INTRODUCTION⁽^1,2,3):

Besides the drug itself, the right dosage over time is crucial for an effective therapy. Rate-controlled release systems allow maintaining the drug concentration within the body at an optimum level. This minimizes the risk of disadvantageous side effects, poor therapeutic activity, or even adverse effects. Over the years, a multitude of different technological approaches addressing this goal have been developed. However, only few of them succeeded in becoming cutting edge technologies applied to versatile therapeutic applications.

A very successful approach for rate controlled drug delivery is represented by osmotic ally controlled drug delivery system. Osmotic systems utilize the principle of osmotic pressure for the delivery of drugs. Drug release from these systems is independent of pH and other physiological parameter to a large extent and it is possible to modulate the release characteristic by optimizing the properties of drug and system. Osmosis can be defined as the spontaneous movement of the solvent from a solution of lower solute concentration to a solution of higher solute concentration through an ideal semi permeable membrane, which is permeable only to the solvent but impermeable to the solute. The pressure applied to the higher concentration side to inhibit solvent flow is called the osmotic pressure. Osmotic pressure is a colligative property that depends on the concentration of solute (neutral molecule or ionic species). 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 drug delivery system that results in a constant release rate of drug. Therefore, zero-order release, which is important for a controlled release delivery system when indicated, is possible to achieve using these systems. Drug delivery from these systems, to a large extent, is independent of the physiological factors of the gastrointestinal tract and these systems can be utilized for systemic as well as targeted delivery of drugs. The release of drugs from osmotic systems is governed by various formulation factors such as solubility and osmotic pressure of the core components, size of the delivery orifice, and nature of the rate-controlling membrane.

Osmosis:

Osmosis refers to the process of movement of solvent molecules from lower concentration to higher concentration across a semi permeable membrane. Osmosis is the phenomenon that makes controlled drug delivery a reality. 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. Osmotic pressure 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. Hence the release rate of drugs from osmotic dispensing devices is dependent on the solubility and molecular weight and activity coefficient of the solute (osmogent).

Principles of Osmosis:^(4,5)

The first report of an osmotic effect dates to Abbenollet 1748. But Pfeffer obtained the first quantitative measurement in 1877. In Pfeffer experiment a membrane permeable to water but impermeable to sugar is used to separate a sugar solution from pure water. A flow of water then takes place into the sugar solution that cannot be halted until a pressure π is applied to the sugar solution. Pfeffer showed that this pressure, the osmotic pressure π of the sugar solution is directly proportional to the solution concentration and the absolute temperature. Within few years, Vant Hoff had shown the analogy between these results and ideal gas laws by the expression

π = Ø c RT

Where, p = Osmotic pressure, π = osmotic coefficient, c = molar concentration, 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. Osmotic pressure for concentrated solution of soluble solutes commonly used in controlled release formulation are extremely high ranging from 30 atm for sodium phosphate up to 500 atm for a lactose-fructose mixture, as their osmotic pressure can produce high water flow across semi permeable membrane. The osmotic water flow through a membrane is given by the equation,

dv\dt = A Q Δ π\ L

Where dv\dt = water flow across the membrane of area A in cm2, L = thickness, Q = permeability and Δ π = the osmotic pressure difference between the two solutions on either side of the membrane.

This equation is strictly for completely perm selective membrane that is membrane permeable to water but completely impermeable to osmotic agent.

Osmotically controlled drug delivery systems:⁽⁶⁾

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 Alza and it holds major number of the patents analyzed and also markets several products based on osmotic principle. These systems can be used for both route of administration i.e. oral and parenterals. Oral osmotic systems are known as gastro-intestinal therapeutic systems (GITS). Parenteral osmotic drug delivery includes implantable pumps.

a. Type I: Single compartment. In this design, the drug and the osmotic agent are located in the same compartment and are surrounded by the semi permeable membrane (SPM). Both the core components are dissolved by water, which enters the core via osmosis. A limitation is the dilution of drug solution with the osmotic solution, which affects the release rate of the drug from the system. Additionally, water-incompatible or water-insoluble drugs cannot be delivered effectively from a single compartment configuration.

b. Type II: Multiple compartments. In this design, drug is separated from the osmotic compartment by an optional flexible film, which is displaced by the increased pressure in the surrounding osmotic compartment, which, in turn, displaces the drug solution or suspension.

Fig 1.Classification of osmotic delivery systems: types I and II.

The type II system inherently has greater utility than type I systems and can deliver drugs at a desired rate independent of their solubilities in water. One main advantage of these systems is their ability to deliver drugs that are incompatible with commonly used electrolytes or osmotic agents.

Advantages⁽^10,11)

Osmotic drug delivery system for oral and parenteral use offer distinct and practical advantage over other means of delivery. The following advantages contributed to the popularity of osmotic drug delivery systems.12

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

2. Deliveries may be delayed or pulsed if desired.

3. Drug release is independent of gastric pH and hydrodynamic condition.

4. They are well characterized and understood.

5. The release mechanisms are not dependent on drug.

6. A high degree of in-vitro and in-vivo correlation (ivivc) is obtained in osmotic systems.

7. The rationale for this approach is that the presence of water in git is relatively constant, at least in terms of the amount required for activation and controlling osmotic ally base technologies.

8. Higher release rates are possible with osmotic systems compared with conventional diffusion-controlled drug delivery systems.

9. The release from osmotic systems is minimally affected by the presence of food in gastrointestinal tract.

10. The release rate of osmotic systems is highly predictable and can be programmed by modulating the release control parameters.

Disadvantages⁽^10,11)

· Expensive

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

· Size hole is critical

Key parameters that influence the design of osmotic controlled drug delivery systems⁽^7,8)

Orifice size

To achieve an optimal zero-order delivery profile, the cross-sectional area of the orifice must besmaller than a maximum size to minimize drug delivery by diffusion through the orifice. Furthermore, the area must be sufficiently large, above a minimum size to minimize hydrostatic pressure buildup in the system. Otherwise, the hydrostatic pressure can deform the membrane and affect the zero-order delivery rate. Therefore, the cross sectional area of the orifice should be maintained between the minimum and maximum values. Methods to create a delivery orifice in the osmotic tablet coating are:

1. Mechanical drill

2. Laser drill- This technology is well established for producing sub-millimeter size hole in tablets. Normally, CO2 laser beam (with output wavelength of 10.6μ) is used for drilling purpose, which offers excellent reliability characteristics at low costs.

3. Indentation that is not covered during the coating process Indentation is made in core tablets by using modified punches having needle on upper punch. This indentation is not covered during coating process which acts as a path for drug release in osmotic system.

4. Use of leachable substances in the semi permeable coating : e.g. controlled porosity osmotic pump

Solubility^(9,10)

The release rate depends on the solubility of the solute inside the drug delivery system. Therefore, drugs should have sufficient solubility to be delivered by osmotic delivery. In the case of low solubility compounds, several alternate strategies may be employed. Broadly, the approaches can be divided into two categories. First, swellable polymers can be added that result in the delivery of poorly soluble drugs in the form of a suspension0. Second, the drug solubility can be modified employing different methods such as compression of the drug with other excipients, which improve the solubility. For example, cyclodextrin can be included in the formulation toenhance drug solubility. Additionally, alternative salt forms of the drug can be employed to modulate solubility to a reasonable level. In one case, the solubility of oxprenolol is decreased by preparing its succinate salt so that a reduced saturation concentration is maintained.

Osmotic pressure^{(11, 12)}

The osmotic pressure (π) directly affects the release rate. To achieve a zero-order release rate, it is essential to keep (π) constant by maintaining a saturated solute solution. Many times, the osmotic pressure generated by the saturated drug solution may not be sufficient to achieve the required driving force. In this case, other osmotic agents are added that enhance osmotic pressure. For example, addition of bicarbonate salt not only provides the necessary osmotic gradient but also prevents clogging of the orifice by precipitated drug by producing an effervescent action in acidic media

Semi permeable membrane:⁽¹³⁾

Since the semi permeable membrane is permeable to water and not to ions, the release rate is essentially independent of the pH of the environment. Additionally, the drug dissolution process takes place inside the delivery system, completely separated from the environment

Classifications:

1. Physical mean:

a. Osmotic pressure activated drug delivery system.

b. Hydrodynamic pressure activated drug delivery system

c. Vapour pressure activated drug delivery system

d. Mechanically activated drug delivery system

e. Magnetically activated drug delivery system

f. Sonophoresis activated drug delivery system

g. Ionotrophoresis activated drug delivery system

h. Hydration activated drug delivery system

2. Chemical means

a. pH activated drug delivery system.

b. Ion exchange drug delivery system.

c. Hydrolysis activated drug delivery system.

3. Biochemical means

a. Enzyme activated drug delivery system.

b. Biochemical activated drug delivery system.

Elementary osmotic pump (EOP)^{(16, 17)}

The was introduced in 1970s to deliver drug at zero order rates for prolonged periods, and is minimally affected by environmental factors such as pH or motility. The tablet consists of an osmotic core containing the drug surrounded by a semipermeable membrane laser drilled with delivery orifice. Following ingestion, water in absorbed into system dissolving the drug, and the resulting drug solution is delivered at the same rate as the water entering the tablet. The disadvantages of the elementary pump are that it is only suitable for the delivery of water soluble drugs.

Factors affecting the release rate from EOP

There are following factors which should be considered

while designing an EOP. These factors are also applicable to other

osmotic drug delivery systems:

1. Membrane thickness.

2. Osmotic pressure.

3. Type of membrane and characteristics.

4. Solubility.

5. Seize of the delivery orifice.

6. Use of Wicking agent.

7. Type and amount of plasticizer.

Fig 3 :Elementary osmotic pump

Push–Pull Osmotic Pump (PPOP)⁽¹⁸⁾

The two-layer push–pull osmotic tablet system appeared in 1980s. Push pull osmotic pump is a modified elementary osmotic pump through, which it is possible to deliver both poorly water-soluble and highly water soluble drugs at a constant rate. The push–pull osmotic tablet consists of two layers, one containing the drug and the other an osmotic agent and expandable agent. A semi permeable membrane that regulates water influx into both layers surrounds the system. While the push–pull osmotic tablet operates successfully in delivering water-insoluble drugs, it has a disadvantage that the complicated laser drilling technology should be employed to drill the orifice next to the drug compartment.

Control porosity osmotic pump (CPOP)⁽¹⁹⁾

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

dv / dt = Ak / h (Dp-DR)

Where:-

k = Membrane permeability

A = Area of the membrane

Dp= Osmotic pressure difference

DR = Hydrostatic pressure difference

Fig 4 :Push pull osmotic pump

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.

Fig 5 :Controlled porosity osmotic pump

Monolithic osmotic systems⁽¹⁹⁾

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 volume per liter of the active agents is incorporated in to the device as above this level, significant contribution from the simple leaching of the substance take place.

Osmotic bursting osmotic pump:⁽²⁰⁾

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

Sandwiched osmotic tablet (SOT):⁽²¹⁾

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.

Fig 7 : Sandwiched osmotic tablets

Longitudinally compressed tablet (LCT) multilayer formulation ⁽²²⁾

The LCT multilayer formulation is the advanced design. As with the push-pull system it consists 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.

Fig 8 :Multilayer osmotic pump

As with the push-pull formulation, water is absorbed through the exposed semi permeable 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. After most of the drug release begins from the second compartment at a different rate. Varying the relative viscosity and hydrophilicity of the drug layer components can control the amount of mixing between the multiple drug layers. 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.

CONCLUSION:

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.

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Received on 09.12.2015 Accepted on 30.12.2015

Asian J. Pharm. Res. 6(1): January -March, 2016; Page 49-55

DOI: 10.5958/2231-5691.2016.00009.5