Sustained Release Dosage Forms

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Sustained Release Dosage Forms
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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.

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• 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.

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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

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• 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

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• The disadvantages of sustained release
  formulations
• Administration of sustained release medication
  does not permit the prompt termination of
  therapy.
• The physician has less flexibility in adjusting
  dosage regimens. This is fixed by the dosage form
  design.
• Not all drugs are suitable candidates for
  formulation as prolonged action medication.

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• 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.
• Economic factors must also be assessed, since
  more costly processes and equipment are involved
  in manufacturing many sustained release forms.

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Characteristics of Drugs suitable for oral
Sustained Release Forms
Drugs Characteristics
Riboflavin, ferrous salts Not effectively absorbed in the lower intestine
Penicillin G, furosemide Absorbed and excreted rapidly short biologic halflives (lt1 hr)
Diazepam, phenytoin Long biologic half-lives (gt 12 hr)
Sulfonamides Large doses required (gt1 g)
Phenobarbital, digitoxin Cumulative action and undesirable side effects drugs with low therapeutic index.
Anticoagulants, cardiac glycosides Precise dosage titrated to individual is required
Griseofulvin No clear advantage for sustained release formulation
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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.

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characteristic of multiple dosing therapy of
immediate release forms (conventional drug
therapy).
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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).
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• 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 )

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• 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.

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• 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.

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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.
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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.
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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.
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SUSTAINED RELEASED Formulation
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Components of a sustained- release delivery
systems

• Include
• Active drug
• Release-controlling agents (s)
• Membrane formers
• Matrix formers

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SUSTAINED RELEASED Membrane Systems
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Coated granules

• Coated granules produce a blood level profile
  similar to that obtained with multiple dosing.

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• Some of the granules are left uncoated to
• Provide immediate 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
  sustained-release effect.

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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.

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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

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• The thickness of the wall can vary from 1-200 µm,
  depending on the amount of coating material used
  (3-30 of total weight).

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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.
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• 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.

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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 .

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• 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.

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SUSTAINED RELEASED Matrix Systems
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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.

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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.
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• 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).

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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.

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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 .

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• 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.

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• 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(CH3) 3 CL- D

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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
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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.
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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
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• 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

• 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

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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.
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• 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.

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• 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.
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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.