AN OVERVIEW ON OSMOTIC DRUG DELIVERY SYSTEM. RPA1516259015.pdf · Osmotically controlled drug delivery systems (OCDDS) is one of the most promising drug delivery technology. Osmotic

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International Journal of Universal Pharmacy and Bio Sciences 4(6): November-December 2015

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093***

ICV 5.13***

Pharmaceutical Sciences REVIEW ARTICLE …………!!!

“AN OVERVIEW ON OSMOTIC DRUG DELIVERY SYSTEM”

KhairnarAshwini B1*

.Gondkar S.B1, Saudagar R.B

2.

1*Department of pharmaceutics, R.G. Sapkal college of pharmacy, Anjaneri, Nashik-422213,

Maharashtra, India. 2*

Department of pharmaceutical chemistry, R.G. Sapkal college of pharmacy, Anjaneri, Nashik-

422213, Maharashtra, India.

KEYWORDS:

Osmosis, semipermeable

membrane, osmotic

pump, zero order,

osmotic agent.

For Correspondence:

Khairnar Ashwini B *

Address:

Department of

pharmaceutics, R.G.

Sapkal college of

pharmacy, Anjaneri,

Nashik-422213,

Maharashtra, India.

ABSTRACT

Conventional drug delivery systems have little control over their drug

release and almost no control over the effective concentration at the target

site. The kind of dosing pattern may result in constantly changing,

unpredictable plasma concentrations. The number of marketed oral

osmotically driven systems (OODS) has doubled in the last 10 years.

Osmotic devices which are tablets coated with walls of controlled porosity

are the most promising strategy based systems for controlled drug

delivery. Osmotically controlled drug delivery systems (OCDDS) utilize

osmotic pressure for controlled delivery of active agent(s). In contrast to

common tablets, these pumps provide constant (zero order) drug release

rate. Factors influencing the design of osmotic controlled drug delivery

systems such as solubility and osmotic pressure of the core components,

size of delivery orifice, and nature of the rate controlling membrane. The

present review highlights an overview of OCDDS, types of oral osmotic

drug delivery system, factors affecting the drug delivery system and

marketed products.



INTRODUCTION:

Novel drug delivery systems (NDDS) are the key area of pharmaceutical research and development.

Majority of oral CR dosage forms fall in the category of matrix, reservoir or osmotic systems.

Osmotically controlled drug delivery systems (OCDDS) is one of the most promising drug delivery

technology. Osmotic devices are the most reliable controlled drug delivery systems (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 manner. Osmotic pump tablet (OPT) generally consists of a

core including the drug, an osmotic agent, other excipients and semipermeable membrane coat. Drugs

can be delivered in a controlled pattern over a long period of time by the controlled or modified

release drug delivery systems they include dosage forms for oral and transdermal administration as

well as injectable and implantable systems. Osmotic drug delivery systems release the drug with the

zero order kinetics which does not depend on the initial concentration and the physiological factors of

GIT.

Development of osmotic drug delivery systems was founded by Alza Corporation of the USA (now

merged with Johnson & 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. (3)

Basic concepts

Osmosis

Osmosis is defined as the process of movement of solvent molecules from lower concentration to

higher concentration across a semi permeable membrane.

Osmotic pressure

It is a colligative property of a solution in which the magnitude of osmotic pressure of the solution is

independent on the number of discrete entities of solute present in the solution.

Principle of Osmosis(12,13,14)

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 low is called the osmotic pressure.



Advantages and Disadvantages of Osmotic Controlled Drug Delivery systems(9-15)

Advantages:

Delivery of drug from osmotic pumps can be designed to follow true zero-order kinetics.

Drug release is independent of gastric pH and hydrodynamic condition.

A high degree of in vitro / in vivo correlation can be obtained from osmotic pumps.

Deliveries may be delayed or pulsed if desired.

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

They are well characterized and understood.

Higher release rates are possible with osmotic systems compared with conventional

diffusion-controlled drug delivery systems.

Disadvantages:

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

Dose dumping.

Expensive.

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

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

Basic Components of OCDDS

1. Drug(11,21)

Short biological half-life (2-6 hrs)

High potency

Required for prolonged treatment

2.Wicking agents(32)

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 may be swellable or non-swellable in nature.

The function of wicking agent is to carry water to surfaces inside the core of the tablet,

thereby creating channels or a network of increased surface area.

The examples are colloidal silicon dioxide, PVP and sodium lauryl sulphate.

3.Osmogens(33)

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 the delivery orifice.

Examples are potassium chloride, sodium chloride, and mannitol.



4.Semipermeable membrane(33)

The membrane should possess following characteristics,

Should be biocompatible

Sufficient wet strength

Should be sufficient thick to withstand the pressure within the device

Rapid and non-swelling

5.Surfactants

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.

Surfactants such as polyoxyethylenated glyceryl recinoleate, polyoxyethylenated castor oil having

ethylene oxide, and glycerol are in corporate into the formulation.

6.Hydrophilic and hydrophobic polymers(20)

These polymers are used for making drug containing matrix core. The selection is based on the

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

Hydrophilic polymers such as hydroxyl ethylcelluose, carboxy methylcellulose, hydroxyl propyl

methyl cellulose, and hydrophobic polymers such as ethyl cellulose and wax materials can be used

for this purpose.

7.Pore forming agents(34)

The pore formers should be non-toxic, and on their removal, channels should be formed. The

channels should be transport path for fluid.

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, diols,

polyvinyl pyrrolidone.

8.Plasticizers(35,36)

Plasticizers or low molecular weight diluents are added to modify the physical properties and

improve film forming characteristics of polymers.

Generally from 0.001 to 50 parts of a plasticizer or a mixture of plasticizers are incorporated into

100 parts costing materials.

PEG-600, PEG-200, triacetin(TA), dibutylsebacate, ethylene glycolmono acetate, ethylene glycol,

diacetate, and diethyl tartrate used as plasticizer in formulation of semipermeable membrane.



9.Coating solvents(11,12)

Inert inorganic and organic solvents that do not adversely harm the core, wall and other materials

are used as coating solvents. They include methylene chloride, acetone, methanol,ethanol,

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

Factors affecting drug release rate from osmotic controlled devices(22,25)

1. Osmotic pressure

Osmotic pressure is one of the most rate controlling factor that must be optimized is the osmotic

pressure gradient between inside the compartment and the external environment. The rate of drug

release is mainly depends upon the atmospheric pressure created by osmogen. The simplest and

most predictable way to achieve a constant osmotic pressure for constant delivery of drug is to

maintain a saturated solution of suitable osmotic agent in the compartment. Sometimes combination

of osmotic agents is also used for desired osmotic pressure.

2. Membrane thickness

A principle factor controlling the rate of penetration of water into the dispenser is the thickness of

the membrane. The permeability of water into the membrane can be enhanced by the choice of a

suitable type of the membrane material. The time of release the active constituent can be easily

varied by as much as 1000 fold based upon the thickness of the membrane. In general the rate of

drug release can be achieved by varying the membrane material. While small change up to a five

percent can be best achieve by varying the thickness of the membrane.

3. Delivery orifice

Majority of osmotic delivery systems contain at least one delivery orifice (preformed or formed in

situ) in the membrane for drug release.

Size of delivery orifice must be optimized to control the drug release from osmotic system. The size

of delivery orifice must be smaller than maximum size Smax to minimize drug delivery diffusion

through the orifice.

4. Type of membrane and characteristics

Drug release from an osmotic system is largely independent of the pH and agitation intensity of GIT

tract. This is because of its selective water permeable membrane and effective isolation of

dissolution process of drug core from the gut environment. Among the cellulose polymer cellulose

acetate membrane are mostly used because of its high water permeability characteristics and it can

be adjusted varying the degree of acetylation of the polymer. The permeability of this membrane

can be increased by adding plasticizer to the polymer, which increases the water diffusion

coefficient or hydrophilic flux enhancer which increases the water sorption of the membrane.



Classification of osmotically controlled drug delivery system(37)

Oral osmotic drug delivery system

Single chamber osmotic pump:

Elementary osmotic pump

Multi-chamber osmotic pump:

Push pull osmotic pump

Osmotic pump with nonexpanding second chamber

Implantable osmotic drug delivery system

Rose Nelson pump

Higuchi Leeper pump

Higuchi Theeuwes pump

Miscellaneous

Controlled porosity osmotic pump

Osmotic bursting osmotic pump

Liquid OROS

Telescopic Capsule for Delayed Release

OROS-CT (colon targeting)

Sandwiched osmotic tablet system

Oral osmotic drug delivery system

Single chamber osmotic pump

Elementary osmotic pump (EOP)(23,16,18)

Rose-Nelson pump was further simplified in the form of elementary osmotic pump. Which made

osmotic delivery as a major method of achieving controlled drug release. EOP is the most basic

device made of a compressed tablet. The EOP consists of an osmotic core with the drug, surrounded

by a semipermeable membrane. This membrane contains an orifice of critical size through which

agent is delivered. The dosage form after coming into contact with aqueous fluids, imbibes water at

a rate determined by the fluid permeability of the membrane and osmotic pressure of the core

formulation. Normally EOP deliver 60-80% of its content at constant rate but it has short lag time of

30-60 minute. It is applicable for moderately soluble drug.



fig: Elementary osmotic pump

Multi chamber osmotic pump

Push-pull osmotic pump (PPOP)(23)

Two compartments: upper compartment (drug compartment) contains the drug along with

osmotically active agents. Lower compartment (push compartment) contains the polymeric osmotic

agents. Mechanism of action of PPOP is when the dosage form comes in contact with the aqueous

environment, both compartments imbibe water simultaneously. Because the lower compartment is

devoid of any orifice, it expands and pushes the diaphragm into the upper drug chamber, thereby

delivering the drug via the delivery orifice. PPOP deliver both highly water-soluble (oxybutynin)

and practically water-insoluble (nifedipine, glipizide) drugs.

fig: Push-pull osmotic pump

Limitation

Complicated laser drilling technology should be employed to drill the orifice next to the drug

compartment.



Osmotic Pump with Non-Expanding Second Chamber(26)

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

chamber. This group can be divided into two sub groups depending on the function of second

chamber. This type of devices consist of two rigid chamber, the first chamber contains a

biologically inert osmotic agent, such as sugar or a simple salt like sodium chloride, the second

chamber contains the drug. In use water is drawn into both the chamber through the surrounding

semipermeable membrane. The solution of osmotic agent formed in the first chamber then passes

through the connecting hole to the drug chamber where it mixes with the drug solution before

exiting through the micro porous membrane that form a part of wall surrounding the chamber. The

device could be used to deliver relatively insoluble drugs.

Implantable osmotic drug delivery system

Rose-Nelson Pump(3)

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

developed an implantable pump, which consists 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

semipermeable membrane. The design and mechanism of this pump is comparable to modern push

pull osmotic pump. Disadvantage of this pump was the water chamber, which must be charged

before use of the pump.

Higuchi-LeeperPump(4,5)

Several simplifications in Rose-Nelson pump were made by Alzacorporation in early 1970s. 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 a rigid housing, and the

semipermeable membrane is supported on a perforated frame. It has a salt chamber containing a

fluid solution with excess solid salt.

Higuchi-TheeuwesPump(6)

The pump comprises a rigid, rate controlling outer semipermeable membrane surrounding a solid

layer of salt coated on the inside by an elastic diaphragm and on the outside by the membrane. In

use, water is osmotically drawn by the salt chamber, forcing drug from the drug chamber. Most of

the Higuchi-Theeuwes pumps use a dispersion of solid salt in a suitable carrier for the salt chamber

of the device.



Miscellaneous

Controlled porosity osmotic pump (CPOP)(23)

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

water soluble pore-forming agents incorporated in semipermeable membrane (SPM) (e.g., urea,

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

thickness, solubility of drug in tablet core, level of leachable pore-forming agent(s) and the osmotic

pressure difference across the membrane.

fig: Controlled Porosity Osmotic Pump

Osmotic Bursting Osmotic Pump(23)

This system is similar to 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 content are released to the environment. Varying the thickness as well as

the area the semipermeable membrane can control release of drug. This system is useful to provide

pulsated release.

Liquid Oral Osmotic system (L-OROS)

Two types: L-OROS Soft cap and L-OROS hard cap. In soft cap, liquid drug formulation is present

in a soft gelatin capsule, which surrounded with the barrier layer, the osmotic layer, and the release

rate-controlling membrane. In hard cap, it consists of a liquid drug layer and an osmotic engine, all

escaped in a hard gelatin capsule and coated with SPM. The expansion of the osmotic layer results

in the development of hydrostatic pressure, thereby forcing the liquid formulation to break through

the hydrated gelatin capsule shell at the delivery orifice. Water is imbibed across the SPM

expanding the osmotic engine, which pushes against the barrier, releasing the drug through the

delivery orifice.

Telescopic capsule for delayed release(28,29)

This device consists of two chambers, first one contains the drug and an exit port, and the second

contains osmotic engine. Layer of wax-like material separates the two sections. As fluid imbibed



the housing of the dispensing device, the osmotic engine gets expand and exerts pressure on the

slidable connected first and second wall sections.

OROS-CT(24)

OROS-CT (Alza corporation) is used as a once or twice a day formulation for targeted delivery of

drugs to the colon. It can be a single osmotic agent or comprised of as many as five to six push pull

osmotic pump unit filled in a hard gelatin capsule.

fig: OROS-CT

Sandwiched Osmotic Tablet (SOT)(24)

In sandwiched osmotic tablet (SOTS), a tablet core consisting of a middle push layer and two

attached drug layers is coated with a SPM. As seen in Fig. 10, both the drug layers are connected to

the outside environment via two delivery orifices (one on each side). After coming in contact with

the aqueous environment, the middle push layer containing swelling agents swell and the drug is

released from the delivery orifices. The advantage with this type of system is that the drug is

released from two orifices situated on two opposite sides of the tablet thus can be advantageous in

case of drugs which are prone to cause local irritation of gastric mucosa.

fig: Sandwiched osmotic pump



Evaluation parameters for osmotic tablet [30, 38]

Visual inspection:

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

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)

In vitro drug release:[35]

The invitro drug release rate of drug from osmotic system can be determined using diverse

methodologies, conventional USP dissolution apparatus I &II .

Table no 3: Marketed Product

Brand Name API Type Marketed by

UT-15C Treprostinildiethanolamine SEOP United therapeutics

LCP-Lerc Lercanidipine DOEOP Osmotica

Cadura CRD Doxazosinmesylate PPOP Alza/Pfizer

Oxycontin Oxycodone PPOP Alza

Elafax XR Valenfexine HCL EOP Phoenix

Invega Paliperidone PPOP Xian-Janssen

Volmax Albuterol EOP GSK/Muro

Fortamet Metformin/pioglitazone SCOT Andrax

Alto plus XR Metformin SCOT Takeda

Dynacric CR Isradipine PPOP Alza/Novartis

Jusnista Hydromorphone PPOP J&J



Brand Name API Type Marketed by

Altoprev Lovastatin EOP Andrex

Allegra D24 h Fexofenadine DOEOP Osmotica

Topamax Toperamate PSOP Alza

Mildugen D Astemizole DOEOP Osmotica

Alpress LP Prazosin PPOP Pfizer

Acutrim Phenylpropanolamine EOP Alza

Glucotrol XL Glipizide PPOP Pfizer

Minipress XL Prazocin EOP Alza

CONCLUSION:

Development efforts of oral osmotic controlled drug delivery systems during recent years have been

very dynamic with the emergence of new technologies and products. With the expiration of oral

osmotic controlled drug delivery systems primary patents and the increasing demands of health

authorities for improved patient treatment compliance and tolerability, the oral osmotic controlled

drug delivery systems is primed to increase their market within oral modified-release dosage forms.

Nowadays, the large variety of OODS technologies available allows an interesting adaptation of the

system to the drug properties and dosage strength. Despite of controversy concerning the safety in

the administration of non-disintegrable tablets, the reported clinical benefits have opened up new

perspectives to the future development of drugs as oral osmotically driven systems.

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AN OVERVIEW ON OSMOTIC DRUG DELIVERY SYSTEM. RPA1516259015.pdf · Osmotically controlled drug delivery systems (OCDDS) is one of the most promising drug delivery technology. Osmotic