This document discusses modified-release oral dosage forms, including extended-release and delayed-release forms. It describes various technologies used to modify drug release rates, such as coatings, matrices, and osmotic pumps. It also covers terminology, drug candidates suited for modified dosing, clinical considerations, and FDA/USP regulations regarding testing, labeling and in vitro-in vivo correlations. The goal of these dosage forms is to reduce dosing frequency while maintaining therapeutic drug levels over time.

1. 8. MODIFIED-RELEASE DOSAGE
FORMS AND DRUG DELEVERY
SYSTEMS

2. CONTENTS
I. The rationale for extended-release
pharmaceuticals
II. Terminology
III. Extended-release oral dosage forms
IV. Delayed-release oral dosage forms
V. USP requirements and FDA Guidance for
modified-release dosage forms
VI. Clinical considerations in the use of oral
modified-release dosage form
VII. Packaging and storing modified-release tablets
and capsules

3.  In contrast to conventional forms,
modified-release products
provide either delayed-release or
extended-release of drug.
 Delayed-release products usually
are enteric-coated tablets or
capsules designed to pass
through the stomach unaltered,
later to release their medication
within the intestinal tract.

4.  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.

5. I. The rationale for extended-
release pharmaceuticals
 Extended-release tablets and
capsules are commonly taken only
once or twice daily, compared with
counterpart conventional forms that
may have to be taken three or four
times daily to achieve the same
therapeutic effect.

6.  Typically, extended-release
products provide an 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.

10. II. Terminology
 Modified-release use to describe
dosage forms having drug release
features based on time, course, and
/or location which are designed to
accomplish therapeutic or
convenience objectives not offered
by conventional or immediate-
release forms.

11.  An Extended-release dosage forms are
defined as one that allows a reduction in
dosing frequency to that presented by a
conventional dosage form.
 A Delayed-release dosage form is
designed to release the drug from the
dosage form at a time other than
promptly after administration. The delay
may be time-based or based on the
influence of environmental conditions, as
gastrointestinal pH.

12.  Repeat-action forms usually contain two
single doses of medication, one for
immediate release and the second for
delayed release.
 Targeted release describes drug release
directed toward isolating or concentrating
a drug in a body region, or site for
absorption or for drug action.

13. III. Extended-release oral dosage
forms
1. Drug-candidates for extended-
release products
The drugs best suited for
incorporation into an extended-
release product have the following
characteristics:
- They exhibit neither very slow nor
very fast rates of absorption and
excretion.

14. - They are uniformly absorbed from
the gastrointestinal tract.
- They are administered in relatively
small doses.
- They possess a good margin of
safety.
- They are used in the treatment of
chronic rather than acute
conditions.

15. The rate of drug release from solid
dosage forms may be modified by
the technologies described below:
- Modifying drug dissolution by
controlling access of biologic fluids
to the drug through the use of
barrier coatings.
2. Extended-release technology for
oral dosage forms

16. - Controlling drug diffusion rates from
dosage forms.
- Chemically reacting or interacting
between the drug substance or its
pharmaceutical barrier and site-
specific biologic fluids.

18. 1) Coated beads, granules, or
microspheres
- In these systems, the drug is
distributed onto beads, pellets,
granules, or other particulate
systems.

19. - Using conventional pan coating or
air suspension coating, a solution
of the drug substance is placed on
small inert nonpareil seeds or
beads made of sugar and starch or
on microcrystalline cellulose
spheres.

20. 2) Multitablet system
 Small spheroid compressed tablets
3 to 4 mm in diameter may be
prepared to have varying drug
release characteristics.
 They may be placed in gelatin
capsule shells to provide the
desired pattern of drug release.
 Each capsule may contain 8 to 10
minitablets, some uncoated for
immediate release and others
coated for extended drug release.

21. 3) Microencapsulated drug
Microencapsulation is a process by
which solids, liquids, or even gases
may be enclosed in microscopic
particles by formation of thin
coatings of wall material around the
substance.

22.  The typical encapsulation process
usually begins with dissolving the
wall material, say gelatin, in water.
 The material to be encapsulated is
added and the two-phase mixture
thoroughly stirred.
 With the material to be
encapsulated broken up to the
desired particle size, a solution of a
second material, usually acacia, is
added.

23.  This additive material concentrates the
gelatin into tiny liquid droplets.
 One of the advantages of
microencapsulation is that the
administered dose of a drug is
subdivided into small units that are
spread over a large area of the
gastrointestinal tract, which may
enhance absorption by diminishing
localized drug concentration.

24. By this process, the drug
substance is combined and made
into granules with an excipient
material that slowly erodes in
body fluids, progressively
releasing the drug for absorption.
4) Embedding drug in slowly
eroding or hydrophilic matrix
system

25. When these granules are mixed
with granules of drug prepared
without the excipient, the
uncombined granules provide the
immediate drug effect whereas the
drug-excipient granules provide
extended drug action.

26. 5) Embedding drug in inert plastic
matrix
 By this method, the drug is
granulated with an inert plastic
material such as polyethylene,
polyvinyl acetate, or
polymethacrylate, and the
granulation is compressed into
tablets.
 The drug is slowly released from
the inert plastic matrix by diffusion.
 The inert tablet matrix, expended of
drug, is excreted with the feces.

27. 6) Complex formation
 Certain drug substances when
chemically combined with certain
other chemical agents form
chemical complexes that may be
only slowly soluble in body fluids,
depending upon the pH of the
environment.
 This slow dissolution rate provides
the extended release of the drug.

28.  Salts of tannic acid, tannates （鞣酸 合盐复
物） , provide this quality in a variety of
proprietary produces by the tradename
Rynatan.

29. 7) Ion-exchange resins
 A 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.
 The resin-drug complex is then washed
and may be tableted, encapsulated, or
suspended in an aqueous vehicle.
 The release of the drug is dependent
upon the pH and the electrolyte
concentration in the gastrointestinal
tract.

31.  Release is greater in the acidity of the
stomach than in the less acidic environment
of the small intestine.
 Examples of drug products of this type
include hydrocodone polistirex and
chlorpheniramine polistirex suspension and
phentermine resin capsules.

32. The mechanism of action of drug release
In the stomach:
1. Drug resinate+HClacidic resin+drug
hydrochloride
2. Resin salt+HClresin chloride+sodium salt of
drug

33. In the intestine
1. Drug resinate+NaClsodium
resinate+drug hydrochloride
2. Resin salt+NaClresin chloride+sodium
salt of drug

34. 8) Osmotic pump
 The pioneer oral osmotic pump drug
delivery system is the Oros system,
developed by Alza.
 The system is composed of a core
tablet surrounded by a
semipermeable membrane coating
have a 0.4 mm diameter hole
produced by laser beam.

35. Osmotic core
containing drug
Osmotic delivery
orifice
Semipermeable
membrane
Osmotic pressure-controlled drug delivery system

36.  The system is designed such that only a
few drops of water are drawn into the
tablet each hour.
 The rate of inflow of water and the
function of the tablet depends upon the
existence of an osmotic gradient between
the contents of the bi-layer core and the
fluid in the GI tract.
 Drug delivery is essentially constant as
long as the osmotic gradient remains
constant.

37. The drug release rate may be altered by
 Changing the surface area,
 The thickness or composition of the
membrane,
 Changing the diameter of the drug release
orifice.
The drug-release rate is not affected by
gastrointestinal acidity, alkalinity, fed
conditions, or GI motility.

38. Effect of coating membrane thickness on the rate and duration of
zero-order release of indomethacin from osmotic pressure-controlled
gastrointestinal delivery system

39. 9) Repeat action tablets
 Repeat action tablets are prepared so that an
initial dose of drug is released immediately
followed later by a second dose.
 The tablets may be prepared with the
immediate-release dose in the tablet’s outer
shell or coating with the second dose in the
tablet’s inner core, separated by a slowly
permeable barrier coating.

40.  Repeat action dosage forms are best suited
for the treatment of chronic conditions
requiring repeated dosing.
 The drugs utilized should have low dosage
and fairly rapid rates of absorption and
excretion.

41. IV. Delayed-release oral dosage
forms
The release of a drug from an oral
dosage form may be intentionally
delayed until it reaches the
intestines for several reasons.
- to protect a drug destroyed by
gastric fluids,

42. - to reduce gastric distress caused
by drugs particularly irritating to the
stomach.
- to facilitate GI transit for drugs
which are better absorbed from the
intestines.

43.  Capsules and tablets specially coated to
remain intact in the stomach and to yield
their ingredients in the intestines are
termed enteric coated.
The enteric coating may be
 pH dependent, breaking down in the less
acidic environment of the intestine,
 time dependent, eroding by moisture over
time during gastrointestinal transit,

44.  enzyme dependent, deteriorating as a
result of the hydrolysis-catalyzing action
of intestinal enzymes.
Among the many agents used for enteric
coating of tablets and capsules are fats,
fatty acids, waxes, shellac, and cellulose
acetate phthalate （ 二甲酸醋酸邻苯 纤维
素） .

45. V. USP requirements and FDA guidance
for modified-release dosage forms
1) Drug release
The USP test for drug release for extended-
release and delayed-release articles is based
on drug dissolution from the dosage unit
against elapsed test time.
Time (hr) Amount dissolved
1.0 between 15% and 40%
2.0 between 25% and 60%
4.0 between 35% and 75%
8.0 not less than 70%

46. 2) Uniformity of dosage units
Uniformity of dosage units may be
demonstrated by either of two methods,
weight variation or content uniformity.
3) In vitro/in vivo correlations
(IVIVCs)
IVIVCs is critical to the development of
oral extended-release products.
Assessing IVIVCs is important
throughout the periods of product
development, clinical evaluation,
submission of an application for FDA-
approval for marketing, and during
postapproval for any formulation or

47. Three categories of IVIVCs are included
in the document
- Level A
A predictive mathematical model for the
relationship between the entire in vitro
dissolution/release time course, e.g., the
time course of plasma drug concentration
or amount of drug absorbed.

48. - Level B
A predictive mathematical model of the
relationship between summary
parameters that characterize the in vitro
and in vivo, time courses.
- Level C
A predictive mathematical model of the
relationship between the amount
dissolved in vitro at a particular time (or
T50%) and a summary parameter that
characterizes the in vivo time course
(e.g. Cmax or AUC).

49. 4) Labeling
The USP indicates labeling
requirements for modified-release
dosage form articles in addition to
general labeling requirements.

50. VI. 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 to not
use them interchangeably or
concomitantly with immediate-release
forms of the same drug.
 Patients should be advised that modified-
release tablets and capsules should not
be crushed or chewed since such action
would compromise their drug release
features.

51.  Patients and caregivers should be
advised that 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.

52. VII. Packaging and storing modified-
release tablets and capsules
Modified-release tablets and capsules
are packaged and stored in the same
manner as conventional products.