Transcript Slide 1

Presentation
on
Osmotic drug delivery system
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INDEX
1) Introduction
2) Principle of osmosis
3) Classification of osmotic drug delivery system
4) Factors affecting release of medicament from osmotic DDS
5) Basic components of osmotic system
6) Evaluation
7) Advantages
8) Disadvantages
9) Marketed products
10) Patents
11) Current issues
12) References
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1.Introduction
• Osmotic drug delivery uses the osmotic pressure for
controlled delivery of drugs by using osmogens
• Osmosis : the net movement of water across a selectively
permeable membrane driven by a difference in osmotic
pressure across the membrane
• Osmotic pressure : the pressure which, if applied to the
more concentrated solution, would prevent transport of
water across the semipermeable membrane
• Osmotic pressure is a colligative property
• These systems can be used for both route of administration
i.e. oral and parenterals
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2.Principle of Osmosis
• The solvent membrane control delivery of agent from the
osmotic system across the semi permeable membrane,
which in turn drive the agent out. Water influx of osmotic
pump can be describe as,
dv = A LP σ (ΔП – ΔP)
dt h
Where dv = water influx
dt
A = membrane area
h = membrane thickness
P = mechanical permeability
ΔП = osmotic pressure
ΔP = hydrostatic pressure difference between inside and outside the
system
σ = describes the lickages of solute through the membrane.
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• The general expression for the solute delivery rate,
dM / dt obtained by pumping through the orifice
of the reservoir is given by,
•
dM = dV C
dt
dt
Where C is concentration of solute if dispersed fluid
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3.Classification of Osmotic drug
delivery system
3.1 Implantable Osmotic Drug Delivery System
3.2 Oral Osmotic Drug Delivery System
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3.1 Implantable Osmotic Drug Delivery System
A. Rose nelson pump
•
•
•
the first osmotic pump developed in 1955 for the
delivery of drugs to the sheep and cattle gut
Composed of three chambers
Water to be loaded prior to use was the drawbacks of rose
Salt
nelson osmotic pump
Drug
Water
Chamber
Rigid Semi permeable
membrane
Chamber
Chamber
Delivery
orifice
Elastic
Diaphragm
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B. Higuchi leeper osmotic pump
• No water chamber
• The activation of device occurs after imbibition of the
water from the surrounding environment
• Employed for veterinary use
• Either swallowed or implanted in body of animal for
delivery of antibiotic or growth hormones to animals
• Pulsatile delivery can be achieved
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Higuchi leeper osmotic pump
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C. Higuchi Theeuwes Osmotic Pump
• The release of the drug from the device is governed by the
salt used in the salt chamber and the permeability
characteristics of outer membrane.
• Diffusional loss of the drug from the device is minimized by
making the delivery port in shape of a long thin tube.
• Small osmotic pumps of this form are available under the
trade name Alzet®.
• Delivery of DNA by agarose hydrogel implant facilitate
genetic immunization in cattle by using Alzet osmotic
pumps
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Higuchi Theeuwes Osmotic Pump
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3.2 Oral Osmotic Drug Delivery System
A. Elementary osmotic pump
B. Multichamber osmotic pump
- expandable
- non expandable
C. Modified osmotic pump
D. Controlled porosity osmotic pump
E. Multiparticulate delayed release system
F. Monnolithic osmtic system
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A. Elementary osmotic pump
• Major method of achieving controlled drug release
• The EOP was developed by Alza undre the name OROS for
controlled release oral drug delivery formulations
Delivery Orifice
Semi permeable membrane
Core
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MECHANISM OF EOP
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• Fabricated as tablet coated with semipermeable membrane
usually cellulose acetate
• Small orifice is drilled through the membrane coating
• Eliminates separate salt chamber
• Tablet working as a small pump withdrawing water from
external environment
• Ex. Swellable elementary osmotic pump (SEOP): An
effective device for delivery of poorly water-soluble drug
indomethacin
- The results showed that concentration of wetting agent in
the core formulation was a very important parameter in
D24h and release pattern of indomethacin from SEOP
system. Increasing the amount of wetting agent to an
optimum level (60 mg) significantly increased D24h and
improved zero order release pattern of indomethacin
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B.Multichamber osmotic pump
i.

•
•
•
•
•
Expandable MCOP
Expandable for solid osmotic system
PPOP ( push pull osmotic system )
They contain two or three compartment separated by
elastic diaphragm
Upper compartment contain drug with or without
osmogen (drug compartment nearly 60 – 80 %) and lower
compartment (Push compartment) contain Osmogen at 20
– 40 %.
Example ProcardiaXL for Nifedipine
In vitro and in vivo evaluation of PPOP controlled release
tablet of vinpocetine using numerical deconvolution
technique. (Chemical Abstract, 63- Pharmaceutical Vol. 164., No. 6., August
2010)
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MECHANISM OF PPOP
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 Expandable for liquid osmotic system
• A liquid formulation is use for delivering insoluble drugs and
macromolecules.
• Such molecules require external liquid components to assist in
solubilization, dispersion, protection from enzymatic
degradation and promotion of gastrointestinal absorption.
• Thus the L-OROS system was designed for continuous
delivery of liquid drug.
•
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ii. Non expandable MCOP
Depending on
function of
second chamber
non–expandable
osmotic pump
are divided into,
Drug solution
get diluted in
second chamber
before leaving
device.
Two separate
EOP tablet
formed in
single tablet
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Drug solution get diluted in second chamber before
leaving device
• Before the drug can exit from the device, it must pass
through a second chamber
• Water is also drawn Osmotically into this chamber due to
osmotic pressure of the second chamber that bears watersoluble osmogen
• Such is useful when saturated solution of drug irritate GIT
• Reason behind the withdrawl of
Osmosin (sodium
indomethacin)
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Two separate EOP tablet formed in single tablet
 also known as sandwiched osmotic tablet system
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 A more sophisticated version of these devices consists of
two rigid chambers : one chamber contains osmogen and
second chamber contain drug
Osmogen
SPM
Drug
Microporous
membrane
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C. Modified osmotic pump
 particles of osmotic agent are coated with an elastic
semipermeable film. These particles are then mixed with
the insoluble drug and compressed in the form of a tablet
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D. Controlled porosity osmotic pump
• the delivery orifice is formed by incorporation of a
leachable water-soluble component in the coating material
• Drug release from the whole surface of device rather than
from a single hole which may reduce stomach irritation
problem
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• The release rate from these types of systems has been
reported to be dependent on :
• the coating thickness (20-500 𝜇m)
• level of soluble components in the coating solubility of the
drug in the tablet core
• osmotic pressure difference across the membrane (8-500
atm)
• independent of the pH and agitation of the release media
• EX. Chitosan-based controlled porosity osmotic pump for
colon-specific delivery system: screening of formulation
variables and in vitro investigation : microbially triggered
colon-targeted osmotic pump (MTCT-OP)
The gelable property at acid condition and colon-specific
biodegradation of chitosan
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E. Multiparticulate delayed release system
• In the multiparticulate delayed-release system, pellets
containing drug with or without osmotic agent are coated
with an SPM-like cellulose acetate.
• On contact with an aqueous environment, water penetrates
into the core and forms a saturated solution of soluble
components.
• The osmotic pressure gradient induces a water influx,
resulting in a rapid expansion of the membrane, leading to
the formation of pores.
• The osmotic ingredient and the drug are released through
these pores according to zero order kinetics.
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F.
Monnolithic osmtic system
• Dispersion of water soluble drug is made in a polymeric
matrix and compressed as tablet.
• Tablet is then coated with semi permeable membrane or
drilled on both side of tablet.
• When MOS comes in contact with aqueous environment,
the water penetrates in the core and forms a saturated
solution of component which will generate osmotic
pressure which results in the rupturing of membrane of
polymeric matrix surrounding the agent. Thus liberating
drug to move outside the environment.
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• MOS is simple to prepare but the system fails if more then
20 – 30 % volume of active agent is incorporated in device
because above this level significant contribution is from
leaching of substance
• Ketoprofen Monolithic Osmotic Pump Control Release
Tablet made up of PEG 6000, NaCl, CMC-Na and Polyvinyl
pyrrolidone which releases drug at 93.51 % for 24 hrs
(Chemical Abstract, 63- Pharmaceutical Vol. 147., No. 6.,
August 6. 2007. P=1912., 215217m)
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4.Factors affecting release of medicament
from Osmotic DDS
A.
B.
C.
D.
Solubility
Osmotic pressure
Delivery orifice
Membrane type
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4A. solubility
•
Solubility of drug is one of the most important factors since kinetic of
osmotic release is directly related to the drug solubility.
•
The fraction of a drug release with zero order kinetic is given by
•
F (z) = 1 – S
P
Where F (z): fraction release by zero order
S: drug solubility in g / cm 3
P: density of core tablet.
• Drug with density of unity and solubility less than 0.05 g / cm 3 would
release greater than or equals to 95 % by zero order kinetics
• Drug with density > 0.3 g / cm 3 solubility would demonstrate with higher
release rate > 70 % by zero order.
• Both highly soluble and poorly soluble drugs are not good candidates for
osmotic drug delivery
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Solubility modifying approaches
i. Co-compression of drug with excipients
 the modification in solubility of CPOP of a highly watersoluble drug, diltiazem hydrochloride
 Co-compression of drugs along with solubility
modulating agents can also be utilized for pulsatile
delivery of drugs
Ex. Demonstrated by salbutamol, highly water soluble drug
ii. Use of encapsulated excipients
 Solubility modifier excipient used in form of mini-tablet
coated with rate controlling membrane
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iii. Use of swellable polymers
 for drugs having poor aqueous solubility
 Ex. Carbamazapine, theophylline (US patent no. 4,992,278)
vinylpyrrolidone
/vinyl
acetate
copolymer
and
polyethylene oxide were used as swelling agent
iv. Use of effervescent mixtures
 Another approach to deliver poorly water-soluble drugs
form osmotic drug delivery system
 Citric acid and sodium bicarbonate were used as the
effervescent couple for the delivery of acetyl salicylic acid
(US Patent no. 4,036,228)
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v. Use of cyclodextrin derivatives
 CPOP of Testosterone : increase in solubility of drug from
0.039 mg/ml to 76.5 mg/ml through complexation with
sulfobutyl ether-b-cyclodextrin sodium salt
 Comparative study of CPOP of Testosterone with (SBE)- β -CD
and HP- β –CD
vi. Resin modulation approach
 Release of a highly water-soluble drug, diltiazem
hydrochloride from a CPOP was modulated effectively using
positively charged anion-exchange resin poly (4-vinyl
pyridine)
 Pentaerythritol was used as osmotic agent and citric and
adipic acids were added to maintain a low core pH to assure
that both the drug and resin carry a positive charge.
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vii. Use of alternative salt form
 In case of metoprolol, use of fumarate salt instead of
tartarate salt achieves optimum solubility and provided
extended release up to 24 hr.
viii. Use of crystal habit modifiers
 a slightly soluble drug, carbamazepine along with crystal
modifying agents (combination of hydroxymethyl cellulose
and hydroxyethyl cellulose) and other excipients was
formulated. (US patent no. 5,284,662)
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ix. Use of lyotropic crystals
 swell in presence of water
 Ex. phosphatidyl choline (lecithin),phosphatidylethanolamine,
phosphatidylserine, phosphatidylglycerol
 for osmotic delivery of prazosin lecithin and mixture of soybean
phospholipids was utilized (US patent no. 5,108,756)
x. Use of wicking agents
 an approach for poorly water-soluble drugs
 Ex. of wicking agent : colloidal silicon dioxide, PVP, sodium
lauryl sulfate
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4B Osmotic pressure
• The next release-controlling factor that must be optimized
is the osmotic pressure gradient between inside the
compartment and the external environment
• The simplest and most predictable way to achieve a
constant osmotic pressure is to maintain a saturated
solution of osmotic agent in the compartment
• The release rate of a drug from an osmotic system is
directly proportional to the osmotic pressure of the core
formulation
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4C. Delivery orifice
• 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 build up in
the system
• The typical orifice size in osmotic pumps ranges from 600µ
to 1 mm.
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Methods to create a delivery orifice in the
osmotic tablet coating
•
•
•
•
Mechanical drill
Laser drilling : CO2 laser beam
Use of modified punches
Use of pore formers : used in controlled porosity osmotic
pump
Ex. of pore formers: dimethyl sulfone, nicotinamide,
saccharides, amino acids, sorbitol, pentaerythritol,
mannitol, organic aliphatic, and aromatic acids, including
diols and polyols
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4D. Membrane type
 Type and nature of polymer
• polymer that is permeable to water but impermeable to
solute can be selected
• Ex. cellulose esters such as cellulose acetate, cellulose
diacetate, cellulose triacetate, cellulose propionate,
cellulose acetate butyrate
 Membrane thickness
• release rate from osmotic systems is inversely proportional
to membrane thickness
 Type and amount of plasticizer
• Chlorpromazine release from CPOP was found to increase
with decreasing amounts of TEC (triethyl citrate)
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5.Basic components of osmotic system
 Drug : itself may act as osmogen otherwise osmogenic salt
can be added in formulation
 Semipermeable membrane:
criteria:
• Sufficient wet strength and water permeability
• Should be biocompatible, rigid and non swelling
• Should be sufficient thick to withstand the pressure within
the device
• Any polymer that is permeable to water but impermeable
to solute can be used as a coating material in osmotic
devices
• Ex. Cellulose esters like Cellulose Acetate, Cellulose Acetate
Butyrate, Cellulose Triacetate and Ethyl Cellulose And
Eudragits
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 Hydrophilic and hydrophobic polymers ( CMC, HEC, HPMC )
 Wicking agent : the material with ability to draw water into
the porous network of a delivery device ( SLS, PVP,
bentonite )
 Solubilizing agent (PVP, CD, PEG )
 Osmogens
 Surfactants : act by regulating the surface energy of
materials to imrove their blending into the composite
 Coating solvent : ( methanol, IPA, acetone, cyclohexane )
 Plasticizer : ( phalates, alkyl adipates, TEC )
 Flux regulator : ( poly propylene, poly butylene )
 Pore forming agent
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6.Evaluation
•
•
•
•
•
•
•
Pore diameter
Coating thickness
Hardness
Friability
Weight variation
In vitro evaluation
In vivo evaluation
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IN VITRO DELIVERY RATE MEASUREMENTS
1.Method used by theeuwes and co workers
• osmotic pumps are placed in loosely woven mesh bags of
nylon or polyethylene, and the bags are attached to a rod,
which in turn is attached to a horizontal transfer arm
connected to a vertically reciprocating shaker. The arms
containing several systems are then positioned over test
tubes/containers containing a known amount of release
media
• The release rate (mg/hr) is determined by dividing the
amount of drug in each container by the time (in hours) of
the test interval
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2. Conventional USP dissolution apparatus 1 and 2
3. flow-through apparatus
4. In vitro release of
phenylpropanolaminehydrochloride (PPA) from the oral osmotic
pump system and a marketed long-acting product (spansules)
was compared using a calibrated Ghannam-Chien diffusion
system as the dissolution apparatus
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IN VIVO DELIVERY RATE MEASUREMENT
• Carrid out mainly in dogs
• Theeuwes et al. studied the in vivo release of indomethacin
from OROS pumps in mongrel dogs
• Gastrointestinal transit of an osmotic tablet was measured
by radiolabeling an intact osmotic tablet (placebo osmosin
tablets) and monitoring the movement of the unit in the GI
tract of young and old healthy volunteers using gamma
scintiography (47). The units were observed to move
through the GI tract at about the same rate as the released
contents, arriving at the cecum about 7 hr after dosing
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7. Advanteges
Zero order release
Delivery may be delayed or pulsed
High release rate
For oral osmotic system, drug release is independent of
gastric pH, agitation, presence of food, GI motility
• The release rate is predictable
• high degree of IVIVC
• Production scale up is easy
•
•
•
•
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8. Disadvantages
•
•
•
•
•
•
Expensive
Chance of toxicity due to dose dumping
Rapid development of tolerance
Hypersensitivity reaction may occur
Integrity and consistency are difficult
Release of drug depends on :
- size of hall
- surface area
- thickness and composition of membrane
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9. Marketed products
ELEMENTARY OSMOTIC PUMP
BRAND NAME
API
Efidac 24®
Chlorpheniramine
Acutrim ®
Phenylpropanolamine
Sudafed 24®, Efidac 24®
Pseudoephedrine
Volmax ®
Albuterol
Minipress XL®
Prazosin
IMPLANTABLE OSMOTIC
SYSTEMS
Viadur®
Leuprolide acetate
Chronogesic™
Sufentanil
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PUSH-PULL OSMOTIC SYSTEMS
Ditropan XL ®
Oxybutynin chloride
Procardia XL®
Nifedipine
Glucotrol ®
Glipizide
Covera HS ®
Verapamil HCl
DynaCirc CR®
Isradipine
Invega®
Paliperidone
Alpress LP®
Prazosin
Cardura XL®
Doxazosin
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10. Patents
PATENTS OF ELEMENTARY OSMOTIC PUMP
YEAR
US PATENT NO.
DRUG
1981
4,265,874
Indomethacin formulation
1981
4,305,927
Acetazolamide formulation
1984
4,439,195
Theophylline formulation
1986
4,610,686
Haloperidol
1987
4,662,880
Pseudoephedrine and
bromopheniramine
1988
4,751,071
Salbutamol formulation
1991
4,986,987
Dimenhydrinate
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1993
5,200,194
Mucosal delivery of antiplaque agents and nicotine
1998
5,776,493
Mucosal delivery of nystatin
1999
5,869,096
Covers mucosal osmotic device of levodopa
2002
6,352,721
Combined diffusion/osmotic pumping drug delivery
system
2003
6,534,090
Oral osmotic controlled drug delivery system for a
sparingly soluble durg (carbamazepine)
2006
7,008,641
Osmotic device containing venlafaxine and an anti
psychotic agent
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Patents of multichamber Osmotic Pumps
1986
4,612,008
Diclofenac sodium formulation
1988
4,765,989
Nifedipine and a blockers
1989
4,837,111
Doxazosin formulation
1989
4,859,470
Diltiazem formulation
1990
4,904,474
Beclomethasone (colonic)
1991
5,024,843
Glipizide formulation
1992
5,160,744
Verapamil dosage form
1993
5,185,158
Tandospirone
1993
5,248,310
Beclomethasone (oral)
1997
5,591,454
Glipizide formulation
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2000
6,113,938
Implant capsule
2000
6,284,276
Soluble form osmotic dose delivery system
2006
CN-1872031
Hydroxy camptothecin osmotic tablet
2008
7,338,663
Expandable osmotic composition and coating
suspension
2009
CN101422442
levetiracetam
2010
CN101829069
Pitavastatin calcium
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11. CURRENT ISSUES
1. Microporous bilayer osmotic tablet for colon-specific
delivery (Eur J Pharm Biopharm. 2011 Jan 19)
 Microporous bilayer osmotic tablet bearing dicyclomine
hydrochloride and diclofenac potassium was developed
using a new oral drug delivery system for colon targeting
 The colon-specific biodegradation of pectin could form in
situ delivery pores for drug release
 The effect of formulation variables like inclusion of
osmogen, amount of HPMC and NaCMC in core, amount of
pore former in semipermeable membrane was studied
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2. Push-pull osmotic pump for zero order delivery of lithium
carbonate: Development and in vitro characterization
3. Development and evaluation of push-pull based osmotic
delivery system for pramipexole
 offer significant patient benefits by providing enhanced
efficacy and reduced side effects and may also reduce the
number of daily doses compared to conventional therapies
4. A controlled porosity osmotic pump system with biphasic
release of theophylline
 The developed system was composed of a tablet-in-tablet
(TNT) core and a controlled porosity coating membrane
 osmotic agent: sodium phosphate, sodium chloride
 coating solution: cellulose acetate-polyethylene glycol 400diethyl phthalate (54.5-36.4-9.1%, w/w)
 micro-environmental osmotic pressure and microenvironmental pH
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5. Release mechanisms of sparingly water-soluble drug from
controlled porosity-osmotic pump pellets using Sulfobutyl
ether-β-Cyclodextrin as both solubilizing & osmotic agent.
(JPS, VOL-98, NO.-6, JUNE-2009, Page NO.-1992)
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12. REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
A Review Article on Osmotic Drug Delivery System. Authors: Gohel M.C , Parikh R.K. ,
Shah N.Y., from L.M. College Of Pharmacy, Ahmedabad. (www.pharmainfo.net)
L.F. Prescott. The need for improved drug delivery in clinical practice, In: Novel Drug
Delivery and Its Therapeutic application, John Wiley and Sons, West Susset, U.K., 1-11;
1989.
Dr. P.P. Bhatt. Osmotic drug delivery systems for poorly water soluble drugs,
Pharmaventures Ltd., Oxford, UK, 26-29; 2004.
R.K. Verma, D. M. Krishna and S. Garg. Review article on Formulation aspects in the
development of Osmotically controlled oral drug delivery systems, J. Control. Release,
79, 7-27; 2002.
Chemical Abstract, 63- Pharmaceutical Vol. 147., No. 6., August 6. 2007. P=1912.,
215217m
Chemical Abstract, 63- Pharmaceutical Vol. 164., No. 6., August 2010
Microporous bilayer osmotic tablet for colon-specific delivery,Chaudhary A, Tiwari N,
Jain V, Singh R. , School of Pharmaceutical Sciences, Shobhit University, Meerut, UP,
India., Eur J Pharm Biopharm. 2011 Jan 19
J. Pharm. Res. Vol. 5. No. 2. April 2006. P=34.
9.
Ind. J. Pharm. Sci. May – June 2006, P= 295-300.
10.
J. Pharm. Sci. Vol. 96. No. 5. May 2007. P= 1008.
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12 F. Theeuwes and S.I. Yum. Principles of the design and operation of generic osmotic pumps
for the delivery of semisolid or liquid formulations, Ann. Biomed. Eng.,4, 343-53; 1976.
13 G.M. Zentner, K.J. Himmelstein and G.S. Rork. Multiparticulate controlled porosity osmotic.
US Patent 4851228; 1989.
14 R.W. Baker. Controlled release delivery system by an osmotic bursting mechanism. US Patent
3952741; 1976
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THANK YOU
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