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Controlled Release Oral Drug Delivery System
Controlled Release Oral Drug Delivery System
Delivery System
07/25/23 1
Contents
Overview of Digestive system
Introduction
Advantages
Disadvantages
Dissolution
Diffusion
Combination of Dissolution & Diffusion
Osmotic pressure controlled system
Hydrodynamically balanced systems
pH controlled
Ion exchange controlled systems
References
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Concept
Controlled drug delivery is one which delivers the
drug at a predetermined rate, for locally or
systemically, for a specified period of time.
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Controlled Release System
Matrix
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Plasma concentration time profile
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Challenges in Oral Drug Delivery
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Advantages
Total dose is low.
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Disadvantages
Dose dumping.
Stability problem.
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Mechanism aspects of Oral drug
delivery formulation
1.Dissolution : 1. Matrix
2. Encapsulation
2.Diffusion : 1. Matrix
2. Reservoir
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Matrix Type
Also called as Monolith dissolution
controlled system. Soluble drug
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Encapsulation
Called as Coating dissolution
controlled system.
Soluble drug
Dissolution rate of coat depends
upon stability & thickness of
coating.
Slowly
Masks dissolving
colour,odour,taste,minimising GI or erodible
irritation. coat
No energy required.
Rate controlling
step:
Diffusion of dissolved
drug in matrix.
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Advantage and Disadvantage of
Matrix and Reservoir system
• Film thickness
The drug release rate from an insoluble membrane is expected to
increase as the membrane thickness decreases.
• Hardness of microcapsule
The hardness of microcapsule increase, prolong the time of drug
release.
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Higuchi Equation
Where ,
Q=amt of drug release per unit surface area at time t.
D=diffusion coefficient of drug in the release medium.
E=porosity of matrix.
Cs=solubility of drug in release medium.
T=tortuosity of matrix.
A=concentration of drug present in matrix per unit
volume.
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Reservoir System
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Reservoir System
Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.
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Dissolution & Diffusion
Controlled Release system
Drug encased in a partially soluble
membrane. Insoluble
membrane
Pores are created due to dissolution
of parts of membrane. Entry of
dissolution
fluid
It permits entry of aqueous medium
into core & drug dissolution. Drug
diffusion
Diffusion of dissolved drug out of
system. Pore created by
dissolution of
Eg. Ethyl cellulose & PVP mixture soluble fraction of
dissolves in water & create pores of membrane
insoluble ethyl cellulose membrane.
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Osmotic Pressure Controlled
Drug Delivery System
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Introduction
The oral drug delivery has been popular most widely utilized route
of administration among all the routes that have been explored for
the systemic delivery of drugs.
The drug release can be modulated by different ways but the most of
novel drug delivery systems are prepared using matrix, reservoir or
osmotic principle.
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Introduction
Osmotic pressure is used as driving force for these systems to
release the drug in controlled manner. Osmotic drug delivery
technique is the most interesting and widely acceptable among all
other technologies used for the same.
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Principle
Here osmotic pressure is used as the power/source or energy to
activate and control the release of drug from the device. In this
system, the drug reservoir contains the drug either in the form of
solid or as solution, which is enclosed within a semipermiable
housing having controlled water permeability. The drug is activated
to release in solution form at a constant rate through a special
delivery orifice.
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Oral controlled release:
Osmotic tablet technology
Once- or twice-daily dosing regimens for crystalline and enhanced-
bioavailability drugs is often desired and needed to maximize therapeutic
effect, patient safety, and compliance.
Bend Research has developed two proprietary tablet technologies that provide
drug release in a predictable, reliable manner. Both dosage forms are driven
by osmotic/hydrostatic pressure and provide steady-state, zero-order release
that is generally independent of GI pH and agitation.
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Osmotic swellable-core
technology
A bi-layer tablet containing
an insoluble, semipermeable
coating with a delivery
orifice
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Osmotic asymmetric membrane
technology
A single-layer tablet containing an insoluble,
asymmetric microporous coating produced by
controlled phase separation
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Oral osmotic pumps
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Elementary osmotic pump
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Elementary osmotic pump
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Elementary osmotic pump
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Acutrim tablet
It is an oral osmotic pressure controlled G.I. DDS. this systems are fabricated by
encapsulating an osmotic drug core containing an osmotically active drug or a
combination of an osmotically inactive drug with an osmotically active salt like
Nacl, within a semipermiable membrane made from cellulose acetate polymer.
The polymer membrane is not only semipermiable in nature but is also rigid &
capable of maintaining the structural integrity of the G.I. DDS during the course
of drug release. It is permeable to the influx of water in G.I.T. but impermeable
to drug solutes.
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Acutrim tablet
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Modifications
The external surface of the semipermiable membrane can be coated with a
layer of bioerodable polymer like enteric coating, it regulate the penetration
of GI fluid through the semipermiable membrane & target the delivery of a
drug to the lower region of the GIT.
The coating membrane of the DDS can be constructed from a laminate of two
or more semipermiable membranes with differential permeabilities.
The osmotic pressure controlled GI delivery system can be further modified
to constitute two compartments separated by a movable partition. The
osmotically active compartment absorbs water from GI fluid to creat an
osmotic pressure that acts on the partition forces it to move upward and to
reduce the volume of the drug reservoir compartment and to release the drug
formulation through the delivery orifice .
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Modifications
07/25/23 41
Modifications
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Push pull osmotic pump
Push pull osmotic pump is a modified EOP. through, which it is possible to
deliver both poorly water-soluble and highly water soluble drugs at a constant
rate.
This system resembles a standard bilayer coated tablet. One layer (depict as
the upper layer) contains drug in a formulation of polymeric, osmotic agent
and other tablet excipients.
This polymeric osmotic agent has the ability to form a suspension of drug in
situ. When this tablet later imbibes water, the other layer contains osmotic and
colouring agents, polymer and tablet excipients. These layer are formed and
bonded together by tablet compression to form a single bilayer core. The
tablet core is then coated with semipermeable membrane.
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Push pull osmotic pump
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Push pull osmotic pump
After the coating has been applied, a small hole is drilled through
the membrane by a laser or mechanical drill on the drug layer side of
the tablet.
When the system is placed in aqueous environment water is
attracted into the tablet by an osmotic agent in both the layers. The
osmotic attraction in the drug layer pulls water into the compartment
to form in situ a suspension of drug.
The osmotic agent in the non-drug layer simultaneously attract
water into that compartment, causing it to expand volumetrically
and the expansion of non drug layer pushes the drug suspension out
of the delivery orifice.
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Osmotic pump with non-
expanding second chamber
The second category of multi-chamber devices comprises system
containing a non-expanding second chamber. This group can be
divided into two sub groups, depending on the function of second
chamber.
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Osmotic pump with non-
expanding second chamber
Example: - The problem that lead to withdrawal of
osmosin, the device consist of a normal drug
containing porous tablet from which drug is released as
a saturated solution. However before the drug can
escape from the device it must pass through a second
chamber.
Water is also drawn osmotically into this chamber
either because of osmotic pressure of drug solution or
because the second chamber contain, water soluble
diluents such as NaCl.
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Osmotic pump with non-
expanding 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
semi permeable membrane.
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Osmotic bursting pump
This system is similar to an EOP except 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.
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Controlled Porosity Osmotic
Pumps
In this type two layers of membrane are applied on pumps .
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Pumps for insoluble drugs
In this system particles of osmotic agents are coated with an elastic
semipermeable membrane.
These coated particles are then mixed with the relatively insoluble
drug and tableted and coated with the rigid semipermeable
membrane in usual way.
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Sandwiched osmotic tablets
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Osmotic Pressure Controlled
System
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Osmotic Pressure Controlled
System
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Advantages
Osmotic drug delivery system for oral and parenteral use offer
distinct and practical advantage over other means of delivery. The
following advantages contributed to the popularity of osmotic drug
delivery system.
They typically give a zero order release profile after an initial lag.
Deliveries may be delayed or pulsed if desired.
Drug release is independent of gastric pH and hydrodynamic
condition.
They are well characterized and understood.
The release mechanisms are not dependent on drug.
A high degree of in-vitro and in vivo correlation .
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Advantages & Disadvantages
The rationale for this approach is that the presence of water in
GIT is relatively constant, at least in terms of the amount
required for activation and controlling osmotically base
technologies.
Disadvantages
Costly .
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Marketed products
Product name Active Design Dose
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Principle
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Principle
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Rate controlling factors:
Fluid permeability ,
Effective area of wall with openings ,
Hydrodynamic pressure gradient.
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Formulation and development of
Hydrodynamically balanced system (HBS)
or Floating drug delivery system(FDDS)
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FORMULATION
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Classification of FDDS
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EFFERVESCENT FLOATING
DOSAGE FORMS
These floating drug delivery system employ matrices from swellable polymers like
Methocel or Chitosan & effervescent components such as Sodium bicarbonate &
Tartaric or Citric acid or matrices having chambers of liquid components that
gasify at body temperature.
The matrices are prepared in such a manner that when they come in contact with
stomach fluid , CO2 is generated, & retained entrapped in hydrocolloid gel.
This leads to an upward flow of the dosage form and maintains it in a floating
condition.
A single layered tablet can be prepared by initially mixing the CO 2 generating
component in tablet matrix. A bilayered tablet may be compressed in which gas
liberating component is present in hydrocolloid layer and the drug is compressed
in other layer of sustain release
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Multiple type of floating dosage
system
Multiple type of floating dosage system composed of effervescent layers and
swellable membrane layers coated on sustained release pills.
The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid
was divided into 2 sublayers to avoid direct contact between the 2 agents. These
sublayers were surrounded by a swellable polymer membrane containing polyvinyl
acetate and purified shellac.
When this system was immersed in the buffer at 37ºC, it settled down and the
solution permeated into the effervescent layer through the outer swellable membrane.
CO2 was generated by the neutralization reaction between the 2 effervescent agents,
producing swollen pills (like balloons) with a density less than 1.0 g/mL.
It was found that the system had good floating ability independent of pH and
viscosity and the drug (para-amino benzoic acid) released in a sustained
manner(Figure ,A and B).
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Multiple type of floating dosage
system
The design of the delivery system was based on the swellable asymmetric
triple-layer tablet approach. HPMC and PEO were the major rate-controlling
polymeric excipients.
Tetracycline and metronidazole were incorporated into the core layer of the
triple-layer matrix for controlled delivery, while bismuth salt was included in
one of the outer layers for instant release.
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Triple-layer tablet floating
dosage system
The floatation was accomplished by incorporating a gas-generating layer
consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with
the polymers.
The in vitro results revealed that the sustained delivery of tetracycline and
metronidazole over 6 to 8 hours could be achieved while the tablet remained
afloat.
The floating feature aided in prolonging the gastric residence time of this
system to maintain high-localized concentration of tetracycline and
metronidazole.
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Triple-layer tablet floating
dosage system
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MECHANISM
Gel forming hydrocolloids swells in contact with gastric fluid after oral
administration and maintains a relative integrity of shape and a bulk density of
less than unity within gastric environment. The air thus trapped by the swollen
polymer imparts buoyancy to the dosage form.
The gel barrier controls the rate of solvent penetration into the device & the
rate of drug release from the device.
It maintains a bulk density of less than 1 and thus remains buoyant in the
gastric fluid inside the stomach for up to 6 hrs; conventional dosage forms
disintegrate completely within 60 min and are emptied totally from the
stomach shortly afterward.
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Advantages of HDDS
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Disadvantages of HDDS
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Marketed products
PRODUCT ACTIVE INGREDIENT
VALRELEASE DIAZEPAM
TOPALKAN ALUMINIUM MAGNESIUM
ANTACID
ALMAGATE FLAT COAT ANTACID
LIQUID GAVISON ALGINIC ACID & NaHCO3
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CONCLUSION
HBS system can remain in the stomach for longer period hence can release
the drug over a prolong period of time.
These systems are particularly advantageous for drugs that are specifically
absorbed from stomach or proximal part of small intestine ( e.g., Riboflavin
& Furosemide).
Drugs that have poor bioavailability because of site specific absorption from
the upper part of GIT are potential candidates to be formulated as floating
drug delivery systems, thereby maximizing their absorption.
FDDS also serves as an excellent drug delivery system for the eradication of
Helicobacter pylori, which can cause chronic gastritis & peptic ulcers.
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pH controlled GI delivery
systems
This type of GI delivery system is designed for
the controlled release of acidic or basic drugs in
GIT, at a rate independent of the variation in GI
pH.
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Formulation
This system is prepared by first blending acidic or basic
drug with one or more buffering agents,
Eg. Pri, sec, ter salt of citric acid.
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Mechanism
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pH controlled GI Drug Delivery
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pH responsive hydrogels
This system have been targeted for per-oral controlled
drug delivery, taste masking of bitter drugs and
intravascular drug release during elevated blood pH in
certain CVS defects.
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Mechanism
In aqueous media of appropriate pH and ionic
strength, pendant groups, ionised and
developed fixed charges on the fixed charges
generating electrostatic repulsive forces
responsible for pH dependent swelling or
deswelling of the hydrogel, thereby controlling
the drug release.
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Drug release pattern
This system is designed in a monobasic or pulsatile
pattern.
Peroral controlled drug delivery requires uniform drug
delivery with increase in drug pH, gradient in different
segments of GI Lumen.
Eg. Albumin cross-linked 1-vinyl-2-pyrrolidinone
hydrogels were studied for their swelling behaviour at
different values.
Swelling increases above pH 7, thus correlating with
the maximal transit time of the drug delivery system
through the intestine.
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Drug release pattern
Pulsatile pattern of drug release is required in the
diseased state exhibiting a rhythmic pattern.
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pH- Activated Drug Delivery System
This system permits targeting the delivery of a drug only in the region with a
selected pH range.
Since most drugs are weak acids or weak bases, their release is pH dendent.
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pH- Activated Drug Delivery
System
pH Activated Drug Delivery System is fabricated by coating the drug-
containing core with a pH–sensitive polymer combination.
After gastric emptying the Dosage form reaches the small intestine and comes
in contact with intestinal fluid (pH>7.5) which activates the erosion of
polymer - Hydroxylmethylcellulose phthalate from the coating membrane.
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pH- Activated Drug Delivery
System
This leaves a microporous membrane of intestinal
fluid insoluble polymer of Ethylcellulose, which
controls the release of drug from the core tablet.
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pH- Activated Drug Delivery
System
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Ion Exchange Resinates As
Controlled Release Drug
Delivery Systems
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Introduction
It is an attractive method for Sustained Release drug
delivery systems.
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Principle
Resins are water-insoluble materials containing anionic or
cationic groups in repeating units on the resin chain.
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Mechanism
07/25/23 98
Drugs Suitable for Resinate Preparation
2. Biological half life should be between 2-6 hrs, drugs with t1/2 < 1
hr or > 8 hrs are difficult to formulate.
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Some Important Properties of
Ion-Exchange Resins
Particle Size and form :
The rate of ion exchange reactions depend on the size of the resin particles.
Most of the ion exchange resins are available in the form of spherical beads.
When the beads are immersed in water, they imbibe a limited amount of
water to form a homogenous gel like structure.
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Some Important Properties of
Ion-Exchange Resins
Ion exchange resins have hydrocarbon network to which ionizable sulphonic
acid groups are attached. The hydrogen ions are completely dissociated in the
imbibed water and are free to diffuse through out the entire resin bead and
hence can be exchanged for an equivalent amount ions of like charge.
Porosity : Porosity is defined as the ratio of the volume of the material to its
mass. The limiting size of ions which can penetrate into a resin matrix
depends strongly on the porosity.
Swelling :The swelling behavior of the resin has a marked effect on the
release characteristics of drug resinates. The amount of swelling is inversely
proportional to the degree of divinylbenzene crosslinking present in the resin.
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Some Important Properties of
Ion-Exchange Resins
Ion exchange capacity:
It is expressed in the terms of milliequivalents per gram of ion exchange
resin.
eg. The exchange capacity of a cation exchange resin is usually found in the
laboratory by determining the number of milligram equivalents of sodium
ion which are absorbed by 1 gram of the dry resin in the hydrogen form.
The Resin ion exchanger should be Stable, Pure and free from toxicity.
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General Preparation Of Drug Resinates
Coated and uncoated drug resin complexes can be mixed in certain ratios and can be
filled into capsules with excipients or suspended in a palatable flavored vehicle
containing suitable suspending agents.
The release of drug from uncoated resin beads is expected to begin immediately while
release from the coated form would be delayed giving sustained effect.
The drug containing resin granules are first treated with an impregnating polymer such
as PEG 6000 to retard the rate of swelling in water and further coated with a water
permeable polymer such as Ethyl Cellulose to control the rate of release.
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General Preparation Of Drug
Resinates
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Applications
Adsorbents of Toxins
As Antacids
As Bile Acid binding agents
In treatment of Liver diseases
In Renal insufficiency
In Ophthalmology for glaucoma
07/25/23 106
Therapeutic applications
1. Cholestyramine It is a quaternary ammonium anion
exchange resin with basic groups attached to a
stryne – divinyl benzene copolymer.
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