1. INTRODUCTION:

In current years, considerable awareness has been focused on the development of novel drug delivery system (NDDS) osmotically controlled drug delivery system (ODDS) are the type of NDDS which make use of osmotic pressure for controlled delivery of active agent. The release of drug from osmotic system is independent of gastric pH and gastric motility. However, drug release from oral controlled release dosage forms may be affected by pH, GI motility and presence of food in the GI tract. Osmotically controlled drug delivery system (OCDDS) is one of the most favourable drug delivery technologies that use osmotic pressure as a driving force for controlled delivery of active agents.

Drug release from OCDDS is independent of pH and hydrodynamic conditions of the body because of the semi permeable nature of the rate-controlling membrane and the design of deliver orifice used in osmotic systems, so a potency of In vitro/ In vivo correlation is achieved. Osmosis refers to process of movement of solvent from lower concentration of solute towards higher concentration of solute across a semipermeable membrane. Osmotic pressure is least pressure which needs to be applied to a solution to prevent the inside flow of its pure solvent across a semipermeable membrane. Osmotic Pump Controlled Release Preparation is a novel drug delivery system with inner drug deliver rate as characteristic and controlled with the osmotic pressure difference between inside and outside of the semipermeable membrane as drug delivery capacity^1,2.

Now a days, osmotic tablets have been expanded in which the delivery orifice is formed by the incorporation of a leachable component in the coating. Once the tablet comes to contact with the aqueous environment, the water-soluble component breakdown, and an osmotic pumping system result. later, the water diffuses into the core through the micro porous membrane, to create an osmotic gradient and thereby controlling the release of drug. Osmosis can be defined as the spontaneous movement of a solvent from a solution of lower solute concentration to a solution of higher solute concentration through an ideal semipermeable 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. Recently, osmotic tablets have been developed in which the delivery orifice is formed by the incorporation of a leachable component in the coating. When the tablet interacts with the fluid condition, the water-solvent part separated, and the osmotic siphoning framework result. Subsequently, water diffuses into the core through the micro porous membrane, setting up an osmotic gradient and thereby controlling the release of drug^2,3.

1.1 Advantages:

Drug release from osmotic pumps is independent of the gastric pH and hydrodynamic Condition of the body. Higher release rates are possible from osmotic systems than with conventional Diffusion based drug delivery systems. The delivery rate of drug(s) from these systems is highly expected and programmable by modulating the release control parameters.

The advantages of osmotic drug delivery system include:

1. Improved patient compliance with lower dosing frequency.

2. It is possible to attain better release rates than those obtained with conventional diffusion.

3. Drug release from the osmotically controlled drug delivery system exhibits significant in vitro-in vivo correlation (IVIVC) within specific limits.

4. Increased safety margin of high potency drugs.

5. Reduced side effects.

6. Drug release from the osmotic systems is slightly affected by the presence of food.

7. Delivery may be delayed or pulsed, if desired.

8. They are suitable for a wide range of drug.

9. Sustained and consistent blood levels within the therapeutic window.

10. They are well characterized and understood.

11. Reduced interpatient flexibility⁴.

1.2 Disadvantages:

If the coating process is not well controlled there is a risk of film fault, which results in dose dumping. The disadvantages include:

1. Hole size is critical in case of elementary osmotic system.

2. Drug release from the osmotic systems is affected to some extent by the presence of food.

3. Retrieval of therapy is not possible in the case of unexpected adverse event.

4. Fast development of tolerance.

5. Integrity and uniformity of the coating process is not well controlled there is dose dumping. The film beads or particles must be instigated to combine into a film with steady properties.

6. Laser drilling is capital intensive.

7. Hypersensitivity reaction may happen after implantation^4,5.

1.3 Principle of osmotic drug delivery system:

It is based on the principle of osmotic pressure. Osmotic pressure is a colligative effect, which is dependent on concentration of solute that gives to osmotic pressure. Solutions of different concentrations having the same solvent and solute system show an osmotic pressure proportionate to their concentrations. Thus, a constant osmotic pressure, and thereby a constant influx of water can be attained by an osmotic drug delivery system. This results a constant zero order release rate of drug. The rate of drug release from osmotic pump depends on the osmotic pressure of the core and the drug solubility; hence, these systems are acceptable for delivery of drugs with moderate water solubility. Osmotic pressure is proportionate to temperature and concentration and the association can be described by following equation.

π = n₂RT

Where,

π = osmotic coefficient

n₂ = molar concentration of solute in the solution

R = gas constant

T = Absolute temperature⁶.

2. BASIC COMPONENTS OF OSMOTIC SYSTEMS:

A. Drug:

Drugs which have short biological half-life (2-6 Hours), highly potent and which are used for extend treatment are ideal candidates for osmotic systems. Various drug candidates such as Diltiazem HCl, Carbamazepine, Metoprolol, Oxprenolol, Nifedipine, Glipizide, verapamil etc. are formulated as osmotic delivery⁷.

B. Osmotic agent:

Osmotic agents are crucial ingredient of the osmotic formulation. Osmotic components generally are ionic compounds consisting of either inorganic salts hydrophilic polymers or carbohydrates. normally, combinations of osmotic agents are used to achieve optimum osmotic pressure inside the system. Different type of osmogents can be used for such systems are classified as water-soluble salts of inorganic acids like magnesium chloride or sulfate; lithium, sodium, or potassium chloride; sodium or potassium hydrogen phosphate; water soluble salts of organic acids like sodium and potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate; Carbohydrates like mannose, sucrose, maltose lactose; water-soluble amino acids and organic polymeric osmogents, etc. Polymeric osmogents are mainly used in the fabrication of osmotically controlled drug delivery systems and other alter devices for controlled release of relatively insoluble drugs. Osmotic pressures for concentrated solution of soluble solutes commonly used in controlled release formulations are extremely high, ranging from 30 atm for sodium phosphate up to 500 atm for a lactose-fructose mixture. These osmotic pressures can produce high water flows across semipermeable membranes^7,8.

C. Semipermeable membrane:

A major part of the osmotic drug delivery system is the Semipermeable membrane. Therefore, the polymeric membrane choice is crucial to osmotic delivery formulation. Any polymer that is permeable to water but impermeable to solute (drug and excipients) 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. Cellulose acetate is normally used for semi permeable membrane. It is available in different acetyl content like 32%, 38% are widely used. The membrane must possess certain performance criteria such as:

1. The membrane should be stable to both outside and inside environments of the device.

2. The material must have sufficient wet strength (10-5 Psi) and wet modules so (10-5 Psi) as to retain its dimensional integrity during the operational lifetime of the device.

3. It must exhibit sufficient water permeability so as to attain water flux rates (dv/dt) in the desired range.

4. It must be sufficiently rigid so as to resist the pressure within the device, to retain its dimensional integrity during the operational lifetime of the device.

5. Polymer membranes must be more permeable to water.

6. It should also be relatively impermeable to the contents of dispenser so that osmogent is not.

7. lost by diffusion across the membrane.

8. It should be non- swelling.

9. It should be biocompatible.⁹

D. Pore forming agents (Channeling agents):

These are the water-soluble components which play a main role in the controlled drug delivery systems. When the dissolution medium comes into contact with the semipermeable membrane it dissolves the channelling agent and forms pores on the semipermeable barrier. Then the dissolution fluid enters the osmotic system and releases the drug in a controlled manner over a long period of time by the process of osmosis. This agent develops controlled porosity or multi-particulate osmotic pumps. Pore forming agent makes a microporous membrane. The micro porous wall may be formed in situ by a pore former by its leaching during the operation of the system. Pore formers can be inorganic or organic and solid or liquid in nature. Some examples pore formers are alkaline metal salts. Such as NaCl, NaBr, KCl, potassium sulfate, potassium phosphate etc. alkaline earth metal like CaCl₂, calcium nitrate. Carbohydrates such as sucrose, glucose, fructose, mannose, lactose, sorbitol, mannitol, and diols and polyols like polyhydric alcohol, dibutyl phthalate, polyvinyl pyrrolidone. The volatile pore formers used were ethanol and butanol. The non-volatile pore formers used were glycerol and water. It should be nontoxic, and on their removal, channels should be formed^9,10.

E. Plasticizers:

Plasticizers used in coating membrane also have a significant importance in the formulation of osmotic systems. It is under the temperature of the second order phase transition of the wall or the elastic modules of the wall and also increases the workability. They can change visco-elastic behaviour of polymers and these changes may influence the permeability of the polymeric films. Some of the plasticizers used are as below:

1. Polyethylene glycols

2. Ethylene glycol monoacetate; and diacetate- for low permeability

3. Tri ethyl citrate

4. Diethyl tartarate or Diacetin for more permeable films

5. Dialkyl phthalate, Trioctyl phosphate

6. Alkyl adipates, Acetate, Propionate, Glycolate¹¹.

F. Coating Solvent:

For making polymeric membrane, suitable solvent should be used. There are various organic and inorganic solvent are obtainable. Solvents should not be toxic, should not be alter the chemical nature of polymer, should be solubility to polymer completely. Some examples of solvents are acetone, isopropyl alcohol, ethanol, methanol, carbon tetrachloride, water, ethyl acetate, cyclohexane, butyl alcohol. The mixture of solvents like acetone, ethanol, methylene chloride-methanol, isopropyl alcohol, acetone-water, methylene Chloride-methanol-water.¹²

G. Wicking agent:

A wicking agent is described 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 identified by having the ability to undergo physical absorption 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, by which creating channels or a network of increased surface area. Materials which suitably act as wicking agents include colloidal silicon dioxide, kaolin, titanium dioxide, alumina, niacinamide, sodium lauryl sulphate (SLS), low molecular weight polyvinyl pyrrolidone (PVP), m-pyrol, bentonite, magnesium aluminium silicate, polyester and polyethylene^12,13.

3. CLASSIFICATION OF OSMOTIC DRUG DELIVERY SYSTEM:

The osmotic drug delivery system can be classified into 2 types:

A. Implantable Osmotic Pump

B. Oral Osmotic Pump

A. Implantable Osmotic Pump:

1. Rose and Nelson Osmotic Pump:

In year 1955, Rose and Nelson implement the principle of osmotic applied to drug delivery for the first time¹⁴. They related two systems that were able to deliver drug at controlled doses of 0.02ml/day for 100 days and 0.5 ml/day for four days. A schematic diagram of the Rose-Nelson pump is given in figure 1. The device containing three chambers, first one is a drug chamber, second one is a salt chamber and third one is a water chamber. The salt chamber is separated from the water chamber by a semipermeable solid membrane, while the drug chamber is separated from the salt chamber by an elastic diaphragm. Over time, the osmotic inhibition of water through the SPM (semipermeable membrane) increases the volume of the salt chamber, disrupting the elastic diaphragm that eventually extrude the drug from the delivery system through the delivery orifice. The osmotic pressure (of the saturated salt solution in the chamber) is the driving force for release of the drug from the system. Therefore, as long as enough solid salt remains in the salt chamber the water penetration rate through the SPM is constantly same, producing a constant rate of drug release.

One of the problems with the Rose-Nelson pump is that the osmotic flow occurs as soon as the salt chamber meets the water. Therefore, the pump had to be kept empty and to be loaded with water immediately before use, which make a process that was problematic for delivery of drugs. Moreover, although these systems have a large amount of research, their complex design makes them poor system in large-scale production which makes them of limited use.

The Rose-Nelson pump rate is followed by this equation

dM/dt = dv/dt* C

Where, dM/dt is the drug release rate, dV/dt is the volume flow of water into the salt chamber, and C is the concentration of drug in the drug chamber¹⁵.

Figure 1: Rose and Nelson Osmotic Pump

2. Alzet Osmotic Pump:

Alzet pumps are operate due to the difference in osmotic pressure between the inner chamber of the pump, called the salt sleeves, and the area of tissue where the pump implanted. The water flux into the tap through the semipermeable membrane due to the high osmolality of the salt sleeve that forms the outer side of the pump. When water enters the salt sleeve, it compresses the flexible reservoir, removing the test solution from the pump at a controlled, pre-determined rate.^16,17 Limitation of this pump are designed for single use only because compressed reservoir cannot be refilled.

Figure 2: Alzet Osmotic Pump

B. Oral Osmotic Pumps:

a. Elementary Osmotic Pump (EOP):

Elementary osmotic pump is a single osmotic pump. EOP was a modified and simple version of Rose-Nelson device. Theeuwes, made this device in 1974. In this device an osmotic agent is used which a proper osmotic pressure^18,19. This agent can also be called as active agent. Pill is covered with a semipermeable membrane. A minor aperture is pierced in the casing. When this device contact with water, water is attracted inside the device by selectively permeable membrane. A solution of drug is formed when it is mixed with water. Now the pressure of inside system will be increased, which forces the drug to move out of the device. In start the pump, delivers the drug at a speed which is explained by the following equation;

dMt dt = dV/dt · C_s

Where, dV/dt depicts the water flow into the tablet and

C_sis the solubility of the agent inside the tablet.

When there is surplus solid in the device the release of medicament is persistent but as the amount of drug decreases the delivery of drug no longer remains constant. Now it does not follow the zero order. 60 - 80% of drug is delivered with constant sped. A gap time of 30 - 60 mins is detected before all the operation starts. The drug which are moderately soluble in water are delivered by this technique.

Figure 3: Elementary Osmotic Pump

b. Push Pull Osmotic Pump (PPOP):

The two-layer push–pull osmotic tablet system was being in the year1980s. Push pull osmotic pump is a modified an 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 containing of two layers, one containing the drug and the other an osmotic agent and expandable agent. A semipermeable membrane that regulates water influx into both layers surrounds the system. While the push– pull osmotic tablet operates well to delivering water-insoluble drugs, it has a disadvantage that are complicated laser drilling technology should be employed to drill the orifice next to the drug compartment²⁰.

Figure 4: Push–Pull Osmotic Pump (PPOP)

c. Controlled Porosity Osmotic Pump (CPOP):

The controlled osmotic porosity pump contains water-soluble additives in the coating membrane, which after contact with liquid environment, it dissolves and results in the formation of a microporous membrane in situ, as shown in figure 5. The controlled porosity wall can be described like a sponge-like shape. Generally, materials that produce from 5 to 95% pores with a pore size from 10A - 100 μm can be used^21,22. The resulting membrane is permeable to both, dissolved solute and water. Water-soluble additives used for this purpose are dimethyl sulfone, saccharides, amino acids, sorbitol, etc.

Figure 5: Controlled Porosity Osmotic Pump (CPOP)

d. Osmotically Rupturable Pumps:

Another popular category is the osmotic systems that release the active ingredient through an osmotic bursting device. The system was developed by Baker and consists of an osmotic core surrounded by an SPM. When it placed in a liquid environment, water is osmotically drawn into this device, which leads to inflammation of the membrane. This process continues until the internal pressure inside the device becomes greater than the cohesive force of the membrane and the membrane breaks down in to a weak area, usually around the edges. When the membrane is raptured, the device becomes like an elementary osmotic pump and the drug compound is withdrawn from the cracked area with mechanism of osmotic pumping. Rapture time of SPM can be controlled by.

a) Varying type, area or thickness of SPM

b) Changing the osmotic agents embedded in the osmotic core^23,24.

e. Liquid Oral Osmotic System (L-OROS):

The various LOROS systems were obtainable to allow controlled delivery of liquid formulations required a L-OROS soft cap, L-OROS hard cap and a delayed liquid bolus delivery system. Each of these systems includes a layer of liquid drugs, an osmotic engine or a Push layer and a SPM. When this system comes in contact with a water, the water penetrates inside the layer through SPM and will activate an osmotic layer. The extension of the osmotic layer leads to the formation of hydrostatic pressure within the system, thereby forcing the liquid formulation to extrude it from orifice at the delivery site. While, L-OROS hard caps and L-OROS soft cap systems are designed to provide continuous drug delivery, the L-OROS delayed delivery of liquid bolus system is designed to deliver pulse of liquid drug²⁵.

Figure 6: Cross-sectional diagram of Liquid Oral Osmotic System (L-OROS)

f. Colon Targeted Oral Osmotic System (OROS-CT):

OROS-CT is used to make once or twice a day the delivery of drug to the colon region. It comprises hard gelatin capsule filled with 5-6 enteric-coated push-pull osmotic units for targeted drug delivery to colon region. After contact with GI fluid, the gelatin capsule dissolves but the enteric coating will avoid the entry of fluid from the stomach fluid into the system²⁶.

Figure 7: Cross-sectional Diagram of OROS-CT Delivery System

As the OROS-CT system enters the small intestine, the enteric coating dissolves and water drawn into the core, that causing swelling of push layer. At that time, a flowable gel is formed into the drug layer, which is then released out of the orifice at a rate that is precisely controlled by the transport rate of water across the SPM. About 80% of the drug will be delivered into a large intestine by OROS-CT.

Figure 8: Schematic Diagram of Sandwiched Osmotic Tablet (SOTS)

g. Sandwiched Osmotic Tablets (SOTS):

It consists of a polymeric push layer sandwich sandwiched between two layers of the drug with two delivery orifices. When it is placed on a liquid environment, the central push layer containing the swellable polymer start to swell and the drug start to release from the delivery orifice. The advantage of this type of system is that the drug is extruded from two opposite side layers of the tablet and therefore SOTS may be suitable for drugs that tend to cause local irritation of the abdominal cord (gastric mucosa)²⁷.

h. Multi-particulate Delayed-Release System:

In this system, pellets containing water soluble drug optionally with osmotic agents are coated with a SPM. When it comes in contact with water, The water enters into a core and forms a saturated solution of drug substances. The osmotic pressure gradient causes fluid influx, leading to rapid fluid enlargement that cause expansion of membrane and the formation of pores. The release of drug ingredients through these holes usually follows zero-order kinetics. In studies conducted by Schultz and Kleinebudde it was found that lag times and release rates depend on the level of thickness of coating layer and the osmotic pressure of the dissolution media²⁸.

4. CONCLUSION:

In osmotic delivery systems, osmotic pressure gives a 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 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. Even though all drugs available for treating different diseases require such precise release rates, every day 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. Other than oral osmotic delivery systems, implants that work on osmotic principles are favourable for delivery of a wide variety of molecules with an accurate 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 clear the way for osmotic delivery systems to play a progressively main role in drug delivery.

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Received on 30.09.2022 Modified on 15.10.2022

Asian J. Pharm. Tech. 2023; 13(1):70-76.

DOI: 10.52711/2231-5713.2023.00014