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 dosage 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
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 Riboflavin, ferrous salts
intestine
Absorbed and excreted rapidly; short Penicillin G, furosemide
biologic halflives (<1 hr)
Long biologic half-lives (> 12 hr) Diazepam, phenytoin

Large doses required (>1 g) Sulfonamides

Cumulative action and undesirable side Phenobarbital, digitoxin

effects; drugs with low therapeutic index.
Precise dosage titrated to individual is Anticoagulants, cardiac
required glycosides
No clear advantage for sustained release Griseofulvin
formulation
 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 constant-rate intravenous

infusion (E). (Non acceptable )
 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 dosage form after a single
administration.
 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 Inner Coat
Provide immediate 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 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 coating
material used (3%-30% of total weight).
 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 + Anaionic drug

(Atropin) (Deltiazem HCL)

Resin-SO3- D+ Resin-N(CH3) 3+ D-

GI (HCL) GI (HCL)

Resin-SO3- H + + D Resin-N(CH 3) 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 active agent has a
progressively longer distance to travel and therefore
requires a longer diffusion time to release
 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 of the surface and continuous
exposure of fresh surface from which drug is
dissolved.