CHAPTER 9: Delayed Release
SOLID ORAL MODIFIED-RELEASE DOSAGE
FORMS and DRUG DELIVERY SYSTEMS
OUTLINE:
 Differentiate the following dosage forms:
a) extended-release c) repeat action
b) delayed-release d) targeted release
 Advantages and disadvantages of extended release
dosage forms over conventional forms?
 Characteristics of drugs best suited for incorporation
into an extended release product?
 Mechanisms by which extended drug action are
achieved.
 Explanation of 3 ways by which the rate of drug
release from the solid dosage forms be modified
 Explanation of the different technologies employed
in the modification of drug release rate. Give the
products employing these modifications:
a) coated beads, pellets, granules, microspheres
b) multitablet system
c) microencapsulated drugs
d) embedding drug in slowly eroding/hydrophilic
matrix system
e) embedding drug in inert plastic matrix
f) complex formation
g) ion-exchange resins
h) osmotic pump
 Reasons why drugs must remain intact until it reaches
the intestines? How are these be achieved?
 Development of an IVIVC model
 Clinical considerations in the use of oral modified-
release dosage forms?
 How extended drug action is achieved by routes other
than oral administration
Extended Release
 Allows a reduction in dosing frequency from that
necessitated by a conventional dosage forms, such as
a solution of an immediate-release dosage form U.S.
Food and Drug Administration (FDA)
 Tablets & capsules
o taken once or twice daily
 Provides immediate release of drug:
o provides promptly desired therapeutic
effect
o followed by gradual & continual release
of additional amounts of drug
maintaining effect over predetermined
period of time
 Release the drug at a time other than promptly after
administration
 Delay is time based or based on the influence of
environmental conditions, like gastrointestinal pH
 Example – Enteric coating Aspirin
Examples of Proprietary Modified-Release Oral Dosage
Forms:
1. Delayed Release
 Prilosec (Omeprazole)
 Enteric coated granules of
Omeprazole placed in capsules.
 Omeprazole is acid labile and is
degraded by gastric acid.
 Use: treatment of duodenal ulcer
Repeat Action
 Contain two single doses of medication:
o one - for immediate release
o second - for delayed release.
 example: Two layer tablets:
o one layer of drug for immediate release
o second layer to release drug later as a
second dose/in an extended-release
manner
Targeted Release
 release towards isolating or concentrating a drug in
body
 region, tissue, or site for absorption or for drug
action.
Advantages of Extended-Release Dosage Forms over
Conventional Forms:
1. Less fluctuation in drug blood levels
2. Frequency reduction in dosing
3. Enhanced convenience and compliance
4. Reduction in adverse side effects
5. Reduction in overall health care costs
Disadvantages of Extended-Release Dosage Form:
1. Loss of flexibility in adjusting the drug dose &/or
dosage regimen
2. Risk of sudden & total drug release/dose dumping
due to failure of technology
Characteristics of drugs best suited for incorporation into
extended release product:
1. They exhibit neither very slow nor very fast rates
of absorption and excretion.
 a. Drugs with slow rates of absorption and
excretion are usually inherently long acting.
b. Drugs with very short half-lives, that is, less
than 2 hours, are poor candidates for ER
2. They are uniformly absorbed from gastrointestinal
tract.
a. Drugs prepared in extended-release forms
must have good aqueous solubility and
maintain adequate residence time in the
gastrointestinal tract.
b. Drugs absorbed poorly or at varying and
unpredictable rates are not good candidates
for extended-release products.
3. They are administered in relatively small doses.
a. Drugs with large single doses frequently are
not suitable for ER because the tablet or
capsule needed to maintain a sustained
therapeutic blood level of the drug would be
too large for the patient to swallow easily.
4. They possess a good margin of safety.
a. The most widely used measure of the margin
of a drug’s safety is its therapeutic index.
b. For very potent drugs, the therapeutic index
may be narrow or very small. The larger the
therapeutic index, the safer the drug.
5. They are used in the treatment of chronic rather than
acute conditions.
a. Drugs for acute conditions require greater
adjustment of the dosage by the physician than
that provided by the extended-release
products.
Mechanism by which extended drug action are achieved
 For orally administered dosage forms, extended drug
action is achieved by:
 Affecting the rate at which the drug is released
from the dosage form and/or
 By slowing the transit of the dosage form
through the gastrointestinal tract
3 ways by which the rate of drug release from the solid
dosage forms is modified:
1. Modifying drug dissolution by controlling
access of biologic fluids to the drug through
the use of the barrier coatings.
2. Controlling drug diffusion rates from dosage
forms.
3. Chemical reaction or interaction between the
drug substances or its pharmaceutical barrier
and the site-specific biologic fluid.
Different technologies employed in the modification of
drug release rate:
1. Coated beads, pellets, granules, microspheres.
 The drug is distributed using conventional
pan coating or air suspension coating.
 A solution of the drug substance is placed on
small intact nonparent seeds or beads made
of sugar and stand or on microcrystalline
cellulose.
a. Nonpareil seed – 425-850 mcm
b. Microcrystalline cellulose – 170-600 mcm
i. More durable during production than
sugar-based cores.
 Lipid materials used to coat granules:
 Beeswax
 Carnaubawax
 Glycerylmonostearate
 Cetyl alcohol
 Cellulosic material (ethyl cellulose)
1. Aqueous coating system eliminates
the hazards and environmental
concerns associated with organic
based solvent systems.
2. The thicker the coat, the more
resistant to penetration and the more
delayed will be the drug release and
dissolution.
3. Spansule
2. Multitablet System
 Small spheroid compressed tablets 3 to 4
mm diameter may be prepared to have
varying drug-release characteristics.
 Each capsule may contain 8 to 10
minitablets, some uncoated for immediate
release and others coated for extended drug
release.
3. Microencapsulated drugs
 Microencapsulation
 A process by which solid or even gases
may be enclosed in microscopic particles
by formation of thin coatings of wall
material around the substance.
 Gelatin
 A common wall forming material and
synthetic polymers, such as polyvinyl
 alcohol, ethyl cellulose, polyvinyl
chloride and other materials may be used
dissolving the wall materials
 A solution to second material is added,
usually acacia
 The final dry microcapsules are free-
flowing discrete particles of coated
material
 Wall material constitute 2% to 20% of
the total particle weigh
 Advantage of microcapsulation:
o Administered dose of a drug is
subdivided into small units that are
spread over a large are of the
gastrointestinal, which may
enhance absorption by diminishing
local drug concentration (e.g.
Micro-K Extencaps)
4. Embedding drug slowly eroding or hydrophilic
matrix system
 Drug substance is combined and made into
granules with an excipient material that slowly
erodes in body fluids, progressively releasing
the drug for absorption.
 Hydrophilic cellulose polymers
 Commonly used as the excipient base in
tablet matrix systems.
 The effectiveness of these hydrophilic matrix
systems is based on
 The successive processes of hydration of
the cellulosic polymer,
 Gel formation on the polymer's surface,
 Tablet erosion, and
 The subsequent and continuous release
of drug.
 Hydroxypropyl methylcellulose (HPMC),
 A free-flowing powder, is commonly
used to provide the hydrophilic matrix.
 For a successful hydrophilic matrix system,
 The polymer must form a gelatinous
layer rapidly enough to protect the inner
core of the tablet from disintegrating too
rapidly after ingestion.
 20% of HPMC results in satisfactory
rates of release for an extended-release
tablet formulation.
 Manufacturers may prepare two-layer tablets:
 one layer containing the uncom- bined
drug for immediate release and
 the other layer having the drug
embedded in a hydrophilic matrix for
ER.
 Three-layer tablets may be similarly
prepared, with both outer layers containing
the drug for immediate release.
5. Embedding Drug in Inert Plastic Matrix
 The drug is granulated with an inert plastic
material such as polyethylene, polyvinyl
acetate, or polymethacrylate, and the
granulation is compressed into tablets.
 Slowly released from the inert plastic matrix
by diffusion.
 The compression creates the matrix or plastic
form that retains its shape during leaching of
the drug and during its passage through the
alimentary tract.
6. Complex Formation
 Form complexes that may be only slowly
soluble in body fluids, depending on the pH
of the environment.
 Slow dissolution rate provides the ER of the
drug.
 Salts of tannic acid, tannates, provide this
quality in a variety of proprietary products
7. Ion-Exchange Resins
 Solution of a cationic drug may be passed
through a column containing an ion-exchange
resin, forming a complex by the replacement
of hydrogen atoms.
 Release of the drug depends on the pH and
electrolyte concentration in the
gastrointestinal tract.
 Release is greater in the acidity of the
stomach than in the less acidic environment
of the small intestine.
 In the Stomach.
1. Drug resinate + HCl �acidic resin +
drug hydrochloride
2. Resin salt + HCl �resin chloride +
acidic drug
 In the Intestine.
1. Drug resinate + NaCl � sodium
resinate + drug hydrochloride
2. Resin salt + NaCl �resin chloride +
sodium salt of drug
 8. Osmotic Pump
 The pioneer oral osmotic pump drug
delivery system is the OROS system
developed by Alza.
 Composed of a core tablet surrounded by a
semipermeable membrane coating having a
0.4-mm-diameter hole produced by laser
beam
 Core tablet has two layers, one containing the
drug (the active layer) and the other
containing a poly- meric osmotic agent (the
push layer).
Delayed-release oral dosage forms
 The purpose may be
o To protect a drug destroyed by gastric
fluids,
o To reduce gastric distress caused by drugs
particularly irritating to the stomach, or
o To facilitate gastrointestinal transit for
drugs that is better absorbed from the
intestines.
 Enteric coating
o Capsules and tablets specially coated to
remain intact in the stomach and to yield
their ingredients in the intestines
o Properties:
 pH dependent,
 breaking down in the less acidic
environment of the intestine;
 time dependent,
 eroding by moisture over time
during gastrointestinal transit; or
 enzyme dependent, deteriorating
as a result of the hydrolysis-
catalyzing action of intestinal
enzymes.
Agents used for enteric coating of capsules and tablets
 fats, fatty acids, waxes, shellac, cellulose acetate
phthalate
in Vitro–in Vivo correlations
 Level A:
o The relationship between the entire in
vitro dissolution and release time course
and the entire in vivo response time
course.
 Ex. Time course of plasma drug
concentration or amount of drug
absorbed.
 Level B:
o The relationship between summary
parameters that characterize the in vitro
and in vivo time courses
 Ex. models that relate the mean
in vitro dissolution time to the
mean in vivo dissolution time,
 Ex. the mean in vitro dissolution
time to the mean residence time
in vivo, or
 Ex. the in vitro dissolution rate
constant to the absorption rate
constant
 Level C:
o The relationship between the amount
dissolved in vitro at a particular time (or
the time required for in vitro dissolution
of a fixed percent of the dose, e.g., T50)
and a summary parameter that
characterizes the in vivo time course.
o The level of IVIVCs may be useful in the
early stages of formulation development
when pilot formulations are being
selected.
Among the criteria applicable to the development of
IVIVCs are the following (9):
1. In determining in vitro dissolution, USP
dissolution apparatus, type I (basket) or type II
(paddle), is preferred, although type III
(reciprocating cylinder) or type IV (flow-through
cell) may be applicable in some instances.
2. An aqueous medium with a pH not exceeding
6.8 is preferred as the medium for dissolution
studies. For poorly soluble drugs, a surfactant
(e.g., 1% sodium lauryl sulfate) may be added.
3. The dissolution profiles of at least 12 individual
dosage units from each lot should be determined.
4. For in vivo studies, human subjects are used in
the fasted state unless the drug is not well
tolerated, in which case the studies may be
conducted in the fed state. Acceptable data sets
have been shown to be generated with use of 6 to
36 human subjects.
5. Crossover studies are preferred, but parallel
studies or cross-study analysis may be acceptable
 using a common reference treatment product,
such as an intravenous solution, an aqueous oral
solution, or an immediate-release product.
Clinical considerations in the use of oral modified-release
dosage forms.
 Patients should be advised of the dose and dosing
frequency of modified drug-release products and
instructed not to use them interchangeably or
concomitantly with immediate-release forms of the
same drug.
 Patients stabilized on a modified-release product
should not be changed to an immediate-release
product without consideration of any existing blood
level concentrations of the drug.
 Also, once stabilized, patients should not be
changed to another extended-release product
unless there is assurance of equivalent
bioavailability. A different product can result in a
marked shift in the patient's drug blood level
because of differences in drug-release
characteristics.
 Patients should be advised that modified-release
tablets and capsules should not be crushed or
chewed, since such action compromises their drug-
release features.
 Patients being fed by enteral nutrition through a
nasogastric tube may receive conventional or
modified-release medication.
 Similarly, modified-release tablets and capsules
should not generally be used as the source of a drug
to prepare other dosage forms, that is, pediatric oral
liquids.
 Patients and caregivers should be advised that no
erodible plastic matrix shells and osmotic tablets
remain intact throughout gastrointestinal transit and
the empty shells or ghosts from osmotic tablets may
be seen in the stool.
 The patient should be assured of the normalcy of
this event and that drug absorption has taken place.
Extended drug action is achieved by routes other than
oral administration
1. Ocular Drug Products (Opthalmics)
 Problem: rapid loss of administered drug
due to the blinking of the eye and the
flushing effect of lacrimal fluids.
 Up to 80% of an administered dose may
belost through tears and the action of
nasolac- rimal drainage within 5 minutes
of installa- tion.
 Extended periods of therapy may be
achieved by formulations that increase
the contact time between the medication
and the corneal surface.
a. Gel Extended Release:
i. Designed to extend drug action.
b. Lacrisert:
 Rod-shaped water- soluble form of
hydroxypropyl cellulose.
 Placed in the inferior cul-de-sac of the eye
once or twice daily for the treatment of dry
eyes.
 Soften and slowly dissolve, thickening the
precorneal tear film and prolonging the tear
film breakup.
c. Polocarpine Insert:
 Used in the treatment of glaucoma.
 Sandwiched between two EVA membranes
contains alginic acid, a seaweed carbohydrate,
which serves as a carrier for pilocarpine.
 Placed in the cul-de-sac, where it will float
with the tears.
 Advantage:
1. Enhanced compliance, as the patient
does not have to remember to instill the
drops and has no blurred vision or slight
discomfort that occurs when applying
drops to the eyes.
2. Parenteral Systems:
a. Long Acting Parenteral System
 Extended rates of drug action following
injection may be achieved in a number of
ways,
b. Liposomes
 Composed of small vesicles of a bilayer of
phospholipid encapsulating an aqueous
space ranging from about 0.03 to 10 mm
in diameter.
 Composed of one or many lipid
membranes enclosing discrete aqueous
compartments.
 Advantages:
 Liposome-encapsulated drugs are
delivered intact to various tissues
and cells and can be released
when the liposome is destroyed,
 enabling site-specific and targeted
drug delivery.
 Liposomes can be used for both
hydrophilic and lipophilic drugs
without chemical modification.
 Other tissues and cells of the
body are protected from the drug
until it is released by the
liposomes, decreasing the drug’s
toxicity.
 The size, charge, and other
characteristics can be altered
depending on the drug and the
intended use of the product.
 Disadvantage:
o Tendency to be taken up by cells
of the reticuloendothelial system
(RES) and the slow release of the
drug when the liposomes are
taken up by phagocytes through
endocytosis, fusion, surface
adsorption, or lipid exchange.
c. Stealth Liposomes
 Liposomes that avoid detection by the
body’s immune system, specifically the
cells of the RES.
 Prepared with PEG on the outside of the
membrane.
 Have some type of biological species
attached as a ligand to the liposome in
order to enable binding via a specific
expression on the targeted drug delivery
site.
 Targeting ligands could be monoclonal
antibodies (making an
immunoliposome), vitamins, or specific
antigens.
3. Vaginal Inserts
 Advantages:
 Self-insertion and removal,
continuous drug administration at
an effective dose level, and good
patient compliance.
 Continuous release and local absorption
of drug minimize systemic toxicity that
may result from oral peak-and-valley
drug administration.
a. Intrauterine progesterone drug delivery
system
 Slowly releases an average of 60
mg of pro- gesterone per day for
1 year after insertion.
 Advantages of (a) using a natu-
ral hormone; (b) containing no
estrogens; (c) using a T-shaped
delivery device to ensure
comfort, safety, and retention,
which mini- mizes mechanically
induced irritation; and (d)
confining the hormonal action to
the uterus.
 Dinoprostone Vaginal insert
 Thick, flat, rectangular polymeric
slab enclosed in a pouch of a
knitted polyes- ter retrieval
system.
 Product is designed to release
dinoprostone in vivo at a rate of
about 0.3 mg per hour.
 Estring
A unique method of
administering estradiol is
through the use of the estradiol
vaginal ring
 Crinone gel
 Contains micronized
progesterone and the polymer
polycarbophil in an oil-in-water
emulsion system.
 Insoluble in water, swells within
the vagina and forms a
bioadhesive gel coating on the
walls of the vagina.
4. Subdermal implants
 Long-acting dosage forms that provide
continuous release of the drug, often
for periods of months to years.
 Administered by the parenteral route;
for systemic delivery, they may be
placed subcu- taneously, or for local
delivery, they can be placed in a
specific region in the body.
 Generally consist of the drug and rate-
controlling excipients.
1. Pellets implants:
 Small, sterile, solid masses of the
active drug with or without excipients
and are usually administered using a
suitable special injector (e.g., trocar)
or by surgical incision.
2. Resorbable microparticles or
microspheres
 Generally range from 20 to 100 μm in
diameter
 Administered as an aqueous
suspension subcutaneously or
intramuscularly for systemic delivery,
or they may be injected into a specific
location in the body.
3. Polymer implants can be formed as a
single mass, such as a cylinder.
 Used to deliver potent small
molecules, including steroids, and
large molecules, including peptides.
 Advantage: do not require removal
after release of the entire drug.
4. Liquid–gel/solid implants
 Initially liquid formulations
comprising a polymer, active drug,
and solvent (either aqueous or
organic).
5. Metal/plastic implants
 Formulated from titanium or other
suitable materials and are
administered by an injector or surgical
installation.
6. Drug-eluting stents
 Combine the mechanical effect of the
stent with a prolonged pharmacologic
effect of the incorporated drug.
 Levonorgestrel implants set of six
flexible closed capsules of a
dimethylsiloxane– methyl vinyl
siloxane copolymer, each containing
36 mg of the progestin (16)
 To facilitate sub- dermal implantation
through a 2-mm incision in the mid
upper arm about 8 to 10 cm above
the elbow crease.
7. Gliadel Wafer implant
 A sterile off-white to pale yellow wafer
approximately 1.45 cm in diameter
and 1 mm thick.
 Designed to deliver the carmustine
directly into the surgical cavity created
when a brain tumor is resected, with
numerous wafers being used
depending upon the desired dose.
8. Goserelin implant (Zoladex)
 A sterile, biodegradable product
containing goserelin acetate,
equivalent to 3.6 mg of drug, designed
for subcutaneous injection with
continuous release over 28 days.
 Palliative treatment of advanced
carcinoma of the prostate, offering an
alternative to orchiectomy and/or
estrogen administration when the
standard treatments are not indicated
or are unacceptable to the patient.
 Treatment of endometriosis and
advanced breast cancer.
9. Viadur Implant
A sterile, nonbiodegradable,
osmotically driven miniaturized
implant designed to deliver leuprolide
acetate for 12 months at a controlled
rate.
 Palliative treatment of advanced
prostate cancer.
10. Vitrasert implants
 Used to treat AIDS-related
cytomegalovirus (CMV) retinitis.
 Ganciclovir does not cure the CMV
retinitis, but helps to decrease its
progression.
 Pregnancy category C, and its use in
pediatric patients <9 years of age has
not been established.
 Associated with carcinogenicity and
mutagenicity and should be handled
and disposed of properly according to
antineoplastic guidelines.