V Chapter 9: Solid Oral ModifiedRelease Dosage Forms and Drug

Delivery Systems

Two primary driving forces behind

this market:
1. Patient related factors
2. Market-driven factors
Life cycle of a drug includes:
1. Introduction of the new
molecular entity
2. Initial product introduction
3. New patents or patent
obtained

Example: Augmentin XR
( GlaxoSmithKline), Cipro XR
(Bayer)

Conventional forms
Immediate-release forms
Modified-release products
provide either
Delayed-release
Extended-release (ER)
Delayed release enteric
coated tablets or capsules
designed to pass through the
stomach unaltered, later to
release their medication
within the intestinal tract
Enteric coatings protect
a substance from a
destruction by gastric
fluids
Reduce stomach
distress caused by
irritating drugs

Extended release 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.
Most modified-release
products orally
administered tablets and
capsules
Transdermal patches
provide rate controlled drug
delivery

THE RATTIONALE FOR EXTENDED

RELEASE PHARMACEUTICAL

Multiple daily dosing

inconvenient for patient, may
result in missed doses, madeup doses, non-compliance
with the regimen.
Conventional immediate
release dosage forms
Taken on schedule
more than once daily,
cause sequential
therapeutic blood level
peaks and valleys
(troughs) associated
with taking of each
dose.
When doses are not
administered on
schedule = peaks and

valleys reflects less

than optimum drug
therapy
Doses administered too
frequently = minimum
toxic concentration of
drug may be reached =
toxic side effects
resulting
Doses are missed =
period of
subtherapeutic drug
blood levels or below
the minimum effective
concentration = no
benefit to ptx.
Extended- release capsules
taken once or twice daily.
Provide immediate
release of drug that
promptly produces the
desired therapeutic
effect followed by
gradual release of
additional amounts of
drug to maintain this
effect over a
predetermined period.
Conventional forms taken
3 or 4 times daily to achieve
therapeutic effect.
Sustained-plasma drug
levels provided by
extended release products
eliminates the need for
night dosing
Nonoral rate-controlled drug
delivery systems drug
release pattern ranges in
duration from 24 hours for

transdermal patches to 3
months for estradiol
vaginal ring insert
(Estring, Pharmacia)

Advantages of ExtendedRelease Dosage Forms over

Conventional Forms
1. Less fluctuation in drug blood
levels controlling rate of
release eliminates peaks of
blood levels
2. Frequency reduction in
dosing --> taken less often
than conventional forms
because extended release
deliver more than a single
dose
3. Enhanced convenience and
compliance patient is less
apt to neglect taking a dose
4. Reduction in adverse side
effects because of fewer
blood level peaks outside
therapeutic range
5. Reduction in overall health
care cost because of
enhanced therapeutic
benefits, fewer side effects,
reduced time for health care
personnel to dispense and
administer drugs and monitor
ptx.
Disadvantages of Extendedrelease
1. Loss of flexibility in adjusting
the drug dose

2. Risk of sudden and total drug

release
3. Dose dumping due to
technology failure
TERMINOLOGY

Extended or sustained
release (SR) first appeared
as a major new class of
dosage form in late 1940 and
early 1950
Sustained release (SR)
Sustained action (SA)
Prolonged action (PA)
Controlled release (CR)
Extended release (ER)
Timed release (TR)
Long acting (LA)
These terms are used to
describe orally administered
dosage forms
Rate- controlled delivery
rate of delivery is controlled
by features of the device
rather than the physiologic or
environmental conditions like
gastrointestinal pH or drug
transit through the
gastrointestinal tract.
Modified Release
Drug features based on time,
course and/or location that are
designed to accomplish
therapeutic or convenience
objectives not offered by
conventional forms (immediate
release)
2 types of Modified release

1. Extended release allows

reduction in dosing frequency
from that necessitated by a
conventional dosage forms
2. Delayed release release a
drug at a time other than
promptly after administration
Delay may be because
of the influence of
environmental
conditions like GI pH
Repeat action contains two
single doses of medication,
one for immediate release
and second for delayed
release
Example: two-layered tablets

Targeted Release drug

release directed toward
isolating or concentrating a
drug in a body region, tissue,
or site for absorption.

EXTENDED RELEASE ORAL

DOSAGE FORMS
Drug conditions for Extendedrelease products
Successful extended-release
product
Release from the
dosage form at a
predetermined rate
Dissolved in the GI
fluids

Maintained at a
sufficient GI residence
time
Absorbed at a rate that
will replace the amt of
drug being metabolized
and excreted.
1. They exhibit neither
very slow nor very fast
rates of absorption and
excretion
Short-half lives less than 2
hrs, poor candidates
2. They are uniformly
absorbed from the GI
tract good aqueous
solubility and maintain
adequate residence
time in the GI tract
3. They are administered
in relatively small
doses
4. They possess a good
margin of safety
Therapeutic index median
toxic dose divided by median
effective dose; the larger it
is, the safer the drug
They are used in the
treatment of chronic rather
than acute disease

released form the

dosage form and/or by
slowing the transit time
of the dosage form
through the GI tract.
Technologies are based on:
1. Modifying drug dissolution by
controlling access of biologic
fluid to the drug through the
use of barrier coatings
2. Controlling drug diffusion
rates from dosage forms
3. Chemical reaction or
interaction between the drug
subs or its pharmaceutical
barrier and site-specific
biologic fluids

Coated Beads, Granules and

Microspheres

Extended Release technology for

Oral Dosage Forms

Orally administered forms

extended drug action is
achieved by:
Affecting the rate at
which the drug is

Conventional pan coating or

air suspension coating
soln of drug subs is placed in
a small inert nonpareil seeds
or beads made of sugar and
starch or microcrystalline
cellulose spheres.
Nonpareil seeds range
of 425-850 mm
Microcrystalline cellulose
spheres 70-600 mm
More durable during
production than sugarbased cores
Dose is large starting
granules materials composed
of drug itself

 Some granules remain

uncoated

Provides different
desired rates and
targeting of coated
beads to desired
segments of GI tract
Example: Spansule
(SmithKline Beecham)

Examples of coatings:

Beeswax
Carnauba wax
Glyceryl monostearate
Cetyl alchol
Ethylcellulose
Colored coatings
distinguish granules or beads
of diff coating thickness
( depth of color) and provide
distinction
Various commercial aqueous
coating systems use
Ethylcellulose
Plasticizer( Aquacoat [FMC
Corporation] Surelease
[Coloorcon])
Aqueous coating systems
eliminate the hazards and
environmental concerns
associated with organic
solvent-based systems

Variation of coating thickness

affects rate of body fluids
penetration

Thicker coat = more resistant

to penetration and more
delayed will be the drug
released and dissolution
Coated beads 1mm
diameter
Combined to have 3 or
4 release groups
among the more than
100 beads contained in
dosing unit (10)

Multitablet System
Small spheroid
compressed tablets 3-4
mm in diameter may
be prepared to have
varying drug release
characteristics
Placed in gelatin
capsule shells = each
capsule contains 8-10
minitablets, some are
coated for extended
release some or
uncoated for
immediate release
Microencapsulated Drug

Microencapsulation solids,
liquids, gases may be
enclosed in microscopic
particles by formation of thin
coatings of wall materials
around the subs.
From the carbon paper
and carbon ribbons as
sought by the business
machine industry
(1930s)
Ultimate development in
1950s of reproduction paper

and ribbons that contained

dyes in tiny gelatin capsules
released on impact by a
typewriter key.
Gelatin common wallforming material
Synthetic polymers like:
Polyvinyl alcohol
Ethylcellulose
Polyvinyl chloride
Typical encapsulation
process begins with
dissolving the wall material
(gelatin in water)
Material to be
encapsulated is added
and two-phase mixture
thoroughly stirred.
Material to be
encapsulated is broken,
soln of a second
material (acacia) as
added
Additive material
concentrates the
gelatin (polymer) into
tiny liquid droplets
The droplets
(coacervate) form a
film around the
particles of subs to be
encapsulated.
Final dry microcapsules ->
free flowing discrete particles
of coated materials
Wall material = 2-20%
particle weight
Different rates of drug
release = obtained by
changing the ratio of
core to wall, the

polymer used for

coating, method of
microencapsulation.

Advantages of microencapsulation
1. Administered dose of a drug
is subdivided into small units
that are spread over a large
area of GI tract, enhance
absorption by diminishing
local drug concn
Example of microencapsulated
drug:
Potassium chloride (MicroK Extencaps, Wyeth) [ER]
Embedding Drug in Slowly Eroding
or Hydrophilic Matrix System

Drug subs is combined

and made into granules
with excipient material
that slowly erodes in
body fluids ,
progressively releasing
the drug for absorption.
Granules are mixed with
granules of drug w/o
excipient immediate effect
Drug-excipient granules
extended action
Hydrophilic cellulose
polymers as the excipient
base in tablet matrix systems
The effectiveness is
based on:

Successive processes of
hydration of the cellulosic
polymer
Gel formation on the
polymers surface
Tablet erosion
Subsequent and
continuous release of drug
Hydroxypropyl
methylcellulose (HPMC)
Free-flowing powder
Commonly used to
provide the hydrophilic
matrix.
Tablets are prepared by
distributing HPMC,
preparing granules by
wet granulation or
roller compaction
and manufacturing the
tablets by
compression
Rate of drug release
controlled by diffusion
tablet erosion
Successful hydrophilic
matrix polymer must
form a gelatinous layer
rapidly enough to protect
the inner core of the
tablet from disintegrating
too rapidly after ingestion.
Increase polymer =
increase viscoscity of gel
= decrease in rate of drug
diffusion AND DRUG
RELEASE.

Example: Oramorph SR Tablets

(AllPharma) contains morphine
sulfate

HPMC could also be used in ER

drugs(sam e concept applies)
Manufacturers prepare two-layer
tablets one layer contains
uncombined drug for immediate
release and other layer having drug
embedded in a HPMC for ER

Some commercial tablets

Inner core HPMC (ER)
Outer core immediate
release

Embedding drug in Inert Plastic

Matrix
Inert plastic materials
include:
Polyethylene
Polyvinyl acetate
Polymethacrylate
Drug is slowly released
from the inert plastic
matrix by diffusion
Compression
creates the matrix or
from that retains its
shape during leaching
and its passage thru
alimentary tract
Example: Gradumet
(abbot)
Complex formation
Slow dissolution rate
provides ER of drug.
Examples: Salts of
Tannic acid (tannates) trade
name = Rynatan (Wallace)

Ion- exchange Resins

A soln of cationic drug
may be passed through a
column containing an ionexchange resin, forming a
complex by the
replacement of H atoms.
Examples: hydrocodone polistirex
and chlorpheniramine polisterix
suspension (Tussionex Penkinetic
extended release suspension
[CellTech] Phentermine resin
capsule [ionamine capsules[)
CellTech

The mechanisms of action are as

follows:
In Stomach:

1. Drug resinate + HCL acidic

resin + drug HCl
2. Resin salt+ HCL resin Cl +
acidic drug
In the Intestine:
1. Drug resinate + NaCl
sodium resinate + drug HCl
2. Resin salt + NaCl resin Cl +
sodium salt of drug
Polymer barrier coating and
bead technology addition
to ion exchange mechanism

Osmotic Pump

OROS sytem pioneer oral

osmotic pump

Composed of 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 layer (active drug)
Other layer ( polymer
osmotic agent push
layer)
Osmotic pressure how
system operates
Gastrointestinal therapeutic
system (GITS) Pfizer
employed in the manufacture
Glucotrol XL ER tablets
and Procardia XL ER tablet
Controlled-onset extended
release (COER [Searle])
Used in Covera-HS
tablets initial drug is
released 4-5 hrs after
tablet ingestion.
The delay drug released is
due to:
Slowly solubilized
coated layer between
the active ing core and
outer semipermeable
membrane

Repeat-Action tablets
Initial dose of drug is
released immediately
and second dose
follows after
Prepared with
immediate release in

tablets outer shell and

second dose in tablets
inner core
Separated by slowly
permeable coating
Drug from inner core
released 4- hours

Example: Repetabs ( Schering)

Bes used for treatment
of chronic conditions
requires repeated
dosing.
DELAYED-RELEASE ORAL
DOSAGE FORMS

Protect drug destroyed by

gastric fluids
Reduce gastric distress
particularly irritating to
stomach
Facilitate GI transit for
drugs that are absorbed in
intestines
Enteric coating pH
dependent; breaking down in
less acidic environment of
intestine
Time dependent;
eroding by moisture
over time during GI
transit
Enzyme dependent;
deteriorating as a
result of hydrolysiscatalyzing action of
intestinal enzymes

Agents used for enteric coating:

Fats
Fatty acids
Waxes
Shellac
Cellulose acetate
phthalate

USP REQUIREMENTS AND FDA

GUIDANCE FOR MODIFIEDRELEASE DOSAGE FORMS
a. Drug release
Based on drug
dissolution from the
dosage unit against
elapsed test time.
Individual monograph
contain specific criteria for
compliance with the test and
the apparatus and est to be
used.
b. uniformity of dosage
units
demonstrated by 2 methods
Weight variation
Content uniformity
c. In vitro-in vivo
correlations
Important in product
development, clinical
evaluation, application
for FDA aroval
1997 FDA released a
guidance document
Extended Release Oral
Dosage Forms:
Development, Evaluation,
and Application of In
Vivo/In vitro Correlations.
Provides method on ff:

 Developing an IVIVC and

evaluate its predictability
using an IVIVC to establish
dissolution specifications
applying an IVIVC as
surrogate..
3 categories of IVIVC
1. Level A
Predicative
mathematical model
for the relationship
between the entire in
vitro dissolution and
release time course in
entire in vivo response
time
2. Level B
Predictive
mathematical model of
the relationship
between summary
parameters that
characterize the in vitro
and in vivo time
courses
3. Level c
Predictive
mathematical model of
the relationship
between the amount
dissolved in in vitro at a
particular time.
Level A most common
process for developing an
IVIVC model is to
Develop formulations with
different release rates
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.
Criteria for development of
IVIVC:
1. USP dissolution apparatus
Type 1 basket
Type 2 paddle
Preferred
Type 3 reciprocating
cylinder
Type 4 -> flow- through
cell
2. Aqueous medium
pH not exceeding 6.8 is
preferred
poorly soluble drugs
use surfactant( %
sodium lauryl sulfate)
3. 12 individual dosage units
for dissolution profiles
4. Use of 6-36 human
subjects
5. Cross-over studies are
preferred
Parallel studies and crossstudy analysis used
such in intravenous
solution, aqueous oral
solution, immediaterelease product
Labeling
Aspirin (delayed release
tablets) must state

tablets are enteric

coated
Theophylline (Extended
release) whether the
product is intended for
dosing every 12-24 hrs
and state with which in
vitro drug release test the
product complies)
CLINICAL CONSIDERAIONS IN
THE USE OF ORAL MODIFIEDRELEASE DOSAGE FORMS
Different product can
result in a marked shift in
the patients drug level
Modified release and
immediate release should
not be used
interchangeably
Modified release should
not be crushed or chewed
It should not be generally
used as source of drug to
prepare other dosage

forms like ediatric oral

liquids
Nonerodible plastic matrix
shells and osmoic tablets
remain intact
Osmotic tablets empty
shells must be seen on
stool
PACKAGING AND STORING
MODIFIED-RELEASE TABLETS
AND CAPSULES
Stored like in conventional
products