250 | p a g e international standard serial number (issn .... rpa1516158015.pdfcontrolled drugs...

250 | P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 4(1): January-February 2015

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093*** ICV 5.13*** Pharmaceutical Sciences REVIEW ARTICLE……!!!

OSMOTIC DRUG DELIVERY SYSTEMS- A REVIEW S.Palanichamy, M.Rajesh

*, D.Sherly and P.Solairaj

Sankaralingam Bhuvaneswari College of pharmacy, Anaikuttam, Sivakasi- 626130.

Tamilnadu, India.

KEYWORDS:

Controlled drug delivery,

Osmotic pressure, Osmotic

Pumps, Zero order kinetics.

For Correspondence:

M.Rajesh*

Address: Department of

Pharmaceutics, Sankaralingam

Bhuvaneswari College of

pharmacy, Anaikuttam,

Sivakasi. 626130,

Tamilnadu, India.

Email:

[email protected]

ABSTRACT

A number of design options are available to control or modulate the

drug release from a dosage form. Majority of per oral dosage form fall

in the category of matrix, reservoir or osmotic system. Osmotic pumps

are most promising systems for controlled drug delivery. These systems

are used for both oral administration and implantation. 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. Osmotic

drug delivery systems release the drug with the zero order kinetics,

which does not depend on the initial concentration. This review brings

out new technologies, fabrication and recent clinical research in osmotic

drug delivery.

mailto:[email protected]



INTRODUCTION:

With the conventional dosage forms, it is difficult to achieve and maintain the concentration of the

administered drug within the therapeutic range leading to fluctuations in the plasma drug levels1. In

the recent years, pharmaceutical research has led to the development/ invention of several novel

controlled drugs delivery systems of which oral controlled drug delivery system has received greater

attention since it is the most popular route of drug administration2

. One of such an oral drug delivery

system is an osmotic controlled drug delivery system. Osmotically controlled oral drug delivery

systems utilize osmotic pressure as the energy source for the controlled delivery of drugs. Osmotic

devices are the most promising strategy based systems for controlled drug delivery. They are the

most reliable controlled drug delivery systems and could be employed as oral drug delivery systems

3.In osmotic drug delivery system, it is possible to achieve and sustain a drug plasma concentration

within the therapeutic window of drugs, which reduces the side effects and frequency of

administration4, 5

.

HISTORICAL BACKGROUND:

In 1955, Rose and Nelson utilized the principles of osmotic pressure in drug delivery for the first time

6. They described two systems: one that delivered 0.02ml/day for 100 days and another that delivered

0.5ml/day for 4 days, both for use in pharmacological research. In the 1970s, Higuchi and Leeper

proposed a series of variations of the Rose – nelson Pump7, 8

. Theeuwes further modified the Rose-

Nelson Pump and developed a system9. Small osmotic pumps of these forms are sold under the trade

name ALZET (Alza Corp., CA). The device has a volume of approximately 170µl, and the normal

delivery rate is 1µl/hr. A major milestone was achieved in 1974 with the description by Theeuwes

and Alza’s co-workers of a tablet design composed of a compressed tablet core surrounded by a semi

permeable membrane with a single orifice, so called Elementary Osmotic Pump (EOP) 10

. This design

adaptation for human use was conveniently processable using standard tabletting and coating

procedures and equipments. The first two products indomethacin, osmosin and phenylpropanolamine,

Acutrim TM was launched in the 1980s11, 12

.0ral osmotic drug delivery system (OODS) development

continued with two new OODS designs, the controlled porosity osmotic pumps (CPOP) and the

push- pull osmotic pumps (PPOP). The first of these was the CPOP, which was designed to decrease

the risk of extremely localized drug-induced irritation at the site close to the orifice13

. In the 2000s, a

new drug product based on ODDS technology was formulated to deliver methylphenidate to children

(above the age of 6 years) with Attention –Deficit Hyper Activity disorder (ADHD). These delivery



systems were based on a new design, the Push- Stick Osmotic Pumps (PSOP), which combined

immediate and sustained drug release phase14

.Drug release from these systems is independent of pH

and other physiological parameters to a large extent and it is possible to modulate the release

characteristic by optimizing the properties of drug and system. A number of patents granted in the

last few years and Oral Osmotic Drug Delivery Systems are becoming attractive technologies

because of their abilities to enhance the clinical profile of certain therapeutic agents and to positively

differentiate a drug product from others on the market15

.Osmotically controlled delivery system

utilizes the principle of osmotic pressure for the controlled delivery of active agents16

. They are

among the most probable controlled drug delivery system and could be employed as oral drug

delivery systems or implantable devices. Osmotic Pump Tablet (OPT) generally consists of a core

including the drug, an osmotic agent, other excipients and semi permeable membrane coat 17

.

THEORY:

Osmosis can be defined as spontaneous movement of 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 and impermeable to solute. The pressure applied

to the higher- concentration side to inhibit solvent flow is called osmotic pressure18

.Osmotic pressure

is a colligative property, which depends on concentration of solute that contributes to osmotic

pressure. Solutions of different concentration 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 of drug19

.

PRINCIPLE OF OSMOSIS: 20, 21

An osmotic system releases a therapeutic agent at a predetermined, zero order delivery rate based on

the principle of Osmosis, which is movement of a solvent from lower concentration of solute towards

higher concentration of solute across a semi-permeable membrane22

. After administration of osmotic

system, water is imbibed into the core osmotically through semi-permeable membrane resulting in

development of hydrostatic pressure that pumps drug containing solution or suspensions out of the

core through one or more delivery ports. The delivery from the system is controlled by the water

influx through semi-permeable membrane23

.In 1886; 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=ØcRT

Where,

Π= Osmotic coefficient, Ø =osmotic pressure, c =molar concentration, R=Gas constant and T=

Absolute temperature

ADVANTAGE SOF OSMOTIC DRUG DELIVERY SYSTEM: 24, 25, 26, 27

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 SYSTEM: 28, 26

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

Expensive.

Toxicity due to dose dumping.

Additional patient education and counselling 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.



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

BASIC COMPONENTS OF OSMOTIC DRIG DELIVERY SYSTEMS: 29

The basic components of osmotic drug delivery systems are as follows:

Drug

Osmotic agent

Semi permeable membrane

Pore former

Plasticizer

Wicking agent

Coating solvents

1. DRUG:

All drugs are not suitable candidate for osmotic system as prolonged action medication. Drug with

biological half life > 12 hours E.g. Diazepam and drug which have very short half life i.e. < 1 hour

E.g. Penicillin G, Furosemide are not suitable candidate for osmotic controlled release. Drug which

have biological half-life in between 1-6 hours and which is used for prolonged cure of diseases are

ideal drugs for osmotic systems. A variety of drug candidates such as Diltiazem HCl,

Carbamazepine, Metoprolol, Oxprenolol, Nifedipine, Glipizide etc. are formulated as osmotic drug

delivery systems.

2. OSMOTIC AGENT:

Osmotic components usually are ionic compounds consisting of either inorganic salts or hydrophilic

polymers. Different type of osmogents can be used for such systems are categorized as water –

soluble salts of inorganic acids like magnesium chloride or sulphate; 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; carbohydrates like mannose, sucrose,

maltose lactose; water –soluble amino acids and organic polymeric osmogents30

.The osmotic

pressures of saturated solutions of commonly used osmogens are given in Table -1



Table- 1: Osmotic pressure of saturated solution of commonly used osmogents

Compound of mixture Osmotic pressure(atm)

Laciose – fructose 500

Dextrose – fructose 450

Sucrose – fructose 430

Mannitol –fructose 415

Sodium chloride 356

Potassium chloride 245

Fructose 335

Lactose-Sucrose 250

Lactose –Dextrose 225

Mannitol- Sucrose 170

Sucrose 150

Mannitol – Lactose 130

Dextrose 82

Potassium Sulphate 39

Mannitol 38

Sodium phosphate tribasic.12H2O 36

Sodium phosphate dibasic.7H20 31

Sodium phosphate dibasic. 12H20 31

Sodium phosphate monobasic.H20 28

Sodium phosphate dibasic. Anhydrous 21

3. SEMI PERMEABLE MEMBRANE:

There are various types of polymers used as semi permeable membrane. The selection of polymer is

based on the solubility of drug as well as amount and rate of drug to be released from pump.

Cellulose acetate is a commonly employed as semipermeable polymer for the preparation of osmotic

pumps.It is available in different acetyl content of 32% and 38%. A part from cellulose derivative,

some other polymers such as agar acetate, amylase tri acetate, betaglucan acetate, poly (vinyl) ether

copolymers, Poly (orthoesters) poly acetals and selectively permeable poly (glycolic acid) and poly

(lactic acid ) derivatives can be used as semi permeable film forming materials.



Ideal Properties of Semi Permeable Membrane

1. It should be adequately thick to withstand the pressure generated within the device.

2. It should have enough wet strength and water permeability.

3. It should be biocompatible.

4. It should be rigid and non-swelling.

4. PORE FORMER:

These agents are particularly used in the development of pump for poorly water-soluble drugs and in

controlled porosity tablets. These pore forming agents can cause the formation of micro porous

membrane. The pore formers can be inorganic or organic and solid or liquid in nature. Some

examples of pore former are alkaline metals such as sodium chloride, sodium bromide, potassium

chloride, potassium phosphate, alkaline earth metals such as calcium chloride and calcium nitrate.

Carbohydrates such as sucrose, glucose, fructose, lactose, mannitol31

.

5. PLASTICIZERS:

Plasticizers have a crucial role to play in the formation of a film coating and its ultimate structure.

Plasticizer increases the wetability, flexibility and permeability of fluids. They can change viscous-

elastic behavior of polymers and these changes may affect the permeability of the polymeric films.

Plasticizers can have a marked effect on both qualitatively and quantitatively on the release of active

materials from modified release dosage forms where they are incorporated into the rate-controlling

membrane.

Some of the plasticizers used are as below:

For low permeability- Polyethylene glycols, Glycolate, Glycerolate, Myristates, Ethylene glycol

monoacetate; and diacetate. For more permeable films- Tri ethyl, Diethyl tartarate or Diacetin.

6. WICKING AGENTS:

It is defined as a material with the ability to draw water into porous network of a delivery orifice.A

wicking agent has ability to draw water into the porous network of a delivery device. A wicking

agent is of either swellable or non-swellable in nature. The function of wicking agent is to carry water

to surfaces inside the core of tablet, thereby creating channels or network of increased surface area.

Materials used for wicking agent includes colloidal silicon dioxide, kaolin, alumina, sodium lauryl

sulphate, low molecular weight poly vinyl pyrrolidine, bentonite etc.



7. COATING SOLVENT:

The primary function of solvent system is to dissolve or disperse the polymer and other additives and

convey them to substrate surface.Solvents suitable for making polymeric solution that is used for

manufacturing the wall of the osmotic device include inert inorganic and organic solvents. The

various types of solvents and their combinations are as follows: methylene chloride, ethanol,

isopropyl alcohol, butyl alcohol, ethyl acetate, cyclohexane, carbon tetrachloride and water. The

mixture of solvents such as acetone- methanol (80:20), methylene chloride- methanol (79:21),

methylene chloride-methanol-water (75:22:3) can be used.

The ideal solvent system should have following properties32

.

It should easily and completely dissolve the polymer.

It should easily disperse other coating components into solvent system.

It should not give extremely viscous solution with small concentration of polymer (2-10%).

It should be odourless, colourless, tasteless, inexpensive, nontoxic, and non-irritant.

It should have rapid drying rate.

CLASSIFICATION OF OSMOTIC DRUG DELIVERY SYSTEMS:

A. IMPLANTABLE OSMOTIC PUMPS:33

Implantable osmotic pumps include the following:

1. The Rose Nelson Pump

2. Higuchi –Leeper Pump

3. Higuchi-Theeuwes Pump

4. Implantable Mini Osmotic Pump

B. ORAL OSMOTIC PUMPS:34

Oral osmotic pumps can be grouped into

1. Single chamber osmotic pumps

a) Elementary osmotic pump(EOP)

2. Multiple chamber osmotic pumps

a. Osmotic pump with non-expanding second chamber

b. Push –pull osmotic pump(PPOP)

3. Modified oral osmotic drug delivery system

a. Controlled porosity osmotic pump(CPOP)

b. Osmotic Bursting Osmotic Pump



c. Multi particulate delayed release systems

d. Monolithic osmotic pump

e. Colon targeted oral osmotic system(OROS-CT)

f. Sandwiched osmotic tablet(SOTS)

g. Liquid oral osmotic system(L-OROS)

h. Osmotic matrix tablet

A. IMPLANTABLE OSMOTIC PUMPS:

1. The Rose Nelson Pump

Rose and Nelson, the Australian scientists, were initiators of osmotic drug delivery. In 1955, they

developed an implantable pump, which consist of three chambers: a drug chamber, a salt chamber

contains excess solid salt and a water chamber. The drug and water chambers are separated by rigid

semi permeable membrane. The difference in osmotic pressure across the membrane moves water

from the water chamber into the salt chamber. The volume of the salt chamber increase because of

this water flow, which distends the latex diaphragm separating the salt and drug chambers, there by

pumping drug out of the device35

.

Figure-1. The Rose Nelson Pump

2. Higuchi Leeper Pump

The Higuchi- Leeper pump is modified version of Rose – Nelson Pump. It has no water chamber, and

the device is activated by water imbibed from the surrounding environment. The pump is activated

when it is swallowed or implanted in the body. This pump consists of rigid housing and semi

permeable membrane is supported on a perforated frame, a salt chamber containing a fluid solution

with an excess of solid salt. This type of pump is implanted in body of an animal for delivery of

antibiotics or growth hormones to animals36

.



Figure- 2. Hguchi Leeper Osmotic Pump

3. Higuchi- Theeuwes Pump

Higuchi & Theeuwes developed a similar form of Rose –Nelson Pump. This pump comprises a rigid,

rate controlling outer semi permeable membrane surrounding a solid layer of salt coated on the inside

by an elastic diaphragm and on the outside by the membrane. Water is osmotically drawn by the salt

chamber, forcing drug from the drug chamber37

.Osmotic pump of this type are available under trade

name Alzet. A mixture of citric acid and sodium bicarbonate in salt chamber in presence of water

generate carbon dioxide gas which exert a pressure on the elastic diaphragm, eventually delivers the

drug from the device.

Figure-3. Higuchi- Theeuwes Pump

4. Implantable Mini Osmotic Pump

This is most advanced version in the category of implantable pumps developed byAlza corporation. It

is composed of three concentric layers – the drug reservoir, the osmotic sleeve and the rate

controlling semi permeable membrane. The additional component called flow moderator is inserted

into the body of the osmotic pump after filling.

The inner most compartment is the drug reservoir which is surrounded by an osmotic sleeve, a

cylinder containing high concentration of osmotic agent. The osmotic sleeve was covered by a semi

permeable membrane. When the system is placed in aqueous environment water enters the sleeve



through semi permeable membrane, compresses the flexible drug reservoir and displaces the drug

solution through the flow moderator. These pumps are available with variety of delivery rates

between 0.25 to 10 ml/hr and the delivery duration between one day and four weeks.

Figure- 4. Implantable Mini Osmotic Pump

B.ORAL OSMOTIC PUMPS:

1. Single chamber osmotic pumps

a. Elementary osmotic pump(EOP)

It is fabricated as a tablet coated with semi permeable membrane, usually cellulose acetate. A small

orifice is drilled through the membrane coating. When this coated tablet is exposed to an aqueous

environment, the osmotic pressure of the soluble drug inside the tablet draws water through the semi

permeable coating and a saturated aqueous solution of drug is formed inside the device. The

membrane is no extensible and the increase in volume due to imbibitions of water raises the

hydrostatic pressure inside the tablet, eventually leading to flow of saturated solution of active agent

out of the device through a small orifice38

.

Figure-5. Elementary Osmotic Pump



2) Multiple chamber osmotic pumps

a) Osmotic pump with non –expanding second chamber

The second category of multi- chamber devices comprises system containing a non – exapanding

second chamber. The purpose of second chamber is either dilution of drug solution leaving the device

or simultaneous delivery of two drugs. This device mainly used to deliver insoluble drugs39

.

b) Push-Pull Osmotic Pump (PPOP)

It is a bilayer tablet and is suitable for the delivery of highly or poorly water-soluble drugs. The

upper layer consists of a drug along with osmotic agents. The lower layer consists of polymeric

osmotic agents. The tablet is coated with a semi-permeable membrane and the delivery orifice is

created similar to that of an EOP40

. PPOP can be used to deliver drugs with extremes of water

solubility. It is available in number of modifications such as delayed push pull system, multilayer

push-poll system and push-stick system41

.

Figure- 6. Push – Pull Osmotic Pump (PPOP)

3) Modified oral osmotic drug delivery systems

a) Controlled porosity osmotic pump

It is an osmotic tablet wherein the delivery orifices(holes ) are formed in situ through leaching of

water soluble pore forming agents incorporated in semi permeable membrane(e.g., urea, sorbitol,

nicotinamide ,etc.). Drug release rate from CPOP depends on various factors like coating thickness,

solubility of drug in tablet core, level of leachable pore forming agents and the osmotic pressure

across the membrane42

.



Figure- 7. Controlled porosity Osmotic Pump (CPOP)

b) Osmotic Bursting Osmotic Pump

It 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 contents are released to the environment. This system is useful to provide pulsated

release43

.

c) Multiparticulate Delayed – Release System

In this system, pellets containing pure drug with or without osmotic agent are coated with a semi-

permeable like cellulose acetate. On contact with the aqueous environment, water penetrates into the

core and forms a saturated solution of soluble components. The osmotic pressure gradient induces a

water influx, leading to rapid expansion of the membrane and formation of the pores44

. The release of

osmotic ingredients and the drug through these pores tend to follow Zero-order kinetics.

d) Monolithic Osmotic Systems45

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 the process occurs at the outer environment of the polymer matrix, but

gradually proceeds towards the interior of the matrix in a serial fashion.

e) Colon Targeted Oral Osmotic System (OROS-CT)

OROS-CT is used as once or twice a day formulation for targeted delivery of drugs to the colon. The

OROS- CT can be a single osmotic agent or it comprised with 5-6 push pull osmotic unit filled in a

hard gelatin capsule. After coming in contact with the gastric fluids, gelatin capsule dissolved and the

enteric coating prevents entry of fluids from stomach. As the system enters into the small intestine

the enteric coating dissolves and water is imbibed into the core thereby causing the push



compartment to swell39

. At the same time, flowable gel is formed in the drug department, which is

pushed out of the orifice at the rate precisely controlled by the rate of water transport across the semi-

permeable membrane.

Figure- 8. Colon Targeted Oral Osmotic System

f) Sandwiched Osmotic Tablets (SOTS)

It is composed of polymeric push layer sandwiched between two layers with two delivery orifices.

When placed in the aqueous environment, the middle push layer containing the swelling agent swells

and the drug is released from the two orifices situated on opposite sides of the tablet; thus

sandwiched osmotic tablets (SOTS) can be suitable for drugs prone to cause local irritation of the

gastric mucosa46, 47

.



Figure -9.Sandwiched Osmotic Tablets

g) Liquid Oral Osmotic System 48

Liquid OROS are designed to deliver drugs as liquid formulations. 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 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 from the delivery orifice.

Figure -10. Liquid Oral Osmotic System



h) Osmotic Matrix Tablet (OSMAT)

It is a novel osmotically driven matrix system, which utilizes the property of hydrophilic polymers to

swell and gel in aqueous medium forming a semi-permeable in situ. OSMAT combines both matrix

and osmotic characteristics resulting in a quantum improvement in drug delivery from swellable

matrix systems. Osmotic matrix tablets are very simple to manufacture and precludes the procedures

of coating a semi-permeable membrane and drilling a delivery orifice. It is a low cost technology and

can be adapted to a wide variety of drugs49.

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 advantage include precise control of zero order release over an extended time period-

consistent release rates can be achieved irrespective of the environment factors at the delivery site.

Drug delivery from this system is not influenced by the different physiological factors within the gut

lumen and the release characteristics can be predicted easily from the known properties of the drug

and the dosage form.

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