AN OVERVIEW ON OSMOTIC DRUG DELIVERY SYSTEM. RPA1516259015.pdf · Osmotically controlled drug...
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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
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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
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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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