Conventional drug delivery systems are known to provide an immediate release of drug, in which one can not control the release of the drug and can not maintain effective concentration at the target site for longer time. Controlled drug delivery systems offer spatial control over the drug release. Osmotic pumps are most promising systems for controlled drug delivery. These systems are used for both oral administration and implantation. Osmotic pumps consist of an inner core containing drug and osmogens, coated with a semipermeable membrane. As the core absorbs water, it expands in volume, which pushes the drug solution out through the delivery ports. Osmotic pumps release drug at a rate that is independent of the pH and hydrodynamics of the dissolution medium. The historical development of osmotic systems includes development of the Rose-Nelson pump, the Higuchi-Leeper pumps, the Alzet and Osmet systems, the elementary osmotic pump, and the push-pull system. Recent advances include development of the controlled porosity osmotic pump, and systems based on asymmetric membranes. This paper highlights the principle of osmosis, materials used for fabrication of pumps, types of pumps, advantages, disadvantages, and marketed products of this system.
The pharmaceutical field over the past decade has faced continuing challenges in bringing new drug entity to market. In addition, the cost of developing new drug entity keeps rising and today stands at more than US$ 800 M per new drug entity. Drug delivery research continues to find new therapies for the prevention and treatment of exiting and new diseases. So, a valuable role is played by drug delivery system by providing optimized products for existing drugs in terms of either enhanced or improved presentation of drug to the systemic circulation [
Treatment of an acute disease or a chronic illness has been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms. Traditionally, the oral drug delivery has been most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs. Conventional oral drug delivery systems are known to provide an immediate release of drug, in which one cannot control the release of the drug and cannot maintain effective concentration at the target site for longer period of time. The oral bioavailability of some drug by conventional drug delivery is very low due to presence of food, in stabilization at pH of the GI tract, degradation by enzymes of GI fluid, change in GI motility, and so forth [
Controlled drug delivery systems offer temporal and/or spatial control over the release of drug. Such systems release the drug with constant or variable release rates. Oral controlled drug delivery systems represent the most popular form of controlled drug delivery systems for the obvious advantages of oral route of drug administration. These dosage forms offer many advantages, such as nearly constant drug level at the site of action, prevention of peak-valley fluctuations, reduction in dose of drug, reduced dosage frequency, avoidance of side effects, and improved patient compliance [
The oral controlled release system shows a typical pattern of drug release in which the drug concentration is maintained in between the minimum effective concentration (MEC) and maximum safe concentration (MSC) for a prolonged period of time, thereby ensuring sustained therapeutic action (Figure
Plasma concentration profile: for conventional dosage form (- - -) and for controlled release dosage form (—).
Osmotic devices are most promising strategy-based systems for controlled drug delivery [
These systems can be used for both route of administration, that is, oral and implantation. Osmotic pump offers many advantages over other controlled drug delivery systems, that is, they are easy to formulate and simple in operation, improved patient compliance with reduced dosing frequency and more consistence, and prolonged therapeutic effect with uniform blood concentration. Moreover they are inexpensive and their production scaleup is easy [
Osmotic drug-delivery systems suitable for oral administration typically consist of a compressed tablet core that is coated with a semipermeable membrane coating. This coating has one or more delivery ports through which a solution or suspension of the drug is released over time. The core consists of a drug formulation that contains an osmotic agent and a water swellable polymer. The rate at which the core absorbs water depends on the osmotic pressure generated by the core components and the permeability of the membrane coating. As the core absorbs water, it expands in volume, which pushes the drug solution or suspension out of the tablet through one or more delivery ports [
The key distinguishing feature of osmotic drug delivery systems (compared with other technologies used in controlled-release formulations) is that they release drug at a rate that is independent of the pH and hydrodynamics of the external dissolution medium. The result is a robust dosage form for which the in vivo rate of drug release is comparable to the in vitro rate, producing an excellent in vitro/in vivo correlation. Another key advantage of the present osmotic systems is that they are applicable to drugs with a broad range of aqueous solubilities [
The historical development of osmotic systems includes seminal contributions such as the Rose-Nelson pump [
The following are the materials used in formulation of osmotically regulated system.
Since the membrane in osmotic systems is semipermeable in nature, any polymer that is permeable to water but impermeable to solute can be selected [
These polymers are used in the formulation development of osmotic systems for making drug containing matrix core. The highly water soluble compounds can be coentrapped in hydrophobic matrices and moderately water soluble compounds can be coentrapped in hydrophilic matrices to obtain more controlled release. Generally, mixtures of both hydrophilic and hydrophobic polymers have been used in the development of osmotic pumps of water-soluble drugs [
A wicking agent is defined as a material with the ability to draw water into the porous network of a delivery device. The wicking agents are those agents which help to increase the contact surface area of the drug with the incoming aqueous fluid. The use of the wicking agent helps to enhance the rate of drug released from the orifice of the drug. A wicking agent is of either swellable or nonswellable nature [
For osmotic drug delivery system, highly water-soluble drugs would demonstrate a high release rate that would be of zero order. Thus, many drugs with low intrinsic water solubility are poor candidates for osmotic delivery. However, it is possible to modulate the solubility of drugs within the core. Addition of solubilizing agents into the core tablet dramatically increases the drug solubility [
Nonswellable solubilizing agents are classified into three groups, Agents that inhibit crystal formation of the drugs or otherwise act by complexation with the drugs (e.g., PVP, poly(ethylene glycol) (PEG 8000) and a micelle-forming surfactant with high HLB value, particularly nonionic surfactants (e.g., Tween 20, 60, and 80, polyoxyethylene or poly ethylene containing surfactants and other long-chain anionic surfactants such as SLS), citrate esters (e.g., alkyl esters particularly triethyl citrate) and their combinations with anionic surfactants. The combinations of complexing agents such as polyvinyl pyrrolidone (PVP) and poly(ethylene glycol) with anionic surfactants such as SLS are mostly preferred.
Osmogens are essential ingredient of the osmotic formulations. Upon penetration of biological fluid into the osmotic pump through semipermeable membrane, osmogens are dissolved in the biological fluid, which creates osmotic pressure buildup inside the pump and pushes medicament outside the pump through delivery orifice. They include inorganic salts and carbohydrates. Mostly, potassium chloride, sodium chloride, and mannitol used as osmogens. Generally combinations of osmogens are used to achieve optimum osmotic pressure inside the system (Table
List of various osmogens with their osmotic pressure [
Osmotic pressures of saturated solution of commonly used osmogens | Osmotic pressure (atm) |
---|---|
Sodium chloride | 356 |
Fructose 3 | 55 |
Potassium chloride | 245 |
Sucrose | 150 |
Xylitol | 104 |
Sorbitol | 84 |
Dextrose | 82 |
Citric acid | 69 |
Tartaric acid | 67 |
Mannitol | 38 |
Potassium sulphate | 39 |
Lactose | 23 |
Fumaric acid | 10 |
Adipic acid | 8 |
Lactose-fructose | 500 |
Dextrose-fructose | 450 |
Sucrose-fructose | 430 |
Mannitol-fructose | 415 |
Sodium chloride | 356 |
Fructose | 335 |
Lactose-sucrose | 250 |
Potassium chloride | 245 |
Lactose-dextrose | 225 |
Mannitol-dextrose | 225 |
Dextrose-sucrose | 190 |
Mannitol-sucrose | 170 |
Sucrose | 150 |
Mannitol-Lactose | 130 |
Dextrose | 82 |
Potassium sulphate | 39 |
Mannitol | 38 |
Sodium phosphate tribasic·12H2O | 36 |
Sodium phosphate dibasic·7 H2O | 31 |
Sodium phosphate dibasic·12 H2O | 31 |
Sodium phosphate monobasic·H2O | 28 |
Sodium phosphate dibasic. Anhydrous | 21 |
Surfactants are particularly useful when added to wall-forming material. They produce an integral composite that is useful for making the wall of the device operative. The surfactants act by regulating the surface energy of materials to improve their blending into the composite and maintain their integrity in the environment of use during the drug release period. Typical surfactants such as poly oxyethylenated glyceryl recinoleate, polyoxyethylenated castor oil having ethylene oxide, glyceryl laurates, and glycerol (sorbiton oleate, stearate, or laurate) are incorporated into the formulation.
Solvents suitable for making polymeric solution that is used for manufacturing the wall of the osmotic device include inert inorganic and organic solvents that do not adversely harm the core and other materials. The typical solvents include methylene chloride, acetone, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethyl acetate, cyclohexane, carbon tetrachloride, and water. The mixtures of solvents such as acetone-methanol (80 : 20), acetone-ethanol (80 : 20), acetone-water (90 : 10), methylene chloride-methanol (79 : 21), methylene chloride-methanol-water (75 : 22 : 3) can be used.
In pharmaceutical coatings, plasticizers, or low molecular weight diluents are added to modify the physical properties and improve film-forming characteristics of polymers. Plasticizers can change visco elastic behavior of polymers significantly [
These agents are particularly used in the pumps developed for poorly water-soluble drugs and in the development of controlled porosity or multiparticulate osmotic pumps [
Osmotic delivery systems contain at least one delivery orifice in the membrane for drug release. The size of delivery orifice must be optimized in order to control the drug release from osmotic systems. On the other hand, size of delivery orifice should not also be too large, otherwise, solute diffusion from the orifice may take place. If the size of delivery orifice is too small, zero-order delivery will be affected because of development of hydrostatic pressure within the core. This hydrostatic pressure may not be relieved because of the small orifice size and may lead to deformation of delivery system, thereby resulting in unpredictable drug delivery. Optimum orifice diameter is in the range of 0.075–0.274 mm. At orifice size of 0.368 mm and above, control over the delivery rate is lost [
Delivery orifices in the osmotic systems can be created with the help of a mechanical drill [
In some of the oral osmotic systems, there is in situ formation of delivery orifice [
Rose and Nelson, the Australian scientists, were initiators of osmotic drug delivery. In 1955, they developed an implantable pump for the delivery of drugs to the sheep and cattle gut [
The Rose-Nelson implantable pump shown in Figure
Rose Nelson Pump.
The kinetics of pumping from Rose Nelson pump is given by the following equation:
The major problem associated with Rose-Nelson pumps was that the osmotic action began whenever water came in contact with the semipermeable membrane. This needed pumps to be stored empty and water to be loaded prior to use.
Higuchi and Leeper have proposed a number of variations of the Rose-Nelson pump and these designs have been described in US patents [
Higuchi-Leeper osmotic pump.
The Higuchi-Leeper pump has no water chamber, and the activation of the device occurs after imbibition of the water from the surrounding environment. This variation allows the device to be prepared loaded with drug and can be stored for long prior to use. Higuchi-Leeper pumps contain a rigid housing and a semi permeable membrane supported on a perforated frame; a salt chamber containing a fluid solution with an excess of solid salt is usually present in this type of pump. Upon administration/implantation, surrounding biological fluid penetrates into the device through porous and semipermeable membrane and dissolves the
Pulsatile delivery could be achieved by using Higuchi Leeper pump; such modifications are described and illustrated in Figure
Pulsatile release osmotic pump.
Higuchi and Theeuwes in early 1970s developed another variant of the Rose-Nelson pump, even simpler than the Higuchi-Leeper pump [
Higuchi Theeuwes Pump.
In this device, the rigid housing consisted of a semipermeable membrane. This membrane is strong enough to withstand the pumping pressure developed inside the device due to imbibition of water. The drug is loaded in the device only prior to its application, which extends advantage for storage of the device for longer duration. The release of the drug from the device is governed by the salt used in the salt chamber and the permeability characteristics of the outer membrane [
Small osmotic pumps of this form are available under trade name Alzet made by Alza Corporation in 1976. They are used frequently as implantable controlled release delivery systems in experimental studies requiring continuous administration of drugs. Such a implantable Alzet pump is shown in Figure
Alzet pump.
Rose-Nelson pump was further simplified in the form of elementary osmotic pump [
The elementary osmotic pump.
The pump initially releases the drug at a rate given by the following equation;
Push-pull osmotic pump is a modification of EOP (Figure
The push-pull osmotic pump (PPOP).
Figure
Mechanism of action of controlled porosity osmotic pump.
There are several obvious advantages inherent to the CPOP system. The stomach irritation problems are considerably reduced, as drug is released from the whole of the device surface rather from a single hole [
Various L-OROS systems available to provide controlled delivery of liquid drug formulations include L-OROS hardcap, L-OROS softcap, and a delayed liquid bolus delivery system. Each of these systems includes a liquid drug layer, an osmotic engine or push layer, and a semipermeable membrane coating. When the system is in contact with the aqueous environment, water permeates across the rate-controlling membrane and activates the osmotic layer (Figure
The expansion of the osmotic layer results in the development of hydrostatic pressure inside the system, thereby forcing the liquid formulation to be delivered at the delivery orifice. Whereas L-OROS hardcap and L-OROS softcap systems are designed to provide continuous drug delivery, the L-OROS delayed liquid bolus delivery system is designed to deliver a pulse of liquid drug (Figure
Liquid oral osmotic pump.
Figure of L-OROS system before and during operation.
The delayed liquid bolus delivery system comprises three layers: a placebo delay layer, a liquid drug layer, and an osmotic engine, all surrounded by a rate-controlling semipermeable membrane (SPM). The delivery orifice is drilled on the placebo layer end of the capsule shaped device. When the osmotic engine expands, the placebo is released first, delaying release of the drug layer (Figure
Figure
Marketed products of osmotic pump.
Product name | Active pharmaceutical ingredient | Design of osmotic pump |
---|---|---|
Acutrim | Phenylpropanolamine | Elementary pump osmotic pump [ |
Alpress LP | Prazosin | Push-pull osmotic pump [ |
Cardura XL | Doxazosin | Push-pull osmotic pump [ |
ChronogesicTM | Sufentanil | Implantable osmotic system [ |
Covera HS | Verapamil | Push-pull osmotic pump with time delay [ |
Ditropan XL | Oxybutinin chloride | Push-pull osmotic pump [ |
Dynacirc CR | Isradipine | Push-pull osmotic pump [ |
Efidac 24 | Pseudoephiderine | Elementary pump osmotic pump [ |
Efidac 24 | Chlorpheniramine meleate | Elementary pump osmotic pump |
Glucotrol XL | Glipizide | Push-pull osmotic pump [ |
Invega | Paliperidone | Push-pull osmotic pump [ |
Minipress XL | Prazocine | Elementary osmotic pump [ |
Procadia XL | Nifedipine | Push-pull osmotic pump [ |
Sudafed 24 | Pseudoephedrine | Elementary osmotic pump [ |
Viadur | Leuprolide acetate | Implantable osmotic system [ |
Volmex | Albuterol | Elementary osmotic pump [ |
Figure of sandwiched osmotic pump before and during operation.
Osmotic pumps are one of the systems for controlled drug delivery. Osmotic drug delivery systems typically consist of a drug core containing osmogen that is coated with a semipermeable membrane. This coating has one or more delivery ports through which a solution or suspension of the drug is released over time. Various osmotic systems include Rose-Nelson pump, the Higuchi-Leeper pumps, the Alzet and Osmet systems, the elementary osmotic pump, and the push-pull pump. Recent advances include the development of the controlled porosity osmotic pump, L-OROS pump, and sandwiched osmotic tablet. In future, various attempts are made to produce successful osmotic system like pulsatile delivery based on expandable orifice, lipid osmotic pump, telescopic capsule containing mini osmotic pump for delayed release, osmotic bursting osmotic pump, and so forth.