International Scholarly Research Network
`ISRN Pharmaceutics
`Volume 2012, Article ID 528079, 9 pages
`doi:10.5402/2012/528079
`
`Review Article
`Osmotic Drug Delivery System as a Part of Modified
`Release Dosage Form
`
`Rajesh A. Keraliya,1 Chirag Patel,1 Pranav Patel,1 Vipul Keraliya,2 Tejal G. Soni,3
`Rajnikant C. Patel,1 and M. M. Patel1
`
`1 Department of Pharmaceutics, Kalol Institute of Pharmacy, Gujarat, Kalol 382721, India
`2 Department of Pharmaceutics, R. K. College of Pharmacy, Gujarat, Rajkot 360020, India
`3 Department of Pharmaceutics, DDIT Pharmacy College, Nadiad 387001, India
`
`Correspondence should be addressed to Rajesh A. Keraliya, rajeshmpharm21@gmail.com
`
`Received 9 March 2012; Accepted 8 May 2012
`
`Academic Editors: H. Arima, M. Efentakis, and G. Frenning
`
`Copyright © 2012 Rajesh A. Keraliya et al. This is an open access article distributed under the Creative Commons Attribution
`License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
`cited.
`
`Conventional drug delivery systems are known to provide an immediate release of drug, in which one can not control the release
`of the drug and can not maintain effective concentration at the target site for longer time. Controlled drug delivery systems offer
`spatial control over the drug release. Osmotic pumps are most promising systems for controlled drug delivery. These systems are
`used for both oral administration and implantation. Osmotic pumps consist of an inner core containing drug and osmogens,
`coated with a semipermeable membrane. As the core absorbs water, it expands in volume, which pushes the drug solution out
`through the delivery ports. Osmotic pumps release drug at a rate that is independent of the pH and hydrodynamics of the
`dissolution medium. The historical development of osmotic systems includes development of the Rose-Nelson pump, the Higuchi-
`Leeper pumps, the Alzet and Osmet systems, the elementary osmotic pump, and the push-pull system. Recent advances include
`development of the controlled porosity osmotic pump, and systems based on asymmetric membranes. This paper highlights the
`principle of osmosis, materials used for fabrication of pumps, types of pumps, advantages, disadvantages, and marketed products
`of this system.
`
`1. Introduction
`
`The pharmaceutical field over the past decade has faced
`continuing challenges in bringing new drug entity to market.
`In addition, the cost of developing new drug entity keeps
`rising and today stands at more than US$ 800 M per new
`drug entity. Drug delivery research continues to find new
`therapies for the prevention and treatment of exiting and
`new diseases. So, a valuable role is played by drug delivery
`system by providing optimized products for existing drugs in
`terms of either enhanced or improved presentation of drug to
`the systemic circulation [1, 2].
`Treatment of an acute disease or a chronic illness has
`been mostly accomplished by delivery of drugs to patients
`using various pharmaceutical dosage forms. Traditionally,
`the oral drug delivery has been most widely utilized route of
`administration among all the routes that have been explored
`
`for the systemic delivery of drugs. Conventional oral drug
`delivery systems are known to provide an immediate release
`of drug, in which one cannot control the release of the drug
`and cannot maintain effective concentration at the target
`site for longer period of time. The oral bioavailability of
`some drug by conventional drug delivery is very low due
`to presence of food, in stabilization at pH of the GI tract,
`degradation by enzymes of GI fluid, change in GI motility,
`and so forth [3, 4].
`Controlled drug delivery systems offer temporal and/or
`spatial control over the release of drug. Such systems
`release the drug with constant or variable release rates.
`Oral controlled drug delivery systems represent the most
`popular form of controlled drug delivery systems for the
`obvious advantages of oral route of drug administration.
`These dosage forms offer many advantages, such as nearly
`constant drug level at the site of action, prevention of
`(cid:36)(cid:81)(cid:71)(cid:85)(cid:91)(cid:3)(cid:21)(cid:19)(cid:19)(cid:27)
`(cid:36)(cid:88)(cid:85)(cid:82)(cid:69)(cid:76)(cid:81)(cid:71)(cid:82)(cid:3)(cid:89)(cid:17)(cid:3)(cid:36)(cid:81)(cid:71)(cid:85)(cid:91)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:26)(cid:16)(cid:19)(cid:20)(cid:25)(cid:23)(cid:27)
`
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`ISRN Pharmaceutics
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`in volume, which pushes the drug solution or suspension out
`of the tablet through one or more delivery ports [12, 13].
`The key distinguishing feature of osmotic drug deliv-
`ery systems (compared with other technologies used in
`controlled-release formulations) is that they release drug at a
`rate that is independent of the pH and hydrodynamics of the
`external dissolution medium. The result is a robust dosage
`form for which the in vivo rate of drug release is comparable
`to the in vitro rate, producing an excellent in vitro/in vivo
`correlation. Another key advantage of the present osmotic
`systems is that they are applicable to drugs with a broad range
`of aqueous solubilities [14, 15].
`The historical development of osmotic systems includes
`seminal contributions such as the Rose-Nelson pump [16],
`the Higuchi-Leeper pumps [17],
`the Alzet and Osmet
`systems [18], the elementary osmotic pump [19], and the
`push-pull or GITSR system [20]. Recent advances include
`the development of the controlled porosity osmotic pump
`[21, 22], systems based on asymmetric membranes [23–25],
`and other approaches [12].
`
`3. Materials Used in Formulation of
`Osmotic Pumps
`
`The following are the materials used in formulation of
`osmotically regulated system.
`
`(1) Semipermeable Membrane. Since the membrane in
`osmotic systems is semipermeable in nature, any polymer
`that is permeable to water but impermeable to solute can
`be selected [26]. Cellulose acetate is a commonly employed
`semipermeable polymer for the preparation of osmotic
`pumps. It is available in different acetyl content grades.
`Particularly, acetyl content of 32% and 38% is widely used.
`Acetyl content is described by the degree of substitution
`(DS),
`that
`is,
`the average number of hydroxyl groups
`on the anhydroglucose unit of the polymer replaced by
`substituting group. Some of the polymers that can be used
`for above purpose include cellulose esters such as cellulose
`acetate, cellulose diacetate, cellulose triacetate, cellulose
`propionate, cellulose acetate butyrate, and cellulose ethers
`like ethyl cellulose [27]. Apart from cellulose derivatives,
`some other polymers such as agar acetate, amylose triacetate,
`betaglucan acetate, poly(vinyl methyl) ether copolymers,
`poly(orthoesters), poly acetals and selectively permeable
`poly(glycolic acid), poly(lactic acid) derivatives, and Eudrag-
`its can be used as semipermeable film-forming materials
`[28]. The permeability is the important criteria for the
`selection of semipermeable polymers [19].
`
`(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 coentrapped in hydrophobic
`matrices and moderately water soluble compounds can be
`coentrapped in hydrophilic matrices to obtain more con-
`trolled release. Generally, mixtures of both hydrophilic and
`hydrophobic polymers have been used in the development
`
`Higher prevalence of side
`
`effects
`
`in this region
`
`MSC
`
`MEC
`
`Plasma concentration
`
`2
`
`Times
`
`24 hours
`
`Figure 1: Plasma concentration profile: for conventional dosage
`form (- - -) and for controlled release dosage form (—).
`
`peak-valley fluctuations, reduction in dose of drug, reduced
`dosage frequency, avoidance of side effects, and improved
`patient compliance [5, 6].
`The oral controlled release system shows a typical
`pattern of drug release in which the drug concentration
`is maintained in between the minimum effective concen-
`tration (MEC) and maximum safe concentration (MSC)
`for a prolonged period of time, thereby ensuring sustained
`therapeutic action (Figure 1).
`
`2. Osmotically Controlled Drug
`Delivery Systems
`
`Osmotic devices are most promising strategy-based sys-
`tems for controlled drug delivery [7–9]. Osmosis can be
`defined as the net movement of water across a selectively
`permeable membrane driven by a difference in osmotic
`pressure across the membrane. It is driven by a difference
`in solute concentrations across the membrane that allows
`passage of water, but rejects most solute molecules or ions.
`Osmosis is exploited for development of ideal controlled
`drug delivery system. Osmotic pressure created by osmogen
`is used as driving force for these systems to release the drug
`in controlled manner [9].
`These systems can be used for both route of admin-
`istration, that is, oral and implantation. Osmotic pump
`offers many advantages over other controlled drug delivery
`systems, that is, they are easy to formulate and simple
`in operation, improved patient compliance with reduced
`dosing frequency and more consistence, and prolonged ther-
`apeutic effect with uniform blood concentration. Moreover
`they are inexpensive and their production scaleup is easy
`[10, 11].
`Osmotic drug-delivery systems suitable for oral admin-
`istration typically consist of a compressed tablet core that
`is coated with a semipermeable membrane coating. This
`coating has one or more delivery ports through which a
`solution or suspension of the drug is released over time. The
`core consists of a drug formulation that contains an osmotic
`agent and a water swellable polymer. The rate at which
`the core absorbs water depends on the osmotic pressure
`generated by the core components and the permeability of
`the membrane coating. As the core absorbs water, it expands
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`ISRN Pharmaceutics
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`3
`
`of osmotic pumps of water-soluble drugs [29]. 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. The polymers
`are of either swellable or nonswellable nature. Mostly,
`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, the nonswellable polymers are used in case of highly
`water-soluble drugs [30]. Ionic hydrogels such as sodium
`carboxymethyl cellulose are preferably used because of their
`osmogenic nature. More precise controlled release of drugs
`can be achieved by incorporating these polymers into the
`formulations. Hydrophilic polymers such as hydroxy ethyl
`cellulose, carboxy methylcellulose, hydroxy propyl methyl-
`cellulose, high-molecular-weight poly(vinyl pyrrolidone),
`and hydrophobic polymers such as ethyl cellulose and wax
`materials can be used for this purpose [31].
`
`(3) Wicking Agents. A wicking agent is defined as a material
`with the ability to draw water into the porous network of a
`delivery device. The wicking agents are those agents which
`help to increase the contact surface area of the drug with the
`incoming aqueous fluid. The use of the wicking agent helps
`to enhance the rate of drug released from the orifice of the
`drug. A wicking agent is of either swellable or nonswellable
`nature [32]. They are characterized by having the ability to
`undergo physisorption with water. Physisorption is a form
`of absorption in which the solvent molecules can loosely
`adhere to surfaces of the wicking agent via Van der Waals
`interactions between the surface of the wicking agent and the
`adsorbed molecule. The function of the wicking agent is to
`carry water to surfaces inside the core of the tablet, thereby
`creating channels or a network of increased surface area [33].
`The examples are colloidal silicon dioxide, PVP and Sodium
`lauryl sulfate.
`
`(4) Solubilizing Agents. For osmotic drug delivery system,
`highly water-soluble drugs would demonstrate a high release
`rate that would be of zero order. Thus, many drugs with
`low intrinsic water solubility are poor candidates for osmotic
`delivery. However, it is possible to modulate the solubility of
`drugs within the core. Addition of solubilizing agents into the
`core tablet dramatically increases the drug solubility [35].
`Nonswellable solubilizing agents are classified into three
`groups,
`
`(i) Agents that inhibit crystal formation of the drugs
`or otherwise act by complexation with the drugs
`(e.g., PVP, poly(ethylene glycol) (PEG 8000) and β-
`cyclodextrin),
`(ii) a micelle-forming surfactant with high HLB value,
`particularly nonionic surfactants (e.g., Tween 20, 60,
`and 80, polyoxyethylene or poly ethylene containing
`surfactants and other long-chain anionic surfactants
`such as SLS),
`(iii) citrate esters (e.g., alkyl esters particularly triethyl
`citrate) and their combinations with anionic surfac-
`tants. The combinations of complexing agents such
`
`as polyvinyl pyrrolidone (PVP) and poly(ethylene
`glycol) with anionic surfactants such as SLS are
`mostly preferred.
`
`ingredient of the
`(5) Osmogens. Osmogens are essential
`osmotic formulations. Upon penetration of biological fluid
`into the osmotic pump through semipermeable membrane,
`osmogens are dissolved in the biological fluid, which creates
`osmotic pressure buildup inside the pump and pushes
`medicament outside the pump through delivery orifice. They
`include inorganic salts and carbohydrates. Mostly, potassium
`chloride, sodium chloride, and mannitol used as osmogens.
`Generally combinations of osmogens are used to achieve
`optimum osmotic pressure inside the system (Table 1) [36].
`
`(6) 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. The surfactants act by regulating the surface
`energy of materials to improve their blending into the com-
`posite and maintain their integrity in the environment of use
`during the drug release period. Typical surfactants such as
`poly oxyethylenated glyceryl recinoleate, polyoxyethylenated
`castor oil having ethylene oxide, glyceryl laurates, and glyc-
`erol (sorbiton oleate, stearate, or laurate) are incorporated
`into the formulation.
`
`(7) 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 and other materials.
`The typical solvents include methylene chloride, acetone,
`methanol, ethanol, isopropyl alcohol, butyl alcohol, ethyl
`acetate, cyclohexane, carbon tetrachloride, and water. 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) can be used.
`
`(8) Plasticizers. In pharmaceutical coatings, plasticizers, or
`low molecular weight diluents are added to modify the
`physical properties and improve film-forming characteristics
`of polymers. Plasticizers can change visco elastic behavior
`of polymers significantly [37]. Plasticizers can turn a hard
`and brittle polymer into a softer, more pliable material, and
`possibly make it more resistant to mechanical stress [9].
`Plasticizers lower the temperature of the second order-phase
`transition of the wall or the elastic modules of the wall and
`also increase the workability, flexibility, and permeability of
`the coating solvents. Generally from 0.001 to 50 parts of a
`plasticizer or a mixture of plasticizers are incorporated into
`100 parts of costing materials. PEG-600, PEG-200, triacetin
`(TA), dibutyl sebacate, ethylene glycol monoacetate, ethylene
`glycol diacetate, triethyl phosphate, and diethyl tartrate used
`as plasticizer in formulation of semipermeable membrane
`[38, 39].
`
`(9) Pore-Forming Agents. These agents are particularly used
`in the pumps developed for poorly water-soluble drugs and
`
`

`

`4
`
`Table 1: List of various osmogens with their osmotic pressure
`[32, 34].
`
`Water chamber
`
`Salt chamber
`
`ISRN Pharmaceutics
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`Drug chamber
`
`Delivery orifice
`
`Osmotic pressures of saturated solution of
`commonly used osmogens
`Sodium chloride
`Fructose 3
`Potassium chloride
`Sucrose
`Xylitol
`Sorbitol
`Dextrose
`Citric acid
`Tartaric acid
`Mannitol
`Potassium sulphate
`Lactose
`Fumaric acid
`Adipic acid
`Lactose-fructose
`Dextrose-fructose
`Sucrose-fructose
`Mannitol-fructose
`Sodium chloride
`Fructose
`Lactose-sucrose
`Potassium chloride
`Lactose-dextrose
`Mannitol-dextrose
`Dextrose-sucrose
`Mannitol-sucrose
`Sucrose
`Mannitol-Lactose
`Dextrose
`Potassium sulphate
`Mannitol
`Sodium phosphate tribasic·12H2O
`Sodium phosphate dibasic·7 H2O
`Sodium phosphate dibasic·12 H2O
`Sodium phosphate monobasic·H2O
`Sodium phosphate dibasic. Anhydrous
`
`Osmotic pressure
`(atm)
`356
`55
`245
`150
`104
`84
`82
`69
`67
`38
`39
`23
`10
`8
`500
`450
`430
`415
`356
`335
`250
`245
`225
`225
`190
`170
`150
`130
`82
`39
`38
`36
`31
`31
`28
`21
`
`in the development of controlled porosity or multiparticulate
`osmotic pumps [40]. These pore-forming 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, and so forth, alkaline earth metals
`such as calcium chloride and calcium nitrate, carbohydrates
`such as sucrose, glucose, fructose, mannose, lactose, sorbitol,
`
`Semipermeable membrane
`
`Rigid elastic diaphragm
`
`Figure 2: Rose Nelson Pump.
`
`and mannitol, and diols and polyols such as poly hydric
`alcohols, polyethylene glycols, and polyvinyl pyrrolidone
`can be used as pore-forming agents [41]. Triethyl citrate
`(TEC) and triacetin (TA) are also used to create pore in the
`membrane. Membrane permeability to the drug is further
`increased addition of HPMC or sucrose [42].
`
`4. Creation of Delivery Orifice
`
`Osmotic delivery systems contain at least one delivery orifice
`in the membrane for drug release. The size of delivery orifice
`must be optimized in order to control the drug release from
`osmotic systems. On the other hand, size of delivery orifice
`should not also be too large, otherwise, solute diffusion from
`the orifice may take place. If the size of delivery orifice is too
`small, zero-order delivery will be affected because of develop-
`ment of hydrostatic pressure within the core. This hydrostatic
`pressure may not be relieved because of the small orifice
`size and may lead to deformation of delivery system, thereby
`resulting in unpredictable drug delivery. Optimum orifice
`diameter is in the range of 0.075–0.274 mm. At orifice size of
`0.368 mm and above, control over the delivery rate is lost [9].
`Delivery orifices in the osmotic systems can be created
`with the help of a mechanical drill [43]. Laser drilling is one
`of the most commonly used techniques to create delivery
`orifice in the osmotic tablet [44]. Laser beam is fired onto
`the surface of the tablet that absorbs the energy of the beam
`and gets heated ultimately causing piercing of the wall and,
`thus forming orifice. It is possible to control the size of the
`passageway by varying the laser power, firing duration (pulse
`time), thickness of the wall, and the dimensions of the beam
`at the wall.
`In some of the oral osmotic systems, there is in situ
`formation of delivery orifice [45]. The system described
`consists of a incorporation of pore-forming agents into the
`coating solution. Pore-forming agents are water soluble:
`upon contact with the aqueous environment, they dissolve
`in it and leach out from membrane, creating orifice.
`
`5. Types of Osmotic Pumps
`
`5.1. Rose-Nelson Pump. Rose and Nelson, the Australian
`scientists, were initiators of osmotic drug delivery. In 1955,
`they developed an implantable pump for the delivery of
`drugs to the sheep and cattle gut [16].
`The Rose-Nelson implantable pump shown in Figure 2 is
`composed of three chambers: a drug chamber, a salt chamber
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`

`ISRN Pharmaceutics
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`5
`
`Rigid housing
`
`Drug chamber
`
`Movable separator
`
`MgSO4
`
`Drug solution
`
`Elastic cap
`
`Movable piston
`
`Separating barrier
`
`Semipermeable membrane
`
`Saturated solution of
`MgSO4
`containing
`solid
`MgSO4
`
`Semipermeable
`membrane
`
`Porous membrane support
`
`Osmogen
`
`Figure 3: Higuchi-Leeper osmotic pump.
`
`Figure 4: Pulsatile release osmotic pump.
`
`Semipermeable membrane
`
`Osmogen
`
`Delivery orifice
`
`Wall of flexible
`collapsible material
`
`Figure 5: Higuchi Theeuwes Pump.
`
`water from the surrounding environment. This variation
`allows the device to be prepared loaded with drug and can be
`stored for long prior to use. Higuchi-Leeper pumps contain a
`rigid housing and a semi permeable membrane supported on
`a perforated frame; a salt chamber containing a fluid solution
`with an excess of solid salt is usually present in this type
`of pump. Upon administration/implantation, surrounding
`biological fluid penetrates into the device through porous
`and semipermeable membrane and dissolves the MgSO4,
`creating osmotic pressure inside the device that pushes
`movable separator toward the drug chamber to remove drug
`outside the device. It is widely employed for veterinary use.
`This type of pump is implanted in body of an animal for
`delivery of antibiotics or growth hormones to animals [17].
`Pulsatile delivery could be achieved by using Higuchi
`Leeper pump; such modifications are described and illus-
`trated in Figure 4. 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 [49].
`
`holding solid salt, and a water chamber. A semipermeable
`membrane separates the salt from water chamber. The move-
`ment of water from the water chamber towards salt chamber
`is influenced by difference in osmotic pressure across the
`membrane. Conceivably, volume of salt chamber increases
`due to water flow, which distends the latex diaphragm
`dividing the salt and drug chambers: eventually, the drug is
`pumped out of the device.
`The kinetics of pumping from Rose Nelson pump is given
`by the following equation:
`(cid:2)
`(cid:3)
`
`dMt
`dt
`
`=
`
`dV
`dt
`
`· C,
`
`where dMt/dt is the drug release rate, dV/dt is the volume
`flow of water into the salt chamber, and C represents the
`concentration of drug in the drug chamber.
`= AθΔπ
`
`,
`
`C l
`
`dMt
`dt
`
`where, A is the area of semi permeable membrane, Δπ
`is the osmotic pressure gradient, θ is the permeability of
`semipermeable membrane, and l is the thickness of semi
`permeable membrane.These basic equations are applicable
`to the osmotically driven controlled drug delivery devices.
`The saturated salt solution created a high osmotic pressure
`compared to that pressure required for pumping the suspen-
`sion of active agent. Therefore, the rate of water entering into
`the salt chamber remains constant as long as sufficient solid
`salt is present in die salt chamber to maintain a saturated
`solution and thereby a constant osmotic pressure driving
`force is generated.
`The major problem associated with Rose-Nelson pumps
`was that the osmotic action began whenever water came
`in contact with the semipermeable membrane. This needed
`pumps to be stored empty and water to be loaded prior to
`use.
`
`(1)
`
`(2)
`
`5.2. Higuchi-Leeper Osmotic Pump. Higuchi and Leeper have
`proposed a number of variations of the Rose-Nelson pump
`and these designs have been described in US patents [46, 47],
`which represent the first series of simplifications of the Rose-
`Nelson pump made by the Alza Corporation. One of these
`pumps is illustrated in Figure 3.
`The Higuchi-Leeper pump has no water chamber, and
`the activation of the device occurs after imbibition of the
`
`5.3. Higuchi-Theeuwes Osmotic Pump. Higuchi and Thee-
`uwes in early 1970s developed another variant of the Rose-
`Nelson pump, even simpler than the Higuchi-Leeper pump
`[50]. This device is illustrated in Figure 5.
`In this device, the rigid housing consisted of a semiper-
`meable membrane. This membrane is strong enough to
`withstand the pumping pressure developed inside the device
`due to imbibition of water. The drug is loaded in the device
`
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`

`6
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`ISRN Pharmaceutics
`
`Semipermeable membrane
`
`Drug chamber
`
`Semipermeable membrane
`
`Osmotic drug core
`
`Delivery orifice
`
`Delivery orifice
`
`Osmogen
`
`Figure 6: Alzet pump.
`
`Delivery orifice
`
`Polymeric push compartment
`Before operation
`
`Expanded push compartment
`During operation
`
`Figure 8: The push-pull osmotic pump (PPOP).
`
`Semipermeable membrane
`
`Osmotic
`drug core
`
`Rigid semipermeable
`membrane
`
`Microporous membrane
`
`Drug + osmogn
`
`Figure 7: The elementary osmotic pump.
`
`Aqueous
`
`environment
`
`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 [51].
`Small osmotic pumps of this form are available under
`trade name Alzet made by Alza Corporation in 1976. They
`are used frequently as implantable controlled release deliv-
`ery systems in experimental studies requiring continuous
`administration of drugs. Such a implantable Alzet pump is
`shown in Figure 6.
`
`Figure 9: Mechanism of action of controlled porosity osmotic
`pump.
`
`where dV/dt depicts the water flow into the tablet and Cs is
`the solubility of the agent inside the tablet.
`
`5.5. Push-Pull Osmotic Pump (PPOP). Push-pull osmotic
`pump is a modification of EOP (Figure 8). Push-pull osmotic
`pump is delivered both poorly water soluble and highly water
`soluble drugs at a constant rate. This system resembles a
`standard bilayer coated tablet. One layer (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 semipermeable 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 nondrug layer simultaneously
`attracts water into that compartment, causing it to expand
`volumetrically, and the expansion of nondrug layer pushes
`the drug suspension out of the delivery orifice [20, 52].
`
`5.6. Controlled Porosity Osmotic Pump (CPOP). Figure 9
`represents the controlled porosity osmotic pump (CPOP).
`It is an osmotic tablet wherein the delivery orifices (holes)
`are formed in situ through leaching of water soluble pore-
`forming agents incorporated in semipermeable membrane
`(SPM) (e.g., urea, nicotinamide, sorbitol, etc.). Drug release
`rate from CPOP depends on various factors like coating
`
`(3)
`
`5.4. Elementary Osmotic Pump (EOP). Rose-Nelson pump
`was further simplified in the form of elementary osmotic
`pump [20, 52], which made osmotic delivery as a major
`method of achieving controlled drug release. Elementary
`osmotic pump shown in Figure 7 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
`[32, 53]. A 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 semi permeable coating
`and a saturated aqueous solution of drug is formed inside
`the device. The membrane is nonextensible 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 a
`small orifice [19].
`The pump initially releases the drug at a rate given by the
`following equation;
`(cid:2)
`(cid:3)
`
`dMt
`dt
`
`=
`
`dV
`dt
`
`· Cs,
`
`

`

`ISRN Pharmaceutics
`
`7
`
`Delivery orifice
`
`Delivery orifice
`
`Ratecontrolling
`membrane
`
`Drug over
`coat
`
`Osmotic
`push layer
`
`Soft gelatin
`capsule
`
`Barrier inner membrane
`
`Liquid drug formulation
`
`Drug compartment 1
`
`Ratecontrolling
`membrane
`
`Push compartment
`
`Drug compartment 2
`
`Figure 10: Liquid oral osmotic pump.
`
`Delivery orifice
`
`Drug release
`
`Semipermeable
`membrane
`
`Delivery orifice
`
`Push layer
`
`Soft gelatin
`
`Drug layer
`
`Delivery orifice
`
`Water
`imbibing
`
`Expanded
`push layer
`
`Water
`imbibing
`
`Water
`imbibing
`
`Drug release
`
`Ratecontrolling
`membrane
`
`Osmotic
`push layer
`
`Inner layer
`
`Liquid drug formulation
`
`Before operation
`
`During operation
`
`Figure 11: Figure of L-OROS system before and during operation.
`
`thickness, solubility of drug in tablet core, level of leachable
`pore-forming agent(s) and the osmotic pressure difference
`across the membrane [54, 55].
`There are several obvious advantages inherent to the
`CPOP system. The stomach irritation problems are con-
`siderably reduced, as drug is released from the whole of
`the device surface rather from a single hole [56]. Further,
`no complicated laser-drilling unit is required because the
`holes are formed in situ. Scheme describes the drug release
`phenomenon from a typical CPOP [29].
`
`5.7. Liquid-Oral Osmotic (L-OROS) System. Various L-
`OROS systems available to provide controlled delivery of
`liquid drug formulations include L-OROS hardcap, L-OROS
`softcap, and a delayed liquid bolus delivery system. Each of
`these systems includes a liquid drug layer, an osmotic engine
`or push layer, and a semipermeable membrane coating.
`When the system is in contact with the aqueous environ-
`ment, water permeates across the rate-controlling membrane
`and activates the osmotic layer (Figure 11) [9, 57].
`The expansion of the osmotic layer results in the devel-
`opment of hydrostatic pressure inside the system, thereby
`forcing the liquid formulation to be delivered at the delivery
`orifice. Whereas L-OROS hardcap and L-OROS softcap
`systems are designed to provide continuous drug delivery, the
`
`Before operation
`
`During operation
`
`Figure 12: Figure of sandwiched osmotic pump before and during
`operation.
`
`L-OROS delayed liquid bolus delivery system is designed to
`deliver a pulse of liquid drug (Figure 10) [34, 58].
`The delayed liquid bolus delivery system comprises
`three layers: a placebo delay layer, a liquid drug layer, and
`an osmotic engine, all surrounded by a rate-controlling
`semipermeable membrane (SPM). The delivery orifice is
`drilled on the placebo layer end of the capsule shaped device.
`When the osmotic engine expands, the placebo is released
`first, delaying release of the drug layer (Figure 10). Drug
`release can be delayed from 1 to 10 hours, depending on
`permeability of the rate-controlling membrane and the size
`of placebo [59].
`
`5.8. Sandwiched Osmotic Tablet (SOT). Figure 12 shows that
`sandwiched osmotic tablet is composed of polymeric push
`layer sandwiched between two drug layers with two delivery
`orifices. When placed in the aqueous environment, the
`middle push layer containing the swelling agents’ swells and
`the drug is released from the two orifices situated on opposite
`sides of the tablet; thus sandwiched osmotic tablets (SOTS)
`can be suitable for drugs prone to cause local irritation of the
`gastric mucosa (Table 2) [32, 55, 60].
`
`6. Conclusion
`
`Osmotic pumps are one of the systems for controlled drug
`delivery. Osmotic drug delivery systems typically consist
`of a drug core containing osmogen that is coated with a
`
`

`

`8
`
`Product name
`Acutrim
`Alpress LP
`Cardura XL
`ChronogesicTM
`Covera HS
`Ditropan XL
`Dynacirc CR
`Efidac 24
`Efidac 24
`Glucotrol XL
`Invega
`Minipress XL
`Procadia XL
`Sudafed 24
`Viadur
`Volmex
`
`Table 2: Marketed products of osmotic pump.
`
`ISRN Pharmaceutics
`
`Active pharmaceutical ingredient
`Phenylpropanolamine
`Prazosin
`Doxazosin
`Sufentanil
`Verapamil
`Oxybutinin chloride
`Isradipine
`Pseudoephiderine
`Chlorpheniramine meleate
`Glipizide
`Paliperidone
`Prazocine
`Nifedipine
`Pseudoephedrine
`Leuprolide acetate
`Albuterol
`
`Design of osmotic pump
`Elementary pump osmotic pump [9]
`Push-pull osmotic pump [2]
`Push-pull osmotic pump [34]
`Implantable osmotic system [8]
`Push-pull osmotic pump with time delay [48]
`Push-pull osmotic pump [9]
`Push-pull osmotic pump [34]
`Elementary pump o