Sustained Release Sustained Release Dosage FormsDosage Forms
The Sustained Release The Sustained Release ConceptConcept Sustained release, sustained action, prolonged Sustained release, sustained action, prolonged
action, controlled release, extended action, timed action, controlled release, extended action, timed
release, depot, release, depot, and and repository (storage area) repository (storage area)
dosage forms dosage forms
are terms used to identify are terms used to identify drug delivery systemsdrug delivery systems
that are designed to achieve a prolonged that are designed to achieve a prolonged
therapeutic effect by continuously releasing therapeutic effect by continuously releasing
therapeutic agents over an extended period of therapeutic agents over an extended period of
time after administration of a single dose.time after administration of a single dose.
Products of this type have been formulated Products of this type have been formulated
for oral, injectable, and topical use, and for oral, injectable, and topical use, and
include inserts for placement in body cavities include inserts for placement in body cavities
as well.as well.
In the case of injectable dosage forms, the In the case of injectable dosage forms, the
prolonged period may vary from days to prolonged period may vary from days to
months.months.
In the case of orally administered forms, the In the case of orally administered forms, the
period is measured in hours and critically period is measured in hours and critically
depends on the residence time of the dosage depends on the residence time of the dosage
form in the gastrointestinal (GI) tract.form in the gastrointestinal (GI) tract.
Advantages of sustained release system
Avoid problems of drugs have a narrow therapeutic index ( small difference between toxic level and therapeutic level)
• Requires multiple injections
• Poor patient compliance
• Increased incidence of infection and hemorrhages
Avoid danger of systemic toxicity with more potent drugs.
Improves availability of drugs with short half lives in vivo
• Some peptides have half-lives of a few minutes or
even seconds
Targeted delivery is possible
The variable drug-blood level of multiple dosing of conventional dosage forms is reduced, because a more even drug-blood level is maintained. So improve efficacy of the treatment which result in :
cure or control condition more promptly
Improve bioavailability
The total amount of drug administered can be reduced, thus maximizing availability with a minimum dose.
Minimize or eliminate local side effect
Minimize or eliminate systematic side effect
Minimize drug accumulation
Economy for the patient
The disadvantages of sustained The disadvantages of sustained release formulations:release formulations:
1.1. Administration of sustained release Administration of sustained release
medication does not permit the prompt medication does not permit the prompt
termination of therapy.termination of therapy.
2.2. The physician has The physician has less flexibility less flexibility in in
adjusting dosage regimens. This is fixed adjusting dosage regimens. This is fixed
by the dosage form design.by the dosage form design.
3.3. Not all drugs are suitable candidates for Not all drugs are suitable candidates for
formulation as prolonged action formulation as prolonged action
medication.medication.
4.4. Sustained release forms are designed for the Sustained release forms are designed for the
normal population, i.e., on the basis of normal population, i.e., on the basis of
average drug biologic half-lives. average drug biologic half-lives.
Consequently, disease states that alter drug Consequently, disease states that alter drug
disposition as significant patient variation, disposition as significant patient variation,
are not accommodated.are not accommodated.
5.5. Economic factors must also be assessed, Economic factors must also be assessed,
since more costly processes and equipment since more costly processes and equipment
are involved in manufacturing many are involved in manufacturing many
sustained release forms.sustained release forms.
Characteristics of Drugs suitable Characteristics of Drugs suitable for oral Sustained Release Formsfor oral Sustained Release Forms
CharacteristicsDrugsNot effectively absorbed in the lower intestine
Riboflavin, ferrous salts
Absorbed and excreted rapidly; short biologic halfl ives (<1 hr)
Penicillin G, furosemide
Long biologic half-lives (> 12 hr)Diazepam, phenytoin
Large doses required (>1 g)Sulfonamides
Cumulative action and undesirable side effects; drugs with low therapeutic index.
Phenobarbital, digitoxin
Precise dosage titrated to individual is required
Anticoagulants, cardiac glycosides
No clear advantage for sustained release formulation
Griseofulvin
Design (Theory)Design (Theory)
The basic goal of therapy with any drugs is The basic goal of therapy with any drugs is
to achieve a steady-state blood or tissue to achieve a steady-state blood or tissue
level that is therapeutically effective and level that is therapeutically effective and
nontoxic for an extended period of time.nontoxic for an extended period of time.
This is usually accomplished by maximizing This is usually accomplished by maximizing
drug availability to attain a maximum rate drug availability to attain a maximum rate
and extent of drug absorption or to and extent of drug absorption or to
controlling bioavailability to reduce drug controlling bioavailability to reduce drug
absorption rates.absorption rates.
characteristic of multiple dosing characteristic of multiple dosing therapy of immediate release forms therapy of immediate release forms (conventional drug therapy).(conventional drug therapy).
Multiple patterns profiles after profiles after non-sustained peroral
administration of equal doses of a drug using different of equal doses of a drug using different
dosage dosage intervals are: every 8 hoursevery 8 hours ( (AA), ), every 3 hoursevery 3 hours ( (BB), ),
and and every 2 hoursevery 2 hours ( (CC) ) everyevery 3 hr (loading dose is twice the
maintenance dose) (D) Constant rate intravenous infusion
(E).
Selection of the proper dose and dosage interval is a Selection of the proper dose and dosage interval is a
prerequisite to obtaining a blood - drug level pattern that prerequisite to obtaining a blood - drug level pattern that
will remain in the therapeutic range.will remain in the therapeutic range.
Drug must be provided by the dosage form at a rate that Drug must be provided by the dosage form at a rate that
keep drug concentration constant at the absorption site keep drug concentration constant at the absorption site
( To obtain a constant drug level, the rate of drug ( To obtain a constant drug level, the rate of drug
absorption must be equal to its rate of elimination)absorption must be equal to its rate of elimination)
Drug-blood level fluctuation can be avoided either by:Drug-blood level fluctuation can be avoided either by: administration of drugs repetitively using constant dose administration of drugs repetitively using constant dose
interval (A,B,C) (Non acceptable Multiple-dose therapy).interval (A,B,C) (Non acceptable Multiple-dose therapy).
administration of drug through constant-rate intravenous administration of drug through constant-rate intravenous
infusion (E). (Non acceptable )infusion (E). (Non acceptable )
The objective in formulating a sustained release dosage The objective in formulating a sustained release dosage
form is to be able to provide a similar blood level pattern form is to be able to provide a similar blood level pattern
for up to 12 hours after administration of the drug.for up to 12 hours after administration of the drug.
bbody drugody drug level - time profile characterizes an ideal level - time profile characterizes an ideal
peroral sustained release dosage form after a single peroral sustained release dosage form after a single
administration.administration.
TpTp = the peak time. = the peak time.
hh = the total time after administration in which the = the total time after administration in which the
drug is effectively absorbed.drug is effectively absorbed.
CpCp= is the average drug level to be maintained = is the average drug level to be maintained constantly for a period of time equal to (h - Tp) constantly for a period of time equal to (h - Tp) hours; it is also the peak blood level observed hours; it is also the peak blood level observed after administration of a loading dose.after administration of a loading dose.
1- 1- Delayed release (DR):Delayed release (DR): Indicates that the drug is not being released immediately Indicates that the drug is not being released immediately
following administration but at later time, following administration but at later time,
e.g, enteric-coated tablets, pulsatile-release capsules.e.g, enteric-coated tablets, pulsatile-release capsules.
2- Repeated action (RA): 2- Repeated action (RA): Indicates that individual dose is released Indicates that individual dose is released
moderately soon after administration, and second or moderately soon after administration, and second or
third doses are subsequently released at regular third doses are subsequently released at regular
intervals thus provide frequent drug release for intervals thus provide frequent drug release for
drugs having low dosage with short half lives.drugs having low dosage with short half lives.
Terms used to describe Drug ReleaseTerms used to describe Drug ReleaseTerms used to describe Drug ReleaseTerms used to describe Drug Release
3- Extended Release (XR):3- Extended Release (XR):Dosage forms release slowly, so that plasma concentrations
are maintained at a therapeutic level for a prolonged period
of time.
4- Modified Release (MR): 4- Modified Release (MR): Modified Release Dosage forms are those whose
drug release characteristics of time and / or location
are chosen to accomplish therapeutic objectives not
offered by conventional forms.
5- Controlled Release (CR):5- Controlled Release (CR):Systems provide some actual therapeutic control,
whether temporal or prolonged.
6- Sustained Release (SR): 6- Sustained Release (SR): Systems provide medication over an extended
period. With the goal of maintaining therapeutic
blood levels.
SUSTAINED SUSTAINED RELEASEDRELEASED FormulationFormulation
Include:
Active drug
Release-controlling agents (s):
•Membrane formers
•Matrix formers
Components of a sustained- release
delivery systems
SUSTAINED SUSTAINED RELEASEDRELEASED MembraneMembrane
SystemsSystems
Coated granulesCoated granules Coated granules produce a blood level profile similar Coated granules produce a blood level profile similar
to that obtained with multiple dosing. to that obtained with multiple dosing.
Granule Core
Inner Coat
Outer Coat
Coats of a lipid material (e.g., Coats of a lipid material (e.g., beeswaxbeeswax) or a ) or a
cellulosic material (e.g., cellulosic material (e.g., ethylcelluloseethylcellulose) are ) are
applied to the remaining granules.applied to the remaining granules.
Some granules receive few coats, and some Some granules receive few coats, and some
receive many. receive many.
The various coating thicknesses produce a The various coating thicknesses produce a
sustained-release effect.sustained-release effect.
Outer CoatOuter CoatInner CoatInner Coat
GranulGranule e CoreCore
Some of the Some of the
granules are left granules are left
uncoated touncoated to
Provide immediate Provide immediate
release of the drug. release of the drug.
MicroencapsulationMicroencapsulation Microencapsulation is a process by which solids, Microencapsulation is a process by which solids,
liquids, or gases are encased in microscopic liquids, or gases are encased in microscopic
capsules. capsules.
Thin coatings of a "wall" material are formed Thin coatings of a "wall" material are formed
around the substance to be encapsulated. around the substance to be encapsulated.
An example is Bayer timed-release aspirin. An example is Bayer timed-release aspirin.
Hydrophilic Polymers- Alginates- Carbopol- Gelatin- Hydroxypropylcellulose- Methyl and ethyl cellulose- Starches - Cellulose acetate phthalate,.
Hydrophobic Polymers- Carnauba wax- Cetyl alcohol- Hydrogenated vegetable oils- Microcrystalline waxes- Mono-and triglycerides- PEG monostearate
Film-forming substances used as coating Film-forming substances used as coating
material include Natural and synthetic polymersmaterial include Natural and synthetic polymers
The thickness of the wall can vary from The thickness of the wall can vary from 1-1-
200 200 μμmm, depending on the amount of , depending on the amount of
coating material used (coating material used (3%-30% 3%-30% of total of total
weight). weight).
The main goals are to improve drug stability in the
biological environment, to mediate the bio-
distribution of active compounds, improve drug
loading, targeting, transport, release, and
interaction with biological barriers.
NanoparticlesNanoparticles are drug
delivery systems with many
applications, including anti-
tumour therapy, gene therapy.
Nanoparticles of size 10-200 nm are in the solid
state and are either amorphous or crystalline.
They are able to adsorb and/or encapsulate a drug,
thus protecting it against chemical and enzymatic
degradation.
Nanocapsules are vesicular systems in which the
drug is confined to a cavity surrounded by a unique
polymer membrane.
Liposomes are a form of nanoparticles
that consist of phospholipid bilayers.
Hydrocolloid systemsHydrocolloid systems Hydrocolloid systems (e.g., a slow-release form of Hydrocolloid systems (e.g., a slow-release form of
diazepam) diazepam) include a unique, hydrodynamically include a unique, hydrodynamically
balanced system (HBS) for drug delivery .balanced system (HBS) for drug delivery .
The HBS consists of drug dispersed in a polymer The HBS consists of drug dispersed in a polymer
of cellulose derivatives (as CMC, HPMC) so that of cellulose derivatives (as CMC, HPMC) so that
the dosage form, on contact with gastric fluid, the the dosage form, on contact with gastric fluid, the
matrix swell and form gel bulk with density matrix swell and form gel bulk with density less less
than onethan one. .
Thus, it remains floating because aqueous gastric Thus, it remains floating because aqueous gastric
fluid density is around one . fluid density is around one .
When the outermost hydrocolloids come in When the outermost hydrocolloids come in
contact with gastric fluid, they swell to form a contact with gastric fluid, they swell to form a
gel layer that prevents immediate penetration gel layer that prevents immediate penetration
of fluid into the formulation. of fluid into the formulation.
This outer hydrocolloid layer slowly erodes, This outer hydrocolloid layer slowly erodes,
and a new boundary layer forms. and a new boundary layer forms.
The process is continuous, with each new The process is continuous, with each new
outer layer eroding slowly. The drug is outer layer eroding slowly. The drug is
released gradually through each layer as fluid released gradually through each layer as fluid
slowly penetrates the matrix.slowly penetrates the matrix.
SUSTAINED SUSTAINED RELEASEDRELEASED MatrixMatrix
SystemsSystems
It involves the direct compression of blends of drug
and retardant matrix material in a into tablets .
Drug bioavailability is dependent on drug : polymer
ratio
The primary dose, or the portion of the drug to be
released immediately, is placed on the tablet as a
layer, or coat. The rest of the dose is released slowly
from the matrix.
Matrix SystemsMatrix Systems
Two methods may be used to
disperse drug in the retardant base. A solvent evaporation technique :
In which a solution or dispersion of drug is incorporated
into the molten wax phase and the solvent is removed
by evaporation. Dry blends may be slugged and
granulated.
Fusion technique:
A more uniform dispersion can be prepared by the
fusion technique in which drug is blended into the
molten wax matrix at temperatures slightly above the
melting point. The molten material may be spray
congealed, solidified and milled, or poured on a cold
rotating drum to form sheets, which are then milled and
screened to form a granulation.
Matrix materials used are:Matrix materials used are:
Insoluble plasticsInsoluble plastics (e.g., polyethylene, polyvinyl (e.g., polyethylene, polyvinyl
acetate, polymethacrylate);acetate, polymethacrylate);
Hydrophilic polymersHydrophilic polymers (e.g., methylcellulose, (e.g., methylcellulose,
hydroxypropyl methylcellulose); hydroxypropyl methylcellulose);
Fatty compoundsFatty compounds
(e.g., various waxes, glyceryl tristearate).(e.g., various waxes, glyceryl tristearate).
Complex formationComplex formation Complex formation is used for certain drug Complex formation is used for certain drug
substances that combine chemically with other substances that combine chemically with other
agents forming complexes that may be slowly agents forming complexes that may be slowly
soluble in body fluids.soluble in body fluids.
Example:Example:
Amphetamine and antihistamine form low soluble Amphetamine and antihistamine form low soluble
sustained release tannate complexes with tannic sustained release tannate complexes with tannic
acid whose breakdown depended on pH, being some acid whose breakdown depended on pH, being some
what faster in gastric than intestinal fluid.what faster in gastric than intestinal fluid.
Ion-exchange resinsIon-exchange resins Ion-exchange resins can be complexed with Ion-exchange resins can be complexed with
drugs by passage of a cationic or anionic drug drugs by passage of a cationic or anionic drug
solution through a column that contains the solution through a column that contains the
resin Percolation). resin Percolation).
After the components are complexed, the After the components are complexed, the
resin-drug complex is washed and tableted, resin-drug complex is washed and tableted,
encapsulated, or suspended in an aqueous encapsulated, or suspended in an aqueous
vehicle.vehicle.
The drug is complexed with the resin by The drug is complexed with the resin by
replacement of hydrogen atoms .replacement of hydrogen atoms .
Drug release results from exchange of Drug release results from exchange of
"bound" drug ions by ions normally present in "bound" drug ions by ions normally present in
GI fluids depending on the ionic environment GI fluids depending on the ionic environment
within the gastrointestinal tract and on the within the gastrointestinal tract and on the
properties of the resin. properties of the resin.
Ion-exchange resine Ion-exchange resine
(styrene di-vinyl benzene copolymer)(styrene di-vinyl benzene copolymer)
Ananionic groupAnanionic group Cataionic groupCataionic group
COOHCOOH, ,
++ cataionc drug cataionc drug ++ Anaionic drug Anaionic drug
(Atropin)(Atropin) (Deltiazem HCL)(Deltiazem HCL)
Resin-SOResin-SO33-- D D+ + Resin-N(CHResin-N(CH33)) 3 3
++ D D--
GI (HCL) GI (HCL) GI (HCL) GI (HCL)
Resin-SOResin-SO33- - H H + + + D Resin-N(CH+ D Resin-N(CH33)) 3 3
++ CL CL- - + D+ D
Mechanisms by which drugs can be released Mechanisms by which drugs can be released
from matrix sustained delivery system from matrix sustained delivery system There are three primary mechanisms by which
active agents can be released from a delivery
system:
Diffusion
Erosion
Osmotic release
In diffusion controlled delivery systems, rate control
is obtained by the penetration of fluids into the
system.
Two general types of these systems include:
Swelling controlled release systems
Osmotically controlled delivery systems.
Diffusion
Swelling Controlled Systems:Swelling controlled release systems when placed in
the body absorb body fluids and swell.
Swelling increases the aqueous solvent content
within the formulation and the polymer mesh size,
enabling the soluble drug to diffuse through the
swollen network into the external environment.
Swelling Reservoir and Matrix Systems
Thus the release of active
agent from the system is
a function of rate of
uptake of water
Most of the materials used in swelling controlled
release systems that will swell without dissolving,
when exposed to water or other biological fluids as
hydrogels.
As the release continues, its rate normally decreases
with this type of system, since the active agent has a
progressively longer distance to travel and therefore
requires a longer diffusion time to release
Drug Out
Osmotic systemsOsmotic systems Osmotic systems include the Oros system (Alza), which Osmotic systems include the Oros system (Alza), which
is an oral osmotic pump composed of drug with osmotic is an oral osmotic pump composed of drug with osmotic
active agent in a core tablet and a semipermeable active agent in a core tablet and a semipermeable
coating that has a small hole (0.4 mm in diameter) for coating that has a small hole (0.4 mm in diameter) for
drug release. The hole is produced by a laser beam.drug release. The hole is produced by a laser beam.
Schematic diagram of an osmotic tablet.
Drug release is zero order and independent on pH changes in the Drug release is zero order and independent on pH changes in the
environment but occurred only according to osmotic pressure difference.environment but occurred only according to osmotic pressure difference.
After ingestion, the semi-permeable membrane allow entrance of body After ingestion, the semi-permeable membrane allow entrance of body
fluids into the core and dissolve the drug results in pressure builds up in fluids into the core and dissolve the drug results in pressure builds up in
the core which pumps the drug solution out from the orifice.the core which pumps the drug solution out from the orifice.
Osmotic pressure-controlled drug delivery system with
two compartments separated by a movable partition.
The drug-release rate can be changed by The drug-release rate can be changed by
changing the surface area, the thickness of changing the surface area, the thickness of
the membrane, or the diameter of the drug-the membrane, or the diameter of the drug-
release orifice . release orifice .
ErosionIn this process, the release of drug is
maintained by gradual erosion of the surface
and continuous exposure of fresh surface from
which drug is dissolved.