Uy, Alyssa V.

2BPh
CHAPTER 9 - Solid Oral Modified-Release Dosage Form and Drug Delivery  Frequency reduction in dosing
Systems – extended-release products frequently deliver more than less
often than conventional form DepoFoam Drug Delivery System
INTRODUCTION
 Enhanced convenience and compliance
 Describes solid oral dosage forms and drug delivery system that – with less frequency in dosing, a patient is less apt to neglect
virtue of formulation and product design have modified drug taking a dose, also it provides greater convenience with day and
release features night administration

 Modified release products provide either delayed release or  Reduction in adverse side effects
extended release of drug – because of fewer blood level peaks outside therapeutic range
and into toxic range, adverse side effects are less frequent
 Most delayed release products are enteric-coated tablets or
capsules designed to pass through the stomach unaltered, later to
 Reduction in overall health care costs
release their medication within the intestinal tract
– overall cost of treatment may be less because of enhanced
therapeutic benefit, fewer side effects, and reduced time for
 Enteric coatings are used either to protect a substance from
health care personnel to dispense and administer drugs and
destruction by gastric fluids or to irritating drugs
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
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  Products bearing these descriptions differ in design and
performance and must be examined individually to ascertain their
 inconvenient for the patient and can result in missed doses, respective features
made-up doses, and noncompliance with the regimen
 when doses are not administered on schedule, the resulting peaks Rate-Controlled delivery
and valleys reflect the optimum drug therapy  applied to certain types of drug delivery systems in which the rate
 of delivery is controlled by features of service rather than by
ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS OVER physiologic or environmental conditions like gastrointestinal pH or
CONVENTIONAL FORMS drug transit time through the gastrointestinal tract

 Reduction in drug blood levels fluctuation Modified release

– controlling the rate of release eliminatedpeaks and valleys of  has come into general use to describe dosage forms having drug
blood levels release features based on time course and/or location that are

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 designed to accomplish therapeutic or convenience objectives not 5. They are used in the treatment of chronic rather than acute
offered by conventional or immediate-release forms conditions
 drugs for acute conditions require greater adjustment of the
Extended-release dosage by the physician than that provided by extended-release
 dosage forms of this type are the ones that allow a reduction in products
dosing frequency form that necessitated by a conventional dosage  BASIS OF DRUG RELEASE modifying drug dissolution by
forms, such as solution or an immediate-release drug dosage form controlling excess of biologic fluids to the drug through the use of
barrier coatings
Delayed release  controlling drug diffusion rate from dosage forms
 releases the drug at a time other than promptly after  chemical reaction or interaction between the drug substance or
administration. The delay may be time base or base on the its pharmaceutical barrier and site-specific biologic fluids
influence of environmental conditions such as gastrointestinal pH
BASIS OF DRUG RELEASE
Repeat action  modifying drug dissolution by controlling excess of biologic fluids
 two single doses of medication; one for immediate release; to the drug through the use of barrier coatings
another one for modified release  controlling drug diffusion rate from dosage forms
 chemical reaction or interaction between the drug substance or
Targeted release its pharmaceutical barrier and site-specific biologic fluids
 drug release directed toward isolating or concentrating a drug in a
body region, tissue or site of absorption or for drug action COATED BEADS, GRANULES AND MICROSPHERES
 using conventional pan coating or air suspension coating, a
Extended Release Oral Dosage Forms (Successful ER Product) solution of the drug substance is placed on small intact nonparent
1. Release from dosage forms at a predetermine rate seeds or beads made of sugar and stand or on microcrystalline
2. Dissolve in GT cellulose sphere
3. Maintain sufficient Gastrointestinal residence time Nonpareil seeds
4. Be absorbed at a rate that will replace the amount of drug being  425-850μm
metabolized and excreted
Microcrystalline cellulose
CHARACTERISTICS OF EXTENDED-RELEASE PRODUCTS  More durable during production than sugar-based cores
1. They exhibit very slow nor very fast rates of absorption and excretion  170-600μm
 drugs with slow rates of absorption and excretion are usually
inherently long-acting, and it is not necessary to prepare them in Lipid materials used to coat granules
extended-release forms  Beeswax
 drug with very short half-lives, less than 2 hours, are poor  Carnauba wax
candidates for extended release  Glyceryl monostearate
 drugs that act by affecting enzyme systems may be loner acting  Cetyl alcohol
than indicated by their quantitative half-lives because of their  Cellulosic material (ethyl cellulose)
residual effects and recovery of the diminished biosystem  Aqueous coating system eliminate the hazards and environmental
concerns associated with organic based solvent systems
2. They are uniformly absorbed from the gastrointestinal tract  The thicker the coat, the more resistant to penetration and the
 they must have good aqueous solubility and maintain adequate more delayed will be the drug release and dissolution
residence time in the gastrointestinal tract  Spansule

 drugs absorbed poorly or at varying and unpredictable rates are MULTITABLET SYSTEMS
not good candidates for extended-release products  small spheroidal compressed tablets 3 to 4 mm in diameter may
be prepared
3. They are administered in relatively small doses  each capsule contain 8 to 10 minitablets some uncoated for
 drugs with large single doses frequently are not suitable for immediate release and others coated for extended drug release
extended release because the tablet or capsule needed to
maintain a sustained therapeutic blood level of the drug would be MICROENCAPSULATED DRUG
too large for the patient to swallow easily Microencapsulation
 A process by which solid, liquid or even gases may be enclosed in
4. They possess a good margin of safety microscopic particles by formation of thin coatings of wall
 the most widely used measure of the margin of a drug’s safety is
material around the substance
its therapeutic index, that is, the median toxic dose divided by the
median affective dose Gelatin
 the larger the therapeutic index, the safer the drug  A common wall forming material and synthetic polymers, such as
 drugs that are administered in very small doses or possess very polyvinyl alcohol, ethyl cellulose, polyvinyl chloride and other
narrow therapeutic indices are poor candidates for formulations materials may be used
because of technologic limitations of precise control over release  dissolving the wall material
rates and the risk of dose dumping due to a product defect  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  retains its shape during leaching of he drug and during its passage
 the final dry microcapsules are free-flowing discrete particles of through the alimentary tract
coated material  Example: Gradumet
 wall material constitute into 20% of the total particle weigh
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  slow dissolution rate (e.g. Rynatan)
spread over a large area of the gastrointestinal tracts, which may
enhance absorption by diminishing local drug concentration (e.g.  salts of tannic acid, tannates, provide this quality in a variety of
Micro-K ExtenCaps) proprietary products
>Encapsulation. All of the single and combination capsules are
produced here. The empty gelatin capsules are placed in hoppers ION EXCHANGE RESINS
and free-flowing to the machine. The bottom portion of the  solution of a cationic drug may be passed through a column
capsule is filled, which is gravity-fed from a stainless steel bin into containing an ion exchange resin, forming a complex by the
the machine’s hopper. An average of 6 million capsules a day can replacement of hydrogen atoms
be produced.  release of the drug depends on the pH and electrolyte
concentration in the gastrointestinal tract
EMBEDDING DRUG SLOWLY ERODING OR HYDROPHILIC MATRIX SYSTEM  release is greater in the acidity of the stomach than in the less
 drug substance is combined and made into granules with an acidic environment of the small intestine
excipient material that slowly erodes in body fluids, progressively  hydrocodone polistirex (Tussionex) and chlorpheniramine
releasing the drug for absorption polistirex suspension and phentermine resin capsules

Hydrophilic cellulose polymers Mechanism of ion exchange resins:

 commonly used as the excipient base in tablet matrix systems In the stomach
EFFECTIVENESS OF THE HYDROPHILIC MATRIX IS BASED ON: 1. drug resinate + HCl ↔ acidic resin + drug hydrochloride
2. resin salt + HCl ↔ resin chloride + acidic drug
 successive process of hydration on the polymer’s surface In the intestine
 gel formation on the polymer’s surface 1. drug resinate + NaCl ↔ sodium resinate + drug hydrochloride
 tablet erosion 2. resin salt + NaCl ↔ resin chloride + sodium salt of drug
 subsequent and continuous release 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  the pioneer oral osmotic pump drug delivery system is the Oros
shell containing drug for immediate release system developed by Alza
 composed of a core tablet surrounded by a semipermeable
membrane coating having a 0.4mm diameter hole produced by
EMBEDDING DRUG IN INERT PLASTIC MATRIX laser beam. Example: Acutrim
 Drug is granulated with an inert plastic material such as  core tablet has two layers, one containing the drug and the other
polyethylene, polyvinyl acetate, o polymethacrylate and the containing a polymeric osmotic agent
granulation is compressed into tablets
 released from the inert plastic matrix by diffusion
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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  patients using a modified release product should not be changed
between summary parameters that characterize in into immediate release without consideration to the blood
vitro and in vivo time courses concentration
 Example: models that relate the mean in vivo  patients should not be changed to another extended-release
dissolution time to the mean in vitro dissolution time 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
 Level C characteristics
 a predictive mathematical model of the relationship  modified release tablets and capsules should not be crushed or
between the amount dissolved in vitro at a particular chewed
time and a summary parameter that characterizes the  patients if fed through the nasogastric tube may receive modified-
time in vivo time course or area under the curve release medications
 the level of IVIVCs may be useful in the early stages of  nonerodible plastic matrix shells and osmotic tablets remain
formulation development when pilot formulations are intact throughout gastrointestinal transit and the empty shells or
being selected 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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