INTRODUCTION:

Many conventional drug delivery systems have been designed by various researchers to modulate the release a drug over an extended period of time and release. The rate and extent of drug absorption from conventional formulations may vary greatly depending on the factors such as physico-chemical properties of the drug, presence of excipients, physiological factors such as presence or absence of food, pH of the gastro-intestinal tract (GI) and so on. However, drug release from oral controlled release dosage forms may be affected by pH, GI motility and presence of food in the GI tract. Drugs can be delivered in a controlled pattern over a long period of time by the process of osmosis.

Drug delivery from this system is not influenced by the different physiological factors within the gut lumen and the release characteristics can be pre-dicted easily from the known properties of the drug and the dosage form. Osmotically controlled drug delivery system, deliver the drug in a large extent and the delivery nature 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. Osmotically controlled oral drug delivery systems utilize osmotic pressure for controlled delivery of active agents^1-2.

Advantage of Osmotic Drug Delivery System³:

· Desired zero- order delivery rates are achievable with osmotic system.

· Reduced frequency of dosing, improved efficiency, better patient compliance and reduced side effects. Delivery may be pulsed or delayed, if necessary.

· Constant rate of drug release independent of gastric pH and hydrodynamic conditions.

· The attainable delivery rate is significantly greater than that attained with the diffusion based system of comparable size.

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

· The release rate of osmotic systems is highly predictable and can be programmed by modulating

· the release-controlled parameters. The system is applicable to drugs with a wide range of molecular weight and chemical

· composition which are normally difficult to deliver by normal solution- diffusion mechanism Osmotic system can be designed to deliver liquid formulation as well.

· Delivery rate is almost independent of delivery orifice size within limits.

Disadvantages of Osmotic Drug Delivery System³:

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

· Expensive.

· Toxicity due to dose dumping.

· Additional patient education and counseling is required.

· Rapid development of tolerance.

· Hypersensitivity reaction may occur after implantation.

· Poor systemic availability in general.

· It may cause gastric irritation or ulcer due to release of saturated solution of drug.

Principle and basic concept of osmotic drug delivery system⁴:

It is based on the principle of osmotic pressure. Osmotic pressure is a colligative property, which is dependent on concentration of solute that contributes 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 achieved 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 suitable for delivery of drugs with moderate water solubility. Osmotic pressure is proportionate to temperature and concentration and the relationship can be described by following equation.

π = n₂ RT

Where, π = osmotic coefficient

n₂ = molar concentration of solute in the solution

R = gas constant

T = Absolute temperature

Key Parameters That Influence the Design of Osmotic Controlled Drug Delivery Systems^4-6:

Orifice size:

To achieve an optimal zero-order delivery profile, the cross-sectional area of the orifice must be smaller 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:

Mechanical drill/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. 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. Use of leachable substances in the semipermeable coating : e.g. controlled porosity osmotic pump.

Solubility:

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 suspension. Second, the drug solubility can be modified employing different methods such as co compression of the drug with other excipients, which improve the solubility. For example, cyclodextrin can be included in the formulation to enhance 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:

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.

Semipermeable Membrane

Since the semipermeable 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.

Basic Components of Osmotic Systems:^7-9

Drug:.+65

Which have short biological half-life and which is used for prolonged treatment are ideal candidate for osmotic systems. Various drug candidates such as Diltiazem HCl, Carbamazepine, Metoprolol, Oxprenolol, Nifedipine, Glipizide etc are formulated as osmotic delivery.

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 should possess certain characteristics, such as impermeability to the passage of drug and other ingredients present in the compartments. The membrane should be inert and maintain its dimensional integrity to provide a constant osmotic driving force during drug delivery. 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.

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 sulfates 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 such as ferric oxide. Swellable polymers such as poly(alkylene oxide), poly(ethylene oxide), and poly (alkalicarboxymethylcellulose) are also included in the push layer of certain osmotic systems. Further, hydrogels such as Carbopol (acidic carboxypolymer), Cyanamer (polyacrylamides), and Aqua-Keeps (acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polygluran) may be used.

Flux Regulators:

Delivery systems can be designed to regulate the permeability of the fluid by incorporating fluxregulating agents in the layer. Hydrophilic substances such as polyethethylene glycols (300 to 6000 Da), polyhydric alcohols, polyalkylene glycols, and the like improve the flux, whereas hydrophobic materials such as phthalates substituted with an alkyl or alkoxy (e.g., diethyl phthalate or dimethoxy ethylphthalate) tend to decrease the flux. Insoluble salts or insoluble oxides, which are substantially water-impermeable materials, also can be used for this purpose.

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

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 poreforming agents cause the formation of microporous membrane. The microporous 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, mannitol and, diols and polyols such as poly hyric alcohols and polyvinyl pyrrolidone can be used as pore forming agents.

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 alcohal, butyl alcohal, ethyl acetate, cyclohexane, carbon tetrachloride, water etc. 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) etc. can be used. 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 behavior of polymers and these changes may affect the permeability of the polymeric films. 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.

REFERENCES:

1. Srikonda Sastry, Kotamraj Phanidhar, Barclay Brian, Osmotic controlled drug delivery system, in Li Xiaoling, Jasti Bhaskara R (eds), Design of Controlled Release Drug Delivery Systems, McGraw-Hill Companies, INC, New York, pp 203- 229,2006

2. McClelland GA, Sulton SC, Engle K, Zentner GM. The solubility–modulated osmotic pump: invitro / in vivo release of diltiazem hydrochloride. Pharma. Res. 1991; 8:88-92.

3. Rose S, Nelson JF. A continuous long-term injector. Aust J Exp Biol, 1955; 33:415

4. Higuchi T, Leeper HM. Improved osmotic dispenser employing magnesium sulfate and magnesium chloride. US Patent 3760804, 1973.

5. Higuchi T, Leeper HM. Osmotic dispenser with means for dispensing active agent responsive to osmotic gradient. US Patent 3995631, 1976.

6. Theeuwes, F. Elementary Osmotic Pump. J. Pharm. Sci., 1975; 64:1987-1991.

7. Kaushal AM, Garg S. An update on osmotic drug delivery patents. Pharm Tech, Aug 2003; 27:38-44.

8. Bhatt PP. Osmotic drug delivery systems for poorly soluble drugs. The drug delivery companies report autumn/winter 2004.

9. Parmar NS, Vyas SK, Jain NK. Advances in controlled and novel drug delivery. CBS publisher & distributors, New Delhi, pp 18-39, 2001.

Received on 23.03.2017 Modified on 28.04.2017

Res. J. Pharm. Dosage Form. & Tech. 2017; 9(2): 67-70.

DOI: 10.5958/0975-4377.2017.00013.1

Kishor Lohiya