Download Sustained Release Dosage Forms The Sustained

Sustained Release
Dosage Forms
The Sustained Release Concept
 Sustained release, sustained action, prolonged action,
controlled release, extended action, timed release, depot,
and repository (storage area) dosage forms
are terms used to identify drug delivery systems that are
designed to achieve a prolonged therapeutic effect by
continuously
releasing
therapeutic
agents
over
an
extended period of time after administration of a single
dose.
Products of this type have been formulated for oral,
injectable, and topical use, and include inserts for
placement in body cavities as well.
In the case of injectable dosage forms, the
prolonged period may vary from days to months.
In the case of orally administered forms, the period
is measured in hours and critically depends on the
residence
time
of
the
gastrointestinal (GI) tract.
dosage
form
in
the
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
release formulations:
1. Administration of sustained release medication
does not permit the prompt termination of
therapy.
2. The physician has less flexibility in adjusting
dosage regimens. This is fixed by the dosage
form design.
3. Not all drugs are suitable candidates for
formulation as prolonged action medication.
4. Sustained release forms are designed for the
normal population, i.e., on the basis of average
drug
biologic
half-lives.
Consequently,
disease
states that alter drug disposition as significant
patient variation, are not accommodated.
5. Economic factors must also be assessed, since more
costly processes and equipment are involved in
manufacturing many sustained release forms.
Characteristics of Drugs suitable for
oral Sustained Release Forms
Characteristics
Drugs
Not effectively absorbed in the lower
intestine
Absorbed and excreted rapidly; short
biologic halflives (<1 hr)
Long biologic half-lives (> 12 hr)
Riboflavin, ferrous salts
Large doses required (>1 g)
Sulfonamides
Cumulative action and undesirable side
effects; drugs with low therapeutic index.
Precise dosage titrated to individual is
required
No clear advantage for sustained release
formulation
Phenobarbital, digitoxin
Penicillin G, furosemide
Diazepam, phenytoin
Anticoagulants, cardiac
glycosides
Griseofulvin
Design (Theory)

The basic goal of therapy with any drugs is to
achieve a steady-state blood or tissue level that is
therapeutically effective and nontoxic for an
extended period of time.

This is usually accomplished by maximizing
drug availability to attain a maximum rate
and
extent
of
drug
absorption
or
to
controlling bioavailability to reduce drug
absorption rates.
characteristic of multiple dosing therapy of
immediate release forms (conventional drug
therapy).
Multiple
patterns
profiles
after
non-sustained
peroral
administration of equal doses of a drug using different dosage
intervals are: every 8 hours (A), every 3 hours (B), and every 2
hours (C) every 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 prerequisite
to obtaining a blood - drug level pattern that will remain in the
therapeutic range.

Drug must be provided by the dosage form at a rate that keep
drug concentration constant at the absorption site ( To obtain a
constant drug level, the rate of drug absorption must be equal to
its rate of elimination)



Drug-blood level fluctuation can be avoided either by:
administration of drugs repetitively using constant dose interval
(A,B,C) (Non acceptable Multiple-dose therapy).
administration of drug through
infusion (E). (Non acceptable )
constant-rate
intravenous
 The objective in formulating a sustained release dosage form is to
be able to provide a similar blood level pattern for up to 12 hours
after administration of the drug.
 body drug level - time profile characterizes an ideal peroral
sustained
release
administration.
dosage
form
after
a
single

Tp = the peak time.

h = the total time after administration in which the
drug is effectively absorbed.

Cp= is the average drug level to be maintained
constantly for a period of time equal to (h - Tp)
hours; it is also the peak blood level observed
after administration of a loading dose.
Terms used to describe Drug Release
1- Delayed release (DR):
Indicates that the drug is not being released immediately
following administration but at later time,
e.g, enteric-coated tablets, pulsatile-release capsules.
2- Repeated action (RA):
Indicates that individual dose is released moderately soon
after administration, and second or third doses are
subsequently released at regular intervals thus provide
frequent drug release for drugs having low dosage with
short half lives.
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):
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):
Systems provide some actual therapeutic control, whether
temporal or prolonged.
6- Sustained Release (SR):
Systems provide medication over an extended period. With
the goal of maintaining therapeutic blood levels.
SUSTAINED
RELEASED
Formulation
Components of a sustained- release
delivery systems
Include:
Active drug
Release-controlling agents (s):
•Membrane formers
•Matrix formers
SUSTAINED
RELEASED
Membrane
Systems
Coated granules
 Coated granules produce a blood level profile similar to that
obtained with multiple dosing.
Outer Coat
Inner Coat
Granule
Core

Some of the granules
Outer Coat
are left uncoated to
Provide
immediate
Inner Coat
Granule
Core
release of the drug.
 Coats of a lipid material (e.g., beeswax) or a
cellulosic material (e.g., ethylcellulose) are applied
to the remaining granules.
 Some granules receive few coats, and some receive
many.
 The various coating
sustained-release effect.
thicknesses
produce
a
Microencapsulation
 Microencapsulation is a process by which solids, liquids,
or gases are encased in microscopic capsules.
 Thin coatings of a "wall" material are formed around the
substance to be encapsulated.
 An example is Bayer timed-release aspirin.
Film-forming substances used as coating material
include Natural and synthetic polymers
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
 The thickness of the wall can vary from 1-200
μm, depending
on the amount of
material used (3%-30% of total weight).
coating
Nanoparticles
Nanoparticles are drug delivery
systems with many applications,
including
anti-tumour
therapy,
gene therapy.
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.
 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 systems
 Hydrocolloid systems (e.g., a slow-release form of
diazepam) include a unique, hydrodynamically balanced
system (HBS) for drug delivery .
 The HBS consists of drug dispersed in a polymer
of
cellulose derivatives (as CMC, HPMC) so that the dosage
form, on contact with gastric fluid, the matrix swell and
form gel bulk with density less than one.
Thus, it remains floating because aqueous gastric fluid
density is around one .
 When the outermost hydrocolloids come in contact
with gastric fluid, they swell to form a gel layer
that prevents immediate penetration of fluid into
the formulation.
 This outer hydrocolloid layer slowly erodes, and a
new boundary layer forms.
 The process is continuous, with each new outer
layer
eroding
slowly.
The
drug
is
released
gradually through each layer as fluid slowly
penetrates the matrix.
SUSTAINED
RELEASED
Matrix
Systems
Matrix Systems
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.
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 spraycongealed, 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:
 Insoluble plastics (e.g., polyethylene, polyvinyl acetate,
polymethacrylate);
 Hydrophilic polymers (e.g., methylcellulose, hydroxypropyl
methylcellulose);
 Fatty compounds
(e.g., various waxes,
glyceryl tristearate).
Complex formation
 Complex formation is used for certain drug substances
that combine chemically with other agents forming
complexes that may be slowly soluble in body fluids.
 Example:
Amphetamine
and
antihistamine
form
low
soluble
sustained release tannate complexes with tannic acid
whose breakdown depended on pH, being somewhat
faster in gastric than intestinal fluid.
Ion-exchange resins
 Ion-exchange resins can be complexed with drugs
by passage of a cationic or anionic drug solution
through
a
column
that
contains
the
resin
Percolation).
 After the components are complexed, the resin-drug
complex is washed and tableted, encapsulated, or
suspended in an aqueous vehicle.
 The drug is complexed with the resin by replacement
of hydrogen atoms .
 Drug release results from exchange of "bound" drug
ions by ions normally present in GI fluids depending
on the ionic environment within the gastrointestinal
tract and on the properties of the resin.
 Ion-exchange resine
(styrene di-vinyl benzene copolymer)
Ananionic group
Cataionic group
COOH,
+ cataionc drug
(Atropin)
Resin-SO3- D+
GI (HCL)
Resin-SO3- H + + D
+ Anaionic drug
(Deltiazem HCL)
Resin-N(CH3) 3+ DGI (HCL)
Resin-N(CH3) 3+ CL- + D
Mechanisms by which drugs can be released
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
Diffusion
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 .
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
 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.
 Thus the release of active
agent from the system is a
function of rate of uptake of
water
Drug Out
 As the release continues, its rate normally decreases with
this
type
of
system,
since
the
progressively longer distance to
active
agent
travel and
requires a longer diffusion time to release
has
a
therefore
Osmotic systems
 Osmotic systems include the Oros system (Alza), which is
an oral osmotic pump composed of drug with osmotic
active agent in a core tablet and a semipermeable coating
that has a small hole (0.4 mm in diameter) for 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 environment but occurred only according
to osmotic pressure difference.
 After ingestion, the semi-permeable membrane allow
entrance of body 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 drug-release rate can be changed by changing
the surface area, the thickness of the membrane, or
the diameter of the drug-release orifice .
Osmotic pressure-controlled drug delivery system with two
compartments separated by a movable partition.
Erosion
In this process, the release of drug is maintained by
gradual
erosion
exposure
dissolved.
of
of fresh
the
surface
surface
and
continuous
from which
drug
is