Uy, Alyssa V.

2BPh
CHAPTER 9 - Solid Oral Modified-Release Dosage Form and Drug Delivery
Systems

Frequency reduction in dosing

extended-release products frequently deliver more than less
often than conventional form DepoFoam Drug Delivery System

Enhanced convenience and compliance

with less frequency in dosing, a patient is less apt to neglect
taking a dose, also it provides greater convenience with day and
night administration

Reduction in adverse side effects

because of fewer blood level peaks outside therapeutic range
and into toxic range, adverse side effects are less frequent

Reduction in overall health care costs

overall cost of treatment may be less because of enhanced
therapeutic benefit, fewer side effects, and reduced time for
health care personnel to dispense and administer drugs and
monitor patients

INTRODUCTION

Describes solid oral dosage forms and drug delivery system that
virtue of formulation and product design have modified drug
release features

Modified release products provide either delayed release or

extended release of drug

Most delayed release products are enteric-coated tablets or

capsules designed to pass through the stomach unaltered, later to
release their medication within the intestinal tract

Enteric coatings are used either to protect a substance from

destruction by gastric fluids or to irritating drugs

DISADVANTAGE OF ETENDED-RELEASE DOSAGE FORMS OVER

CONVENTIONAL FORMS

Extended release products are designed to release their medication in a

controlled manner at a predetermined rate, duration, and location to
achieve and maintain optimum therapeutic blood levels of drug

loss of flexibility in adjusting the drug dose and/or dosage

regimen
risk of sudden and total drug release
dose dumping due to failure in technology

TERMINOLOGY
1. Sustained Release (SR) Melatonex
2. Sustained Action (SA) Drixoral
3. Extended Release (ER) NOX3
4. Long Acting (LA) Theraflu
5. Prolong Action (PA)
6. Controlled Release (CR) Melatonin
7. Timed Release (TR) Vit-Min 100

RATIONAL FOR EXTENDED RELEASE PHARMACEUTICALS

Extended release tablets & capsules = take once or twice daily

Conventional forms = 3 to 4 times daily to achieve same
TE

For non oral rate-controlled DDSs = 24 hours for most

transdermal patches to months to years

Ex.: Lovenorgestrel subdermal implants (Norplat

System)
MULTIPLE DAILY DOSING

inconvenient for the patient and can result in missed doses,

made-up doses, and noncompliance with the regimen
when doses are not administered on schedule, the resulting peaks
and valleys reflect the optimum drug therapy

ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS OVER

CONVENTIONAL FORMS

Reduction in drug blood levels fluctuation

controlling the rate of release eliminatedpeaks and valleys of
blood levels

Products bearing these descriptions differ in design and

performance and must be examined individually to ascertain their
respective features

Rate-Controlled delivery
applied to certain types of drug delivery systems in which the rate
of delivery is controlled by features of service rather than by
physiologic or environmental conditions like gastrointestinal pH or
drug transit time through the gastrointestinal tract
Modified release
has come into general use to describe dosage forms having drug
release features based on time course and/or location that are

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designed to accomplish therapeutic or convenience objectives not

offered by conventional or immediate-release forms
Extended-release
dosage forms of this type are the ones that allow a reduction in
dosing frequency form that necessitated by a conventional dosage
forms, such as solution or an immediate-release drug dosage form
Delayed release
releases the drug at a time other than promptly after
administration. The delay may be time base or base on the
influence of environmental conditions such as gastrointestinal pH
Repeat action
two single doses of medication; one for immediate release;
another one for modified release
Targeted release
drug release directed toward isolating or concentrating a drug in a
body region, tissue or site of absorption or for drug action
Extended Release Oral Dosage Forms (Successful ER Product)
1. Release from dosage forms at a predetermine rate
2. Dissolve in GT
3. Maintain sufficient Gastrointestinal residence time
4. Be absorbed at a rate that will replace the amount of drug being
metabolized and excreted
CHARACTERISTICS OF EXTENDED-RELEASE PRODUCTS
1. They exhibit very slow nor very fast rates of absorption and excretion
drugs with slow rates of absorption and excretion are usually
inherently long-acting, and it is not necessary to prepare them in
extended-release forms
drug with very short half-lives, less than 2 hours, are poor
candidates for extended release
drugs that act by affecting enzyme systems may be loner acting
than indicated by their quantitative half-lives because of their
residual effects and recovery of the diminished biosystem
2.

They are uniformly absorbed from the gastrointestinal tract

they must have good aqueous solubility and maintain adequate
residence time in the gastrointestinal tract

3.

4.

drugs absorbed poorly or at varying and unpredictable rates are

not good candidates for extended-release products

They are administered in relatively small doses

drugs with large single doses frequently are not suitable for
extended release 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
They possess a good margin of safety
the most widely used measure of the margin of a drugs safety is
its therapeutic index, that is, the median toxic dose divided by the
median affective dose
the larger the therapeutic index, the safer the drug
drugs that are administered in very small doses or possess very
narrow therapeutic indices are poor candidates for formulations
because of technologic limitations of precise control over release
rates and the risk of dose dumping due to a product defect

5.

They are used in the treatment of chronic rather than acute

conditions
drugs for acute conditions require greater adjustment of the
dosage by the physician than that provided by extended-release
products
BASIS OF DRUG RELEASE modifying drug dissolution by
controlling excess of biologic fluids to the drug through the use of
barrier coatings
controlling drug diffusion rate from dosage forms
chemical reaction or interaction between the drug substance or
its pharmaceutical barrier and site-specific biologic fluids

BASIS OF DRUG RELEASE

modifying drug dissolution by controlling excess of biologic fluids
to the drug through the use of barrier coatings
controlling drug diffusion rate from dosage forms
chemical reaction or interaction between the drug substance or
its pharmaceutical barrier and site-specific biologic fluids
COATED BEADS, GRANULES AND MICROSPHERES
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 sphere
Nonpareil seeds
425-850m
Microcrystalline cellulose
More durable during production than sugar-based cores
170-600m
Lipid materials used to coat granules
Beeswax
Carnauba wax
Glyceryl monostearate
Cetyl alcohol
Cellulosic material (ethyl cellulose)
Aqueous coating system eliminate the hazards and environmental
concerns associated with organic based solvent systems
The thicker the coat, the more resistant to penetration and the
more delayed will be the drug release and dissolution
Spansule
MULTITABLET SYSTEMS
small spheroidal compressed tablets 3 to 4 mm in diameter may
be prepared
each capsule contain 8 to 10 minitablets some uncoated for
immediate release and others coated for extended drug release
MICROENCAPSULATED DRUG
Microencapsulation
A process by which solid, liquid 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 material
encapsulated material is added to the mixture and the thoroughly
stirred

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a solution to second material is added, example of acacia

the final dry microcapsules are free-flowing discrete particles of
coated material
wall material constitute into 20% of the total particle weigh

retains its shape during leaching of he drug and during its passage
through the alimentary tract
Example: Gradumet

COMPLEX FORMATION
form complexes that may be slowly soluble in body fluids,
depending on the pH of the environment
ADVANTAGE OF MICROENCAPSULATION
administered dose of a drug is subdivided into small units that are
spread over a large area of the gastrointestinal tracts, which may
enhance absorption by diminishing local drug concentration (e.g.
Micro-K ExtenCaps)
>Encapsulation. All of the single and combination capsules are
produced here. The empty gelatin capsules are placed in hoppers
and free-flowing to the machine. The bottom portion of the
capsule is filled, which is gravity-fed from a stainless steel bin into
the machines hopper. An average of 6 million capsules a day can
be produced.
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
EFFECTIVENESS OF THE HYDROPHILIC MATRIX IS BASED ON:

successive process of hydration on the polymers surface

gel formation on the polymers surface
tablet erosion
subsequent and continuous release of drug

slow dissolution rate (e.g. Rynatan)

salts of tannic acid, tannates, provide this quality in a variety of

proprietary products

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
hydrocodone polistirex (Tussionex) and chlorpheniramine
polistirex suspension and phentermine resin capsules
Mechanism of ion exchange resins:
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
release is extended over 12 hours by ionic exchange

Hydroxypropyl Methyl Cellulose (HPMC)

a free flowing powder; commonly used to provide the hydrophilic
matrix
A successful hydrophilic matrix system must contain the
following:
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 formation (e.g Oramorph SR Tablet)

Manufacturers may prepare two-layer tablets

one layer containing the uncombined drug for immediate release
the other layer having the drug encoded in a hydrophilic matrix
for extended release

Drug suspension or
solution

Osmotic drug core

Deliver orifices

Delivery orifice
Water

Water

Rate controlling
Semipermeable
membrane

Osmotic core

membrane

Polymeric osmotic
push compartment

containing drug

A. Elementary OROS osmotic

B. OROS Push-Pull Osmotic System

pump drug delivery system

they may also prepare a three-layer tablets

outer layers containing the drug for immediate release
some commercial tablets are prepared with an inner core
containing the extended-release portion of the drug and an outer
shell containing drug for immediate release

EMBEDDING DRUG IN INERT PLASTIC MATRIX

Drug is granulated with an inert plastic material such as
polyethylene, polyvinyl acetate, o polymethacrylate and the
granulation is compressed into tablets
released from the inert plastic matrix by diffusion

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 0.4mm diameter hole produced by
laser beam. Example: Acutrim
core tablet has two layers, one containing the drug and the other
containing a polymeric osmotic agent

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the system is designed such that only a few drops of water are
drawn into the tablet each hour
function of the tablet depends on the osmotic gradient between
the contents of the two-layer core and the fluid in the
gastrointestinal tract

Drug release rate may be altered by:

changing the surface area
thickness
composition of the membrane and/or diameter of the drug
release orifice

Release rate is not affected by:

gastrointestinal acidity or alkalinity
fed conditions
gastrointestinal motility
Gastrointestinal therapeutic system (GIT systems)
is employed in the manufacture of Glucotrol XL Extended release
tablets, and Procardia XL release tablets
the initial drug is released 4 to 5 hours after tablet ingestion
REPEAT-ACTION TABLETS
the initial dose of drug is released immediately and a second dose
follows later
released 4 to 6 hours after administration
Example: Repetabs
they are best suited for treatment of chronic conditions requiring
repeated dosing
low dosage and fairly rapid rates of absorption and excretion
DELAYED-RELEASE ORAL DOSAGE FORMS
release of a drug that may be intentionally delayed until it reaches
the intestines for several reasons
protect a drug destroyed by gastric fluids
reduce gastric distress caused by drugs of particularly irritating to
the stomach
to facilitate gastrointestinal transit for drugs that are absorbed
from the intestines
Examples: Enteric Coated Enseals Lilly; Ecotrin SmithKline

PROPERTIES OF AN ENTERIC COATING TABLETS/CAPSULES

pH dependent
breaks down in the less acidic environment of the intestine
time dependent
erodes by moisture over time during gastrointestinal transit
enzyme dependent
deteriorating as a result of hydrolysis-catalyzing action of
intestinal enzyme
AGENTS USED FOR ENTERIC COATING OF CAPSULES AND TABLETS
fats
fatty acids
waxes
shellac
cellulose acetate phthalate

EXAMPLES OF MODIFIED-RELEASE TABLETS AND CAPSULES OFFICIAL IN THE

USP
Delayed release
Aspirin delayed-release tablets
Dirithromycin delayed-release tablets
Doxycycline hyclate delayed-release capsules
Erythromycin delayed-release capsules
Oxtriphylline delayed-release tablets

Extended release
Diltiazem extended-release capsules
Disopyramide phosphate extended-release capsules
Isosorbide dinitrate extended-release tablets and capsules
Propanolol hydrochloride extended-release capsules
Theophylline extended-release capsules
USP Requirements and FDA Guidelines for Modified Release Dosage Forms
1. DRUG RELEASE
based on drug dissolution from the dosage unit against elapsed
test time (e.g. Aspirin Extended-release Tablets)

Aspirin dissolution rate:

Time (hours)
1.0
2.0
4.0
8.0

Amount dissolved
15-40%
25-60%
35-75%
Not less than 70%

2. UNIFORMITY OF DOSAGE UNITS

uniformity of dosage units may be demonstrated by either of two
methods, weight variations or content uniformity
3.

IN VITRO-IN VIVO CORRELATIONS

critical to the development of oral extended-release products
important throughout product devt, clinical evaluation
submission of an application for FDA approval for marketing, &
during post approval for any proposed formulation or
manufacturing changes
it provides guidance to sponsors of new drug applications and
abbreviated new drug applications and abbreviated new drug
applications for extended release of oral products

IVIVC provides methods of:

developing an IVIVC and evaluating its predictability
using an IVIVC to establish dissolution specifications
applying an IVIVC as a surrogate for in vitro-in vivo bioequivalence
during the approval process or during post approval for certain
formulation or manufacturing changes
3 Categories of IVIVCs include in the document
Level A

the relationship between the entire in vitro dissolution

and release time course and the entire in vivo
response time course

Ex.: the time course of plasma drug concentration or

amount of drug absorbed

Level B

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predictive mathematical model of the relationship

between summary parameters that characterize in
vitro and in vivo time courses
Example: models that relate the mean in vivo
dissolution time to the mean in vitro dissolution time

Level C

a predictive mathematical model of the relationship

between the amount dissolved in vitro at a particular
time and a summary parameter that characterizes the
time in vivo time course or area under the curve
the level of IVIVCs may be useful in the early stages of
formulation development when pilot formulations are
being selected

MOST COMMON PROCESS FOR DEVELOPING IVIVC MODEL (LEVEL A)

develop formulations with different release rates or a single
release rate if dissolution is independent of condition
obtain in vitro dissolution profiles and in vivo plasma
concentration profiles for these formulations
estimate the in vivo absorption or dissolution time course for
each formulation and subject using appropriate mathematical
approaches

patients using a modified release product should not be changed

into immediate release without consideration to the blood
concentration
patients should not be changed to another extended-release
product unless there is assurance of equivalent bioavailability
different product can result in a marketed shift in the patients
drug blood level because of differences in drug release
characteristics
modified release tablets and capsules should not be crushed or
chewed
patients if fed through the nasogastric tube may receive modifiedrelease medications
nonerodible 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

Propriety Modified-Release Oral Dosage Forms

Delayed-release

CRITERIA IN DEVELOPMENT APPLICABLE TO THE DEVELOPMENT OF IVIVCS

ARE THE FOLLOWING
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 substances

aqueous medium with a pH not exceeding 6.8 is preferred as the

medium for dissolution studies. For poorly soluble drugs, a
surfactant may be added

the dissolution profiles of at least 12 individual dosage units from

each lot should be determined

for 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

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

Extended-Release Coated Particles and Breads

LABELING
they must be specific for the monograph article
aspirin delayed-release tablets must state that the tablets are
enteric coated
capsules must indicate whether the product is intended for
dosage every 12 to 24 hours and state which in vitro drug release
test the product complies
CLINICAL CONSIDERATIONS
not to be used interchangeably
or concomitantly with immediate-release
forms of the same drug

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Extended-Release Inert Matrix

Extended Release Hydrophilic/Eroding Matrix

Extended-Release Microencapsulated Drug

Extended-Release Osmotic

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