This document discusses modified release drug products, including extended release and delayed release dosage forms. It defines modified release as altering the timing and/or rate of drug release. Extended release aims for twice daily dosing by providing continuous drug levels while delayed release releases the drug at a time other than promptly after administration. The document discusses various extended release drug delivery technologies like coated beads, multilayer tablets, microencapsulation, embedding in eroding matrices, plastic matrices, complexation, and osmotic pumps. It emphasizes the importance of in vitro-in vivo correlations and bioequivalence studies in evaluating these modified release products.

1. MODIFIED-RELEASE DRUG
PRODUCTS
GUIDED BY: PRESENTED BY :
MS. MANJU NAGPAL SOM NATH PRASAD
CCP M.PHARM(PHARMACEUTICS)
SEM- 2nd
SESSION :2016-18

2. INTRODUCTION
 Modified release drug product are those that
alter the timing and/or the rate of release of
drug substance.
 Types of modified release drug products are-
1. Delayed release
2. Extended release
3. Orally disintegrating tablet

3. Continued….
 EXTENDED RELEASE DRUG PRODUCTS
 Two fold release in dosage frequency, examples
include controlled release, sustained release and
long acting drug products.
 DELAYED RELEASE DRUG PRODUCTS
 Releases a discrete portion of drug at a time other
than promptly after administration. e.g – enterric
coated dosage forms like enterric coated aspirin,
other NSAIDS, etc.

4.  ORALLY DISINTEGRATING TABLETS
 Disintegrate rapidly in saliva after oral
administration.
 Can be used without addition of water.
 Drug dispersed in saliva and swallowed.

5. ADVANTAGES
 Reduction in drug blood level fluctuation
 Frequency reduction in dosing
 Patient compliance
 Reduced adverse side effect
 Reduction in health care cost

6. Examples of modified release
dosage forms
Systems Examples of drugs
Oral drug products Diltiazem HCL (extended release)
Diclofenac sodium (delayed release)
Ondansetron (oral soluble film)
Transdermal drug delivery system Clonidine (transdermal therapeutic
system)
Opthalmic drug delivery Controlled release pilocarpine
Intravaginal drug delivery Dinoprostone vaginal insert

7. DOSAGE FORM SELECTION
 Drug with low aqueous solubility generally should not
be formulated into a non-disintegrating tablet, because
risk of incomplete drug dissolution is high.
 Drug with low solubility at neutral pH should be
formulated so that most of drug is released before it
reaches the colon.
 A drug with high water solubility in acidic pH in
stomach but very insoluble at intestine pH may be
difficult to formulate into ER drug product.
 With too much coating, bioavailabilty gets reduced.

8. KINETICS OF EXTENDED
RELEASE DOSAGE FORM
 Dtotal = DI + DM
 Here, Dtotal = total dose required
DI = initial dose released
DM = sum of maintainence dose
also , DM = k˚r td
so, [ Dtotal = DI + k˚r td ]
 However maintainence dose is released after DI
has produced a blood level equal to the
therapeutic drug level.

9. Continued…
 DMstarts to release at t = 0
 For drug following one compartment model, rate of
elimination (R) needed to maintain the drug at a
therapeutic level (Cp) is:
R = k Vd Cp
also the equation can be written as :
R = Cp ClT
here, ClT = clearance of drug

10. Continued…
 Thus to maintain the therapeutic dose level in
the body to Cp, the total dose needed will be
Dtotal = DI + Cp.ClT.Ԏ
here DI = loading dose
Ԏ = dosing interval

11. Continued…
Plasma drug release from a zero order
, extended release drug product
Cp = Ds (1-e-kt
)/ Vd.K
Here, Ds = maintainence dose
Cp = plasma drug conc.
K = elimination constant
Vd = volume of distribution

12. Extended-release oral dosage forms
 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.
 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.

13. 1) Coated beads, granules, or
microspheres
- In these systems, the drug is
distributed onto beads, pellets,
granules, or other particulate
systems.
TYPES OF EXTENDED RELEASE PRODUCTS

14. - 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.

15. 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.

16. 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.

17.  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.

18.  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.

19. 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

20. 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.TYPE TRADE NAME RATIONALE
Erosion tablet Constant-T
Tenuate Dospan
Theophylline
Diethyl propion HCL
dispersed in hydrophilic
matrix
Waxy matrix tablet Kaon CI Slow reduce of potassium
chloride to reduce GI irritation
Pellets in tablet Theo-dur Theophylline
Coated ion exchange Tussionex Ion-exchange resin complex
of hydrocodone and
phenyltoloxamine

21. 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

22. 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.

23. 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.

25.  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.

26. 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

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

28. 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.

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

30.  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.

31. 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.

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

33. OROS OSMOTIC
THERAPEUTIC SYSTEMS
TRADE NAME MAUFACTURE GENERIC NAME
Acutrim Ciba Phenylpropanolamine
Covera-HS Searle verapamil
Dynacirc CR Sandoz Isradipine
Glucotrol XL Pfizer glipizide

34.  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
manufacturing changes which are
EVALUATION OF MODIFIED-RELEASE DRUG
PRODUCTS

35. 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.

36. - 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).

37. DISSOLUTION STUDIES
 Reproducibility of the method
 Proper choice of the medium
 Maintainence of sink condition
 Control of solution hydrodynamics
 Dissolution rate as function of pH, ranging
from 1-8

38. EVALUATION OF IN-VIVO
BIOAVAILABILITY DATA
1. PHARMACOKINETIC PROFILE
 Plasma drug conc.-time curve should adequately
define bioavailabilty of drug from dosage form.
 The bioavailability data should demonstrate the
extended release characteristics of the dosage
form compared to reference/immediate release
product.

39. 2. STEADY STATE PLASMA DRUG
CONCENTRATION
 Fluctuation = C∞
max - C∞
min /C∞
av
 where C∞
av is equal to [AUC]/T

40. 3. RATE OF DRUG ABSORPTION
 For a extended release drug product to claim zero-
order absorption, wagner nelson method is used.
4. OCCUPANCY TIME
 For drugs whose therapeutic window are known,
plasma drug conc. Maintained above the minimum
effective drug concentration.
 The time required to obtain plasma drug levels within
therapeutic window is known as occupancy time.

41. 5. BIOEQUIVALENCE STUDIES
 It includes the study of :
 A fasting study
 A food intervention study
 A multiple dose study

42. REFERENCE
 Shargel leon, WU Pong Susanna, B.C. YU
Andrew, Applied Biopharmaceutics and
Pharmacokinetics, 5th
edition,rights by
McGraw-hill, page no.-516-551