INTRODUCTION:

Oral controlled release (CR) systems most popular amongst all the drug delivery system. Because of pharmaceutical agents can be delivered in a controlled manner over a long period. Conventional oral drug delivery system supply continues release of drug, which 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 factor such as physic-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.

To overcome this problem a number of design option are available to control or modulate the drug release from a dosage form. Majority of oral dosage form fall in the category of matrix, reservoir or osmotic system. There has been increasing interest in the development of osmotic devices over the past 2 decades, due to reservoir systems have a drug core surrounded coated by the rate controlling membrane. Drug delivery from this system is not influenced by the different physiological factors within the gut lumen, and the release characteristic can be predicted easily from the known properties of the drug and the dosage form. 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.^[1,2]Osmotically Controlled Drug Delivery System (OCDDS) Osmotic devices are the most calculable controlled drug delivery system (CDDS) and can be employed as oral drug delivery systems. Osmotic pressure is used as the driving force for these systems to release the drug in a controlled pattern. Osmotic pump tablet (OPT) generally consists of a core including the drug, an osmotic agent, other excipients and semi permeable membrane coat.^[3]The first osmotic effect was reported by Abbe Nollet in 1748. Later in 1877, Pfeffer performed an experiment using semi-permeable membrane for separation of sugar solution from pure water. Osmotic pressure is used as driving force for release the drug in controlled manner for long period.^[4]Osmotic drug delivery has come long way since, Australian pharmacologist Rose and Nelson developed an implantable osmotic pump introduced in 1955, oral osmotic dosage form came in 1972 when Theuwes invented elementary osmotic pump. (1) Osmotic tablet worked on the principle Osmosis i.e. movement of water across a selectively permeable membrane.^[5] It is driven by a difference in osmotic pressure across the membrane. (2) It is driven by a difference in solute concentrations across the membrane that allows water, but rejects most solute molecules or ions.

Development of osmotic drug delivery systems was founded by Alza Corporation of the USA (now merged with Johnson and Johnson, USA) and it holds major number of the patents and also markets several products based on osmotic principle. The first and most important osmotic delivery system patent (U.S. Patent 3,845,770) assigned to Alza in 5 November 1974 and covering Theeuwes original elementary osmotic pump design. Indomethacin (Osmosin®) and Phenyl Propanolamine (Acutrim®) are the first two marketed osmotic based products.^[6]

Osmotic pumps offer following advantages:

The following advantages have contributed to the popularity of osmotic drug delivery systems

1. The delivery rate of zero order is possible with osmotic system.

2. Delivery may be delayed or pulsed.

3. Higher release rates are possible with osmotic system compared with conventional diffusion-controlled delivery system.

4. The release rate of osmotic system is highly predictable.

5. For oral osmotic system, drug release is independent to gastric pH and hydrodynamic condition.

6. The release from osmotic system is minimally affected by presence of food in gastrointestinal tract.

7. A high degree of in vivo-in vitro correlation is obtained in osmotic system.

8. Improve patient compliance with reduced frequency.

Osmotic pumps offer following disadvantages:

1. Dose dumping, if coating is not proper

2. Rapid development of tolerance

3. Special equipment is required for making an orifice in the system

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

5. Hypersensitivity reaction may occur

Need for developing osmotic drug delivery system:

1. In order to reduce dose

2. To decrease dose related side effects

3. To minimize dose related side effects

4. To provide control release and Increase patient compliance.^[7]

Mechanism of osmosis:

Core material contain water soluble osmotically active agent and blended with water soluble or insoluble drug, additives and coating has been carried out which functions as semi permeable membrane. This semipermeable membrane only permeable to water, initial penetration of water dissolves the critical part of the core, resulting in development of an osmotic pressure difference across the device delivers a saturated volume equal to the volume of water uptake through the membrane. Initial lag time (per hour) during which delivery rate increases to its maximum value, drug release is zero order, till all solid material is dissolved. The relation between Osmotic pressure (П) and the concentration of non-electrolyte is given for dilute solution which may be assumed to exhibit ideal behaviour by the Van‘t Hoff equation, membrane.

ПV = n 2 RT

Where, V = is the volume of solution.

n 2 = is number of moles of solute.

T = thermodynamic temperature and

R = is the gas constant.

Principle of 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 semi permeable membrane. 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.

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.^[8]

Components of osmotic drug delivery systems:

· Osmotic pumps contain a drug semi permeable membrane.

· The semi permeable membrane usually contains a plasticizer and in some cases surfactant and also pore forming agents.

· Parts from the above materials, common tabletting aids such as lubricants, binder, diluents, glidants, wetting agents etc.^[9,10]

Drugs:

· Highly potent drug

· Short biological half-life [2 -6 hrs]

· Required for prolonged treatment

Semipermeable membrane:

· Cellulose acetate is a commonly used semi-permeable polymer for the preparation of osmotic pumps.

· It is accessible in different acetyl content of 32% and 38%.

· Polymers are agar acetate, amylase triacetate, poly-(vinyl-methyl)-ether copolymers and selectively permeable poly-(glycolic-acid) and poly-(lactic-acid) derivatives can be used as semi-permeable film forming materials.^[11,12]

Hydrophilic and hydrophobic polymers

· These polymers are used in the formulation development of osmotic system for making drug contain matrix convention.

· The highly water soluble compounds can be co-entrapped in hydrophobic matrices and moderately water soluble compounds can be co-entrapped hydrophilic matrices to obtain more controlled release.

· The non-swellable polymers are used in case of highly water-soluble drugs.

· Ionic hydrogels such as sodium carboxymethyl cellulose, carboxy methylcellulose,

· Hydroxy propyl MC, high molecular weight poly-(vinyl pynolidone) and hydrophobic polymers such as EC and wax materials used for this purpose.^[9,10]

Wicking agents:

· Wicking agent is defined as a material with the ability to draw water into 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 physiosorption with water.

· The function of the wicking agent is to carry water to surface inside the core of the tablet, thereby creating channels or a network of increased surface area.

· Materials, which suitably for act as wicking agents include colloidal silicon-di-oxide, kaolin, titanium-di-oxide, alumina, sodium lauryl sulphate (SLS), colloidal silica and PVPare non swellable wicking agents.^[11,12]

Solubilising agents:

· Agents that inhibit crystal formation of the drugs or otherwise act by complexation with the drugs. Eg – PVP, PEG-8000, cyclodextrins.

· A high HLB micelle-forming surfactant, particularly anionic surfactants.

Eg – tween-20, 60 and 80, poly-oxy-ethylene or poly-ethylene containing surfactants and other long chain anionic surfactant such as SLS Citrate esters and their combinations with anionic surfactants. Eg – alkyl esters particularly tri ethyl citrate.^[11,12]

Osmogens:

· Osmogen are essential ingredients of the osmotic formulations. Include inorganic salts and carbohydrates.

· Generally combination of osmogen is used to achieve optimum osmotic pressure inside the system.^[13,14]

Surfactants:

· Surfactants are particularly useful when added to wall forming material.

· Typical surfactants are Poly-oxy-ethylenated glyceryl lecinoleate, Poly-oxy-ethylenated castor oil having ethylene oxide, glyceryl laureates and glycerol.^[15]

Coating solvents:

· Solvent suitable for making polymeric solution that is used for manufacturing the wall of the osmotic device include inert inorganic and organic solvents.

· Typical solvents include methylene chloride, acetone, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethyl acetone, cyclo-hexane, carbon tetrachloride, water etc and the mixture of solvent such as acetone : methanol (80:20), acetone : ethanol (80:20).^[15]

Plasticizers:

· Increase the flexibility and permeability of the fluids.

· 0.001 to 50 parts of a plasticizer or a mixture of plasticizers are incorporated into 100parts of wall forming materials.

· PLASTICISERS are triethyl citrate and other citrates, dialkyl phthalates and otherphthalates, tristyl phosphates and other phosphates, acetates, glycolate, glycerolate, benzoate, sulphonamides and halogenated phenyls.^[15]

Flux regulators:

· Flux regulators are added to the wall forming material. It assists in regulating the fluid

· Permeability of flux through wall.

· Heat also increase the flexibility and porosity of the lamina. Usually, from 0.001 parts to 50 parts or high weight fraction of flux regulators can be used.

· Poly-hydric alcohols such as poly alkylene glycols and low molecular weight glycols such as poly propylene, poly butylenes and poly amylene etc; can be used as flux regulators.^[15]

Reforming agents:

· These agents are particularly used in the pumps developed for poorly water soluble drug and in the development of controlled porosity or multi-particulate osmotic pumps.

· These pore-forming agents cause the formation of microporous membrane.

For example alkaline metal salt such as sodium chloride, potassium chloride and potassium phosphate.

· Alkaline earth metals such as CaCl2 and carbohydrates such as glucose, sucrose, fructose, lactose, maltose, mannitol and polyols such as polyvinyl pyrolidone and polyhydric alcohols can be used as pore forming agent.^[15]

Implantable:

1. The Rose and Nelson Pump

2. Higuchi Leeper Pump

3. Higuchi Theuwes pump

4. Implantable Mini osmotic pump

Oral osmotic pump:

1. Single chamber osmotic Pump tablet:

· Elementary osmotic pump tablet (EOP)

2. Multilayer osmotic pump tablet:

· Push- pull osmotic pump tablet

· Sandwiched Osmotic tablet

3. Specific types

· Controlled porosity osmotic pump tablet(CPOP)

· Colon targeted oral osmotic system(OROS-CT)

· Asymmetrical membrane osmotic tablet

· Osmotically Rupturable tablet

· Liquid oral osmotic system(L-OROS)

· Effervescent osmotic tablet(EOT)

· Self-emulsified osmotic tablet

· Monolithic osmotic tablet(MOT)

· Osmotic pellet

Implantable Osmotic Drug Delivery System:

Osmotic principles have been applied to human parenteral therapy, resulting in the development of the DUROS® implantable osmotic drug delivery system. These systems allow drug delivery for site-specific as well as systemic use for delivery periods of days to 1 year. (10) All materials in the DUROS system were selected for their biocompatibility and suitability for implant use. The drug-contacting materials are also screened for compatibility with the drug and the specific drug formulation excipients. Radiation sterilization (gamma) may be utilized to sterilize the final drug product. If the drug formulation cannot bear sterilizing doses of radiation, then a DUROS subassembly is radiation sterilized, and the drug formulation is added in a final aseptic operation. Hence, the materials in the DUROS system were also screened for their ability to withstand sterilizing doses of radiation.

Oral osmotic drug delivery systems:

Oral route is the most popular route of administration of drugs in the body, most of the osmotic systems are developed for oral drug delivery. It is possible to deliver drugs at zero-order release rate, independent of its gastric pH and hydrodynamic conditions by osmotically controlled drug delivery systems. The oral osmotic pump are developed by coating the core tablet with the semi permeable membrane with an orifice or coat containing some leachable material which form In-situ pore for the controlled delivery of the drug. Osmotic tablets are orally active osmotically driven systems (OODS). Elementary osmotic pump was first introduced, but with time number of advances occurs in OODS. Following are different osmotic system and Special technology.^[15]

A. Elementary Osmotic Pump Tablet (EOP):

Theuwes invented elementary osmotic pump in 1972 (Fig.1). EOP consists of single-core system i.e. simple single layer osmotic core tablet surrounded by non-biodegradable coat having orifice (size varies from 0.5 to.1.5 mm). The researchers developed different drilling approaches like mechanical drilling, laser drilling (CO2laser beam with output wavelength of 10.6μ) which offered excellent reliability and indentation made in core tablets by using modified punches having needle on upper punch. EOP required external drilling.^[16-19]

Figure 1: Theuwes design of elementary osmotic pump (U.S. Patent 3,845,770)

B. Multilayer Osmotic Pump Tablet

The osmotic system consists of multiple layers for controlling predetermined release pattern. Multilayer Osmotic Pump Tablet can be easily used for both water insoluble and soluble drug. Following are different multilayer osmotic system,

1. Push Pull Osmotic Tablet

Push pull osmotic tablet (Fig. 2) characterized by swellable layer which pull the drug from osmotic pump. It is a bilayer tablet coated with a semi-permeable membrane. The upper compartment contains the drug and is connected to the outside environment via a small delivery orifice. Carbopol(around 20-40% wt of the tablet) is most commonly used polymer in push layer. This system also have disadvantage of localized release and higher cost.^[20,21,22]

Figure 2: Push pull osmotic tablet

2. Sandwiched Osmotic Tablet

Sandwiched osmotic tablet 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 delivery orifices. Drug is released from the two orifices situated on the opposite sides of the tablet and thus these pumps can be suitable for the drugs prone to cause local irritation of the gastric mucosa.^[23] Fig. 3.

E. Asymmetrical Membrane Osmotic Tablet

Asymmetric membrane capsules consist of a drug containing core surrounded by a membrane which has an asymmetric structure i.e. it has a relatively thin, dense region supported on a thicker, porous region. The capsule wall is made from a water insoluble polymer such as cellulose acetate unlike a conventional gelatin capsule; the asymmetric membrane capsule does not dissolve immediately but provides prolonged release of the active ingredient incorporated in the capsule.^[27,28,29]

F. Osmotically Rupturable Tablet

A controlled-release delivery system utilizing an osmotic bursting mechanism was invented by Baker. The system surrounded by a semipermeable membrane and when placed in an aqueous environment, osmotic components imbibes water into the systems result into swelling, swelling continue until the membrane ruptured and released the active compound to the outside environment. Once the systems ruptured, drug was released by osmotic pumping and diffusion mechanisms through the ruptured area.^[30]

G. Liquid-oral osmotic system (L-OROS)

· Liquid OROS are designed to deliver liquid formulations and combine the benefits of extended release with high bioavailability. They are of three types:

· L-OROS hard cap

· L-OROS soft cap

· 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 through the delivery orifice.^[31]

H. Effervescent Osmotic Tablet:

Drugs which are poorly soluble at low pH may precipitate at the gastric pH and block the delivery orifice, thus affecting the functioning of the osmotic pump. An effervescent compound, such as potassium bicarbonate can be incorporated to overcome the problem. The bicarbonate reacts with the acid in the exterior environment generating carbon dioxide. The expansion of the gas dispenses the precipitated drug and aids in rapid absorption of the drug and preventing the blockage of the orifice (Hou et al.) studied the effervescent osmotic pump tablet of Traditional Chinese Medicine Compound Recipe (TCMCR) named as Fuzilizhong. Sodium chloride and sodium hydrogen carbonate are most commonly used osmogen in EOT.^[32]

I. Self-Emulsified Osmotic Tablet:

Self –Emulsified osmotic tablets are useful for new chemical entities exhibit poor aqueous solubility and present a major challenge to modern drug delivery system, because of their low bioavailability. The Self-emulsifying osmotic pump tablet (SEOPT) has two outstanding features; it could improve the bioavailability by self-emulsifying drug delivery system (SEDDS), control the release rate and make the plasma concentrations more stable. Selfemulsifying drug delivery systems (SEDDS) are usually used to improve the bioavailability of hydrophobic drugs.^[33,34]]

J. Monolithic Osmotic Systems (MOS):

The systems consist of uniformly dispersion of osmotically active therapeutic agents (drugs) in biocompatible polymeric matrices. The drug particles are encapsulated by polymers to form microcapsules throughout the matrix. These osmotic systems display zero-order drug delivery kinetics. The principal energy source leading the release of agents is osmotic pressure. When such a system is placed in an aqueous medium, the tablet imbibes water into the outer most layer of the dispersion at a rate dictated by permeability of the polymer. Water transport into the film continues until rupture of the drug-containing capsules occurs, after which time saturated drug solution is pumped through channels created by the rupture. This process repeats itself in a serial fashion until the system is exhausted of agent. Due to the osmotic functionality of these systems, reduction of the thermodynamic activity of water outside the system can proportionally reduce the release of agent.^[35,36]]

K. Osmotic Pellet:

Osmotic pellet is a new model of drug release by osmotic pumping and diffusion mechanism. Pellets coated with a semipermeable film developing pores created by the leaching of water-soluble compounds initially present in the coating. The model describes dynamically all the main processes occurring during release, i.e. the inflow of solvent driven by the difference in osmotic pressure across the coating film, dissolution of the drug, swelling of the pellet due to mass accumulation, the build-up of hydrostatic pressure inside the pellet, and the outflow of the dissolved drug through the pores. Drug release from a coated formulation can occur by diffusion through the film and pores in the film, or by convection through pores or micro-cracks present in the film. Drug release by diffusion from coated pellets along with osmotic pressure has been extensively studied and reported in the literature.^[37,38]

Elementary osmotic pump (EOP):

Elementary osmotic pump works on the same mechanism as the impalatable pumps it is simplest possible form of osmotic pump as it does not require special equipment and technology. This device was further simplification of Higuchi – Theeuwes pump. EOP was developed in the year 1975 by Theeuwes. The EOP consist of single layered tablet core containing a water soluble drug with or without other osmotic agent. A semi permeable membrane surrounds the core of the tablet. When such a system is absorbed water from the GIT enter through the membrane in the core, the drug dissolved and the drug solution is pumped out through the exit orifice.^[39]

Factors affecting drug release rate

u Solubility

· Medicaments for osmotic delivery should have water solubility in the desired range to get optimize drug release. By modulating the solubility of these drugs within the core, effective release patterns may be obtained for the drugs, which might otherwise appear to be poor candidate for osmotic delivery.

· Solubility-modifying approaches

· Use of swellable polymers – Polyethylene Oxide have uniform swelling rate which causes drug release at constant rate.

· Use of effervescent mixtures – Mixture of citric acid and sodium bicarbonate which creates pressures in the osmotic system and ultimately controls the release rate.

· Use of wicking agents – These agents may enhance the surface area of drug with the incoming aqueous fluid. Eg – Sodium lauryl sulphate, Colloidal silicon dioxide etc.

· Use of encapsulated excipients – Solubility modifier excipients used in form of mini tablet coated with rate controlling membrane.

· Use of Cyclodextrin derivatives – Increases solubility of poorly soluble drugs. The same occurrence can also be used for the osmotic systems.

· Use of crystal habit modifiers – Different crystal form of the drug may have different solubility, so the excipients which may change crystal habit of the drug can be used to modulate solubility. Different excipients can be used to modulate the solubility of APIs with different mechanisms like saturation solubility, pH dependent solubility. Example – Organic acids, buffering agents etc.

· Size of delivery orifice.

· To achieve an optimal zero order delivery profile, the cross section area of the orifice must be smaller than a maximum size to minimize drug delivery by diffusion through the orifice. The typical orifice size in osmotic pumps ranges from 600μ to 1 mm.

· Methods to create a delivery orifice in the osmotic tablet coating are –

· Mechanical drill

· Laser drill – Co2 laser beam (10.6μ) and low costs

· Use of leachable substance in the semi-permeable coating. Eg- controlled porosity osmotic pump. 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.^[40,41]

Evaluation parameters for osmotic tablet:

· Visual inspection:

Visual inspection of the film for smoothness, uniformity of coating, edge overage and lusters

· Coating uniformity:

The uniformity of coating among the tablets can be estimated by determining the weight, thickness and diameter of the tablet before and after coating

· Coat weight and thickness:

The coat weight and thickness can be determined from depleted devices by following careful washing and drying of the film using standard analytical balance and screw guage.

· Orifice diameter:

The mean orifice diameter of the osmotic pump tablet can be determined by using scanning electron microscopy (SEM)^[42,43]

· In vitro drug release:

The in vitro drug release rate of drug from osmotic system can be determined using diverse methodologies, conventional USP dissolution apparatus I and II.^[44]

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Received on 08.02.2017 Accepted on 11.04.2017

Asian J. Res. Pharm. Sci. 2017; 7(2): 68-76.

DOI: 10.5958/2231-5659.2017.00010.8

ABSTRACT: