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.