A Review: Recent Scenario on Osmotic Controlled Drug Delivery System

 

Ravikant S. Murkute*, R. S. Wanare, Krishna J. Dongre

Department of Pharmaceutics Shudhakarrao Naik Institute of Pharmacy, Pusad Dist. Yavatmal Maharashtra (India)

*Corresponding Author E-mail: Ravikant.murkute@gmail.com

 

The immediate release conventional dosage form lack in the efficiency of controlling the proper plasma drug concentration. This results in the development of various controlled drug delivery system. Osmotic drug delivery systems are new approach for a controlled release dosage form. Various patents available for osmotic drug delivery system like Rose-Nelson pump, Higuchi-Leeper pump, Higuchi Theeuwes pump, Elementary Osmotic Pump etc. Among which the Pulsatile drug delivery systems (PDDS)/ osmotic controlled drug delivery system (OCDDS) are gaining importance as these systems deliver the drug at specific time as per the path physiological need of the disease, resulting in improved patient therapeutic efficacy and compliance. They work on the principle of osmotic pressure for controlling the delivery of the drug. The main clinical benefits of OCDDS are their ability to improve treatment tolerability and patient compliance. These advantages are mainly driven by the capacity to deliver drugs in a sustained manner, independent of the drug chemical properties, of the patient’s physiological factors or concomitant food intake. OCDDS are useful for poorly soluble drug, for pulsatile drug release and zero order release. Various techniques available for preparation of OCDDS include push pull osmotic Pump, osmotic Bursting osmotic pump, liquid oral osmotic system, sandwiched osmotic tablets (SOTS), delayed delivery osmotic device,  and controlled porosity osmotic Pump. This review highlights’ the theoretical concept of drug delivery, history, types of oral osmotic drug delivery systems, advantages and disadvantages of this delivery systems , theoretical aspects, applications, marketed status and last but not the least the recent development.

 

 

INTRODUCTION:

For many decades 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 popular as the 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 effective concentration at the target site. The bioavailability of drug from these formulations may vary significantly, depending on factors such as physico-chemical properties of the drug, presence of excipients, various physiological factors such as the presence or absence of food, pH of the GI tract, GI motility, etc⁽¹⁾. To overcome this limitation of oral route is replied by parenteral route.

 

Received on 23.02.2012          Modified on 06.04.2012

Accepted on 07.05.2012         © RJPT All right reserved

 

This route offers the advantage of reduced dose, targeting of site and avoiding GI stability, hepatic by-pass of drug molecule.

 

In the recent years, pharmaceutical research has led to the development of several novel drug delivery systems. The role of drug development is to take a therapeutically effective molecule with sub-optimal physicochemical and/or physiological properties and develop an optimized product that will still be therapeutically effective but with additional benefits such as ⁽²⁾

·         Sustained and consistent  blood levels within the therapeutic window

·         Enhanced bioavailability

·         Reduced interpatient variability

·         Customized delivery profiles

·         Decreased dosing frequency

·         Improved patient compliance

·         Reduced side effects

The drug release can be modulated by different ways but the most of novel drug delivery systems are prepared using matrix, reservoir or osmotic principle. In matrix systems, the drug is embedded in a polymer matrix and the release takes place by partitioning of drug into the polymer matrix and the surrounding medium. In contrast, reservoir systems have a drug core surrounded by a rate controlling membrane. The osmotic systems utilize the principles of osmotic pressure for the delivery of drugs in both the routes oral as well as parenteral⁽³⁾.

 

OSMOSIS

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. Osmotic pressure is the pressure which, if applied to the more concentrated solution, would prevent transport of water across the semipermeable membrane.

 

The first osmotic effect was reported by Abbe Nollet in 1748. Later in 1877, Pfeffer performed an experiment using semi-permeable membrane to separate sugar solution from pure water. He showed that the osmotic pressure of the sugar solution is directly proportional to the solution concentration and the absolute temperature. In 1886, Vant Hoff identified an underlying proportionality between osmotic pressure, concentration and temperature. He revealed that osmotic pressure is proportional to concentration and temperature and the relationship can be described by following equation.

 

   …………………..      (1)

 

Where,  

 π = osmotic coefficient

n₂ = molar concentration of solute in the solution

R = gas constant            

T = Absolute temperature

 

Osmotic pressure is a colligative property, which depends on concentration of solute that contributes to osmotic pressure. 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 ⁽⁴⁾.

 

OSMOTIC CONTROLLED DRUG DELIVERY SYSTEMS

Osmotic pressure is used as driving force for these systems to release the drug in controlled manner. Osmotic drug delivery technique is the most interesting and widely acceptable among all other technologies used for the same. Intensive research has been carried out on osmotic systems and several patents are also published. Development of osmotic drug delivery systems was pioneered by Alzaand it holds major number of the patents analysed and also markets several products based on osmotic principle. These systems can be used for both route of administration i.e. oral and parenteral. Oral osmotic systems are known as gastro-intestinal therapeutic systems (GITS). Parenteral osmotic drug delivery includes implantable pumps.

 

HISTORIC BACK GROUND

The Rose Nelson pump

About 75 years after discovery of the osmosis principle, it was first used in the design of drug delivery systems⁽⁵⁾. Rose and Nelson, the Australian scientists, were initiators of osmotic drug delivery. They were interested in delivery of drugs to the gut of sheep and cattle.  In 1955, they developed an implantable pump, which consisted of three chambers: (Fig.1).

·         A drug chamber with an orifice.

·         A salt chamber with elastic diaphragm containing excesssolid salt.

·         A water chamber.

 

The salt and water chamber are separated by a rigid semi permeable membrane. The difference in osmotic pressure acrossthe membrane moves water from the water chamber into saltchamber. The volume of the salt chamber increases because of this water flow, which distends the latex diaphragm separating saltand drug chamber there by pumping drug out of this device.

 

Thepumping rate of Rose-Nelson pump is given by the equation:

 

  ……………………. (2)

 

Where; = Drug release rate.

= Volume flow of water into salt chamber.

c = Concentration of drug into drug chamber.

 

Figure 1.Rose-Nelson Pump

Higuchi Leeper pump

The design of Higuchi Leeper pump described in thefig.2 represents the first simplified version of the Rose Nelsonpump made by the Alza Corporation in the early 1970. The benefit of this pump over Rose Nelson pump is that it does not have waterchamber and the device is activated by water imbibed from the surrounding environment.This means the pump is first preparedand then loaded with the drug and then store for weeks or months prior to use.

 

Figure 2: Higuchi-Leeper Pump

Higuchi- Theeuwes pump

In the early 1970, Higuchi – Theeuwes developed a similarform of Rose Nelson pump as shown the figure 3. The semipermeable wall itself acts as a rigid outer casing of the pump.Thedevice is loaded with drug prior to use. When thedevice is put in an aqueous environment the release of the drugfollows a time course set by the salt used in the salt chamber andthe permeability of the outer membrane casing.

 

 

Figure 3 .Theeuwes miniature osmotic pump

 

Apart from oral osmotic pumps, the development of miniature implantable osmotic pumps in the mid-1970s was a major breakthrough to deliver wide range of drugs and hormones, including peptides at constant and programmed rate in mice, rat and larger animals. These implants provide a convective stream of drug solution that can be directed through suitable catheter connections to sites in the animal remote from itself⁽⁷⁾.Most recently the implantable pumps for human use are developed to deliver the drug for targeting or systemic application.

 

Some of the development in the osmotic controlled drug delivery system is given in the table No. 1⁽⁶⁾.

Table No. 1
Year	Comment	Ref.
1748	First report of osmosis	(Banker, 1987).
1877	Quantitative measurement of osmotic pressure	(AMartin.,1993)
1955	First osmotic pump by Rose-Nelson developed for pharmaceutical research	(Rose etal,1995)
1973	Higuchi- Leeper introduced a new version of Rose-Nelson pump with certain modification	(Santus et al,1995)
1973	Osmotically powdered agent dispense device with filling means	(Theeuwes,1984)
1975	Introduced the first oral osmotic pump i.e. EOP. It was the major mile stone in the field of oral osmotic drug delivery system.	(Cortese et al,1982)
1976	Patent granted on the design of Alzet osmotic pumps which later extensively used as an experimental research tool in laboratory animal.	(Theeuwes et al, 1984)
1979	Osmotic bursting drug delivery device.	(Chein et al,1984)
1982	Patent issue for an osmotic system which consist of a layer of a fluid swellable hydrogel to deliver insoluble to very soluble drug.	(Corteses, et al,1984)
1984	First report of combination therapy by use of push pull osmotic pump.	(Theeuwes et al, 1984)
1985	Controlled porous osmotic pump was developed from which drug is leached out from the coating, eliminating the need of complicated laser drill procedure.	(Zentner et al,1991)
1986	Patent issue claiming a delivery system for controlled administration of drug to ruminants.	(Mishra et al,2006)
1989	Developed of Push Pull osmotic pump of Nefedipine (Procardia XL) by Pfizer which was the largest selling cardiovascular product in US market until 1995	(Mishra et al,2006)       (Wilson et al,2000)
1995	Patent to an osmotic dosage form for liquid drug delivery. The system consists of an outside semi permeable wall, middle osmotic active layer, capsule containing an active agent and an orifice for delivery of the agent.	(Mishra et al,2006)
1999	Asymmetric membrane capsule is introduced to deliver the drug through the osmotic pressure.	(Mishra et al, 2006)
2000	DUROS Leurpolid implants i.e. Viadur approved as first implantable osmotic pump for human by US FDA.	(Mishra et al, 2006)
2001	Patent granted for dosage form comprising liquid drug formulation that can self-emulsify to enhance the solubility, dissolution, AND bioavailability of drug.	(Mishra et al, 2006)
2003	First report osmotic floating system.	(Mishra et al, 2006)

THEORETICAL ASPECT⁽⁶⁾

The polymer membrane is not only semi permeable in nature but is also rigid and capable of maintaining the structural integrity of the gastrointestinal delivery system during the course of drug release because of its semi permeable nature, it is permeable to the influx of water in the gastrointestinal tract, on the other hand it is permeable to drug solute. When it is in use, water is continuously get absorbed into the drug reservoir compartment through the semi permeable membrane to dissolve the osmotically active drug and/or salt .A gradient of osmotic pressure is thus created, under which the drug solute are continuously pumped out over a prolonged period of time through the delivery orifice at arate define by the following equation:

 

Pw = Water permeability.

Am = Effective Surface area.

hm = Thickness of the semi permeable membrane.

πs = Osmotic pressure of the saturated solution of the osmotically active drug or salt.

πc = Osmotic pressure of G.I. Fluid.

Sp = Solubility of the drug.

 

The equation no. 3 follows zero order drug release from the OCDDS. In represent to the equation no. 3 a non-zero order release pattern can be described by the equation no. 4

 

Where

(Q/t) z = Zero order drug release.

vt= Total volume of the drug reservoir compartment.

tz = Total time length in which the system delivers the drug at azero order rate.

tr = Duration of residence time.

 

The rate of drug release can further be explain by the help of the Rose Nelson equation as given below

 

Where

dm/dt = Solute delivery rate

 

As the delivery orifice increases, hydrostatic pressureinside the system is minimized as expressed by the conditionΔπ>Δp. When the osmotic pressure of the formulation (π) is larger compared to the osmotic pressure of the environment π can be substituted from the equation no. 6 then it can be reduced to much similar expression in which the constant K replaces the Lp^σ so we get

 

 

In case of zero order drug delivery rate the release rate from the elementary osmotic pump is zero when t=0 until a time tz at which the time all the solid in the core has dissolved and it is described by

 

Where S = solubility           

πs = Osmotic pressure at a saturation.

 

Nonzero order drug release rate:-The non-zero order drug release rate from the system (e.q.6) is obtained by the describing the concentration as the rate of time .For simplification the volume flush into the system is replaced by the symbol F:

 

The non-zero order release rate can also be explain by thehelp of the following equation

 

[1+1/SV (dm/dt) z (t- tz)] ²

 

ADVANTAGES AND DISADVANTAGES OF OCDDS

ADVANTAGES

There are various no of advantages of OCDDS which have been listed below^{(8, 9, 10)}

     Decrease frequency of dosing.

     Reduce the rate of rise of drug concentration in the body.

     Delivery may be delayed or pulsed if required.

     Delivery ratio is independent of pH of the environment.

     Delivery is independent of hydrodynamic condition, this suggest that drug delivery is independent of G.I. motility.

     Sustained and consistence blood level of drug within the therapeutic window.

     Improve patient compliance.

     High degree of in vitro- in vivo correlation is obtained in osmotic system.

     Reduce side effect.

     Delivery rate is also independent of delivery orifice size within the limit.

 

DISADVANTAGE AND LIMITATION

OCDDS have produced significant clinical benefit in various therapeutic areas. Some systems have enhanced patient compliance, while other has minimized the side effect of their active compounds. However some limitations of OCDDS have been reported^{(8, 9, 10)}.

     Slightly higher cost of good than matrix tablet or multi particulates ion capsule dosage form.

     Gastro intestinal obstruction cases have been observed with the patient receiving Nifedipine GITS tablet.

     Another case was reported for osmosin (Indomethacin OROS) which was first introduced in the United Kingdom in 1983.A few months later after its introduction requent incidences of serious gastrointestinal reaction was observed leading to osmosin withdrawal. Various explanations were given based on the toxic effect of KCl used in osmosin.

     Magnetic resonance imaging (MRI) of tablet elucidates that non uniform coating leads to different pattern of drug release among the batches.

 

BASIC COMPONENTS OF OSMOTIC CONTROLLED DRUG DELIVERY SYSTEMS

a)Drug:

     Criteria for selection of a drug:

     Short biological Half-life (2- 6 hrs)

     High potency

     Required for prolonged treatment

(e.g: Nifedipine, Glipizide, Verapamil and Chlorpromazine hydrochloride).

 

Vyas.P. et al (2004) developed an oral osmotic system which can deliver theophylline and salbutamol sulphate simultaneously for extended period of time and characterized it. An optimized system was selected to study the effect of concentration of pore forming agents and orifice diameter on the release of the drugs. The release profiles of both drugs were satisfactory when compared with marketed controlled release formulations⁽¹¹⁾. Various drug candidates such as Diltiazem HCl, Carbamazepine, Metoprolol, Oxprenolol, Nifedipine, Glipizide etc are formulated as osmotic delivery.

 

b) Semipermeable membrane:

An important part of the osmotic drug delivery system is the semipermeable membrane housing. Therefore, the polymeric membrane selection is key to the osmotic delivery formulation. The membrane must possess certain performance criteria such as⁽¹²⁾

     Sufficient wet strength and water permeability

     Should be biocompatible

     Rigid and non-swelling

     Should be sufficient thick to withstand the pressure within the device.

 

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⁽¹³⁾.

 

c) Osmotic agent

Osmotic agents maintain a concentration gradient across the membrane. They also generate a driving force for the uptake of water and assist in maintaining drug uniformity in the hydrated formulation. Osmotic components usually are ionic compounds consisting of either inorganic salts or hydrophilic polymers. Osmotic agents can be any salt such as sodium chloride, potassium chloride, or sulphates of sodium or potassium and lithium.

 

Additionally, sugars such as glucose, sorbitol, or sucrose or inorganic salts of carbohydrates can act as osmotic agents. The polymers may be formulated along with poly(cellulose), osmotic solutes, or colorants suchas ferric oxide. Swellable polymers such aspoly(alkylene oxide), poly(ethylene oxide), and poly (alkali carboxymethylcellulose) are also included in the push layer of certain osmotic systems. Further, hydrogels such as Carbopol (acidic carboxypolymer),Cyanamer (polyacrylamides), and Aqua-Keeps (acrylatepolymer polysaccharides composed of condensed glucose units such as diester cross-linked polygluran) may be used.

 

d)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 polyethylene glycols (300 to6000 Da), polyhydric alcohols, polyalkylene glycols, and the like improve the flux, where as hydrophobic materials such as phthalates substituted with an alkyl or alkoxy (e.g., diethylphthalate or dimethoxyethylphthalate) tend to decrease the flux. Insoluble salts or insoluble oxides, which are substantially water-impermeable materials, also can be used for this purpose ⁽¹⁴⁾.

 

e)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 nature. 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 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⁽¹⁵⁾. Materials, which suitably for act as wicking agents include colloidal silicon dioxide, kaolin, titanium dioxide, alumina, niacinamide, sodiumlauryl sulphate (SLS), low molecular weight polyvinyl pyrrolidone (PVP), m-pyrol, bentonite, magnesium aluminium silicate, polyester and polyethylene.

 

f) 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 micro porous membrane. The micro porous 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, and mannitol and, diols and polyols such as poly hydricalcohols and polyvinyl pyrrolidone can be used as pore forming agents.

 

g)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. Themixtures of solvents such as acetone-methanol (80:20), acetone-ethanol (80:20), acetone-water(90:10), methylene chloride-methanol (79:21), methylene chloride-methanol-water (75:22:3) etc. can be used ⁽¹⁶⁾.

 

h) Plasticizers

Different types and amount of plasticizers used in coating membrane also have a significant importance in the formulation of osmotic systems. They can change visco-elastic behaviour of polymers and these changes may affect the permeability of the polymeric films⁽¹⁴⁾. Some of the plasticizers used are as below:

     Polyethylene glycols

     Ethylene glycol monoacetate; and diacetate- for low permeability

     Tri ethyl citrate.

     Diethyl tartarate or Diacetin- for more permeable films.

 

CLASSIFICATION

Many forms of osmotic pumps are reported in the literature but, in general they can be divided in oral and implantable systems. The OCDDS can be conveniently classified in to following types:

A. Oral Osmotic Drug Delivery Systems

a) Single chamber osmotic pump

1.     Elementary osmotic pump

2.     Controlled porosity osmotic pump.

3.     Osmotic bursting osmotic pump.

b) Multi chamber osmotic pump

1.     Push pull osmotic pump.

2.     Osmotic pump with non-expanding second chamber.

3.     Sandwichosmotic tablets (SOTS)

c) Oral osmotic capsules

1. OROS – CT

2. Liquid Oral Osmotic System (L-OROS)

3. Multi particulate delayed release systems (MPDRS)

4. Telescopic Capsule for Delayed Release

 

B. Implantable OsmoticDrug Delivery System

1.DUROS osmotic pump

2.Alzet osmotic pump

A. Oral Osmotic Drug Delivery Systems

a) Single chamber osmotic pump

1. Elementary osmotic pump (EOP)

It was developed in the year 1975 by The euwes. The EOP consist of single layered tablet core containing a water soluble drug with or without other osmotic agent (figure no. 4).A semi permeable membrane surrounds the tablet core. When such a system is swallowed water from the GIT enter through the membrane in the core, the drug dissolved and the drug solution is pumped out through the exitorifice. This process continues at a constant rate until the entire solid drug inside the tablet has been dissolved drug continues to be delivered but at a declining rate until the osmotic pressure between outside environment and saturated drug solution. Normally the EOP delivers 60 - 80% of its content at a constant rate and there is a short lag time of 30- 60 min as the system hydrates before zero order drug release from the EOP is obtained. The disadvantages of the elementary pump are that it is only suitable for the delivery of water soluble drugs⁽¹⁷⁾.

 

Figure4: Elementary osmotic pump

 

2. Controlled porosity osmotic pump (CPOP)

Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channelling agents in the coating as in figure no. 5. The CPOP contains water soluble additives in coating membrane, which after coming in contact with water; dissolve resulting in an in-situ formation of a microporous membrane. Then the resulting membrane is substantially permeable to both water and dissolved solutes and the mechanism of drug release from this system was found to be primarily osmotic, with simple diffusion playing a minor role.

 

Drug delivery from asymmetric membrane capsule is principally controlled by the osmotic pressure of the core formation. In-situ formed delivery orifice in the asymmetric membrane in mainly responsible for the solubilisation in the core for a drug with poor water solubility⁽¹⁸⁾.

 

CPOP is an attempt to circumvent the need for a laser or mechanical drilled orifice. In CPOP the orifice through which drug is released are formed by incorporation of a leachable water soluble component in the coating material.

The rate of flow dv/dt of water into the device can be represented as

 

Where;

k = Membrane permeability

A = Area of the membrane

Dp= Osmotic pressure difference

DR = Hydrostatic pressure difference

h = Thickness of the membrane

 

The CPOP has an advantage as drug is released from the whole surface of device rather than from the single hole which may reduce stomach irritation problem. Hole is formed by a coating procedure hence complicated laser drilling is not required and the tablet can be made as very small by using drug pills coated by appropriate membrane.

 

Figure 5:Controlled porosity osmotic pump

 

3. Osmotic bursting osmotic pump

This system is similar to an EOP expect delivery orifice is absent and size may be smaller. When it is placed in an aqueous environment, water is imbibed and hydraulic pressure is built up inside until the wall rupture and the content are released to the environment. Varying the thickness as well as the area the semi permeable membrane can control release of drug. This system is useful to provide pulsated release. Osmotic bursting osmotic pump is shown in figure no. 6.

 

Figure 6: Osmotic bursting osmotic pump

 

b)  Multi chamber osmotic pump

1.     Push pull osmotic pump

Push pull osmotic pump is a modified EOP through which it is possible to deliver both poorly water-soluble and highly water soluble drugs at a constant rate. This system resembles a standard bilayer coated tablet. Push pull osmotic pump is shown in figure no. 7.  One layer (depict as the upper layer) contains drug in a formulation of polymeric, osmotic agent and other tablet excipients. This polymeric osmotic agent has the ability to form a suspension of drug in situ. When this tablet later imbibes water, the other layer contains osmotic and colouring agents, polymer and tablet excipients. These layers are formed and bonded together by tablet compression to form a single bilayer core. The tablet core is then coated with semi permeable membrane. After the coating has been applied, a small hole is drilled through the membrane by a laser or mechanical drill on the drug layer side of the tablet. Whent he 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. PPOP has a disadvantage that the complicated laser drilling technology should be employed to drill the orifice next to the drug compartment.

 

Figure 7: Push pull osmotic pump

 

2.             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 one category of these devices, the second chamber is used to dilute the drug solution leaving the devices. This is useful because in some cases if the drug leaves the oral osmotic devices a saturated solution, irritation of GI tract is a risk. Example: The problem that leads to withdrawal of osmosin, the device consists of a normal drug containing porous tablet from which drug is released as a saturated solution. However before the drug can escape from the device it must pass through a second chamber. Water is also drawn osmotically into this chamber either because of osmotic pressure of drug solution or because the second chamber contain, water soluble diluents such as NaCl. This type of devices consist of two rigid chamber, the first chamber contains a biologically inert osmotic agent, such as sugar or a simple salt like sodium chloride, the second chamber contains the drug. In use water is drawn into both the chamber 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

 

c) Oralosmotic capsules.

1.     OROS – CT

OROS-CT (Alza corporation) is used as a once or twice a day formulation for targeted delivery of drugs to the colon⁽¹⁹⁾. 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 (as in Figure no. 8).After coming in contact with the gastric fluids, gelatin capsule dissolved and the enteric coating prevents entry of fluids from stomach to the system as the system enters into the small intestine the enteric coating dissolves and water is imbibed into the core thereby causing the push compartment toswell. At the same time flow able gel is formed inthe drug compartment, which is pushed out of the orifice at a r of water transport across the semipermeable membrane. Incorporation of the cyclodextrin-drug complex has also been used as an approach for delivery of poorly water soluble drugs from the osmotic systems. Ex. Sulfobutylether-βcyclodextrin sodium salt serves as a solubilizer and osmotic agent.

 

Figure 8: OROS-CT

 

2.     Liquid Oral Osmotic System(L-OROS)

To overcome the drug solubility issue Alza developed the L-OROS system where the liquid soft gelatin product containing the drug in a dissolved state is initially manufactured and then coated with a barrier membrane, then the osmotic push layer and then semi permeable membrane containing a drilled orifice as shown in figure no. 9. Liquid OROS are designed to deliver drugs as liquid formulations and combine the benefits of extended release with high bioavailability ⁽²⁰⁾.

They are of three types: -

1. L- OROS hard cap,

2. L- OROS soft cap

3. Delayed liquid bolus delivery system

 

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. Whereas L-ORO Shard cap or soft cap systems are designed to provide continuous drug delivery, the L-OROS delayed liquid bolus drug delivery system is designed to deliver a pulse of liquid drug. 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 1 to 10 hour, depending on the permeability of the rate controlling membrane and thickness of the placebo layer ⁽²¹⁾.

 

Figure 9:Durososmotic pump

Liquid Oral Osmotic System(L-OROS)

 

3.Multi particulate delayed release systems (MPDRS)

MPDRS consist of pellets comprises of drug with or without osmotic agent, which are coated with a semipermeable membrane. When this system comes in contact with the aqueous environment, water penetrates in the core and forms a saturated solution of soluble component^{(22, 23)}. The osmotic pressure difference results in rapid expansion of the membrane, leading to the formation of pores. The osmotic agent and the drug released through the pores according to zero order kinetics. The lag time and dissolution rate were found to be dependent on the coating level and the osmotic properties of the dissolution medium.

 

B. Implantable Osmotic Drug Delivery System

1.Duros osmotic pump

More recently, osmotic principles have been applied to human parenteral therapy, resulting in the development of the DUROS® technology. These technologies allow drug delivery for site-specific as well as systemic use for delivery periods of days to 1 year.^{(24, 25)}Duros osmotic pump is shown in the figure no.10.

 

Mechanism: Through osmosis, water from the body is slowly drawn through the semi-permeable membrane into the pump by osmotic agent residing in the engine compartment, which expands the osmotic agent and displaces a piston to dispense small amounts of drug formulation from the drug reservoir through the orifice.

 

Figure 10: Duros osmotic pump

Compounds delivered using DUROS^® Technology

DUROS^® 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.

 

2.Alzet osmotic pump

ALZET osmotic pumps are miniature, implantable pumps used for research in mice, rats, and other laboratory animals. 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. Their unattended operation eliminates the need for repeated night time or weekend dosing ⁽²⁶⁾.

 

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. Due to the presence of a high concentration of salt in a chamber surrounding the reservoir (but isolated from it by an impermeable layer), water enters the pump through its outer surface (a semipermeable 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(as in Figure no. 11).

 

ALZET pumps can be used for systemic administration when implanted subcutaneously or intraperitoneal. They can be attached to a catheter for intravenous, intracerebral, or intra-arterial infusion. ALZET pumps can also be used for targeted delivery, where the effects of a drug or test agent are localized in a particular tissue or organ, by means of a catheter. The pumps have been used to target delivery to a wide variety of sites including the spinal cord, spleen, liver, organ or tissue transplants, and wound healing sites.

ALZET pumps have been used successfully to deliver hundreds of different compounds, including antibodies, chemotherapeutic drugs, cytokines, growth factors, hormones, and Peptide.

 

Figure 11: Alzet osmotic pump

 

RECENT TRENDS ⁽⁶⁾

1. Sandwiched osmotic tablet (SOT)

It 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 and thus SOTS can be suitable for drugs prone to cause local irritation of the gastric mucosa ⁽²⁷⁾.Sandwiched osmotic tablet and its operation to deliver the drug is shown in figure no. 12.

 

Figure 12: Sandwiched osmotic tablet

 

2.Telescopic Capsule for Delayed Release

This device consists of two chambers, the first contains the drug and an exit port, and the second contains an osmotic engine. A layer of wax like material separates the two sections. To assemble the delivery device, the desired active agent is placed into one of the sections by manual or automated fill mechanism. The bilayer capsule with the osmotic engine is placed into a completed cap part of the capsule with the convex osmotic layer pointed in to the closed end of the cap and the barrier into the closed end of the cap and the barrier layer exposed towards the cap opening. The open end of the filled vessel is fitted inside the open end of the cap, and the two pieces are compressed together until the cap, osmotic bilayer tablet and vessel fit together tightly as shown in figure no. 13. As fluid is imbibed the housing of the dispensing device, the osmotic engine expand and exerts pressure on the slid able connected first and second wall sections. During the delay period the volume of reservoir containing the active agent is kept constant, therefore an eligible pressure gradient exists between the environments of use and interior of the reservoir. As a result, the net flow of environmental fluid driven by the pressure enter the reservoir is minimal and consequently no agent is delivered for the period.

 

Figure 13: Telescopic capsule

 

Pulsatile delivery based on expandable orifice

Patent 5318558 (1994) and 5221278 (1993) assigned to Alza claim the pulsatile delivery of agent from osmotic systems based on the technology of an expandable orifice. The system is in the form of capsule from which the drug is delivered by the capsule’s osmotic infusion of moisture from the body. The delivery orifice opens intermittently to achieve a pulsatile delivery effect. The orifice formed in the capsule wall,which is constructed of an elastic material. As the osmotic infusion progresses, pressure rises within the capsule causing the wall to stretch. The orifice is small enough so that when the elastic wall relaxes, the flow of the drug through the orifice essentially stops, but when the elastic wall stretches beyond the threshold because of increase of pressure, the orifice expands sufficiently to allow the drug to be release at a required rate. Elastomers such as Styrene- Butadiene copolymer can be used.

 

Pulsatile delivery by a series of stops

Patent 5209746 also assigned to Alza described an implantable capsule for pulsatile delivery. The capsule consists of drug and absorptive osmotic agent engine that are each placed in the compartments separated by a movable partition. Pulsatile delivery is achieved by a series of stop along the inner wall of the capsule. These stop obstruct the movement of the partition but overcome in succession as the osmotic pressure rises above the threshold level. The no of stops and the longitude in alplacement of the stops along the length of the capsule dictate the number and frequency of pulses and the configuration of the partition control the pulse intensity. Reports document that Porcinesomato tropine has been delivered by this system.

 

Miscellaneous devices

Patent 6352721 (2002) assigned to Osmotic a Corporation (Tortola, British Virgin Islands) report a combined diffusion osmotic pump drug delivery system. The device has a centrally located expandable core that is completely surrounded by active substances-containing layer, which is completely surrounded by a membrane. The core consists of an expandable hydrophilic polymer and an optional osmogen. The composition is completely surrounding the core comprises active substances, an osmogent and an osmopolymer. The membrane is micro porous in nature and may have a delivery orifice. The device is capable of delivering insoluble, slightly soluble, sparingly soluble and very soluble drug to the environment.

 

Figure 14: Miscellaneous device

 

PATENTS ON OSMOTIC DRUG DELIVERY SYSTEM

The patent on osmotic drug delivery system is given in the Table No. 2, 3AND 4⁽⁶⁾.

 

Table no. 3.  Patent of drug formulation in the form of Multi chamber osmotic pump
Year	US Patent No.	Drug
1986	4612008	Diclofenac sodium
1988	4765989	Nifedipine and α blocker
1988	4783337	Calcium antagonist, ACE inhibitor
1989	4812263	Isadipine
1989	4837111	Doxazocin
1989	4859470	Diltiazem
1990	4904474	Beclomethasone
1990	4948593	Contraceptive Steroid
1991	5024843	Glpizide
1991	5028434	Nivadipine
1992	5160744	Verapamil
1992	5091190	Glipizide
1993	5185158	Tandospirone
1993	5192550	Antiparkinsons drug
1993	5248310	Beclomethasone(oral)
1996	5545413	Glipizide
1997	5591454	Glipizide
2003	20030224051	Oxycodone
2004	20040091529	Topiramine
2005	20050232995	Resperidone and Paliperidone

 

VARIOUS DRUGSAVAILABLE IN MARKET WITH OSMOTIC DRUG DELIVERY SYSTEM:

Various drugs available in market with osmotic drug delivery system is given in the Table no. 5⁽⁶⁾

 

CONCLUSIONS

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 by the biotechnology industry, 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.     L.F. Prescott. The need for improved drug delivery in clinical practice, In: Novel Drug Delivery and Its Therapeutic application, John Wiley and Sons, West Susset, U.K., 1-11; 1989.

2.     Dr. P.P. Bhatt. Osmotic drug delivery systems for poorly water soluble drugs, Pharmaventures Ltd., Oxford, UK, 26-29; 2004.

3.     R.K. Verma, D. M. Krishna and S. Garg. Review article on Formulation aspects in the development of osmotically controlled oral drug delivery systems, J. Control. Release, 79, 7-27; 2002.

4.     X. Li and B.R. Jasti. Osmotic controlled drug delivery systems, In: Design of controlled release of drug delivery systems, McGraw Hill, 203-229; 2006.

5.     Rose S, Nelson JF. A continuous long-term injector. Aust J ExpBiol, 1955; 33:415

6.     TanmoyGhosh, AmitavaGhosh, drug delivery through osmotic systems– an overview, Journal of Applied Pharmaceutical Science 01 (02); 2011: 38-49.

7.     F. Theeuwes and S.I. Yum. Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid formulations, Ann. Biomed. Eng., 4, 343-53; 1976.

8.     Brahma P Gupta, Navneet Thakur, Nishi P Jain, Jitendra Banweer, Surendra Jain, Osmotically Controlled Drug Delivery System with Associated Drugs, J Pharm Pharmaceut Sci  13(3) 571 - 588, 2010.

9.     Fix J, In: Encyclopedia of controlled drug delivery, Edmathiowitz, vol-2, John Wiley and sons, Inc 700.

10.   Kaushal A M and Garg S; An update on osmotic drug delivery patents, Pharm Tech. Aug 2003; 38-44.

11.   Suresh Vyas P., Prabakaran D., Paramjit Singh, ParijatKanaujia, Jaganathan K.S., AmithRawat. Modified push-pull osmotic system for simultaneous delivery of Theophylline and Salbutamol: development and in vitro characterization. Int. J. Pharm. 2004; 284: 95-108.

12.   Eckenhoff B, Theeuwes F, Urquhart J. Osmotically actuated dosage forms for rate-ocontrolleddrugdelivery. Pharm Technol 1987; 11, 96–105.

13.   Jensen JL, Appel LE, Clair JH, Zentner G. M. Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes. J PharmSci, 1995; 84(5) 530-533.

14.   SrikondaSastry, KotamrajPhanidhar, Barclay Brian, Osmotic controlled drug delivery system, in Li Xiaoling, JastiBhaskara R (eds), Design of Controlled Release Drug Delivery Systems, McGraw-Hill Companies, INC, New York, 203-229, 2006.

15.   Mahalaxmi R, Sastri P, kumar R, Kalra A, KanagaleP, Narkhede. Enhancement of Dissolution ofGlipizide from Controlled Porosity Osmotic Pump Using a Wicking Agent and a Solubilizing Agent. Int J PharmTech Res, 2009; 1: 3:705-711.

16.   Vyas, S.P.; Khar, R.K., Controlled drug delivery: concept and advances. VallabhPrakashan, NewDelhi, 477-501, 2001.

17.   Theeuwes, F. Elementary Osmotic Pump, Journal of Pharmaceutical Science, 1975; 64:1987-1991.

18.   CH. Ajay Babu, M. Prasada Rao and, Vijaya Ratna J., controlled-porosity osmotic pump tablets-an overview, JPRHC Jan-2010 Vol. 2 Issue 1 114-126.

19.   Theeuwes F, Wong P S L, Burkoth T L and Fox D A; Osmotic systems for colon-targeted drug delivery. In: Colonic drug absorption and metabolism. Marcel Dekker, NY, 1993; 137-158.

20.   L. Dong, K. Shafi, J. Wan, P. Wong, A novel osmotic delivery system: L-OROS Softcap, in: Proceedings of the International Symposium on Controlled Release of Bioactive Materials, Paris (July), 2000, CD ROM.

21.   L. Dong, P. Wong, S. Espinal, L-OROS HARDCAP: A new osmotic delivery system for controlled release of liquid formulation, in: Proceedings of the International Symposium on Controlled Release of Bioactive Materials, San Diego (June), 2001, CD-ROM.

22.   P. Schultz, P. Kleinebudde, A new multiparticulate delayed release system. Part I. Dissolution properties and release mechanism, J. Control. Release 47 (1997) 181–189.

23.   P. Schultz, I. Tho, P. Kleinebudde, A new multiparticulate delayed release system. Part II. Coating formulation and properties of free films, J. Control. Release 47 (1997) 191–199.

24.J.C. Wright, R.M. Johnoson and S.I. Yum. DUROS® Osmotic Pharmaceutical Systems for Parenteral AND Site-Directed Therapy, http://www.drugdeliverytech.com.

25.   J.C. Wright, C.L. Stevenson, G.R. Stewart, Pumps /osmotic- DUROS osmotic implant for humans, in: E. Mathiowitz (Ed.), Encyclopedia of Controlled Drug Delivery, Vol. 2, Wiley, New York, 1999, pp. 909–915.

26.   http://www.alzet.com

27.   Zentner G M, Rork G S and Himmelstein K J; Osmotic flow through controlled porosity films: An approach to delivery of water soluble compounds. J Control Release. 1985; 2, 217-229.

 

 

Received on 25.02.2012                                   Modified on 15.03.2012

Accepted on 05.04.2012                                © RJPT All right reserved