Uy, Alyssa V.
2BPh
CHAPTER 9 - Solid Oral Modified-Release Dosage Form and Drug Delivery
Systems
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
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
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
 of delivery is controlled by features of service rather than by
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
 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
DISADVANTAGE OF ETENDED-RELEASE DOSAGE FORMS OVER
CONVENTIONAL FORMS
 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
 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
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
 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
 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
4. They possess a good margin of safety
 the most widely used measure of the margin of a drug’s 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
 425-850μm
Microcrystalline cellulose
 More durable during production than sugar-based cores
 170-600μm
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
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 machine’s 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
 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
 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

Hydrophilic cellulose polymers Mechanism of ion exchange resins:

 commonly used as the excipient base in tablet matrix systems
EFFECTIVENESS OF THE HYDROPHILIC MATRIX IS BASED ON:
 successive process of hydration on the polymer’s surface
 gel formation on the polymer’s surface
 tablet erosion
 subsequent and continuous release of drug
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 Drug suspension or
solution
 A successful hydrophilic matrix system must contain the
following: Osmotic drug core Deliver orifices
 polymer must form a gelatinous layer rapidly enough to protect
the inner core of the tablet from disintegrating too rapidly after
ingestion Delivery orifice
 20% of HPMC results in satisfactory rates of release for an
extended-release tablet formation (e.g Oramorph SR Tablet) Water Water

Manufacturers may prepare two-layer tablets Rate controlling Polymeric osmotic

 one layer containing the uncombined drug for immediate release Semipermeable Osmotic core membrane push compartment
 the other layer having the drug encoded in a hydrophilic matrix membrane containing drug

for extended release 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 OSMOTIC PUMP
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
 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 EXAMPLES OF MODIFIED-RELEASE TABLETS AND CAPSULES OFFICIAL IN THE
drawn into the tablet each hour USP
 function of the tablet depends on the osmotic gradient between
the contents of the two-layer core and the fluid in the Delayed release
gastrointestinal tract Aspirin delayed-release tablets
Dirithromycin delayed-release tablets
Drug release rate may be altered by: Doxycycline hyclate delayed-release capsules
 changing the surface area Erythromycin delayed-release capsules
 thickness Oxtriphylline delayed-release tablets
 composition of the membrane and/or diameter of the drug
release orifice

Extended release
Diltiazem extended-release capsules
Release rate is not affected by: Disopyramide phosphate extended-release capsules
 gastrointestinal acidity or alkalinity Isosorbide dinitrate extended-release tablets and capsules
 fed conditions Propanolol hydrochloride extended-release capsules
 gastrointestinal motility Theophylline extended-release capsules

Gastrointestinal therapeutic system (GIT systems) USP Requirements and FDA Guidelines for Modified Release Dosage Forms
 is employed in the manufacture of Glucotrol XL Extended release 1. DRUG RELEASE
tablets, and Procardia XL release tablets  based on drug dissolution from the dosage unit against elapsed
 the initial drug is released 4 to 5 hours after tablet ingestion test time (e.g. Aspirin Extended-release Tablets)
 Aspirin dissolution rate:
REPEAT-ACTION TABLETS
 the initial dose of drug is released immediately and a second dose Time (hours) Amount dissolved
follows later 1.0 15-40%
 released 4 to 6 hours after administration 2.0 25-60%
 Example: Repetabs 4.0 35-75%
8.0 Not less than 70%
 they are best suited for treatment of chronic conditions requiring
repeated dosing
2. UNIFORMITY OF DOSAGE UNITS
 low dosage and fairly rapid rates of absorption and excretion
 uniformity of dosage units may be demonstrated by either of two
methods, weight variations or content uniformity
DELAYED-RELEASE ORAL DOSAGE FORMS
 release of a drug that may be intentionally delayed until it reaches
3. IN VITRO-IN VIVO CORRELATIONS
the intestines for several reasons
 critical to the development of oral extended-release products
 protect a drug destroyed by gastric fluids  important throughout product dev’t, clinical evaluation
 reduce gastric distress caused by drugs of particularly irritating to submission of an application for FDA approval for marketing, &
the stomach during post approval for any proposed formulation or
 to facilitate gastrointestinal transit for drugs that are absorbed manufacturing changes
from the intestines  it provides guidance to sponsors of new drug applications and
 Examples: Enteric Coated Enseals – Lilly; Ecotrin SmithKline abbreviated new drug applications and abbreviated new drug
applications for extended release of oral products

PROPERTIES OF AN ENTERIC COATING TABLETS/CAPSULES

IVIVC provides methods of:
 pH dependent
 developing an IVIVC and evaluating its predictability
 breaks down in the less acidic environment of the intestine
 using an IVIVC to establish dissolution specifications
 time dependent
 applying an IVIVC as a surrogate for in vitro-in vivo bioequivalence
 erodes by moisture over time during gastrointestinal transit
during the approval process or during post approval for certain
 enzyme dependent
formulation or manufacturing changes
 deteriorating as a result of hydrolysis-catalyzing action of
intestinal enzyme
3 Categories of IVIVCs include in the document
 Level A
AGENTS USED FOR ENTERIC COATING OF CAPSULES AND TABLETS  the relationship between the entire in vitro dissolution
 fats and release time course and the entire in vivo
 fatty acids response time course
 waxes  Ex.: the time course of plasma drug concentration or
 shellac amount of drug absorbed
 cellulose acetate phthalate
 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
 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 patient’s
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 modified-
release 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

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 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  Extended-Release Coated Particles and Breads
product, such as an intravenous solution, an aqueous oral
solution, or an immediate-release product

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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