A REVIEW ON OSMOTIC PUMP DRUG DELIVERY SYSTEM

A REVIEW ON OSMOTIC PUMP DRUG DELIVERY SYSTEM

M. Mathur * and R. Mishra

Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmadabad- 382 481, Gujarat, India

ABSTRACT: Drug release from novel drug delivery systems are desired to be controlled at target site in effective concentration for required therapeutic action with predictable plasma concentrations, unlike conventional ones, thereby reducing the dose, dosage frequency, toxic adverse effects, reduction of blood level fluctuations, improved patient compliance and minimization of drug accumulation. As this can be achieved by the phenomenon called osmosis, osmotic pump drug delivery systems are proved as one of the most promising oral drug delivery systems in the recent times. They are tablets coated with semipermeable membrane which causes pores in water and desired drug release occurs. Drug delivery from this system is not influenced by the different physiological factors within the gut lumen and the release characteristics can be predicted easily from the known properties of the drug and the dosage form. In the present review, a summary of the collected information on the osmotic drug delivery system has been discussed in detail.

Osmosis, Osmotic Pumps,

Controlled Drug Delivery, Osmogen, Semi Permeable Membrane, Water Soluble Pore Formers

INTRODUCTION: Novel drug delivery systems have made significant advancements in the past three decades due to noteworthy developments and innovations in the various aspects of pharmacy like biopharmaceutics, formulation, pharmacokinetics and pharmacodynamics. The reason for this revolutionary shift is relatively low development cost and time required for introducing a NDDS as compared to a new chemical entity because of which an existing drug molecule can be incorporated in the form of NDDS increasing its market value, competitiveness, and patent life ¹.

Oral controlled release (CR) systems continue to be the most popular amongst all the drug delivery systems. Conventional oral drug delivery systems supply an instantaneous release of drugs, which is not controlled and effective concentration of the drug at the target site is not achieved. The drug bioavailability from these dosage forms are highly dependent on several physicochemical properties of the drug and excipients as well as different physiological factors such as the presence or absence of food, pH of the gastro intestinal tract, GI motility etc. ².

Hence, most of the novel drug delivery systems are optimized in such a way that the drug dose and dosing interval are reduced thereby maintaining drug concentration within the therapeutic window and ensuring efficacy while minimizing toxic effects to enhance patient compliance. They have been designed in such a way so as to modulate the release a drug over an extended period of time and release. Efforts have been made to design the novel drug delivery systems in such a way that the rate and extent of drug absorption remain independent of physico-chemical properties of the drug and excipients, and physiological factors such as presence or absence of food, pH of the gastro-intestinal tract (GIT) thereby overcoming the limitations of the conventional drug delivery system ³.

One of the most promising and effective dosage form is osmotic pump controlled release preparation which is not only independent of all the physiological and physiochemical factors but also modulate the rate and pattern of drug release by optimizing the process and formulation parameters such as solubility, concentration and osmotic pressure of the core component(s), size of the delivery orifice, and nature of the rate-controlling membrane ⁴.

The noteworthy development in the osmotic delivery devices of today is the capability of delivering the drugs with moderate solubility as well as with extreme solubilities. Furthermore, these devices deliver drugs as liquids which help to enhance permeability and to deliver insoluble drugs that can dispense sub saturated solutions of drugs. Osmotic pump drug delivery technology can also be used to deliver high drug doses meeting high drug loading requirements ⁵.

History:

The history of osmotic drug delivery system dates back to 1748 when the phenomenon of osmosis became prevalent and known to all. It was further supported by the quantitative measurement of osmotic pressure in the year 1877. The first osmotic was devised by Australian pharmacologist Rose and Nelson who developed an implantable osmotic pump in 1955 named as the Rose and Nelson osmotic pump. Higuchi and Leeper made a few modifications in this pump and introduced to the pharmaceutical world in the year 1973. In the same year, a dispensing device with a filling means containing osmotically powdered agent was also designed. The oral osmotic pumps have certainly came a long way and the available products and patents available on this technology in the last few years makes its presence felt in the market.3 The oral osmotic pumps are also known as gastro intestinal therapeutic system. In 1975, the first oral osmotic pump came into existence which is called as the Elementary osmotic pump (EOP). In 1976, patent was granted to Alza Corporation of the USA as they were the first to develop an oral osmotic pump and today also they are the leaders in this field with a technology named OROS. ALZA osmotic pump was initially used only on the laboratory animals. The first osmotic bursting drug delivery device came into existence in 1979.

In 1982, patent was issued for an osmotic system which consists a layer of fluid swellable hydrogel. In 1984, combination therapy by using push pull osmotic pumps was reported for the first time. Controlled porosity osmotic pumps were introduced for the first time in 1985 which necessitates the removal of the mechanically drilled orifice and a patent was granted for the same in the year 1986. Development of a marketed formulation of push pull osmotic pump of Nifedipine was named as Procardia XL by Pfizer Inc in 1989 which became the largest selling cardiovascular product in US in 1995. Patent to an osmotic drug delivery of liquid active pharmaceutical agents was granted in 1995. This device consisted of a capsule containing an active agent and an orifice for the delivery of the active agent surrounded by an osmotic active layer which is covered by a semipermeable wall. Asymmetric membrane capsule was introduced to deliver the drug through osmotic pressure in 1999.

DUROS Leupolid implants named as Viadur was approved as the first implantable osmotic pump for humans in USA in the year 2000. In 2001, patent was granted for dosage form comprising of liquid drug formulation that can emulsify to enhance the solubility, dissolution and bioavailability of the drug. First report of floating osmotic pump was given in 2003. This proves that the controlled delivery of drug through osmotic pump systems is a successful method to deliver the drugs which has been investigated and studied since past three decades and is still continuing to develop and mature to provide a controlled release of drugs in a zero order fashion for a prolonged period of time making it independent of the various physiological factors in the human body ^{6, 7}.

Advantages of osmotically controlled drug delivery systems:

Osmotic drug delivery systems for oral use offer distinct and practical advantages over other means of delivery. The following advantages have contributed to the popularity of osmotic drug delivery systems ⁸.

• They typically give a zero order release profile after an initial lag.

• Deliveries may be delayed or pulsed if desired.

• Drug release is independent of physiological and physico-chemical factors such as gastric pH and hydrodynamic condition.

• A high degree of in-vitro and in-vivo correlation (ivivc) is obtained in osmotic systems.
• Activation and control of drug release from the osmotic drug delivery system is based on the presence of required amount of water in the GIT which is relatively constant.

• 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.

Disadvantages of osmotically controlled drug delivery systems: ⁹

• Expensive, as special equipment is required for making an orifice in the system.

• If the coating process is not well controlled there is a risk of film defects, which results in dose dumping

• Size of the pores is critical.

• Retrival therapy is not possible in the case of unexpected adverse events.

• Residence time of the system in the body varies with the gastric motility and food intake.

• It may cause irritation or ulcer due to release of saturated solution of drug.

Phenomenon of Osmosis:

Osmosis is the spontaneous net movement of solvent molecules through a semi-permeable membrane into a region of higher solute concentration, in the direction that tends to equalize the solute concentrations on the two sides. It is driven by a difference in solute concentrations across the membrane that allows passage of water, but rejects most solute molecules or ions. Osmotic pressure is the pressure which, if applied to the more concentrated solution, would prevent transport of water across the semi permeable membrane. It is a colligative property of a solution in which the magnitude of osmotic pressure of the solution is independent on the number of discrete entities of solute present in the solution. This means that solutions of different concentrations having the same solute and solvent system exhibit an osmotic pressure proportional to their concentrations. Thus a constant osmotic pressure, and thereby a constant influx of water can be achieved by an osmotic delivery system that results in a constant zero order release rate of drug ¹⁰.

Osmotic pressure created due to imbibitions of fluid from external environment into the dosage form regulates the delivery of drug from osmotic device. Rate of drug delivery from osmotic pump is directly proportional to the osmotic pressure developed due to imbibitions of fluids by osmogen. Hence the release rate of drugs from osmotic dispensing devices is dependent on the solubility and molecular weight and activity coefficient of the osmogen ¹¹.

The first osmotic effect was reported by Abbe Nollet in 1748. Later in 1877, Pfeffer obtained the first quantitative measurement by performing an experiment using semipermeable 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 ^{8, 11}.

Π = Ø c RT

Where,

p = Osmotic pressure

Π = osmotic coefficient

c = molar concentration

R = gas constant

T = Absolute temperature

Osmotic pressure can range from 30 atm to 500 atm by using the different concentrations and types of soluble solutes which flow across semipermeable membrane. The osmotic water flow through a membrane is given by the equation ¹².

dvdt = A Q Δ π L

Where,

dvdt = water flow across the membrane

A= area of the membrane in cm²

L = thickness

Q = permeability

Δ π = the osmotic pressure difference between the two solutions on either side of the semipermeable membrane.

This equation is strictly for a membrane which is permeable to water but completely impermeable to osmotic agent.

General Mechanism for drug release from Osmotic Pumps

The basic equation which applies to osmotic systems is

dM/dt = dV/dt * c ……………..(equation 1)

Where,

dM/dt= mass release

dV/dt= volumetric pumping rate

c = concentration of drug.

But, volumetric pumping rate is described in the following equation as

dV/dt = (A/ h) Lp σ (Δπ -Δp)

Where,

A = membrane area

h = thickness of membrane

Lp= mechanical permeability

σ = reflection coefficient

Δπ = osmotic pressure difference

Δp = hydrostatic pressure difference

As the size of orifice delivery increases, Δp decrease, so Δπ >> Δp and hence the equation becomes

dV/dt = (A/ h) Lp (σ Δπ )

When the osmotic pressure of the formulation is large compared to the osmotic pressure of the environment, Δπ can be substituted with π. Mechanical permeability and reflection coefficient are constant for a particular osmotic system, hence they can be substituted by a constant k ¹³.

dV/dt=(A/h)(Lpσ)πdV/dt=(A/h)kπ…. (equation 2)

Substituting the value of equation (2) in equation (1), we get

dM/dt = (A/h) k π c

From the derived equation, it is clearly evident that, in any given osmotic system, difference in the osmotic pressure is directly proportional to the mass release and thickness of membrane, while inversely proportional to the membrane area and the concentration of the drug ¹⁴.

Basic components of Osmotically Controlled Drug Delivery System (Osmotic Pumps)

Drug:

Both water soluble and water insoluble drugs can be used in the osmotic pump systems. The drug candidate used in the osmotically controlled drug delivery should possess short biological half-life (2-6h), high potency and should be required for a chronic treatment. To name a few, the ideal drug candidates which can be used for the formulation and evaluation of osmotic pump drug delivery systems are antihypertensive agents- Nifedipine, Virapamil, Metoprolol, Captopril, Diltiazem hydrochloride, Carvedilol,Valsartan; anti diabetic agents- Glipizide, Glimpiperide; NSAIDs like ketorolac, Ibuprofen, Diclofenac sodium, Aceclofenac etc ³.

Osmotic agents:

Osmotic agents usually are ionic compounds consisting of either inorganic salts such as sodium chloride, potassium chloride magnesium sulphate, sodium sulphate, potassium sulphate and sodium bicarbonate or hydrophilic polymers like Sodium carboxymethyl cellulose, Hydroxypropylmethyl cellulose, Hydroxyethylmethylcellulose, Methylcellulose, Polyethylene oxide, polyvinyl pyrollidine. Additionally, sugars such as glucose, sorbitol, sucrose and inorganic salts of carbohydrates can also act as effective osmotic agents. They are used for the fabrication of the osmotic device  maintain a concentration gradient across the membrane by generating a driving force for the uptake of water and assist in maintaining drug uniformity in the hydrated formulation ¹⁵. The classifications along with the examples of compounds which can be used as osmogens are given in Table 1.

TABLE 1: COMPOUNDS WHICH CAN BE USED AS OSMOGENS

Semi Permeable Membrane:

Semipermeable membrane plays an important role in the modulation of dug release from the osmotic drug delivery system. It should be stable to both outer and the inner environment of the device. The membrane should be rigid and inert and should maintain its dimensional integrity to provide a constant osmotic driving force during drug delivery. This membrane should be selectively permeable as the osmogen should not be lost by diffusion across the membrane during the passage of drugs and other ingredients present in the compartment. It should be biocompatible. It should exhibit sufficient water permeability so as to retain water flux rate in the desired range. The water vapour transmission rates can be used to estimate water flux rates. 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. The semipermeable membrane must possess sufficient wet strength (-105) and wet modulus so as to retain its dimensional integrity during the operational lifetime of the device ^{8, 16}.

Plasticizers:

Plasticizers are used in the coating membrane during the formulation of osmotic system as they can change the visco-elastic behaviour of the polymers and theses changes affect the permeability of the polymeric films. These changes can be modulated by using different types and amount of plasticizers. Examples of some of the plasticizers are polyethylene glycols, Ethylene glycol monoacetate, ethylene glycol diacetate for low permeability, tri ethyl citrate and diethyl tartarate or Diacetin ^{3, 8}.

Flux regulators:

Delivery systems can be designed to regulate the permeability of the fluid by incorporating flux regulating 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 ^{8, 15}.

Wicking agent: 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 in nature. They are characterized by having the ability to undergo physisorption with water which is a form of absorption in which the solvent molecules can loosely adhere to surfaces of the wicking agent via Vander 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.

Materials, which suitably for act as wicking agents include colloidal silicon dioxide, kaolin, titanium dioxide, alumina, niacinamide, sodium lauryl sulphate (SLS), low molecular weight poly vinyl pyrrolidone (PVP), m-pyrol, bentonite, magnesium aluminium silicate, polyester and polyethylene ¹⁶.

Pore forming agent:

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 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 etc., alkaline earth metals such as calcium chloride and calcium nitrate, carbohydrates such as sucrose, glucose, fructose, mannose, lactose, sorbitol, mannitol, diols and polyols such as poly hydric alcohols and polyvinyl pyrrolidone can be used as pore forming agents ^{3, 16}.

Coating solvent:

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 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), methylene chloride-methanol-water (75:22:3) etc. are generally used widely as coating solvents ^{8, 17}.

Classification of Osmotic Drug Delivery System:

Many forms of osmotic pumps are reported in the literature but, in general they can be divided in oral and implantable systems.

1. Implantable osmotic drug delivery system:
2. DUROS® technology:

DUROS technology, as shown in figure 1, provides a bi-compartment system separated by a piston. One of the compartments consists of osmotic engine specifically formulated with an excess of solid NaCl, such that it remains present throughout the delivery period and results in a constant osmotic gradient. It also consists of a semi permeable membrane on one end through which water is drawn into the osmotic engine and establishes a large and constant osmotic gradient between the tissue water and the osmotic engine. Other compartment consists of a drug solution with an orifice from which the drug is released due to the osmotic gradient. This helps to provide site specific and systemic drug delivery when implanted in humans. The preferred site of implantation is subcutaneous placement in the inside of the upper arm. The delivery period ranges from some days to 1 year ¹⁸.

Materials used in this technology are screened for compatibility and the suitable and biocompatible ones are used. Radiation sterilization (gamma) was utilized to sterilize the final drug product. If the drug formulation cannot withstand sterilizing doses of radiation, then a DUROS subassembly is radiation sterilized and the drug formulation is added in a final aseptic operation. Hence, the materials of the system were also screened for their ability to withstand sterilizing doses of radiation.

This technology has the potential to provide more flexibility than competitive products regarding the types of drugs that can be administered, including proteins, peptides and genes because the drug dispensing mechanism is independent from the drug substance ¹⁹.

FIG. 1: DUROS TECHNOLOGY

1. ALZET osmotic Pumps:

ALZET osmotic pumps, as shown in Fig. 2, are miniature, implantable pumps used for research in animals like mice, rats etc. These infusion pumps continuously deliver drugs, hormones and other test agents at controlled rates from one day to six weeks without the need for external connections or frequent handling which eliminates the need for repeated night time or weekend dosing. ALZET pumps can be used for systemic administration for targeted drug delivery when implanted subcutaneously or intraperitoneally. They can be attached to a catheter for localization of the effect of the drug and for intravenous, intracerebral, or intra-arterial infusion to deliver hundreds of different compounds, including antibodies, chemotherapeutic drugs, cytokines, growth factors, hormones, and peptides ²⁰.

ALZET pumps operate by osmotic displacement. An empty reservoir within the core of the pump is filled with the drug or hormone solution to be delivered, which is isolated from the chamber containing salt by a semi permeable membrane. Due to the presence of a high concentration of salt in a chamber surrounding the reservoir, water enters the pump through the semi permeable layer. The entry of water increases the volume in the salt chamber, causing compression of the flexible reservoir and delivery of the drug solution into the animal via the exit port ²¹.

FIG. 2: ALZET OSMOTIC PUMP

1. Rose and Nelson Pump:

In the year 1955, these two Australian physiologists reported the first osmotic pump to the gut of sheep and other cattle. The pump is constructed of three chambers (Fig.3) viz., a drug chamber with an orifice, a salt chamber with elastic diaphragm containing excess solid salt, and a water chamber. A semipermeable membrane separates the drug and water chamber. The difference in osmotic pressure across the membrane moves water from the water chamber into the salt. The volume of chamber increases because of this water flow, which distends the latex diaphragm separating the salt and drug chambers, there by pumping drug out of the device ²².

FIG. 3: ROSE AND NELSON PUMP

1. Higuchi- Theeuwes Pump:

In the early 1970 Higuchi-Theeuwes developed a similar form of Rose-Nelson pump (Fig. 4) as shown in the figure 4. The semipermeable wall itself acts as a rigid outer casing of the pump. The device is loaded with drug prior to use. When the device is put in an aqueous environment the 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 ²³.

FIG.4: ROSE AND NELSON PUMP

e.Mini Osmotic Pumps

Mini osmotic implantable pumps (Fig. 5) were initially designed by Alza Corp. for experimental studies in animal models. These pumps operate on osmotic pressure difference between a compartment within the pump, called the salt sleeve and the tissue environment in which the pump is implanted. The high osmolality of the salt sleeve causes water to flux into the pump through a semipermeable membrane which forms the outer surface of the pump. As the water enters the salt sleeve, it compresses the flexible reservoir, displacing the test solution from the pump at a controlled, predetermined rate. Because the compressed reservoir cannot be refilled, the pumps are designed for single use only ^{24, 25}.

FIG.5: MINI OSMOTIC PUMP

1. Higuchi-Leeper Pump:

The Higuchi-Leeper pump (Fig. 6) is modified version of Rose-Nelson Pump. It has no water chamber, and the device is activated by water imbibed from the surrounding environment. The pump is activated when it is swallowed or implanted in the body. This pump consists of a rigid housing, and the semipermeable membrane is supported on a perforated frame. It has a salt chamber containing a fluid solution with excess solid salt. Recent modification in Higuchi-Leeper pump accommodated pulsatile drug delivery. The pulsatile release was achieved be the production of a critical pressure at which the delivery orifice opens and releases the drug ^{26, 27}.

FIG. 6: HIGUCHI-LEEPER PUMP

2. Oral osmotic Pump:
3. Single chamber osmotic pump:

-Elementary osmotic pump

1. Multi chamber osmotic pump:

-Push pull osmotic pump

-Osmotic pump with non expanding second chamber

1. Specific types:

• -Bursting osmotic pump
• -Liquid oral osmotic system (L-OROS)
• -Multiparticulate
• -Delayed Delivery Osmotic device
• -Telescopic capsule
• -Colon targeting oral osmotic system (OROS CT)
• -Sandwiched oral therapeutic system
• -Monolithic osmotic system
• -OSMAT
• -Controlled Porosity Osmotic Pump

Elementary Osmotic Pump (EOP):

Elementary osmotic pump (Fig. 7) is constructed by coating an osmotically active agent with the rate controlling semipermeable membrane. This membrane contains an orifice of a critical size through which the drug is delivered. Drug release through this system occurs in a controlled pattern because of the water permeation characteristics of a semi permeable membrane surrounding drug and osmotic properties of the osmogen in the formulation. The dosage form after coming into contact with aqueous fluids, imbibes water from the surroundings at a rate determined by the fluid permeability of the membrane and osmotic pressure of the core formulation. This osmotic imbibitions of water result in formation of a saturated solution of drug within the core, which is dispensed at controlled rate from the delivery orifice in the membrane. Though 60 -80 percent of drug is released at a constant rate from the EOP, a lag time of 30-60 minute is observed in most of the cases as the system hydrates before zero order delivery from the system begins. This system is suitable or delivery of drugs having moderate water solubility ²⁸.

FIG.7: ELEMENTARY OSMOTIC PUMP

Push Pull Osmotic Pump (PPOP):

Push pull osmotic pump (Fig. 8) is a modified EOP which can be used for the delivery of both poorly water-soluble and highly water soluble drugs at a constant rate. This system resembles a standard bilayer tablet of which the upper layer contains drug and the lower layer, along with the tablet excipients, contains a polymeric osmotic agent which has the ability to form a suspension of drug in-situ. These layers are formed separately and bonded together to form a single bilayer core tablet which is further coated with a semi permeable membrane.

A small hole is then 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 ^{29, 30}.

FIG. 8: PUSH PULL OSMOTIC PUMP

Osmotic pump with Non Expanding Second Chamber:

The second category of multi-chamber devices comprises system containing a non-expanding second chamber. This group can be divided into two sub groups, depending on the function of second chamber. In the first device, this second chamber is used to dilute the drug solution which is released in the body because in certain cases where the drug is released in a concentrated form, it causes the problem of irritation in the gastrointestinal tract. In the second device, there are two rigid chambers, wherein the first one contains a biologically inert osmotic agent, such as sugar or a simple salt like sodium chloride and the second chamber contains the drug. Water is drawn into both the chambers through the surrounding semi permeable membrane. The solution of osmotic agent formed in the first chamber then passes through the connecting hole to the drug chamber where it mixes with the drug solution before exiting through the micro porous membrane that form a part of wall surrounding the chamber. The device could be used to deliver relatively insoluble drugs ^{31, 32}. A schematic diagram can be seen in the Fig. 9.

FIG.9: OSMOTIC PUMP WITH NON EXPANDING SECOND CHAMBER

Bursting Osmotic Pump:

This system is similar to an EOP expect delivery orifice is either absent or size may be small. When it is placed in an aqueous environment, water is imbibed through the semipermeable membrane and hydraulic pressure is built up inside until the membrane ruptures and the content is released. Drug release can be modulated by varying the thickness and area of the semipermeable membrane. This system is useful to provide pulsated drug release ³³.

Pulsatile delivery system:

Pulsatile systems are gaining a lot of interest as they deliver the drug at the right site of action at the right time and in the right amount, thus providing spatial and temporal delivery and increasing patient compliance. These systems are designed according to the circadian rhythm of the body. The principle rationale for the use of pulsatile release is for the drugs where a constant drug release, i.e., a zero order release is not desired. The release of the drug as a pulse after a lag time has to be designed in such a way that a complete and rapid drug release follows the lag time. This type of tablet system consist of core coated with two layer of swelling and rupturable coatings herein they used spray dried lactose and microcrystalline cellulose in drug core and then core was coated with swelling polymer croscarmellose sodium and an outer rupturable layer of ethylcellulose.

Pulsatile systems can be classified into single and multiple-unit systems. Single-unit systems are formulated either as capsule-based or osmosis based systems. Single-unit systems are designed by coating the system either with eroding/soluble or rupturable coating. In multiple-unit systems, however, the pulsatile release is induced by changing membrane permeability or by coating with a rupturable membrane ³⁴.

Liquid Oral Osmotic System:

Liquid oral osmotic system (OROS) as shown in Fig. 10 and 11, is designed to deliver drugs as liquid formulations and combine the benefits of extended release with high bioavailability. They are of three types namely L- OROS hard cap, L- OROS soft cap and delayed liquid bolus delivery system.

FIG.10: L-OROS SOFT CAP

FIG.11: L-OROS HARD CAP

Each of these systems includes a liquid drug layer, an osmotic engine or push layer and a semi permeable membrane coating. When the system is in contact with the aqueous environment water permeates across the rate controlling membrane and activate the osmotic layer. The expansion of the osmotic layer results in the development of hydrostatic pressure inside the system, thereby forcing the liquid formulation to be delivered from the delivery orifice. L-OROS hardcap and softcap systems are designed to provide a continuous drug delivery while L-OROS delayed liquid bolus drug delivery system is designed for pulsatile drug delivery. The delayed liquid bolus delivery system comprises three layers: a placebo delay layer, a liquid drug layer and an osmotic engine, all surrounded by rate controlling semi permeable membrane.

The delivery orifice is drilled on the placebo layer end of the capsule shaped device. When the osmotic engine is expands, the placebo is released first, delaying release of the drug layer. Drug release can be delayed from up to 10 hours, depending on the permeability of the rate controlling membrane and thickness of the placebo layer ^{35, 36}.

Multiparticulate Delayed-Release osmotic system:

In the multiparticulate delayed-release system (Fig.12), 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. In a study by Schultz and Kleinebudde ³⁷, lag time and dissolution rates were found to be dependent on the coating level and osmotic properties of the dissolution medium. Furthermore, dissolution characteristics were found to be influenced by such membrane components as incorporation of plasticizer and its concentration and lipophilicity. Because of their semi permeable walls, an osmotic device inherently show lag time before drug delivery begins. Although this characteristic is usually cited as a disadvantage, it can be used advantageously. The delayed release of certain drug (drugs for early morning asthma or arthritis) may be beneficial. ²⁴

FIG.12: MULTIPARTICULATE DELAYED RELEASE OSMOTIC SYSTEM

Telescopic Capsule for Delayed Release: 

A bilayer osmotic tablet is prepared, whose one of the chambers contains a drug with an orifice and other chamber contains an osmotic engine. The filling of the drug is either performed manually or by an automated filling machine. These two layers are separted by a waxy material. This tablet is fitted inside a capsule in such a way that the osmotic layer faces towards the completed end of the cap and the drug with the exit port faces towards the open end of the cap.

The cap, bilayer tablet and the body are fitted together tightly. As the water is imbibed in the housing of the dispensing device, the osmotic engine expands and exerts pressure on the slidable walls of the bilayer tablet and the capsule. A negligible pressure gradient between the external environment and the interior of the system is developed as a result of which there is a minimal net flow of environmental water.  Consequently, no agent is delivered for this delayed period of time ³⁸. A schematic diagram is seen in the Fig.13.

FIG.13: TELESCOPIC CAPSULE FOR DELAYED RELEASE

Longitudinally compressed tablet (LCT) multilayer formulation:

It is an advanced design consisting of an osmotic push layer and can be configured to contain several drug layers. The opinion of multiple drug layers provides increased flexibility and control over the pattern of release of medication from the system, as opposed to the single layer used in the push-pull system, which can deliver a drug only in a zero order fashion. For example, two drug layers could be formulated with different drug concentration to provide modulation in the release rate profile. As with the push-pull formulation, water is absorbed through the exposed semipermeable tablet shell, expanding the push compartment and releasing the drug primarily through the first compartment through the laser drilled orifice at a predetermined controlled rate. Varying the relative viscosity and hydrophilicity of the drug layer components can control the amount of mixing between the multiple drug layers. This allows even greater flexibility to achieve the target release profile. The LCT multilayer formulation can also be formulated with different drugs in different layers to provide combination therapy.

Similar to the push-pull system, drug delivery by the LCT multilayer formulation can be unaffected by gastric pH, gut motility and the presence of food, depending on where in the GI tract the drug is released ^{17, 39}. A schematic diagram can be seen in the Fig.14.

FIG.14: LONGITUDINALLY COMPRESSED TABLET (LCT) MULTILAYER FORMULATION

Colon targeting oral osmotic system (OROS-CT):

OROS-CT (Fig. 15) 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. The push-pull osmotic unit is coated with an enteric coating. After coming in contact with the gastric fluids, gelatin capsule is dissolved, while the tablets remain intact. 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 ^40-42.

FIG.15: COLON TARGETING ORAL OSMOTIC SYSTEM (OROS-CT)

Sandwiched Osmotic Tablets (SOTS):

It is composed of polymeric push layer sandwiched between two drug layers with two delivery orifices with a semi permeable membrane coated on the tablet. When placed in the aqueous environment, the middle push layer containing the swelling agents imbibes water from the surrounding areas via semipermeable membrane and the drug is released from the two orifices situated on opposite sides of the tablet. Hence, SOTS can be suitable for drugs prone to cause local irritation of the gastric mucosa ^43-46. A schematic diagram of sandwiched osmotic tablets can be seen in the Fig.16.

FIG.16: SANDWICHED OSMOTIC TABLETS

Monolithic Osmotic System:

It constitutes a simple dispersion of water-soluble agent in polymer matrix. When the system comes in contact in with the aqueous environment, water imbibitions by the active agents takes place rupturing the polymer matrix capsule surrounding the drug, thus liberating it to the outside environment. Initially this process occurs at the outer environment of the polymeric matrix, but gradually proceeds towards the interior of the matrix in a serial fashion. However, this system fails if more than 20 –30 units per litre of the active agents are incorporated in to the device as above this level, significant contribution from the simple leaching of the substance take place ^{47, 48}. A schematic diagram of the same is seen in the Fig.17.

FIG. 17: MONOLITHIC OSMOTIC SYSTEM

OSMAT:

It is a novel osmotically driven matrix system which utilizes the hydrophilic polymers to swell and gel in aqueous medium forming a semipermeable membrane in-situ. This helps to release the drug from matrix system which can be modulated by the osmotic phenomenon. OSMAT thus judiciously utilizes matrix osmotic characteristics resulting in a quantum improvement in drug delivery from swellable matrix system. OSMAT produces controlled drug release with adequate delivery rates in an agitation in dependent manner. Thus this system represents simple, versatile, and easy to fabricate osmotically driven controlled drug delivery system based upon low cost technology ⁴⁹.

Controlled Porosity Osmotic Pump:

This is a widely investigated osmotic pump consisting of a single or multicompartment model. It comprises of a core consisting of a drug and an osmogen surrounded by a semi permeable membrane having an asymmetric structure. This semipermeable membrane is selectively permeable to water but impermeable to solute. It contains an insensitive pore forming additive dispersed throughout the wall. When exposed to water, low levels of water-soluble additive are leached from the membrane rendering the membrane porous. This sponge like structure formed is substantially permeable to both water and dissolved drug agents. Rate of drug delivery depends upon the factors like water permeability of the semi permeable membrane and the osmotic pressure of the core formulation, thickness and total surface area of coating. All of these variables are under the control of the formulator and do not vary under physiological conditions like pH and agitational intensity ^50-52. A schematic diagram of the controlled porosity osmotic pump can be seen in Fig.18.

FIG.18: CONTROLLED POROSITY OSMOTIC PUMP

Marketed Products: ^{53, 54}

The details of various marketed products of various osmotic pump drug delivery systems are furnished in Table 2.

TABLE 2: MARKETED PRODUCTS OF OSMOTIC PUMP DRUG DELIVERY SYSTEMS

Novel Technologies in Osmotic Drug Delievry Systems:

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 ⁵⁵. Osmodex® technologies can be divided into the following categories of application:

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) ⁵⁵.

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 ⁵⁵.

Osmodex® IR/CR combination:

This platform technology provides a combination of immediate release and controlled release of either one or two drugs. This innovative approach allows an immediate release profile to be safely and uniformly combined with a programmed release according to the pharmacokinetic or pharmacodynamic needs of the product (Example – Allegra-D 224 Hour Tablet) ⁵⁶.

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 ⁵⁶.

Osmodex® Triple combination tablet:

This delivery system incorporates compressed drug layers 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 ^{55, 56}.

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 drug dispensing 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 drug solutions can be both aqueous and non-aqueous in nature. DUROS drug formulations must exhibit stability at body temperature (37°C) for extended periods of time, usually ranging from 3 months to 1 year.

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.

Radiation sterilization (gamma) may be utilized to sterilize the final drug product. If the drug formulation cannot withstand sterilizing doses of radiation, then a DUROS subassembly is radiation sterilized, and the drug formulation is added in a final aseptic operation ⁵⁷.

Duros Advanced Applications of Duros Technology:

CHRONOGESIC^TM (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 ⁵⁷.

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 no absorptive 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-molecular weight 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 (PE 60).

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. In this section, two examples of such precision drug delivery using DUROS with a miniature catheter are presented.

DUROS® Intrathecal Opioid Delivery System Intrathecal delivery of opioids is indicated for a number of chronic pain conditions, which include chronic back and leg pain, chronic cancer pain, complex regional pain syndromes (usually in the foot or hand), and painful neuropathy. By directly delivering opioids, such as morphine or hydromorphone, into the intrathecal space surrounding the spinal cord using the DUROS system, significantly smaller doses of the drug are required to elicit pain relief. A DUROS Intrathecal (opioid) Delivery system is at the preclinical stage ⁵⁸.

DUROS Intratumoral Delivery of Antineoplastic Agents in to the Brainstem:

Local or site-specific delivery of chemotherapeutic agents increases drug concentration at the tumour target, decreases systemic exposure and toxicities, and increases the duration of exposure of the tumour to the drug. Experimental and clinical studies have demonstrated statistically significant increases in survival associated with local therapy for brain tumours. Drugs have been delivered via controlled release 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 have 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 ⁵⁹.

CONCLUSIONS: The drug delivery systems have become advanced in recent years. In this era of modern science and technology Novel drug delivery systems has been an attractive and recognized drug delivery system for the pharmaceutical and health industry. Among various NDDS, osmotic pumps have matured from their use with laboratory animals to the most reliable controlled release systems for human. The conventional dosage forms have less control over the drug release and no control over the effective concentration at the target site, whereas, the osmotic drug delivery system can deliver the drug at a pre-programmed  rate which results in predictable plasma concentration. In osmotic delivery systems, osmotic pressure provides the driving force for drug release. Increasing pressure inside the dosage form from water incursion causes the drug to release from the system. The major advantages include precise control of zero-order or other patterned release over an extended time period—consistent release rates can be achieved irrespective of the environmental factors at the delivery site.

Controlled delivery via osmotic systems also may reduce the side-effect profile by moderating the blood plasma peaks typical of conventional (e.g., instant release) dosage forms. Moreover, since efficacious plasma levels are maintained longer in osmotic systems, avoidance of trough plasma levels over the dosing interval is possible. However, a complex manufacturing process and higher cost compared with conventional dosage forms limit their use. Although not all drugs available for treating different diseases require such precise release rates, once-daily formulations based on osmotic principles are playing an increasingly important role in improving patient compliance. Therefore, most of the currently marketed products are based on drugs used in long-term therapies for diabetes, hypertension, attention-deficit disorder, and other chronic disease states. Besides oral osmotic delivery systems, implants that work on osmotic principles are promising for delivery of a wide variety of molecules with a precise rate over a long period of time. Further, with the discovery of newer and potent drugs, the need to deliver such compounds at a precise rate certainly will pave the way for osmotic delivery systems to play an increasingly important role in drug delivery

REFERENCES:

1. Verma RK, Garg S: Current status of drug delivery technologies and future directions. Pharmaceutical Technology, 2001; 25:1-14.
2. Verma RK, Mishra B, Garg S: Osmotically controlled oral drug delivery. Drug Development and Industrial Pharmacy, 2000; 26 (7): 695-708.
3. Verma RK, Krishna DM, Garg S: Formulation aspects in the development of osmotically controlled oral drug delivery system. Journal of Controlled Release, 2002; 79: 7-27.
4. Vasant VR and Mannfred AH: Drug delivery systems, 2nd Edition, CRC Press, 10, 11.
5. Babu CA, Rao MP, Vijaya Ratna J: Controlled Porosity osmotic pump tablets- An Overview. Journal of Pharmaceutical Research and Healthcare. January 2010; 2(1): 114-126.
6. Theeuwes F, Swanson DR, Guitttard G, Ayer A, Khanna S: Osmotic delivery systems for the β-adrenoceptor antagonists Metoprolol and Oxprenolol: Design and evaluation of systems for once-daily administration. British Journal of Clinical Pharmacology, 1985; 19, 69-76.
7. Sanap SL, Savkare AD: Controlled porosity osmotic pump- an overview. International Journal of Pharmaceutical Research and Development, February 2012; 5 (12): 71-80.
8. Parmar NS, Vyas SK, Jain NK: Advanced in controlled and novel drug delivery, CBS publisher, 28-29.
9. Fix J. Advantages and disadvantages, Encyclopedia of controlled drug delivery. Volume 2, John Wiley and sons.
10. Santus G, Baker R W: Osmotic drug delivery: A review of the patent literature. Journal of Controlled Release, 1995; 35: 1-21.
11. Herbig SM, Cardinal JR, Korsmeyer RW, Smith KL: Asymmetric membrane tablet coatings for osmotic drug delivery. Journal of Controlled Release, 1995; 35: 127-136.
12. Okimoto K, Tokunaga Y, Ibuki R, Irie T, Uekama K, Rajewski RA, Stella VJ: Applicability of (SBE)7m-β-CD in controlled-porosity osmotic pump tablets (OPTs). International Journal of Pharmaceutics. 2004; 286: 81–88.
13. Thombre AG, Zentner GM, Himmelstein KJ: Mechanism of water transport in controlled porosity osmotic devices. Journal of Membrane Science, 1989; 40: 279-310.
14. Thombre AG, Appel LE, Chidlaw MB, Daugherity PD, Dumont F, Evans LAF, Sutton SC: Osmotic drug delivery using swellable-core technology. Journal of Controlled Release, 2004; 94: 75– 89.
15. Padma priya S, Ravichandran V, Suba V: A Review on Osmotic Drug Delivery System. International Journal of Research in Pharmaceutical and Biomedical Sciences, July– September 2013; 4 (3): 810-821.
16. Pandey S, Devmurari V: Osmotic Pump Drug Delivery Devices: From Implant to Sandwiched Oral Therapeutic System. International Journal of PharmTech Research, January-March 2010; 2 (1): 693-699.
17. Gupta BP, Thakur N, Jain NP, Banweer J, Jain S: Osmotically Controlled Drug Delivery System with Associated Drugs, Journal of Pharmacy and Pharmaceutical Sciences. 2010; 13(3): 571 – 588.
18. Wright J.C., Johnoson R.M. and Yum S.I: DUROS® Osmotic Pharmaceutical Systems for Parenteral & Site-Directed Therapy, www.drugdeliverytech.com
19. Deepak singla, SL. Hari Kumar and Nirmala: Osmotic Pump Drug Delivery- A Novel Approach. International Journal of Research in Pharmacy and Chemistry, 2012; 2 (2): 661-670.
20. alzet.com assessed on 30/03/2011.
21. Ali M, Senthilkumar SK, Parthiban S.: Review on Natural Pumps: A Novel Drug Delivery System. International Journal of Pharmaceutical Development & Technology, 2013; 3(2): 52-62.
22. Li X, Jasti BR.: Osmotic controlled drug delivery systems, In: Design of controlled release of drug delivery systems, McGraw Hill, 2006; 203-229.
23. Theeuwes F: Osmotically powered agent dispersing device with filling means. US Patent 3760, 984, 1973.
24. Zentner GM, Himmelstein KJ, Rork GS: Multiparticulate controlled porosity osmotic. US Patent 4851228; 1989.
25. Amidon GL, Higuchi T, Dressman JB: Lipid osmotic pump. US Patent 4685918; 1987.
26. Higuchi T, Leeper HM: Improved osmotic dispenser employing magnesium sulphate and Magnesium chloride. US Patent 3760804, 1973.
27. Higuchi T, Leeper HM: Osmotic dispenser with means for dispensing active agents responsive to osmotic gradient. US Patent 3995631, 1976.
28. Theeuwes F: Elementary Osmotic Pump. Journal of Pharmaceutical Sciences; 1975; 64: 1987-1991.
29. Bhatt PP: Osmotic drug delivery systems for poorly water soluble drugs, Pharmaventures Ltd., Oxford, UK, 2004; 26-29.
30. Jerzewski RL, Chien YW: In: A Kydonieus (ed), Treatise on Controlled Drug Delivery: Fundamentals, Optimization, Application, Marcel Dekker, New York, 1992; 225-253.
31. Tanmay G, Amitava G: Drug delivery through osmotic system: A overview. Journal of Applied Pharmaceutical Sciences, 2011; 1(2): 38-49.
32. Khan I, Arjariya P, Ratnakar D, Farheen F: A Review: An Article of Importance in its field of osmotic pump controlled drug delivery system. Indo American Journal of Pharmaceutical Research, 2013: 3 (4): 3147-3157.
33. Baker RW: Controlled release delivery system by an osmotic bursting mechanism. US Patent 3952741; 1976
34. Arora S, Ali J, Ahuja A, Baboota S, Qureshi J: Pulsatile drug delivery systems: An approach for controlled drug delivery. Indian Journal of Pharmaceutical Sciences, 2006; 68(3): 295-300.
35. Dong L, Shafi K, Wan J and Wong P: A novel osmotic delivery system: L-OROS Soft cap. In: Proceedings of the International Symposium on controlled Release of Bioactive Materials, Paris; 2000.
36. Bonsen P, Wong PS and Theeuwes F: Method of delivering drug with aid of effervescent activity generated in environment of use. US Patent 4265874; 1981.
37. Wilson CG, Crowle PJ: Controlled Release in Oral Drug Delivery, CRS Press, 2011.
38. Keraliya RA, Patel C, Patel P, Keraliya V, Soni TG, Patel RC, Patel MM: Osmotic Drug Delivery System as a Part of Modified Release Dosage Form; Pharmaceutics, 2012: 1- 9.
39. Conley R, Gupta SK, Satyan G: Clinical spectrum of the osmotic controlled release oral delivery system (OROS): an advanced oral delivery form. Current medical research and opinion, 2006; 22:1879-1892.
40. Swanson DR, Barclay BL, Wong PSL, Theuwes F: Nifedipine gastrointestinal therapeutic system. American Journal of Medicine, 1987; 83: 3-9.
41. Theuwes F, Wong PSL, Burkoth TL, Fox DA, Bicek PR: (ed) In: colonic drug absorption and metabolism, Marcel Decker, New York, 1993; 137-158.
42. Theeuwes F, Wong PSL, Burkoth TL, Fox DA: Osmotic systems for colon-targeted drug delivery. In: Colonic drug absorption and metabolism. Marcel Dekker, NY, 1993; 137-158.
43. Liu L, Ku J, Khang G, Lee B, Rhee JM: Nifedipine controlled delivery by sandwiched osmotic tablet system. Journal of Controlled Release, 2000; 68: 145-156.
44. Pandey S, et al., Osmotic Pump drug delivery devices: Form implant to sandwiched oral therapeutic system. International Journal of Pharma Technology, 2012; 2(1): 693-699.
45. Gaebler F: Laser drilling enables advanced drug delivery systems, Coherent article for Pharmaceutical Manufacturing, Jan-2007: 1-7.
46. Theeuwes F, Saunders RJ, Mefford WS: Process for forming outlet passageways in pills using a laser. US Patent 4088864; 1978.
47. Yang X, Zhang G, Wei LI, Peng B, Liu Z, Pan W: Design and Evaluation of Monolithic Osmotic Pump Tablet. Chemical and Pharmaceutical Bulletin, 2006; 54(4): 465-469.
48. Wakode R, Bajaj A, Bhanushali R: Monolithic Osmotic Tablets for Controlled Delivery of Antihypertensive Drug. Journal of Pharmaceutical Innovation, 2009; 4: 63-70.
49. Gupta R, Gupta R, Basniwal PK, Rathore GS: Osmotically Controlled Oral Drug Delivery System, International Jouranl of Pharmaceutical Sciences, 2009; 1(2): 269-275.

50. Zentner GM, Rork GS and Himmelstein KJ: The Controlled Porosity Osmotic Pump. Journal of Controlled Release. 1985; 1: 269-282
51. Zentner GM, Rork GS, Himmelstein KJ: Osmotic flow through controlled porosity films: An approach to delivery of water soluble compounds. Journal of Controlled Release, 1985; 2: 217-229
52. Zentner GM, Rork GS, Himmelstein KJ: Controlled porosity osmotic pump. US Patent 4968507; 1990.
53. Jerzewski R, Chien Y: Osmotic drug delivery. In: Treatise on controlled drug delivery: Fundamentals, optimization, Application. Marcel Dekker, 1992; 225-253.
54. Prescott L F: The need for improved drug delivery in clinical practice, In: Novel Drug Delivery and Its Therapeutic application, John Wiley and Sons, West Susset, UK, 1989, 1-11.
55. Jensen JL, Appel LE, Clair JH, Zentner GM: Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes, Journal of Pharmaceutical Sciences, 1995; 84(5): 530-533.
56. Reza MS, Quadir MA and Haider SS: Comparative evaluation of plastic, hydrophobic and hydrophilic polymers as matrices for controlled-release drug delivery.J Pharm Pharm Sci. 2003;6(2):282-291.
57. Wright JC, Johnoson RM, Yum SI: DUROS® Osmotic Pharmaceutical Systems for Parenteral & Site-Directed Therapy.
58. Reddy DP, Swarnalatha D.: Recent Advances in Novel Drug Delivery systems. International Journal of Pharm Tech Research, 2010; 2(3): 2025–2027.
59. Lu xu Sanming, Hisakazu L: Preparation and evaluation in vitro and in vivo of Captopril elementary osmotic pump tablets. Asian Journal of Pharmaceutical Sciences, 2006; 1: 236-245.
    

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    How to cite this article:

    Mathur M and Mishra R: A Review on Osmotic Pump Drug Delivery System. Int J Pharm Sci Res 2016; 7(2): 453-71.doi: 10.13040/IJPSR.0975-8232.7(2).453-71.

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