias.
13. Effect of agitational intensity - Dissolution apparatus with different rotational
spped are used to chech its effect on the in-vitro profile.
14. Effect of osmotic pressure - Release mechanism study is carried out at different
osmotic pressure to see its effect on the formulation.
15. Kinetics of drug release - By using different time intervals & statistics , we can
see its effect on the given formulation. Weigh the empty pump & then fill it
using a syringe. Hold it in a upright position & insert the filling tube through
opening at the top of the pump until it can go no further. This places the tip of
the tube near the bottom of the pump reservoir. Push the plunger of the syringe
slowly & when solution appears at the outlet , stop this process & remove the
tube. Wipe of the excess solution & weigh the filled pump.

54. MARKETED FORMULATIONS
TRADE
NAME
API DESIGN DOSE USE
ALPRESS LP PRAZOSCIN PUSH PULL 2.5-
5mg
HYPERTENSION
ACUTRIM PHENYLPROPAN-
OLAMINE
ELEMENT-
ARY PUMP
75mg AlLLERGIES
CARDURA DOXAZOSCIN PUSH PULL 4-8mg HYPERTENSION
COVERA VERAPAMIL PUSH PULL 180mg ANGINA
DITROPAN XL OXYBUTININ PUSH PULL 5mg URINARY
PROBLEMS
INVEGA PALIPERIDONE PUSH PULL 3-9mg SCHIZOPHRENIA
GLUCOTROL
XL
GLIPIZIDE PUSH PULL 5mg HYPERGLYCEMIA
MINIPRESS PRAZOSCIN ELEMENT-
ARY PUMP
2.5-
5mg
HYPERTENSION
PROCARDIA XL NIFEDIPINE PUSH PULL 30mg ANGINA

55. REFERENCES
 Gennaro,Alfonso R.,Remigton:The Science & practice of pharmacy, Vol-I &II,
Lipincott Williams & Wilkins, New York. Page No. 903-915
 B. P. Gupta, N. Thakur, N. P. Jain, J. Banweer, and S. Jain, “Osmotically Controlled
Drug Delivery System with Associated Drugs,” vol. 13, no. 3, pp. 571–588, 2010.
 T. Sanitorium, “A Review on Osmotic Drug Delivery System,” vol. 4, no. 3, pp.
810–821, 2013.
 K. Singh, M. Walia, and S. L. Harikumar, “REVIEWARTICLE OSMOTIC PUMP
DRUG DELIVERY SYSTEM : A NOVALAPPROACH,” vol. 3, no. 5, pp. 156–
162, 2013.
 Controlled & novel drug delivery by N.K.Jain, CBS publishers & distributors. Page
No. 15-20
 Drug Delivery principles & applications by Binghe Wang, Teruna Siahaan &
Richard A. Soltero, Wiley publications. Page No.105-110
 Novel drug delivery systems by Dr.Dheeraj T. Bhavsar & Dr.Dinesh K. Jain, Nirali
prakashan. Page No.115-118
 Controlled drug delivery, Fundamentals & applications, second edition, by Joseph
R. Robinson & Vincent H. Lee, Williams publications & press. Page No.89-96

56. THANK
YOU