Advanced Drug Delivery

Systems
Drug delivery refers to approaches, formulations,
technologies, and systems for transporting a
pharmaceutical compound in the body as needed
to safely achieve its desired therapeutic effect.

The goal of any drug delivery system is:

i) To provide a therapeutic amount of drug to the
proper site in the body
ii) Controlling the drug release to maintain the
desired drug concentration.

The first drug delivery system developed was the

syringe, invented in 1855, used to deliver
medicine by injection. The modern transdermal
patch is an example of advanced drug delivery
system.
Most common routes of administration include the
preferred non-invasive oral (through the mouth),
topical (skin), transmucosal (nasal, buccal/sublingual,
vaginal, ocular and rectal) and inhalation routes.

Current efforts in the area of drug delivery include the

development of:
a) targeted delivery in which the drug is only active in
the target area of the body (for example, in
cancerous tissues) and
b) sustained release formulations in which the drug is
released over a period of time in a controlled manner
from a formulation.
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 conventional dosage form of a drug that
follows one – compartment open model for disposition:
Dosage Kr Ka Body Compartment
Form Absorption Pool
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
drug across the biological membrane is the rate–timing
step. But the rate of absorption is difficult to control
(depends on number of factors) which leads the
development of non-immediate release dosage form.

In non–immediate–release dosage forms, Kr <<< Ka

(rate of drug release is much slower than that of
absorption), where the absorptive phase of the kinetic
scheme becomes insignificant. Thus the effort to
develop a non–immediate release dosage form must be
primarily directed at altering the value of release rate, Kr
(i.e. the drug release considered as the rate limiting
step).
Thus the above scheme reduces to the following:
Kr Ke
Dosage Body Compartment
Urine
Form
Drug Elimination
Release

Hence, a typical drug blood level Vs time profile for

non–immediate–release regimen obtained as:
MSC

MEC

D D D D D D D D

Time
At the start of the non-immediate release dosage
regimen, the blood levels of drug tends to increase in
successive doses. But the rate of drug elimination will
increase as the average blood level of drug rises (first
order kinetics) and a situation is eventually reached
when the overall rate of elimination of drug becomes
equal to the overall rate of supply. This situation is
called “Steady State”.

For a drug administered at equal time intervals,

the time required for the average blood levels to
reach the 95% of the steady state value is 4.3 times
the biological half–life (t½) of the drug. The
corresponding figure for 99% is 6.6 times.
 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.
7. The fluctuations in drug levels may lead to precipitation of
adverse effects especially of a drug with small Therapeutic
Index.
8. Overall health care cost is high.
 Non-Immediate Release Dosage Form
Non-immediate release dosage form is those which do not
release whole amount of drugs contained, immediately after
administration.

Why Non-Immediate Release Dosage Form?

a) Delayed release of an immediate release unit. Ex: Enteric
coated tablet or capsule.
b) Repetitive intermittent release of two or more immediate
release unit incorporated into a single dosage form. Ex:
Repeat action tablet or capsule.
*Although a repeat action dosage form exhibits the same
“peak and valley” pattern as associated with conventional
dosage forms, but it improves patient compliance by reducing
dosing frequency.
Types of Non-Immediate Release
Dosage Form

1. Delayed release dosage form

2. Sustained release dosage form
a) Control release
b) Prolonged release
3. Site specific release dosage form
4. Receptor release dosage form
Site Specific Release and Receptor
Release Dosage Forms

Site specific release dosage forms offer

targeted delivery of a drug directly to a
certain biological location.

In case of receptor release dosage forms,

the target is the specific receptor for the
drug within an organ or tissue.
 Sustained Release Dosage Forms
Sustained release dosage forms are those
dosage forms which are designed to release
drug continuously at sufficiently slow or
controlled rate over an extended period of time
to provide prolonged therapeutic effect.

Sustained release has been constantly used to

describe pharmaceutical dosage forms
formulated to retard the release of a drug such
that its appearance in the systemic circulation is
delayed and/or prolonged (8-12 hrs). But in case
of parenterals it is in days and months.
Sustained release dosage forms can further
be categorized as:
a) Controlled release dosage forms: those
sustained–release dosage forms which are
designed to release drug at a sufficiently
controlled rate to maintain a constant blood
level over an extended period of time.

b) Prolonged release dosage forms: which

cannot maintain a constant blood level, but
the blood level declines at such a
sufficiently slow rate that it remains within
the therapeutic range for a satisfactory
prolonged period of time.
 MSC

B
MEC

Time (hrs)
Fig: The blood level–time profile of (A) Controlled–
release (B) Prolonged–release dosage form
 Drug property considerations for SR formulations
Physicochemical properties:
1. Dose Size: If dose size is greater than 500 mg, than it’s a poor
candidate for SRDF.
2. Aqueous Solubility: If low water soluble drug difficult to
incorporate into SRDF (difficult to control release rate).
If highly water soluble drug  difficult to incorporate into
SRDF (difficult to control release rate).
pH dependent solubility, particularly in the physiological pH
range would be another problem.
3. Partition coefficient: if very lipid soluble or very water
soluble  extreme partition coefficient  either rapid flux or
low flux into the tissues.
4. Drug stability: If drug is unstable at the environment of
intestine  difficult to formulate SRDF.

Biological properties:
1. Absorption: If the drug is slowly or variably absorbed 
poor candidates for SRDF. (lower limit of absorption rate
constant is 0.25 hr-1)
2. Distribution: If high apparent volume of distribution VD
 influences the rate of elimination  poor candidates.
3. Metabolism: If metabolism rate is too high or variable
 poor candidates.
4. Duration of half-life (t1/2) : Drugs with short t1/2 (<2hrs) &
high dose  impose a constraint because of the dose size
needed. (Levodopa, Nitroglycerine).
Drugs with long t1/2 (>8hrs)  inherently sustained.
(Warfarin, Phenytoin).
5. Therapeutic window: Drugs with narrow therapeutic
window  requires precise control over plasma drug level
 not a suitable candidate.
6. Route of administration: Most convenient  oral route
No SRDF for rectal route.
7. Other factors: • Side effects • Margin of safety
• Role of diseased state • Role of circadian
rhythm
 Formulation Methods for Oral SRDF
Common methods used in the design of orally
administered SDRF include three general principles:
A. Barrier principle
1. Reservoir systems or devices
2. Osmotic Pumps or Systems
B. Embedded matrix principle
1. Matrix Systems or Devices
C. Drug Modification
1. Ion–Exchange Resins
2. Complex Formation
3. Drug-Adsorbate Preparation
4. Pro-drug Synthesis
 1. Reservoir Systems or Devices
(Barrier Principle)
These systems or devices consists of a core of drug
material is surrounded by a coat of retardant barrier
(polymeric membrane). The layer of retardant material
separates the drug and the elution medium.

AD
C

Drug
Reservoir
B A
 Mechanism of drug release from a reservoir device:
The release of drug from the reservoir can occur by four
mechanisms:
• i. Diffusion of drug present in the reservoir as a solution
or suspension through the barrier. Here the barrier is
impermeable to the elution medium. For the case of
solution, the release is first order. This principle has
been successfully applied in the development of
ophthalmic, intra-vaginal and transdermal controlled
release devices.
• ii. Penetration / permeation of elution medium through
the barrier occurs followed by dissolution of the drug in
the reservoir. Later diffusion of the dissolved drug
through the barrier results in availability of drug for
absorption.
• iii. Timed erosion of the barrier after sufficient moisture/
elution medium has permeated the membrane.
• IV. Rupture of the barrier after sufficient moisture has
permeated the membrane.
Common methods employed to develop
reservoir systems/devices Include:
A. Coating
B. Microencapsulation
A. Coating: A number of reservoir
devices can be prepared by applying the
technology of coating which includes:
a. Mixed release coated granules/ pellets
b. Uniform release coated granules/
pellets
c. Microdialysis cells
d. Drug coat of retardant material over
placebo pellets
a. Mixed release coated granules
Drug pellets/ granules are divided into 3 to 4
groups. One group is left uncoated to provide
the initial loading dose and the other groups of
pellets/ granules are coated to different
thicknesses.
The various groups are mixed together and
placed in capsules or compressed into tablets.

Mechanism of drug release: Moisture

penetration through the barrier → swelling of
the core → rupture of the barrier.
The retardant materials used for coating
includes:
-Combination of waxes, fatty acids, alcohols and
esters.
-Enteric materials such as cellulose acetate
phthalate and formalized gelatin.
-Mixture of solid hydroxylated lipids such as
hydrogenated castor oil or glyceryl trihydroxy-
stearate mixed with modified celluloses.

Examples of drugs designed as SRDF by this

method include Erythromycin, Pancreatin etc.
b. Uniform release coated granules / pellets
In this method, drug granules / pellets are
uniformly coated by a retardant material that
slowly release drug over sufficiently prolonged
period of time.
Retardant materials employed for this purpose
include hydrolyzed styrene maleic acid co-
polymer, partially hydrogenated cotton seed oil
etc.
Examples of drugs designed as SRDF by this
technique include crystals of Ascorbic acid,
Methyl prednisolone etc.
c. Microdialysis cells
Drug pellets are coated with a mixture of ethyl
cellulose (a water insoluble and pH insensitive
polymer) and sodium chloride particles or some other
water soluble materials (e.g. polyethylene glycol).
Release mechanism: Ethyl cellulose when in contact
with GI fluid, the water soluble material will dissolve
and salt will leach out forming pores which acts as a
dialytic membrane. The elution media then permeates
through dialytic membrane causing dissolution of the
drug and the drug solution then diffuses through the
essentially intact membrane.
Examples of drugs designed as SRDF by this
technique are Nitroglycerin, Propoxyphene, Aspirin etc.
d. Drug coat of retardant material over
placebo pellets
The drug is suspended in the coating of retardant
material applied onto placebo pellets. The
prepared pellets are placed in capsules. The
drug is released by erosion or rupture of the
barrier.
Retardant materials employed include
polyethylene glycol, modified ethyl cellulose,
shellac or cellulose acetate phthalate.
Example of drugs designed as SRDF by this
technique is Theophylline.
B.Microencapsulation
Microencapsulation is a process by which solids,
liquids or even gases may be encapsulated into
microparticles whose size ranges from several
tenths of 1µ to 5000µ in size through the
formation of thin coating of wall forming material
around the substance being encapsulated.

Retardant coating materials used are gelatin,

polyvinyl alcohol, ethyl-cellulose, polyvinyl
chloride. The most common method of
microencapsulation is coacervation.
Coacervation: In this technique, the prospective
wall–forming material e.g. gelatin, is dissolved in
water. The drug material to be microencapsulated is
added to the solution and the two–phase mixture is
thoroughly stirred until the drug material is broken
up to the desired particle size.
Then a solution of a second material (usually
acacia) is added which concentrates gelatin into tiny
liquid droplets called “coacervates” that encircle
drug particles.
The particles are coated to different thicknesses,
mixed together and compressed into tablets or
placed in capsules. The drug is released by
dissolution of coating materials.
2. Osmotic Systems / Pumps (Barrier Principle)
This is an example of membrane- controlled
release technology. These systems employ
osmotic pressure as the driving force to cause the
release of drug. A constant release of drug can be
achieved if a constant osmotic pressure is
maintained and a few other features of the system
are controlled.
A number of osmotic pumps / systems have been
designed by pharmaceutical manufacturers
including:
1. Oral osmotic systems
2. Push–pull osmotic system
Mechanism of Drug Release: GI fluid enters the
tablet core across the semi-permeable membrane
→ dissolve drug → creates an osmotic gradient
across the membrane → pumps the drug out
through the delivery orifices.
The rate of drug solution release is approximately
one to two drops per hour.
 1. Matrix System/ Devices
(Embedded Principle)
• In this case, the drug is dispersed (embedded)
in a matrix of retardant material, which may be
encapsulated in particulate form or
compressed into tablets. The drug may be
insoluble (Network model) or soluble
(Dispersion model) in the retardant material.
• Among the innumerable method used in
controlled release drug from pharmaceutical
dosage form, the matrix system is the most
frequently applied; due to (i) it’s delay and
control release of the drug, (ii) that remains in
dissolved or dispersed form, giving resistant to
disintegration.
 Fig. Network model (Drug is
insoluble in the retardant material)

Fig. Dispersion model (Drug is

soluble in the retardant material)
 Types of matrix material/ devices:
On the basis of the solubility of the materials
matrix devices can be classified into two:
1. Matrix may be soluble:
Hydrophilic polymers
2. Matrix may be insoluble:
a. Insoluble polymer matrix (plastic matrix)
b. Lipid matrix
c. Insoluble but potentially erodable matrix
1. Soluble Matrix: (Hydrophillic Matrix)
Drug can be dispersed in soluble matrix and drug
release depends on slow dissolution of the matrix by
elution media. This delivery system is also called
swellable soluble matrix.
In general they comprise a compressed mixture of
drugs and water swellable hydrophilic polymer. The
systems are capable of swelling, followed by gel
formation, erosion and dissolution in aqueous media.
Hydrated matrix layer on contact of water further
controls the diffusion of water. When outer layer is
fully hydrated, it erodes and drug contained is
released. Thus, drug diffusion and tablet erosion
controls the rate of drug release.
Hydrophilic materials:
Hydroxy propyl methyl cellulose,
Sodium CMC, Methylcellulose,
Hydroxy ethyl cellulose.
Natural gums: Galacto-mannose,
Chitosan, Gum acacia, Sodium alginate,
Pectins, Xanthan gum etc.
Examples of Drugs:
Sodium diclofenac
Oramorph SR tablets (Morphine sulfate)
 2. Insoluble matrix
a. Plastic or “Skeleton” matrix: These are insoluble
inert polymers such as polyethylene, polyvinyl
chloride, methacylate copolymer and ethyl
cellulose. The mixture of drug and ground polymer
may be directly compressed into tablets.
• Release mechanism: Drug is slowly released from
the inert matrix by diffusion following liquid
penetration. If channeling agent is used, diffusion
occurs through channels. Release rate can be
modified by changes in the porosity (pore-forming
salts) and compression force of the matrix.
This occurs when the matrix is insoluble in water, and
the drug is insoluble in the matrix but soluble in water.
• b. Lipid matrix: These are also water
insoluble matrix. Here drug delivered by
diffusion or by surface erosion.
Release mechanism: In this model, it is
assumed that drug is released by primarily
diffusion of drug through the matrix and
secondarily partition between matrix and water.

This occurs when the matrix is insoluble in

water, but the drug is soluble in the matrix and
has a high solubility in water/elution media.
c. Insoluble erodable matrix: This matrix is water
insoluble but potentially erodable. The matrix
includes waxes, lipids and related materials.
Examples include Carnauba wax, Castor wax
(hydrogenated castor oil) and Triglycerides.
• The drug and additives are generally depressed in
molted wax, which is then congealed, granulated
and placed into capsules and compressed into
tablets. The loading dose is provided as untreated
granules or as an outer core.
Release mechanism: In this model, it is assumed
that solid drug dissolves from the surface layer of
the device first; when this layer completes
delivering drug, the next layer begins to be
depleted by dissolution and diffusion through the
matrix to the external solution.
 1. Ion–Exchange Resins
(Chemical modification)
Ion–exchange resins are water insoluble polymers
containing salt forming groups on the polymer
chain.
Resins used are special grades of styrene / divinyl
benzene copolymers that contain substituted
acidic groups (carboxylic and sulfonic for cation
exchanges) or basic groups (quaternary
ammonium for anion exchanges).
Drug is bound to the resin by repeated exposure of
the resin to the drug in a chromatographic column
or by prolonged contact of the resin with the drug
solution.
For example, drug-resin salts may be prepared by percolation
of the sodium salt of the resin with a concentrated solution of a
drug hydrochloride salt. The following equation represents the
drug release in-vivo:
Resin – SO3Na + Drug HCl → NaCl + Resin-SO3. Drug H

Similarly drug-resinates are prepared by reaction of sodium salts

of acidic drugs with resin chloride.
Resin – NH4Cl + Drug Na → NaCl + Resin-NH4. Drug

The resin.drug complex is then washed with ion-free water and

dried. The resulting product can be encapsulated, tableted or
suspended in ion-free vehicles.

Release in-vivo :
Resin – NH4.Drug + NaCl (body fluid) → Drug Na + Resin-NH4Cl
 2. Complex Formation
(Chemical modification)
Certain drug substances that are only slowly soluble in the
body fluids are inherently long acting (Griseofulvin).
Thus drugs that are, high water soluble may be bound to
suitable complexing agents to form complexes which are
poorly water soluble and consequently give sustained action.
The steps or mechanism involved in controlling the
release of drug from drug complexes in GI fluid can be
illustrated as follows:
Dissolution Dissociation
DC . solid DC . solution D

Examples include: Tannic acid complexes of basic drugs like

amphetamine and antihistamines.
 3. Drug Adsorbate Preparation
(Physical modification)
Drug adsorbates represent a special case of complex
formation in which the product is essentially insoluble.

Drug availability is determined only by the rate of dissociation

(desorption) and access of the adsorbent surface to water as
well as the effective surface area of the adsorbate.

The mechanism involved in controlling the release of drug

from adsorbates can be illustrated as follows:
Desorption
AD. Solid D

The adsorbate, can be formulated as liquid suspensions,

tablets or capsules.
 4. Pro drug Synthesis
(Chemical modification)
Pro drugs are therapeutically inactive drug derivatives that
regenerate the parent drug in-vivo by enzymatic or non-
enzymatic hydrolysis.
The steps or mechanisms involved in controlling release of
drug from a prodrug can be depicted by the following scheme:

Dissolution Absorption
PD. Solid PD. Solution PD. Plasma
Metabolism

D
Elimination
PARENTERAL SUSTAINED RELEASE

Up to the present, efforts in developing

controlled release parenteral dosage forms
seems to have concentrated the subcutaneous
and intramuscular routes, resulting in such
products as aqueous and oil solutions, and
implants.
There are currently a number of injectable depot
formulations on the market. As for example,
Penicillin G procaine suspensions, Fluphenazine
in oil solution, Insulin-zinc suspensions.
 Mechanism of drug release
 When these formulations are injected into
subcutaneous or muscular tissues, a depot is formed at
the site of injection which acts as a reservoir for drug.
 Drug Molecules will be released continuously from the
reservoir at a rate determined by the characteristics of
each formulation.
 This continuous release of drug molecules will result in
a prolonged drug blood level.
The rate of drug absorption and hence duration of
therapeutic activities will be determined by:
• The nature of the vehicle
• The physicochemical characteristics of the drug
• The interaction of drug with vehicles and tissues/fluid
 Types of depot formulation
Ø Dissolution controlled depot preparation:
 In this type of formulation the rate of drug
absorption controlled by slow dissolution of drug
particle in the formulation or in the tissue fluid.
 There are two approaches that can be utilized to
control the dissolution of solid drug to prolong
absorption.
1. Formation of salt complex with low aqueous
solubility
2. Suspension of micro crystals
Ø Adsorption type depot preparation:
 This type of depot preparation is produced
by binding of drug molecules to adsorbents.
In this case only unbound, free species of
the drug is available for absorption.
Example: Vaccine preparation in which the
antigens are bound to highly dispersed
aluminum hydroxide gel.
Ø Encapsulation type depot preparation:
 This type of preparation is formed by encapsulating drug
solids within a diffusion barriers or dispersing drug particles in
diffusion matrix.
 Release of the drug molecules is controlled by diffusion
barrier or the rate of biodegradation of microcapsules.
Example: Nitroxone releasing biodegradable microcapsules.

Ø Esterification type depot preparation:

 This type of depot preparation is formed by synthesizing the
bioerodible esters of a drug and then formulating it in an
injectable formulation, which forms a drug reservoir at the site
of injection.
Example: Testosterone cypionate, Fluphenazine enathate.
SUSTAINED RELEASE PARENTERAL
DOSAGE FORMS
 1. AQUEOUS/ OIL SOLUTION
Increasing viscosity of the vehicle, the diffusion
coefficient of the drug from the solution will be
reduced, thereby delayed in drug transport.
They should be sterile, pyrogen free, stable,
injectable, isotonic & non-irritating.

Viscosity imparting agents commonly used are:

1. Methyl cellulose
2. Sodium carboxy methyl cellulose
3. Polyvinyl pyrollidine
 2. SUSPENSION
 It mist be stable, syringable and re-suspendable. In
this dosage form there is increased resistance to
hydrolysis & oxidation as drug is present in the solid
form.
 BUT parenteral suspension limits the formulator in
what ingredients are parenterally acceptable as
suspending agent, viscosity induce, wetting agent,
stabilizers and preservative.
 Some of the official preparations are;
1) Tetanus toxoid adsorbed USP '95 - Aq. Suspension.
2) Insulin Zinc suspension USP 95 Aq. suspension.
 3. EMULSIONS
It is recommended that emulsions designed for the
intravenous route have a submicron droplet size.
As drug targeting systems: Emulsions are helpful to
deliver drug at particular site. This is achieved by
conjugating antibodies to the distal ends of the emulsifiers,
provided the emulsion droplets in a submicron size.
The magnetically responsive oil-in-water type emulsion
described with its capacity to localize the
chemotherapeutic agent by application of an
electromagnet.
Reduces drug toxicity: Water-in-oil emulsion of
amphotericin deoxycholate, reduces the incidence and
severity of renal impairment while still maintaining the
antifungal efficacy of the drug.
 4. LIPOSOMES
LIPOSOME STRUCTURE
 Bilayered structure of phospholipids and cholesterol

 Capable of entrapping both water soluble and lipid soluble drugs

 Can alters bio-distribution; protect drug & body from each other

 Special liposomes usable for target delivery

SUSTAINED EFFECT
 Encapsulation of drug into multi-vesicular liposomes offers a

novel approach to sustained release drug delivery. Drug into

unilamellar and multilamellar liposomes and complexation of drug
with lipids, resulted in products with better performance, lasting
several hours to a few days after intravascular administration. 
 5. NIOSOMES
Differs from liposomes in having surfactant in place of
phospholipid. They can be used in the treatment of cancer
and also used as vaccine adjuvant. Some of its
applications are discussed here:
i) Anticancer niosomes - Niosomal encapsulation of
methotrexate and doxorubicin increases drug delivery to
the tumour and tumoricidal activity.
ii) Niosomes at targeted site - Uptake by the liver and
spleen make niosomes ideal for targeting diseases
manifesting in these organs. Niosomal formulations of
sodium stibogluconate improve parasite suppression in the
liver, spleen and bone marrow.
iii) Niosomes as vaccine adjuvants - It was studied that
niosomal antigens are potent stimulators of the cellular and
humoral immune response.
 6. MICROSPHERES
1. Microcapsules
• They are spherical particles containing drug
concentration in the center core, which is enveloped
by polymeric wall (rate controlled membrane).
2. Micromatrices
• Micromatrices are solid, spherical particles
containing dispersed drug molecules either in
solution or in crystalline form.
The microsphere release drug in a zero order fashion
over 1 to 3 months after intramuscular or
subcutaneous injection into animals.
 7. IMPLANT
Implant represents novel approach in the
use of solid dosage forms as parentral
product.
This method finds particular applicability to
cases where chronic administration of
drug over period ranging from days to
years.
Risk Factor: Danger of toxic effect in case
of leakage or burst release of drug.
Comparison between conventional and sustained-release drugs

Conventional Drug Therapy Sustained-Release Drug Therapy

1. Rapid and complete release of 1. Slow/controlled release of drug over

drug immediately after
administration.
2. Absorption is the rate-limiting
step (kr >>> ka).
3. Blood level fluctuates (Peak and
Valley).
4. There is risk of overmedication
or under medication at periods
of time.
5. Frequent dosing.
6. Patient non compliance.
Therapeutic inefficiency / failure.
7. Inconvenience of patient.
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).
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. 
21.
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
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