MODIFIED RELEASE

(MR) DRUG DELIVERY

SYSTEMS

mohd_kaleemullah
@msu.edu.my
Conventional Dosage Form or Immediate – Release
Dosage Form
Conventional / Immediate – release dosage form is a dosage form
which is formulated / designed to give rapid and complete release
of the drug contained therein immediately after administration.

Kinetic scheme for the extra vascular administration the

conventional dosage form of a drug that follows one –
compartment open model for disposition:
Kr Ka
Dosage Absorption Pool Body Compartment
Form
Drug Absorption
Release ( INPUT )

Ke
Urine
Elimination
( OUTPUT )
Kr, Ka and Ke : first order rate constants for drug release, absorption and overall elimination
respectively.
Immediate release from a convenient dosage form implies that
Kr >>> Ka. This means that absorption of a drug across a
biological membrane (e.g. GI epithelium) is the rate–timing
step in delivery of the drug to the body compartment.
For non–immediate–release dosage forms Kr <<< Ka.
i.e. release of drug from the dosage form is the rate limiting
step. Therefore the above scheme reduces to the following:

Kr Ke
Dosage Body
Urine
Form Compartment
Drug Elimination
Release

Essentially, the absorptive phase of the kinetic scheme

becomes insignificant compared to the drug release. Thus the
effort to develop a non–immediate–release dosage form must
be primarily directed at altering the release rate by affecting the
value of Kr.
Typical drug blood level vs. time curve / profile for
extra vascular administration of a single dose of the
conventional dosage form of a drug following one –
compartment open model for disposition:
Absorption
phase Toxic range

IV rout
MTC /
MSC
Rate of drug input
= Rate of drug output Therapeutic
range

MEC

Ineffective
range

Time
Advantages of Conventional Dosage Form:

1.Per unit cost of conventional dosage form is less

than non-immediate release dosage form.
2.More flexibility for the physician for adjusting
dosage form in conventional dosage form.
3. Conventional dosage form can accommodate
the patient variation.
4.No problems with drug having too small half life.
5.Potent drugs can’t be formulated as sustained
release dosage form.
Limitations of Conventional Drug Therapy:
1. Unable to maintain therapeutic blood level for a
prolonged period of time.
2. Fluctuation of blood level over successive dosing
intervals (giving peak and valley pattern).
3.Risk of over medication or under-medication because
of drug blood level fluctuation.
4. Require frequent dosing Patient inconvenience
+ Poor patient compliance Therapeutic failure /
Inefficiency.

5. No therapeutic action during overnight no dose

period Risk of symptom break through in chronic
disease.
6.Total amount of drug required is higher over the entire
course of therapy. (compared to SRDF)
7. Local/systemic side effect + overall health care cost is high.
Conventional Drug Therapy VS Modified-release drug delivery
MODIFIED - RELEASE
ORAL DRUG DELIVERY
 Modified-release drug delivery

 Modified-release drug delivery refers to the

manipulation or modification of drug release
from a dosage form (e.g. tablet, pellet, capsule)
with the specific aim of delivering active
pharmaceutical ingredients (API) at:

1. desired rates

2. pre-defined time points, or
3. specific sites in the gastrointestinal tract.
 Modified-release drug delivery

 The objective of MR drug products for oral

administration is to control the release of the
therapeutic agent and thus control drug absorption from
gastrointestinal tract.

 Types of MR drug products include, but not limited to,

delayed-release (eg, enteric-coated),
extended-release (ER), and
orally disintegrating tablets (ODT).
 Types of MR products

 1. Extended-release drug products.

 A dosage form that allows at least a twofold reduction in
dosage frequency as compared to that drug presented as an
immediate-release (conventional) dosage form. Examples of
extended-release dosage forms include controlled-release,
sustained-release, and long-acting drug products.

 2. Delayed-release drug products.

 A dosage form that releases a discrete portion/portions of
drug at a time other than the promptly release after
administration. An initial portion may be released promptly
after administration. Enteric-coated dosage forms are
common delayed-release products (eg, enteric-coated aspirin
and other NSAID products).
Types of MR products
 Types of MR products

 3. Targeted-release drug products. A dosage form

that releases drug at or near the intended physiologic site
of action. Targeted-release dosage forms may have either
immediate- or extended-release characteristics.

 4. Orally disintegrating tablets (ODTs). ODTs have

been devel-oped to disintegrate rapidly in the saliva after
oral administration.
ODTs may be used without the addition of water. The
drug is dispersed in saliva and swallowed with little or
no water.
Characteristics of modified release oral solids
DESIGNING A MODIFIED-RELEASE
FORMULATION:
 Matrix formulation or coated formulation

The release of an active pharmaceutical ingredient can be modified

by two main methods.

 Firstly, the release modifying ingredients can be incorporated

throughout the matrix of the dosage form wherein the whole
dosage form encompasses the modified-release element.

 The second option is the application of a modified-release coating

to a dosage form, wherein the drug is usually contained in the core
and is released through, or via the dissolution of, the MR coat.
TYPE OF RELEASE RATE
 Type of release rate

Two basic mechanisms can control the rate and extent of drug release.
 These are

(1) dissolution of the active drug component and

(2) diffusion of dissolved species.

There are four processes operating in a modified-release dosage form to

facilitate this:
1. hydration of the device (either swelling or dissolution of some
component of the modified-release dosage form)
2. diffusion of water into the device
3. dissolution of drug
4. diffusion of the dissolved drug out of the device.
◼ However, drug that is in contact with the surface of the dosage form
does not need to diffuse and is often quickly dissolved in a ‘burst
release’.
 Diffusion layer model for drug dissolution

DIFFUSION LAYER MODEL (FILM THEORY):

It is a simplest model where dissolution of crystal immersed in liquid, takes
place without involving reactive or electrical forces. Consist of two consecutive
steps:
Solution of the solid to form
a thin film or layer at the solid
/ liquid interface called as
stagnant film or diffusion
layer which is saturated with
the drug , this step is usually
rapid (instantaneous).

Diffusion of the soluble

solute from the stagnant layer
to the bulk of the solution this
step is slower and is
therefore the rate
determining step in the drug
dissolution.
 The following Parameters can be manipulated to give slow dissolution.

I. The solubility can be reduced by choosing a low solubility form

of the drug (e.g., weak acid/base instead of the salt).

II. The pH in the diffusion layer can be modified to reduce S, by

adding acidic or basic excipients.

III. Surface area can be reduced by not allowing the product to

disintegrate or deaggregate.

IV. Diffusion layer thickness can be increased by adding viscosity-

increasing excipients; this will also decrease diffusion
coefficient D of the drug.

V. Drug particles can be coated with a slow dissolving excipient, so

the medium cannot reach the drug rapidly.
SUSTAINED RELEASE
DOSAGE FORM
 What is a sustained release dosage form???
“Drug Delivery systems that are designed to achieve
prolonged therapeutic effect by continuously
releasing medication over an extended period of time
after administration of single dose.”

Basic goal of the therapy

to achieve steady state blood level that is
therapeutically effective & non toxic for an
extended period of time.
Also referred to as prolonged-release
(PR), slow release (SR), sustained
action (SA), prolonged action (PA) or
extended-release (ER).
28
 Merits.
➢ Improved patient convenience and compliance due to less
frequent drug administration.

➢Reduction in fluctuation in steady-state level and therefore better

control of disease condition.

➢Increased safety margin of high potency drug due to better

control of plasma levels.

➢Maximum utilization of drug enabling reduction in total amount

of dose administered.

➢ Reduction in health care cost through improved therapy, shorter

treatment period.
➢Less frequency of dosing and reduction in personnel time to
dispense, administer monitor patients.

➢Better control of drug absorption can be obtained, since the high

blood level peaks that may be observed after administration of a
dose of high availability drug can be reduced.
 Demerits..
➢ Decreased systemic availability in comparisn to immediate
release conventional dosage forms; this may be due to incomplete
release, increased first-pass metabolism, increased instability,
insufficient residence time for complete release, site specific
absorption, pH dependent solubility etc.,

➢Poor in-vivo, in-vitro correlation.

➢Possibility of dose dumping due to food, physiologic or

formulation variable or chewing or grinding of oral formulation by
the patient and thus increased risk of toxicity.
➢Retrieval of drug is difficult in case of toxicity, poisoning or
hypersensitivity reaction.

➢ The physician has less flexibility in adjusting dosage regimens.

This is fixed by the dosage form design.

➢Sustained release forms are designed for the normal population

i.e. on the basis of average drug biologic half-life‟s. Consequently
disease states that alter drug disposition, significant patient variation
and so forth are not accommodated.

➢Economics factors must also be assessed, since more costly

processes and equipment are involved in manufacturing many
sustained release forms.
The difference between controlled release and sustained release,

Controlled drug delivery- which delivers the drug at a pre

determined rate for a specified period of time

Controlled release is perfectly zero order release that is the

drug release over time irrespective of concentration.
Sustain release dosage form- is defined as the type of dosage
form in which a portion i.e. (initial dose) of the drug is released
immediately, in order to achieve desired therapeutic response more
promptly, and the remaining(maintanance dose) is then released
slowly there by achieving a therapeutic level which is prolonged,
but not maintained constant.

Sustained release implies slow release of the drug over a time

period. It may or may not be controlled release.
 MSC

MEC
A
B

Time (hrs)

Fig: The blood level–time profile of (A) Controlled–

release (B) Prolonged–release dosage form
Criteria of a Drug Required for Designing as
Sustained Released Dosage Form:
• They exhibits neither very slow nor very fast
rates (t½<2hrs) of absorption and excretion.
[Drugs having biological half lives of between 4
& 6 hours make good candidates in sustained –
release formulations.]
• They are uniformly absorbed from the GIT.
• They are administered in relatively low dose.
• They are used in the treatment of chronic rather
than acute conditions.
• They possess a good margin of safety.
[Accidental dose dumping from potent drugs
may be strongly hazardous.]
 Characteristics of Drugs Unsuitable for Peroral
SRDF
1. Those which are absorbed and excreted rapidly; short biological
half life(<1 hr). Ex- Penicillin G , Furosemide.
2. Those with long biologic half life(>12 hrs). Ex- Diazepam,
Phenytoin.
3. For those which require large doses(>1 gm) Ex- Sulfonamides.
4. Extensive binding of drugs to plasma proteins will have long
elimination half life and such drugs generally do not require to
be formulated to SRDF.
5. Those with cumulative action and undesirable side effects. Ex
Phenobarbital
6. Those with low therapeutic indices. ex- Digitoxin.
7. Those requiring precise dosage titration for every individual.
Ex- Warfarin, Digitoxin.
8. In general a very highly soluble drug or a highly insoluble drug
are undesirable for formulation into SRDF product.
Characteristics of Drugs suitable for SRDDS
Comparison between conventional and sustained-release drugs

Conventional Drug Therapy Sustained-Release Drug Therapy

1. Rapid and complete release
of drug immediately after
administration.
2. Absorption is the rate-
limiting step (kr >>> ka).
3. Blood level fluctuates (Peak
and Valley).
4. There is risk
overmedication or under
medication at periods of time.
5. Frequent dosing.
6. Patient non compliance.
Therapeutic inefficiency / failure.
7. Inconvenience of patient.
1.Slow/controlled release of drug over
an extended period of time.
2.Drug release from the dosage form is
the rate-limiting step (ka >>> kr ).
3.Constant blood level is maintained
over a prolonged period (Reduced
fluctuation).
of 4.Reliable therapy as the risk is
minimized.
5.Reduced frequency of dosing.
6.Improved patient compliance.
7.Enhanced patient convenience with
day-time and night-time medication.
8. No therapeutic action
during overnight no dose
period.
9. Risk of symptom
breakthrough.
10.Incidence and severity of
untoward effects related to high
-peak plasma concentration .
11.More total dose over the entire
course of therapy.
12.More side effects.
13.Health care cost .
14.Permits prompt testing of
therapy.
15.Incidence of severity of GI side
effects due to dose dumping of
irritant drugs .
16.More flexibility for physician in
adjusting dosage required.
8.Maintains therapeutic action during
overnight no dose period.
9.Improved treatment of many chronic
diseases (minimizing symptom
breakthrough).
10.Incidence and severity of untoward
effects related to high – peak plasma
concentration .
11.Less total dose over the entire
course of therapy.
12.Minimize/eliminate incidence of
local/systemic side effects.
13. Health care cost .
14. Does not prompt.
15.Incidence of severity of GI side
effects due to dose dumping of irritant
drugs .
16.Less flexibility.
17.Can accommodate abnormal
cases of disease safety offering
drug disposition etc.
18. Chance of at any site of GIT
(local irritation ).
19.No problems for drugs with too
short half lives.
20.Per unit cost is less. 
Time
17. Can not accommodate.
18. Chance of at any site of GIT (local
irritation).
19.Not suitable for drugs with too short
half lives, drugs needing specific
requirements for absorption from GIT.
20. Per unit cost is more. 
21.
Time
POLYMERS
 Classification of polymers

Natural polymers Semi synthetic Synthetic polymers

eg. Xanthan gum, polymers eg. Polyesters,
polyurethanes, eg. Celluloses such as polyamides,
Guar gum, HPMC, NaCMC, polyolefins etc
polycarbonates, Ethyl
Karaya gum cellulose etc.
etc
Classification Of Polymers Used In Sustained Release Drug Delivery Systems
According To Their Characteristics:
Sr.no Polymer characteristics Material

1. Insoluble, inert Polyethylene, polyvinyl chloride, methyl acrylates-

methacrylate copolymer, ethyl cellulose.
2. Insoluble, erodable Carnauba wax
Stearyl alcohol,
Stearic acid,
Polyethylene glycol.
Castor wax

Polyethylene glycol monostearate

Trigycerides
3. Hydrophilic Methylcellulose, Hydroxyethylcellulose, HPMC,
Sodium CMC, Sodium alginate, Galactomannose
Carboxypolymethylene.
 Hydrophilic Matrix Systems

 Hydrophilic matrix systems can also be referred to as swellable

soluble matrices.

 They are used for extended (sustained) release. Drug is mixed with
a water-swellable, hydrophilic polymer (usually along with some
other excipient materials) and com-pressed into a tablet.

 The polymer is usually in the form of a powder or granule, and

tablets will be manufactured by direct compression or roller
compaction (dry granulation processes). The resulting tablet has
drug material interspersed between polymer particles.


 Hydrophilic matrix systems

 On exposure to fluid, the polymer material in the tablet

starts to swell, producing a gel matrix.

 The gel can then allow drug release by dissolution of the

gel
and the drug trapped within it

 or erosion of the gel and release and dissolution of drug

particles trapped within it.
Diffusion-based release mechanisms usually follow zero-order or first-order kinetics
 Insoluble polymer matrix

 These are far less commonly used

than their water-soluble/swellable
counterparts.

 They consist of an inert matrix system

in which drug is embedded in an inert
polymer. Their structure has been
likened to that of a sponge. If drug
molecules were interspersed
throughout a sponge and water was
applied, drug could leach out via the
water filled channels (Fig.). The drug release does not follow zero-order
kinetics
 In contrast to hydrophilic matrices,
these systems stay intact throughout
the gastro-intestinal tract.
 Membrane-controlled systems

 Membrane–controlled delivery systems differ from the

matrix formulations in that the rate-controlling part of the
system is a membrane through which the drug must
diffuse, rather than diffusing through the whole matrix.

 Generally, drug is concentrated in the core, and must

traverse a polymeric membrane or film which slows
down the release rate.

 Impor-tant criteria for such a dosage form are that the

drug should not diffuse in the solid state.
 Membrane-controlled systems

 Upon exposure to an aqueous environment, water should be able to diffuse into

the system and form a continuous phase through which drug diffusion and
release can occur (Fig.).

 Drug release through a membrane is controlled by the thickness and the

porosity of the membrane, as well as the solubility of the drug in the
gastrointestinal fluids.
 Osmotic systems

 A drug is included in a tablet core which is water soluble, and which will
dissolve (or suspend) the drug in the presence of water.

 The tablet core is coated with a semi-permeable membrane which will

allow water to pass into the core.

 As the core components dissolve, a hydrostatic pressure builds up and

forces (pumps) drug solution (or suspension) through a hole drilled in the
coating (Fig.).

 The rate at which water is able to pass through the membrane and how
quickly the drug solution (or suspension) can pass out of the hole govern
the rate of drug release.
 MARKETED CONTROLLED RELEASE PRODUCT

Composition Product Name Manufacturer

Tablet
Carbamazepine Zen Retard Intas
Diazepam Calmrelease – TR Natco
Diclofenac sodium Dic – SR Dee Pharma
Limited
Diclofenac sodium Nac – SR Systopic

Diclofenac sodium Agile – SR Swift

Diclofenac sodium Dicloram SR Unique

Diclofenac sodium Doflex SR Nicholas Piramal

Diclofenac sodium Mobinase – SR Crosland

Diclofenac sodium Monovac – SR Boehringer –

Mannheim
Diclofenac sodium Relaxyl - SR Franco – Indian

Diclofenac sodium Voveran – SR Ciba – Geigy

Diltiazem Dilzem SR Torrent