Drug selection for Controlled Drug Delivery.ppt

By
Dr. B. Sree Giri Prasad
Associate Professor
Nalla Narasimha Reddy Education Society’s Group of Institutions

2
SELECTION OF DRUG FOR CONTROLLED DRUG
SELECTION OF DRUG FOR CONTROLLED DRUG
DELIVERY
DELIVERY
Not all drugs are suitable candidates for controlled
Not all drugs are suitable candidates for controlled
delivery system .
delivery system .
The selection of drug must be based on sound scientific
The selection of drug must be based on sound scientific
principles.
principles.
The basic rationale (restructuring) of a controlled release
The basic rationale (restructuring) of a controlled release
drug delivery system is to optimise the biopharmaceutic,
drug delivery system is to optimise the biopharmaceutic,
pharmacokinetic and pharmacodynamic properties of a
pharmacokinetic and pharmacodynamic properties of a
drug in such a way that its utility is maximized through
drug in such a way that its utility is maximized through
reduction in side effects and cure or control of condition
reduction in side effects and cure or control of condition
in the shortest possible time by using smallest quantity of
in the shortest possible time by using smallest quantity of
drug, administered by the most suitable route.
drug, administered by the most suitable route.

3
 PCP & Biopharmaceutical
PCP & Biopharmaceutical
Properties of drug
Properties of drug
Reduction in side effects
Reduction in side effects
Pharmacokinetic Properties
Pharmacokinetic Properties
Pharmacodynamic Properties
Pharmacodynamic Properties
Of a
Drug
in such a way
in such a way
that its
that its
utility is
utility is
maximized
maximized
through
through
and
and cure or control of
cure or control of
condition
condition
in the
in the shortest
shortest
possible time
possible time
by using
by using smallest
smallest
quantity of drug
quantity of drug
administered by the
administered by the
most suitable route
most suitable route

4
Physicochemical Basis of Selecting the Drug:
Physicochemical Basis of Selecting the Drug:
The physicochemical properties are those properties of
The physicochemical properties are those properties of
drug molecules which can be estimated
drug molecules which can be estimated without the use
without the use
of
of isolated organ
isolated organ or
or animal
animal.
.
 Molecular Weight of the drug
Molecular Weight of the drug
 Aqueous Solubility of Drug
Aqueous Solubility of Drug
 Drug pKa and Ionization at Physiological pH
Drug pKa and Ionization at Physiological pH
 Apparent Partition Co-efficient
Apparent Partition Co-efficient
 Mechanism and Site of Absorption
Mechanism and Site of Absorption
 Drug Stability
Drug Stability

5
Molecular Weight of the drug :
Molecular Weight of the drug :
The lower the M.Wt of the drug, the faster & more
The lower the M.Wt of the drug, the faster & more
complete is its absorption.
complete is its absorption.
 Drugs which gets absorb by
Drugs which gets absorb by
pore transport
pore transport,the
,the M.Wt
M.Wt
threshold
threshold is:
is:
 But most drugs (95%) gets absorbed by
But most drugs (95%) gets absorbed by passive
passive
diffusion
diffusion, the
, the M.Wt Upper Limit
M.Wt Upper Limit is
is 600 daltons
600 daltons.
.
 Drugs with large molecular size
Drugs with large molecular size > 600 daltons
> 600 daltons are
are
poor candidates for controlled drug delivery.
poor candidates for controlled drug delivery.
Ex: Proteins and Peptides.
Ex: Proteins and Peptides.
Spherical
Spherical
Compounds
Compounds
Linear
Linear
Compounds
Compounds.
.
150 daltons
150 daltons
400
400
daltons
daltons

6
A drug should have good aqueous solubility in
A drug should have good aqueous solubility in
the entire range of GIT for Oral Absorption.
the entire range of GIT for Oral Absorption.
A pH-independent solubility profile, serves as a
A pH-independent solubility profile, serves as a
good candidate for controlled-release dosage
good candidate for controlled-release dosage
forms
forms
Ex: Pentoxifylline.
Ex: Pentoxifylline.
If the aqueous solubility of a drug is more than
If the aqueous solubility of a drug is more than
1%
1% in the
in the pH
pH range of
range of 1 – 7
1 – 7 at
at 37
370
0
C
C, there will
, there will
not be problem for dissolution. Hence such
not be problem for dissolution. Hence such
candidates are suitable for controlled drug
candidates are suitable for controlled drug
delivery.
delivery.
Aqueous Solubility of the drug :
Aqueous Solubility of the drug :

7
7
Drugs with
Drugs with pH-dependent aqueous solubility
pH-dependent aqueous solubility
Drugs with solubility in non-aqueous solvents
Drugs with solubility in non-aqueous solvents are
are
suitable for
suitable for parenteral (e.g. i.m depots) controlled-
parenteral (e.g. i.m depots) controlled-
release dosage forms
release dosage forms
Ex. Phenytoin
Ex. Phenytoin
E.X: steroids
E.X: steroids
Drugs having poor aqueous solubility and
Drugs having poor aqueous solubility and
dissolution rate-limited are not suitable for
dissolution rate-limited are not suitable for
controlled drug delivery systems.
controlled drug delivery systems.
The lower limit of solubility of a drug to be
The lower limit of solubility of a drug to be
formulated as CRDDS is 0.1mg/ml..
formulated as CRDDS is 0.1mg/ml..

8
Drug pKa and Ionisation at Physiological pH:
Drug pKa and Ionisation at Physiological pH:
The pKa range for acidic drugs whose
The pKa range for acidic drugs whose
ionisation is pH-sensitive is 3.0 to 7.5.
ionisation is pH-sensitive is 3.0 to 7.5.
The pKa range for basic drugs whose ionisation
The pKa range for basic drugs whose ionisation
is pH-sensitive is 7.0 to 11.0.
is pH-sensitive is 7.0 to 11.0.
For optimum passive absorption, the drugs
For optimum passive absorption, the drugs
should be non-ionised at that site at least to an
should be non-ionised at that site at least to an
extent 0.1 to 5%.
extent 0.1 to 5%.

9
Drugs existing largely in ionised forms are poor
Drugs existing largely in ionised forms are poor
candidates for controlled delivery.
candidates for controlled delivery.
Ex: Hexamethonium
Ex: Hexamethonium
The extent of ionization and absorption can be predicted
The extent of ionization and absorption can be predicted
by pH – partition theory using Henderson-Hasselbalch eq.
by pH – partition theory using Henderson-Hasselbalch eq.
Apparent Partition Coefficient/Lipophilicity of the Drug:
Apparent Partition Coefficient/Lipophilicity of the Drug:
Greater Partition Co-efficient, greater the lipid solubility,
Greater Partition Co-efficient, greater the lipid solubility,
the greater the rate and extent of absorption.
the greater the rate and extent of absorption.
Further these compounds can usually stay in the body for
Further these compounds can usually stay in the body for
longer periods due to localization in the lipid membrane.
longer periods due to localization in the lipid membrane.
Ex: Phenothiazines.
Ex: Phenothiazines.

10
Low Partition Co-efficient drugs are not suitable for
Low Partition Co-efficient drugs are not suitable for
Controlled Drug Delivery System as they difficulty in
Controlled Drug Delivery System as they difficulty in
penetrating the membrane, resulting in poor
penetrating the membrane, resulting in poor
bioavailability.
bioavailability.
Such drugs have a tendency to cross biological barriers,
Such drugs have a tendency to cross biological barriers,
including BBB.
including BBB.
 Drugs absorbed by carrier-mediated transport
Drugs absorbed by carrier-mediated transport
processes are poor candidates for controlled-release
processes are poor candidates for controlled-release
systems
systems e.g. Riboflavin
e.g. Riboflavin.
.
 Drugs absorbed through a window are poor candidates
Drugs absorbed through a window are poor candidates
for controlled-release systems
for controlled-release systems e.g. several B vitamins
e.g. several B vitamins.
.

11
Drug Stability:
Drug Stability:
 Drugs unstable in GI environment cannot be
Drugs unstable in GI environment cannot be
administered as oral controlled-release formulation
administered as oral controlled-release formulation
because of bioavailability problems
because of bioavailability problems e.g. nitroglycerine
e.g. nitroglycerine.
.
 A different route
A different route of
of administration
administration should then be
should then be
selected such as the transdermal route
selected such as the transdermal route.
.
 Drugs unstable in gastric pH
Drugs unstable in gastric pH can be
can be designed for
designed for
sustained delivery in intestine
sustained delivery in intestine with
with limited or no
limited or no
delivery in stomach
delivery in stomach. e.g. propantheline
. e.g. propantheline.
.
 On the other hand,
On the other hand, a drug unstable in intestine
a drug unstable in intestine can be
can be
formulated as
formulated as gastroretentive dosage form
gastroretentive dosage form.
. e.g.
e.g.
Probanthine.
Probanthine.

12
Drug Permeability:
 The three major drug characteristics that determine the
The three major drug characteristics that determine the
permeability of drugs for passive transport across
permeability of drugs for passive transport across
intestinal epithelium are:
intestinal epithelium are:
 Lipophilicity, expressed as log
P.
 Polarity of drug which is measured by the
Polarity of drug which is measured by the
number of H-bond acceptors and number of H-
number of H-bond acceptors and number of H-
bond donors on the drug molecule
bond donors on the drug molecule.
.
 Molecular size
Molecular size

13
BIOPHARMACEUTIC ASPECTS OF ROUTE OF
BIOPHARMACEUTIC ASPECTS OF ROUTE OF
ADMINISTRATION
ADMINISTRATION
 Oral Route
Oral Route
 Intramuscular/Subcutaneous Routes
Intramuscular/Subcutaneous Routes
 Transdermal Route
Transdermal Route
Oral
Oral and
and parenteral (i.m.) routes
parenteral (i.m.) routes are the
are the most popular
most popular
followed by
followed by transdermal application
transdermal application.
.
Routes of minor importance
Routes of minor importance in controlled drug delivery
in controlled drug delivery
are
are buccal/sublingual
buccal/sublingual,
, rectal
rectal,
, nasal,
nasal, ocular
ocular,
,
pulmonary
pulmonary,
, vaginal
vaginal and
and intrauterinal
intrauterinal.
.
The desirable features for a drug to be given by a
The desirable features for a drug to be given by a
particular route are discussed below.
particular route are discussed below.

14
 Oral Route
Oral Route
 For a drug to be successful as oral CRF, it must get
For a drug to be successful as oral CRF, it must get
absorbed all along the length of GIT.
absorbed all along the length of GIT.
 The
The Limitation of this route
Limitation of this route is
is transit time
transit time (a mean
(a mean
of 14 hr
of 14 hr)
) and
and duration of action
duration of action can be
can be extended
extended for 12
for 12
– 24 hrs
– 24 hrs
 The route is suitable for the drugs given at a dose as
The route is suitable for the drugs given at a dose as
high as 1000mg.
high as 1000mg.
 Drugs
Drugs
 Whose absorption is pH dependent.
Whose absorption is pH dependent.
 Who destabilizes at GI Fluids/Enzymes.
Who destabilizes at GI Fluids/Enzymes.
 Who undergoes extensive presystemic
Who undergoes extensive presystemic
metabolism.
metabolism. Ex: Nitroglycerine
Ex: Nitroglycerine
 whose absorption is influenced by GI Motility.
whose absorption is influenced by GI Motility.
 Absorbed actively from Absorption Window
Absorbed actively from Absorption Window Ex:
Ex:
 Poor
Poor
Candidates
Candidates
for CDDS
for CDDS

15
 Intramascular/Subcutaneous Routes
Intramascular/Subcutaneous Routes
 This route is suitable, when duration is to be prolonged
This route is suitable, when duration is to be prolonged
from 24 hrs to 12 months.
from 24 hrs to 12 months.
 Only about
Only about 2 ml or 2 gms
2 ml or 2 gms can be administered by
can be administered by
these routes.
these routes.
 Important factors for drug release by such routes are:
Important factors for drug release by such routes are:
 Solubility of Drug in surrounding tissues.
Solubility of Drug in surrounding tissues.
 Molecular Weight.
Molecular Weight.
 Partition Co-efficient
Partition Co-efficient
 pKa of Drug.
pKa of Drug.
 Contact Surface between drug &
Contact Surface between drug &
Surrounding Tissues
Surrounding Tissues.
.

16
 Transdermal Route
Transdermal Route
 This route is best suited for drugs having extensive pre-
This route is best suited for drugs having extensive pre-
systemic metabolism upon oral administration.
systemic metabolism upon oral administration.
 Low dose drugs such as
Low dose drugs such as Nitroglycerine
Nitroglycerine is
is
administered by this route.
administered by this route.
 Important features required for drug to be administered
Important features required for drug to be administered
by this route includes:
by this route includes:
 Contact Area of skin.
Contact Area of skin.
 Partition Co-efficient of drug
Partition Co-efficient of drug
 Skin Condition.
Skin Condition.
 Skin Permeability to drug & Skin Perfusion rate
Skin Permeability to drug & Skin Perfusion rate.
.

17
 Dose of Drug:
Dose of Drug:
 Drug that are to be administered in large doses (>1gm)
Drug that are to be administered in large doses (>1gm)
are not suitable for controlled release drug delivery.
are not suitable for controlled release drug delivery.
 Ex: Sulfamethoxazole
Ex: Sulfamethoxazole.
.
 Further, when large doses (Drugs with low therapeutic
Further, when large doses (Drugs with low therapeutic
index) of drug is to be administered then
index) of drug is to be administered then safety margin
safety margin
shown by such drugs will be less
shown by such drugs will be less.
.
 Transport of Drug across membranes:
Transport of Drug across membranes:
 Drugs absorbed by passive
Drugs absorbed by passive
diffusion:
diffusion:  CRDDS
CRDDS
 Drugs absorbed by
Drugs absorbed by Carrier
Carrier
Mediated/Active Transport
Mediated/Active Transport:
: X
X CRDDS
CRDDS
Suitability to
Suitability to
convert in to
convert in to
 Ex: Riboflavin,
Ex: Riboflavin, FeSO
FeSO ,
, Hydrochlorthiazide
Hydrochlorthiazide

18
 AUC:
AUC:
 Area under plasma drug concentration time curve
Area under plasma drug concentration time curve
indicates the extent of unchanged drug reaching the
indicates the extent of unchanged drug reaching the
systemic circulation..
systemic circulation..
 Important parameter for the evaluation of dosage form
Important parameter for the evaluation of dosage form
(both B.A & B.E) and estimation of Clearance (Cl) and
(both B.A & B.E) and estimation of Clearance (Cl) and
V
Vd
d of drugs.
of drugs.
 AUC is normally determined by Trapezoid Method.
AUC is normally determined by Trapezoid Method.
 If dose administered and AUC values obtained after
If dose administered and AUC values obtained after
Oral and I.V
Oral and I.V are same
are same, then there are better chances of
, then there are better chances of
designing CRDDS.
designing CRDDS.

19
 Dosage Form Index (DI):
Dosage Form Index (DI):
 Dosage Form Index (DI)
Dosage Form Index (DI) is the ratio of
is the ratio of C
CSS
SS
max
max to
to
C
CSS
SS
min
min within the
within the dosing interval
dosing interval.
.
 If
If DI = 1
DI = 1 for a dosage form, drug levels can be
for a dosage form, drug levels can be
maintain within the therapeutic window, suitable for
maintain within the therapeutic window, suitable for
desiring CRDDS.
desiring CRDDS.
 The concentration of any drug in the plasma is always
The concentration of any drug in the plasma is always
to its therapeutic effect.
to its therapeutic effect.
 The pharmacokinetics of multiple dosing and constant
The pharmacokinetics of multiple dosing and constant
rate infusion is useful for predicting the C
rate infusion is useful for predicting the Css
ss.
.
 Mean Steady State Concentration (C
Mean Steady State Concentration (C1
1
ss
ss
):
):
 C
Css
ss =
= C
Cmax
max
ss
ss
=
= C
Cmin
min
ss
ss

20
 Steady State Concentration (C
Steady State Concentration (C1
1
ss
ss
) of drug is the target
) of drug is the target
concentration that must be maintained by the controlled
concentration that must be maintained by the controlled
release drug delivery system.
release drug delivery system.
Pharmacokinetic Characteristics of a
Drug in the Design of CRDDS
 Drug Pharmacokinetic studies on humans provide
Drug Pharmacokinetic studies on humans provide
valuable information for the design of CRDDS.
valuable information for the design of CRDDS.
 Though CRDDS implies the release of drug for
Though CRDDS implies the release of drug for
prolonged period, it is essential to achieve the ultimate
prolonged period, it is essential to achieve the ultimate
objectives, i.e:
objectives, i.e:
 Maintaining Steady State drug concentration in:
Maintaining Steady State drug concentration in:
 Blood
Blood  Site of Tissue or Organ
Site of Tissue or Organ

21
 The basic expression that govern the steady state drug
The basic expression that govern the steady state drug
concentration in plasma, (C
concentration in plasma, (C1
1
ss
ss
) is:
) is:
 Rate of Input
Rate of Input =
= Rate of Output
Rate of Output
 Dosing Rate
Dosing Rate =
= Total Clearance
Total Clearance
 If One/Two parameters are satisfactory, a drug can be
If One/Two parameters are satisfactory, a drug can be
selected for formulating into controlled drug delivery
selected for formulating into controlled drug delivery
systems. These parameters are the guiding principles.
systems. These parameters are the guiding principles.
 A detailed knowledge of the ADME characteristics
A detailed knowledge of the ADME characteristics
of a drug is essential in the design of a controlled-
of a drug is essential in the design of a controlled-
release product.
release product.
 An optimum range of a given pharmacokinetic parameter
An optimum range of a given pharmacokinetic parameter
of a drug is necessary beyond which controlled delivery is
of a drug is necessary beyond which controlled delivery is
difficult or impossible.
difficult or impossible.

22
For a drug to be administered as controlled-release
For a drug to be administered as controlled-release
formulation, its absorption must be efficient since the
formulation, its absorption must be efficient since the
desired rate-limiting step is rate of drug release Kr
desired rate-limiting step is rate of drug release Kr
i.e. Kr << Ka.
i.e. Kr << Ka.
 Absorption Rate:
Absorption Rate:
A drug with slow absorption
A drug with slow absorption is
is a poor candidate
a poor candidate
for such dosage forms
for such dosage forms since continuous release
since continuous release will
will
result in a pool of unabsorbed drug
result in a pool of unabsorbed drug e.g. iron
e.g. iron.
.
Aqueous soluble
Aqueous soluble but
but poorly absorbed potent
poorly absorbed potent
drugs
drugs like
like decamethonium
decamethonium are also
are also unsuitable
unsuitable
candidates
candidates since a
since a slight variation
slight variation in the
in the
absorption may precipitate potential toxicity.
absorption may precipitate potential toxicity.

24
 Plasma Elimination Half – Life (t
Plasma Elimination Half – Life (t1/2
1/2):
):
 Plasma Elimination half life is defined as the time
Plasma Elimination half life is defined as the time
required for the drug concentration to decrease to half
required for the drug concentration to decrease to half
of its initial concentration in blood.
of its initial concentration in blood.
 The rate of drug entering the circulation must be
The rate of drug entering the circulation must be
approximately equivalent to the rate of elimination.
approximately equivalent to the rate of elimination.
 It is normally determined from the terminal portion
It is normally determined from the terminal portion
of the elimination half-life from the plot of Log C vs
of the elimination half-life from the plot of Log C vs
t.
t.
An ideal CRDDS
An ideal CRDDS is the
is the one from whose rate of
one from whose rate of
drug of absorption
drug of absorption (for extended period of time)
(for extended period of time) is
is
equal to the rate of elimination
equal to the rate of elimination.
.

25
1.
1. Drugs having very short plasma elimination
Drugs having very short plasma elimination
half –life
half –life (< 2 hrs
(< 2 hrs)
) are not suitable for CRDDS
are not suitable for CRDDS.
.
 Ex: Penicillin G,
Ex: Penicillin G, Levodopa
Levodopa.
.
 The Shorter the t
The Shorter the t1/2
1/2 the
the greater the choice
greater the choice of
of
selection of drug for CRDDS
selection of drug for CRDDS,
, provided the t
provided the t1/2
1/2 is
is
correlated to pharmacologic response
correlated to pharmacologic response.
.
 The following ground rules are useful for the
The following ground rules are useful for the
selection of the drug:
selection of the drug:
Because these drugs are to be administered
Because these drugs are to be administered
in
in high doses
high doses to
to maintain controlled drug
maintain controlled drug
release
release which is not possible
which is not possible.
.

26
2. Drugs with
2. Drugs with intermediate
intermediate plasma elimination half –
plasma elimination half –
life
life (
(2 - 4 hrs
2 - 4 hrs) are
) are very much suitable for
very much suitable for
CRDDS
CRDDS.
.
 Ex:
Ex: Propranolol
Propranolol.
.
3. Drugs
3. Drugs having High plasma elimination half –life
having High plasma elimination half –life
(> 8 hrs)
(> 8 hrs) need not be formulated as
need not be formulated as CRDDS
CRDDS.
.
 Ex:
Ex: Amlodipine
Amlodipine, Diazepam
, Diazepam,
, Phenytoin
Phenytoin.
.
Because these in their
Because these in their conventional dosage form
conventional dosage form
inherently produce prolonged action.
inherently produce prolonged action.
4. Drugs
4. Drugs having High lipid solubility
having High lipid solubility produce long
produce long
duration action
duration action up to 2 days ( t
up to 2 days ( t1/2
1/2 1 – 3 hrs
1 – 3 hrs)
) need
need
not be formulated as
not be formulated as CRDDS
CRDDS.
.
 Ex:
Ex: Prednisolone
Prednisolone, Methyl Predinisolone
, Methyl Predinisolone

27
 Rate of Metabolism/ Total Clearance (Cl
Rate of Metabolism/ Total Clearance (ClT
T):
):
 Clearance is defined as the volume of
Clearance is defined as the volume of
blood/plasma from which the drug is completely
blood/plasma from which the drug is completely
removed in unit time.
removed in unit time.
 Since clearance (Cl
Since clearance (ClT
T) represents
) represents output
output, it is
, it is
helpful in
helpful in calculating the input (Dose Rate)
calculating the input (Dose Rate),
, based
based
on the principle of Mass Balance
on the principle of Mass Balance.
.
 Thus it is possible to fix dose for achieving the
Thus it is possible to fix dose for achieving the
steady state plasma drug concentration (C
steady state plasma drug concentration (Css
ss). The
). The
following ground rules are useful.
following ground rules are useful.
A drug which is
A drug which is extensively metabolized (liver)
extensively metabolized (liver) is
is
suitable for controlled-release system
suitable for controlled-release system as long as
as long as
the rate of metabolism is not too rapid (
the rate of metabolism is not too rapid (i.e Slow
i.e Slow).
).

28
 A drug capable of
A drug capable of inducing
inducing or
or inhibiting
inhibiting
metabolism
metabolism is a
is a poor candidate
poor candidate for
for CRDDS
CRDDS since
since
steady-state blood levels
steady-state blood levels would be
would be difficult to
difficult to
maintain
maintain.
.
 The release and availability of the drug in the body
The release and availability of the drug in the body
can be controlled thereby the rate of metabolism can
can be controlled thereby the rate of metabolism can
be reduced.
be reduced.
 Intrinsic Absorption Rate Constant(k
Intrinsic Absorption Rate Constant(ka
a):
):
 Intrinsic absorption rate constant
Intrinsic absorption rate constant is a
is a
quantitative expression
quantitative expression for the
for the drug to absorb
drug to absorb
from the solution (Dosage form)
from the solution (Dosage form) in
in to systemic
to systemic
circulation
circulation.
.

29
 It can be
It can be estimated by
estimated by Compartment
Compartment and
and Non-
Non-
Compartment Models
Compartment Models.
.
 If the
If the drug is in a readily available dosage form
drug is in a readily available dosage form,
,
intrinsic rate constant
intrinsic rate constant has a
has a maximum value
maximum value and it
and it
is
is usually assumed as first order
usually assumed as first order.
.
i.
i. If the drug is absorbed rapidly,
If the drug is absorbed rapidly, then it is
then it is
possible to design such a drug into controlled
possible to design such a drug into controlled
drug delivery system
drug delivery system. In this case the
. In this case the drug
drug
release
release is made
is made rate limiting step
rate limiting step, because as
, because as
soon as the drug is released it is absorbed readily
soon as the drug is released it is absorbed readily
(
(k
kr
r <<<k
<<<ka
a). Thus
). Thus Zero Order absorption
Zero Order absorption of drug
of drug
is achieved.
is achieved.

30
ii.
ii. Poorly absorbable drugs
Poorly absorbable drugs,
, Iron
Iron, and
, and poorly water
poorly water
soluble drugs
soluble drugs,
, Griseofulvin
Griseofulvin,
, are not suitable
are not suitable
drugs for
drugs for designing the controlled drug delivery
designing the controlled drug delivery
systems
systems.
.
 Presystemic Drug Elimination (First Pass Effect):
Presystemic Drug Elimination (First Pass Effect):
 When a drug is administered orally, sometimes the
When a drug is administered orally, sometimes the
drug goes to liver and gets metabolized before
drug goes to liver and gets metabolized before
reaching the systemic circulation.
reaching the systemic circulation.
 This phenomenon is know as First Pass Effect.
This phenomenon is know as First Pass Effect.
 Similarly a part of orally administered drug may
Similarly a part of orally administered drug may
get degraded and inactivated in the GIT.
get degraded and inactivated in the GIT.
 Such phenomenon is know as Presystemic Drug
Such phenomenon is know as Presystemic Drug
Elimination.
Elimination.

31
 This amount of drug loss can be avoided by
This amount of drug loss can be avoided by
changing the route of administration.
changing the route of administration.
 Ex: Transderm - Nitro.
Ex: Transderm - Nitro.
 Drugs that are extensively metabolized in small
Drugs that are extensively metabolized in small
intestine are poor candidates for CRDDS.
intestine are poor candidates for CRDDS.
 In such cases, if drug release is slow, it
In such cases, if drug release is slow, it
immediately gets metabolized.
immediately gets metabolized.
 Ex: Alloprenolol.
Ex: Alloprenolol.
 Such drugs to show prolonged effect
Such drugs to show prolonged effect change the
change the
route of administration
route of administration or
or change to prodrug
change to prodrug
approach.
approach.

32
 Mean Residence Time (MRT):
Mean Residence Time (MRT):
 It is defined as the duration of time during which
It is defined as the duration of time during which
the drug resides in the body.
the drug resides in the body.
It corresponds to
It corresponds to 63.2% elimination
63.2% elimination of drug from
of drug from
the body.
the body.
 From CRDDS point of view,
From CRDDS point of view, MRT value should
MRT value should
be longer for CRDDS
be longer for CRDDS than that of
than that of Conventional
Conventional
Dosage forms
Dosage forms.
.
 Apparent Volume of Distribution (V
Apparent Volume of Distribution (Vd
d):
):
 Apparent Volume of Distribution may be defined
Apparent Volume of Distribution may be defined
as the hypothetical volume of body fluids into which
as the hypothetical volume of body fluids into which
a drug is distributed.
a drug is distributed.

33
 The total amount of drug present in the body X
The total amount of drug present in the body X
=Vd C.
=Vd C.
Thus X values should be maintained constant level
Thus X values should be maintained constant level
by administering the CRDDS.
by administering the CRDDS.
 The Larger the Vd values (100 litres) indicates that
The Larger the Vd values (100 litres) indicates that
the drug is extensively distributed into extravascular
the drug is extensively distributed into extravascular
spaces.
spaces.
 The smaller the Vd values (10 litres) indicates that
The smaller the Vd values (10 litres) indicates that
the drug is largely confined to Plasma.
the drug is largely confined to Plasma.

34
 A candidate drug should have a therapeutic range wide
A candidate drug should have a therapeutic range wide
enough such that variations in the release rate do not
enough such that variations in the release rate do not
result in a concentration beyond this level are suitable for
result in a concentration beyond this level are suitable for
CRDDS.
CRDDS.
 Therapeutic Range:
Therapeutic Range:
 Drugs whose pharmacological activity is independent
Drugs whose pharmacological activity is independent
of its concentration are poor candidates for controlled-
of its concentration are poor candidates for controlled-
release systems
release systems. Ex: such as Reserpine
. Ex: such as Reserpine
 Plasma Concentration-Response (PK/PD) Relationship:
Plasma Concentration-Response (PK/PD) Relationship:
Pharmacodynamic Characteristics of a
Drug in the Design of CRDDS

35
 The release rate of a drug with narrow therapeutic
The release rate of a drug with narrow therapeutic
index should be such that the plasma concentration
index should be such that the plasma concentration
attained is within the therapeutically safe and effective
attained is within the therapeutically safe and effective
range.
range.
 Therapeutic Index (TI):
Therapeutic Index (TI):
 This is necessary because such drugs have toxic
This is necessary because such drugs have toxic
concentration nearer to their therapeutic range.
concentration nearer to their therapeutic range.
 Precise control of release rate of a potent drug with
Precise control of release rate of a potent drug with
narrow margin of safety is difficult.
narrow margin of safety is difficult.
 A drug with short half-life and narrow therapeutic index should
A drug with short half-life and narrow therapeutic index should
be administered more frequently than twice a day. One must also
be administered more frequently than twice a day. One must also
consider the activity of drug metabolites since controlled delivery
consider the activity of drug metabolites since controlled delivery
system controls only the release of parent drug but not its
system controls only the release of parent drug but not its

36
CLASSIFICATION OF CRDDS
CLASSIFICATION OF CRDDS
CRDDS can be classified in various ways:
CRDDS can be classified in various ways:
1. On the basis of Technical Sophistication
2. On the basis of Route of Administration
2. On the basis of Route of Administration
CRDDS can be categorized into 4 major classes:
CRDDS can be categorized into 4 major classes:
1. Rate-programmed DDS
1. Rate-programmed DDS
4. Site-targeted DDS
4. Site-targeted DDS
2. Activation-controlled DDS
2. Activation-controlled DDS
3. Feedback-controlled DDS
3. Feedback-controlled DDS

37
In the former three cases
In the former three cases i.e. except site-targeted
i.e. except site-targeted
DDS,
DDS, the formulation comprise of
the formulation comprise of three basic
three basic
components
components:
:
i. The drug
i. The drug
ii. The rate controlling element
ii. The rate controlling element
iii. Energy source that activates the DDS.
iii. Energy source that activates the DDS.
1. Rate-programmed DDS:
1. Rate-programmed DDS:
These DDS are those from which the drug release
These DDS are those from which the drug release
has been programmed
has been programmed at specific rate profiles.
at specific rate profiles.
They are further subdivided into following
They are further subdivided into following
subclasses:
subclasses:

38
1. Dissolution-controlled DDS
2. Diffusion-controlled DDS
2. Diffusion-controlled DDS
3. Dissolution and diffusion-controlled DDS.
3. Dissolution and diffusion-controlled DDS.
All the above systems can be designed in one of the
All the above systems can be designed in one of the
following ways :
following ways :
a. Reservoir systems (membrane-controlled DDS)
a. Reservoir systems (membrane-controlled DDS)
b. Matrix systems (
b. Matrix systems (soluble
soluble/
/erodible
erodible/
/swellable/degradable
swellable/degradable)
)
c. Hybrid systems (i.e. membrane cum matrix
c. Hybrid systems (i.e. membrane cum matrix
systems)
systems)

39
These systems are those where the rate-limiting
These systems are those where the rate-limiting
phenomenon responsible for imparting the controlled-
phenomenon responsible for imparting the controlled-
release characteristics to the DDS is either of the two
release characteristics to the DDS is either of the two
-
- (a) Slow dissolution rate of the drug:
(a) Slow dissolution rate of the drug:
The drug present in such a system may be one of the
The drug present in such a system may be one of the
following two types:
following two types:
i. Drug with inherently Slow Dissolution Rate:
Such drugs act as natural prolonged-release products
Such drugs act as natural prolonged-release products
Ex: Griseofulvin
Ex: Griseofulvin Digoxin
Digoxin Nifedipine.
Nifedipine.

40
ii. Drug that transforms into slow dissolving
ii. Drug that transforms into slow dissolving
forms
forms
on contact with GI fluids.
on contact with GI fluids.
(b) Slow dissolution rate of the reservoir
(b) Slow dissolution rate of the reservoir
membrane or matrix
membrane or matrix
The drug present in these systems may be the one
The drug present in these systems may be the one
having high aqueous solubility and dissolution rate.
having high aqueous solubility and dissolution rate.
The challenge in designing such systems
The challenge in designing such systems lies in
lies in
controlling the drug dissolution rate
controlling the drug dissolution rate by employing
by employing
either
either or
or combination
combination of following techniques:
of following techniques:
Ex: Pentoxifylline
Ex: Pentoxifylline Metformin
Metformin
Ex: Ferrous sulphate.
Ex: Ferrous sulphate.

41
i. Embedment in slowly
i. Embedment in slowly dissolving
dissolving,
, degrading
degrading or
or
erodible matrix
erodible matrix.
. The
The matrix in addition
matrix in addition may have
may have
low porosity
low porosity or
or poor wettability
poor wettability.
.
ii.
ii. Encapsulation or coating with slow-dissolving
Encapsulation or coating with slow-dissolving,
,
degrading
degrading or
or erodible substances
erodible substances.
. In this approach
In this approach,
,
the rate of dissolution fluid penetration and/or
the rate of dissolution fluid penetration and/or
wettability of the reservoir system are controlled.
wettability of the reservoir system are controlled.

42
Slowly soluble
Slowly soluble &
& erodible materials
erodible materials commonly
commonly
employed to
employed to achieve these objectives
achieve these objectives include
include
hydrophobic substances
hydrophobic substances such as:
such as:
Ethyl Cellulose
Ethyl Cellulose (
(containing an added water-
containing an added water-
soluble release modifying agent such as PVP
soluble release modifying agent such as PVP).
).
Polymethacrylates with pH independent solubility
Polymethacrylates with pH independent solubility
(e.g. Eudragit RS and RL 100)
(e.g. Eudragit RS and RL 100).
.
Waxes
Waxes such as
such as Glyceryl Monostearate
Glyceryl Monostearate, &
, &
Hydrophilic materials like
Hydrophilic materials like Sodium CMC
Sodium CMC.
.

43
2. Diffusion-Controlled DDS:
2. Diffusion-Controlled DDS:
These systems are those where diffusion of dissolved
These systems are those where diffusion of dissolved
drug molecule is rate-limiting, but not dissolution.
drug molecule is rate-limiting, but not dissolution.
The rate-controlling element in such a system is thus
The rate-controlling element in such a system is thus
neither soluble
neither soluble,
, erodible, nor degradable
erodible, nor degradable but they
but they
are
are water-swellable
water-swellable or
or water-insoluble
water-insoluble.
.
However because of their
However because of their porous nature
porous nature, they allow
, they allow
diffusion of dissolved drug
diffusion of dissolved drug through them.
through them.
Porous Matrix Controlled Systems:
Porous Matrix Controlled Systems:
Depending upon the
Depending upon the mechanism
mechanism how the
how the rate
rate
controlling element controls
controlling element controls drug diffusion
drug diffusion,
, these
these
systems can be
systems can be classified into
classified into two categories
two categories:
:
Here the rate controlling element are:
Here the rate controlling element are:

44
Water Soluble polymers:
Water Soluble polymers:
 High viscosity grades of:
High viscosity grades of:
 Hydrophilic Polymers and Gums:
Hydrophilic Polymers and Gums:
Ex: Xanthun Gum
Ex: Xanthun Gum Guar Gum
Guar Gum
Ex:
Ex: HPMC
HPMC HPC
HPC Alginates, etc.
Alginates, etc.

45
Porous Membrane Controlled Systems:
Porous Membrane Controlled Systems:
Here the rate controlling element is a
Here the rate controlling element is a non-swellable
non-swellable,
,
water insoluble polymer
water insoluble polymer such as:
such as:
Controls the drug release
Controls the drug release
through
through micropores
micropores present
present
in the membrane (or)
in the membrane (or)
matrix structure
matrix structure.
.
Ex: Ethyl Cellulose
Ex: Ethyl Cellulose
Polymethacrylates
Polymethacrylates

46
3. Erosion - Controlled DDS:
3. Erosion - Controlled DDS:
Erosion:
Erosion: It is defined as the
It is defined as the physical disintegration
physical disintegration
of a
of a polymer
polymer/
/wax matrix
wax matrix/
/Coating
Coating, as a result of
, as a result of
degradation
degradation which is
which is characterized by material
characterized by material
loss from the polymer generally in physical state
loss from the polymer generally in physical state.
.
polymer
polymer/
/wax
wax
matrix
matrix/
/Coating
Coating
Degradation
Degradation
/
/Hydrolysis
Hydrolysis
Brought about by
Brought about by
Enzymes
Enzymes
pH change
pH change
Osmotic Pressure
Osmotic Pressure
Since erosion is effected by some external stimuli
Since erosion is effected by some external stimuli
such systems can be often be classified under
such systems can be often be classified under
“Stumuli Activated DDS”
“Stumuli Activated DDS”

47
Depending upon the
Depending upon the type of stimuli
type of stimuli, such systems
, such systems
can be often be classified under
can be often be classified under “Stumuli
“Stumuli
Activated DDS”
Activated DDS”
Physical Stimuli:
Physical Stimuli: Osmotic Pressure
Osmotic Pressure
Chemical:
Chemical: pH
pH
Ethyl Cellulose,
Ethyl Cellulose, Waxes
Waxes
Examples of
Examples of Erodible materials
Erodible materials include
include
hydrophobic materials
hydrophobic materials such as:
such as:
Biological:
Biological: Enzyme
Enzyme
Depending upon the
Depending upon the type of Erosion mechanism
type of Erosion mechanism
Polymer/Waxes
Polymer/Waxes undergo either:
undergo either:
Surface Erosion
Surface Erosion
Bulk Erosion
Bulk Erosion

48
 Surface Erosion:
Surface Erosion:
 In these systems erosion occurs from the surface
In these systems erosion occurs from the surface
layer of the system.
layer of the system.
 It results in gradual decrease in the size of the
It results in gradual decrease in the size of the
device while bulk phase remains unchanged.
device while bulk phase remains unchanged.
 Since these is a difference in erosion between the
Since these is a difference in erosion between the
surface and the centre of the matrix, the process
surface and the centre of the matrix, the process
termed as
termed as “Heterogeneous Erosion”.
“Heterogeneous Erosion”.
 Surface erosion occurs when
Surface erosion occurs when water penetration
water penetration
is restricted to device surface.
is restricted to device surface.

49
 Bulk Erosion:
Bulk Erosion:
 In these systems erosion occurs throughout the
In these systems erosion occurs throughout the
bulk polymer of the system.
bulk polymer of the system.
 Thus this process is termed as
Thus this process is termed as “Homogeneous
“Homogeneous
Erosion”.
Erosion”.
 Bulk erosion occurs when
Bulk erosion occurs when water is readily able
water is readily able
to penetrate the matrix of the device.
to penetrate the matrix of the device.
4. Dissolution, Diffusion and/or Erodible - Controlled
4. Dissolution, Diffusion and/or Erodible - Controlled
DDS:
DDS:
These systems are those where the rate of drug release is
These systems are those where the rate of drug release is
controlled by
controlled by drug or polymer
drug or polymer dissolution
dissolution,
, diffusion
diffusion

50
Approaches in the Design of Rate-
Approaches in the Design of Rate-
Programmed DDS
Programmed DDS
 The system is a combination of the two systems or
The system is a combination of the two systems or
more of the three types of systems as discussed
more of the three types of systems as discussed
above.
above.

51
i. Reservoir systems (membrane-controlled DDS) :
 These systems are those where the drug is
These systems are those where the drug is
present as a core in a compartment of
present as a core in a compartment of specific
specific
shape
shape encased
encased or
or encapsulated
encapsulated with a
with a rate-
rate-
controlling wall
controlling wall,
, film
film or
or membrane
membrane having a
having a well-
well-
defined thickness
defined thickness.
.
 The
The drug in the core
drug in the core must
must dissociate
dissociate
themselves from the crystal lattice
themselves from the crystal lattice and
and dissolve
dissolve
in the surrounding medium
in the surrounding medium,
, partition and
partition and
diffuse
diffuse through the membrane
through the membrane.
.
 Depending upon the
Depending upon the physical properties
physical properties of the
of the
membrane
membrane,
, two types
two types of
of reservoir systems
reservoir systems are
are
possible:
possible:

52
(a) Non-Swelling Reservoir Systems:
(a) Non-Swelling Reservoir Systems:
 These systems are those where the
These systems are those where the polymer
polymer
membrane
membrane do not swell
do not swell or
or hydrate
hydrate in
in aqueous
aqueous
medium
medium.
.
Ex: Ethyl Cellulose
Ex: Ethyl Cellulose
 Such materials
Such materials
control drug release
control drug release
owing to their:
owing to their:
Polymethacrylates
Polymethacrylates
Most commonly used
Most commonly used
polymers in such
polymers in such
systems
systems
1. Thickness
1. Thickness
4. Porosity
4. Porosity
2. Insolubility
2. Insolubility
3. Slow Dissolution
3. Slow Dissolution

 Reservior of this type
Reservior of this type
is most common and
is most common and
includes:
includes:
1. Coated Drug Particles
1. Coated Drug Particles
4. Pellets
4. Pellets
2. Crystals
2. Crystals
3. Granules
3. Granules
5. Minitablets
5. Minitablets
6. Tablets
6. Tablets
(b) Swelling Controlled Reservoir Systems:
(b) Swelling Controlled Reservoir Systems:
These systems are those where the polymer
polymer
membrane
membrane swell
swell or
or hydrate
hydrate in
in aqueous
aqueous
medium
medium.
.

54
 In such systems
In such systems drug release is delayed
drug release is delayed for the
for the
time period required for hydration
time period required for hydration of
of barrier
barrier
and after attainment of barrier hydration
and after attainment of barrier hydration,
, drug
drug
release proceeds at a constant rate
release proceeds at a constant rate.
.
Ex: HPMC
Ex: HPMC Most commonly used polymers
Most commonly used polymers
in such systems
in such systems
ii. Matrix systems (Monolithics-controlled DDS) :
 These systems are those
These systems are those where the drug
where the drug is
is
uniformly dissolved
uniformly dissolved or
or dispersed
dispersed in
in release-
release-
retarding
retarding materia
material.
l.
 Such devices
Such devices can be
can be formulated
formulated as
as conventional
conventional
matri
matrix
x, or
, or bi-or tri-layered matrix systems
bi-or tri-layered matrix systems.
.

55
Depending upon the physical properties
physical properties of the
of the
membrane
membrane,
, two types
two types of
of Matrix systems
Matrix systems are
are
possible:
possible:
(a) Hydrophilic Matrix Systems:
(a) Hydrophilic Matrix Systems:
These systems are those where the release
release
retarding material is a
retarding material is a water swellable
water swellable or
or
swellable
swellable cum
cum erodible hydrocolloid
erodible hydrocolloid such as
such as
high molecular weight
high molecular weight
1. HPMCs
1. HPMCs
4. Xanthan gum
4. Xanthan gum
2. HPC
2. HPC
3. HEC
3. HEC
5. sodium alginate
5. sodium alginate
6. guar gum
6. guar gum
7. locust bean Gum
7. locust bean Gum
8. PEO (polyethylene oxide)
8. PEO (polyethylene oxide)
9. cross linked polymers of
9. cross linked polymers of
acrylic acid.
acrylic acid.

56
 Hydrophilic matrices
Hydrophilic matrices are
are porous systems
porous systems
(i) Free-swelling matrix :
(i) Free-swelling matrix :
 It is the one in which swelling is unhindered
It is the one in which swelling is unhindered
Depending upon the Swelling behaviour of
Swelling behaviour of
hydrophilic polymer,
hydrophilic polymer, two types
two types of
of Matrix systems
Matrix systems
are possible:
are possible:
(ii) Resticted-swelling matrix :
(ii) Resticted-swelling matrix :
 It is the one in which the
It is the one in which the surface of the
surface of the
device
device is
is partially coated
partially coated with an
with an impermeable
impermeable
polymer film
polymer film that
that restricts the hydration of
restricts the hydration of
swellable matrix material
swellable matrix material.
.

(b) Hydrophobic Matrix Systems:
(b) Hydrophobic Matrix Systems:
 These systems are the one where the
These systems are the one where the release
release
retarding material
retarding material is either:
is either:
(i) Slowly soluble,
(i) Slowly soluble, erodible
erodible or
or digestible
digestible:
:
 It is the one in which swelling is unhindered
It is the one in which swelling is unhindered
Waxes
Waxes Such as:
Such as:
Glyceryl Monostearate
Glyceryl Monostearate
Cetyl alcohol
Cetyl alcohol
Hydrogenated vegetable oils
Hydrogenated vegetable oils
Beeswax
Beeswax
Carnauba wax
Carnauba wax
(ii) Insoluble or non-digestible:
(ii) Insoluble or non-digestible:
Ethyl cellulose
Ethyl cellulose Polymethacrylates
Polymethacrylates

58
(i) Porous (heterogeneous) matrix :
(i) Porous (heterogeneous) matrix :
 It is the one where the
It is the one where the drug and release retarding
drug and release retarding
matrix microparticles are simply mixed with each
matrix microparticles are simply mixed with each
other and compressed into a tablet
other and compressed into a tablet or
or the drug is
the drug is
dispersed in the polymer solution followed by
dispersed in the polymer solution followed by
evaporation of the solvent
evaporation of the solvent.
.
Depending upon the manner of incorporation
manner of incorporation of
of
drug
drug in the matrix
in the matrix,
, Hydrophobic Matrix systems
Hydrophobic Matrix systems
can be further classified as:
can be further classified as:
(ii) Nonporous (homogeneous) matrix:
(ii) Nonporous (homogeneous) matrix:
 It is the one in which the
It is the one in which the release-retarding matrix
release-retarding matrix
material is first melted and the drug is then
material is first melted and the drug is then
incorporated in it by thorough mixing followed by
incorporated in it by thorough mixing followed by
congealing the mass while stirring
congealing the mass while stirring.
.

59
(i) Dissolved drug nonporous system:
(i) Dissolved drug nonporous system:
It is the one where the drug is dissolved in the
drug is dissolved in the
molten release-retarding matrix material
molten release-retarding matrix material.
.
 Two types
Two types of
of nonporous matrix systems are
nonporous matrix systems are
possible
possible:
:
(ii) Dispersed drug nonporous system :
(ii) Dispersed drug nonporous system :
It is the one where the quantity of drug is
quantity of drug is
greater than its solubility in molten matrix
greater than its solubility in molten matrix
polymer
polymer.
.
iii. Hybrid systems (membrane cum matrix DDS):
 These systems are those where the drug in matrix
These systems are those where the drug in matrix
of release retarding material is further coated with a
of release retarding material is further coated with a
release-controlling polymer membrane.
release-controlling polymer membrane.

60
Such a device thus combines the constant release
Such a device thus combines the constant release
kinetics of reservoir system with the mechanical
kinetics of reservoir system with the mechanical
robustness of matrix system.
robustness of matrix system.
2.
2. STIMULI-ACTIVATED/STIMULI-
STIMULI-ACTIVATED/STIMULI-
RESPONSIVE
RESPONSIVE - DDS
- DDS
In this group of CRDDSs, the
In this group of CRDDSs, the release of drug
release of drug
molecules
molecules from the
from the delivery systems
delivery systems is
is activated
activated
by some stimuli
by some stimuli belonging to either
belonging to either:
:
Physical Stimuli
Physical Stimuli
Chemical
Chemical
Biochemical Process
Biochemical Process
And /or
And /or facilitated by
facilitated by
Energy Supplied
Energy Supplied
externally
externally.
.
The rate of drug release
The rate of drug release in
in response to stimuli
response to stimuli is
is
a result of
a result of dramatic changes brought in
dramatic changes brought in:
:

61
Swelling Behaviour
Swelling Behaviour
 Network Structure
Network Structure
 Permeability/
Permeability/Stability
Stability
Drug Delivery
Drug Delivery
Systems
Systems
 Since these systems releases the drug
Since these systems releases the drug in
in
response to stimuli
response to stimuli, they often called as
, they often called as “
“Smart
Smart or
or
Intelligent DDS
Intelligent DDS”
”
 As they release the drug
As they release the drug due to trigger/In
due to trigger/In
response to
response to external
external stimuli
stimuli,
, they often called as
they often called as
“
“Environment Sensitive DDS
Environment Sensitive DDS”
”
 Certain stimuli responsive DDS are based on
Certain stimuli responsive DDS are based on Hydrogels
Hydrogels
-
- these are
these are three dimensional hydrophilic
three dimensional hydrophilic polymer
polymer
networks capable of swelling in water/biological fluids
networks capable of swelling in water/biological fluids and
and
retaining a large volume of fluid in the swollen state
retaining a large volume of fluid in the swollen state.
.

62
Depending upon the basis of stimulus,
basis of stimulus, these
these
stimuli responsive DDS
stimuli responsive DDS can be further classified into
can be further classified into
two
two categories:
categories:
(i) Open loop/Pulsatile/Externally Regulated
(i) Open loop/Pulsatile/Externally Regulated
System:
System:
 Here in these systems, information about
Here in these systems, information about
controlled variable are not automatically detected
controlled variable are not automatically detected,
,
but
but they are triggered by the external stimuli
they are triggered by the external stimuli such
such
as:
as:
Electrical Current
Electrical Current
Temperature
Temperature Ultrasound
Ultrasound
(ii) Closed loop/Self Regulated/Feed Back
(ii) Closed loop/Self Regulated/Feed Back
Regulated/Internally Regulated System:
Regulated/Internally Regulated System:

63
 Here in these systems, information about
Here in these systems, information about
controlled variable is detected
controlled variable is detected,
, and as a result the
and as a result the
system Output is adjusted accordingly
system Output is adjusted accordingly
 Chemical
Chemical
 Biological
Biological
 Here the
Here the stimuli is produced without any
stimuli is produced without any
external intervention within the body
external intervention within the body to control
to control
the structural changes in DDS and exhibit desired
the structural changes in DDS and exhibit desired
drug release
drug release.
.
 These systems utilizes several approaches such
These systems utilizes several approaches such
as: the
as: the 1. pH Sensitive Polymers
1. pH Sensitive Polymers
2. Enzyme Substrate Interaction
2. Enzyme Substrate Interaction
3. Antibody Interaction
3. Antibody Interaction
By all these they control the release rate of Drug
By all these they control the release rate of Drug

64
 Stimuli activated DDS, especially those that are
Stimuli activated DDS, especially those that are
hydrogel based
hydrogel based,
, are often used for the purpose of
are often used for the purpose of
“
“Chronotherapeutics
Chronotherapeutics” which
” which deal with treatment
deal with treatment
of diseases that demonstrate circadian rhythms
of diseases that demonstrate circadian rhythms
such as
such as:
:
 Asthma
Asthma
 Angina Pectoris/Myocardial Infraction/Stroke
Angina Pectoris/Myocardial Infraction/Stroke
Worsen during sleep period
Worsen during sleep period
More common in early Morining
More common in early Morining
More intense upon wakening
More intense upon wakening
 Arthritis
Arthritis
Depending upon the basis
Depending upon the basis of
of Activation Process
Activation Process
applied
applied (or) type of Energy used
(or) type of Energy used,
, Stimuli Activated
Stimuli Activated
DDS are classified as
DDS are classified as:
:

65
STIMULI ACTIVATED/RESPONSIVE DRUG DELIVERY SYSTEM
ACTIVATION BY
ACTIVATION BY
PHYSICAL PROCESS
PHYSICAL PROCESS
ACTIVATION BY
ACTIVATION BY
CHEMICAL PROCESS
CHEMICAL PROCESS
ACTIVATION BY
ACTIVATION BY
BIOLOGICAL PROCESS
BIOLOGICAL PROCESS
OSMOTIC PRESSURE
OSMOTIC PRESSURE
ACTIVATED DDS
ACTIVATED DDS
HYDRODYNAMIC
HYDRODYNAMIC
PRESSURE
PRESSURE
ACTIVATED DDS
ACTIVATED DDS
VAPOUR PRESSURE
VAPOUR PRESSURE
ACTIVATED DDS
ACTIVATED DDS
MECHANICAL FORCE
MECHANICAL FORCE
ACTIVATED DDS
ACTIVATED DDS
MAGNETICALLY
MAGNETICALLY
ACTIVATED DDS
ACTIVATED DDS
THERMALLY/
THERMALLY/
TEMPERATURE
TEMPERATURE
ACTIVATED DDS
ACTIVATED DDS
PHOTO ACTIVATED
PHOTO ACTIVATED
DDS
DDS
PHOTO
PHOTO
MECHANICAL WAVES
MECHANICAL WAVES
(LASER) ACTIVATED
(LASER) ACTIVATED
DDS
DDS
PHONOPHORESIS/
PHONOPHORESIS/
SONOPHORESIS/ULTRASOUND
SONOPHORESIS/ULTRASOUND
ACTIVATED DDS
ACTIVATED DDS
ELECTRICALLY
ELECTRICALLY
ACTIVATED DDS
ACTIVATED DDS

66
ACTIVATION BY
ACTIVATION BY
CHEMICAL PROCESS
CHEMICAL PROCESS
I. pH ACTIVATED DDS
I. pH ACTIVATED DDS
i. pH DEPENDENT
i. pH DEPENDENT
SOLUBILITY SYSTEM
SOLUBILITY SYSTEM
ii pH DEPENDENT
ii pH DEPENDENT
EROSOIN
EROSOIN
DEGRADATION
DEGRADATION
SYSTEM
SYSTEM
iii pH DEPENDENT
iii pH DEPENDENT
SWELLING SYSTEM
SWELLING SYSTEM
II. ION
II. ION
ACTIVATED DDS
ACTIVATED DDS III.
III.
HYDROLYSIS
HYDROLYSIS
ACTIVATED
ACTIVATED
DDS
DDS
IV.
IV.
CHELATION
CHELATION
ACTIVATED
ACTIVATED
DDS
DDS

67
ACTIVATION BY
ACTIVATION BY
BIOLOGICAL PROCESS
BIOLOGICAL PROCESS
I. ENZYME
I. ENZYME
ACTIVATED DDS
ACTIVATED DDS
i UREA RESPONSIVE
i UREA RESPONSIVE
DDS
DDS
ii GLUCOSE
ii GLUCOSE
RESPONSIVE DDS
RESPONSIVE DDS
II. ANTIBODY
II. ANTIBODY
INTERACTION
INTERACTION
ACTIVATED DDS
ACTIVATED DDS
II. ANTIGEN
II. ANTIGEN
ACTIVATED DDS
ACTIVATED DDS
III. INFLAMMATION
III. INFLAMMATION
ACTIVATED DDS
ACTIVATED DDS

68
ACTIVATION BY PHYSICAL
ACTIVATION BY PHYSICAL
PROCESS
PROCESS
 Osmotic systems release drug at a predetermined
Osmotic systems release drug at a predetermined
rates
rates,
, typically as zero-orde
typically as zero-order
r,
, based on the principle of
based on the principle of
osmosis
osmosis.
.
1. Osmotic Pressure Activated DDS:
1. Osmotic Pressure Activated DDS:
 Osmosis is natural movement of a
Osmosis is natural movement of a solvent through a
solvent through a
semipermeable
semipermeable membrane
membrane into a solution of higher
into a solution of higher
solute concentration
solute concentration,
, leading to equal concentration of
leading to equal concentration of
the solute on either sides of the membrane
the solute on either sides of the membrane.
.

69
 A semipermeable membrane (e.g. cellulose
A semipermeable membrane (e.g. cellulose
acetate) is the one that is permeable to a solvent (e.g.
acetate) is the one that is permeable to a solvent (e.g.
water)
water) but impermeable to ionic (e.g. sodium
but impermeable to ionic (e.g. sodium
chloride) and high molecular weight compounds
chloride) and high molecular weight compounds.
.
 Osmotic systems
Osmotic systems imbibe water from the body
imbibe water from the body
through a semipermeable membrane into an osmotic
through a semipermeable membrane into an osmotic
material which dissolves in it and increase in volume
material which dissolves in it and increase in volume
and generate osmotic pressure that results in slow
and generate osmotic pressure that results in slow
and even delivery of drug through an orifice
and even delivery of drug through an orifice.
.
 In comparison to DDS based on diffusion and
In comparison to DDS based on diffusion and
erosion,
erosion, osmotic systems are more complex in design
osmotic systems are more complex in design
but provide better zero-order drug delivery
but provide better zero-order drug delivery.
.

Schematic representation of the basic model of osmotic pressure-activated DDS
Schematic representation of the basic model of osmotic pressure-activated DDS
Where,
Where,
v
vs
s is
is volume of osmotic agent compartment
volume of osmotic agent compartment
v
vd
d is
is volume of drug compartment
volume of drug compartment
70
• The release of drug molecule from this type of delivery
The release of drug molecule from this type of delivery
system is controlled at a rate determined by:-
system is controlled at a rate determined by:-
1)
1) The water permeability
The water permeability
2)
2) The effective surface area of the semipermeable
The effective surface area of the semipermeable
membrane
membrane
3)
3) Osmotic pressure gradient
Osmotic pressure gradient.
.

Where,
)
( e
s
m
m
w
h
A
P
t
Q

 
 d
e
s
m
m
w
S
h
A
P
t
Q
)
( 
 

71
Pw, - Water Permeability
Am - Effective Surface Area
hm - Thickness of the semipermeable housing
respectively
(πs-πe) is differential osmotic pressure between the drug
delivery system & environment
Sd is the aqueous solubility of drug contained solid

72
 Drug release is identical to Osmotic pressure DDS
Drug release is identical to Osmotic pressure DDS,
,
typically as zero-orde
typically as zero-order
r,
, but differ from osmotic systems
but differ from osmotic systems
in that hydrodynamic pressure generating agents which
in that hydrodynamic pressure generating agents which
is typically a
is typically a water swellable hydrocolloid
water swellable hydrocolloid i
is present in
s present in
one compartment
one compartment.
.
2. Hydration/Hydrodynamic Pressure
2. Hydration/Hydrodynamic Pressure
Activated DDS:
Activated DDS:
Ex: HPMC
Ex: HPMC

73
 Both these compartments are housed in a
Both these compartments are housed in a Rigid
Rigid,
,
shape retaining
shape retaining but water permeable housing
but water permeable housing.
.
 The hydrocolloid imbibes water
The hydrocolloid imbibes water & swells to
& swells to
generate hydrodynamic pressure
generate hydrodynamic pressure that pushes the
that pushes the
drug reservoir compartment
drug reservoir compartment and thus force the drug
and thus force the drug
through an orifice at a slow and uniform rate.
through an orifice at a slow and uniform rate.
 Drug solution/dispersion in
Drug solution/dispersion in another collapsible
another collapsible
reservoir
reservoir.
.
The rate of drug release is defined by following
The rate of drug release is defined by following
equation:
equation:
)
( e
s
m
m
w
h
A
P
t
Q

 


• Pw, - Water Permeability
• Am - Effective Surface Area
• hm - Thickness of the semipermeable housing respectively
• (
(Ө
Өs
s-
-Ө
Өe
e)
) -
- Difference in hydrodynamic pressure between the drug
Difference in hydrodynamic pressure between the drug
delivery system and the environment.
delivery system and the environment.
• Controlled release rate is determined by:-
Controlled release rate is determined by:-
1)
1)Fluid Permeability.
Fluid Permeability.
2)
2)Effective surface Area.
Effective surface Area.
3)
3)Hydrodynamic Pressure Gradient.
Hydrodynamic Pressure Gradient.
74

75
 The pumping compartment contains a liquefied
The pumping compartment contains a liquefied
compressed gas
compressed gas that vaporises at body temperature and
that vaporises at body temperature and
creates vapour pressure that moves the partition to force the
creates vapour pressure that moves the partition to force the
drug out of the device
drug out of the device through a series of flow regulator and
through a series of flow regulator and
delivery cannula into the blood circulation at a constant rate
delivery cannula into the blood circulation at a constant rate.
.
S. No Development of Infusion Pumps
Drug Therapy
1 Heparin Anticoagulant
2 Insulin Control of Diabetes
3 Morphine Intensive pain in Terminal
Cancer
 Identical to hydrodynamic systems in
Identical to hydrodynamic systems in that the pumping
that the pumping
compartment
compartment and the drug solution/dispersion compartment
and the drug solution/dispersion compartment
are separated by a freely movable partition
are separated by a freely movable partition and the whole
and the whole
system is enclosed in a rigid housing.
system is enclosed in a rigid housing.
3. Vapour Pressure - Activated DDS:
3. Vapour Pressure - Activated DDS:

76
4. Mechanical Force - Activated DDS
4. Mechanical Force - Activated DDS
 In these systems the
In these systems the drug reservoir is a solution
drug reservoir is a solution in
in
a container equipped
a container equipped with a
with a mechanically activated
mechanically activated
pumping system
pumping system.
.
 A metered dose of drug formulation
A metered dose of drug formulation can be
can be
reproducibly delivered into a body cavity
reproducibly delivered into a body cavity,
, such as the
such as the
nose
nose,
, through the spray head upon manual
through the spray head upon manual
activation of the drug-delivery pumping system
activation of the drug-delivery pumping system.
.
 The
The volume of solution delivered is fixed
volume of solution delivered is fixed and
and is
is
independent of the force
independent of the force &
& duration of activation
duration of activation.
.
Ex: Intranasal
Administr
ation
Luteinizing
Hormone and its
analogues,
Buserelin

77
5. Magnetically - Activated DDS
5. Magnetically - Activated DDS
 In these systems
In these systems a tiny doughnut-shaped magnet
a tiny doughnut-shaped magnet is
is
positioned in the centre of a hemispherical shaped
positioned in the centre of a hemispherical shaped
drug-dispersing biocompatible polymer matrix
drug-dispersing biocompatible polymer matrix and
and
then
then coating the external surface of the medicated
coating the external surface of the medicated
polymer matrix with the exception of one cavity at
polymer matrix with the exception of one cavity at
the centre of the flat surface of the hemisphere
the centre of the flat surface of the hemisphere,
, with
with
a pure polymer, for instance, ethylene–vinyl acetate
a pure polymer, for instance, ethylene–vinyl acetate
copolymer or silicone elastomers
copolymer or silicone elastomers.
.

78
 This uncoated cavity is designed for allowing a
This uncoated cavity is designed for allowing a
peptide drug to release
peptide drug to release.
. When the magnet is
When the magnet is
activated, to vibrate by an external electromagnetic
activated, to vibrate by an external electromagnetic
field,
field, it releases the drug at a zero-order rate
it releases the drug at a zero-order rate by
by
diffusion process
diffusion process.
.
6. Thermally Activated/Temperature
6. Thermally Activated/Temperature
Responsive DDS
Responsive DDS
 Temperature – Sensitive polymers
Temperature – Sensitive polymers can be classified
can be classified
into
into two groups
two groups based on the
based on the origin of thermo-
origin of thermo-
sensitivity to aqueous media
sensitivity to aqueous media:
:
a. Polymers that interact with water.
a. Polymers that interact with water.
b. Polymers that interact with water as well as also
b. Polymers that interact with water as well as also
show polymer-polymer interaction
show polymer-polymer interaction

79
 Temperature – Sensitive Hydrogels
Temperature – Sensitive Hydrogels can be
can be
classified into
classified into two groups
two groups based on the
based on the thermo-
thermo-
sensitivity
sensitivity:
:
a. Positive thermosensitive hydrogels:
a. Positive thermosensitive hydrogels: These contain
These contain
mostly
mostly hydrophilic monomers
hydrophilic monomers and
and experience
experience
increased swelling
increased swelling with
with increasing temperature
increasing temperature.
.
b. Negative thermosensitive hydrogels:
b. Negative thermosensitive hydrogels: These
These
composed of monomers such as
composed of monomers such as N-methylacrylamide
N-methylacrylamide,
,
N,N-dimethylacrylamide
N,N-dimethylacrylamide and
and N-Isopropylacrylamide
N-Isopropylacrylamide,
,
which contain
which contain hydrophobic substituents
hydrophobic substituents; they exhibit
; they exhibit
increased swelling
increased swelling with
with decreasing temperature
decreasing temperature.
.

80
When a
When a polymer swells in a solvent
polymer swells in a solvent,
, there is negligible
there is negligible or
or
small positive enthalpy
small positive enthalpy, but its aqueous solution shows
, but its aqueous solution shows
opposite effect.
opposite effect.
This
This unusual behaviour is associated with a
unusual behaviour is associated with a
phenomenon of polymer
phenomenon of polymer – phase separation as the
– phase separation as the
temperature is raised to a
temperature is raised to a critical value, known as the
critical value, known as the
Lower Critical Solution Temperature (LCST).
Lower Critical Solution Temperature (LCST).
Polymers characterized by LCST usually shrink as the
Polymers characterized by LCST usually shrink as the
temperature is increased above LCST while they swell
temperature is increased above LCST while they swell
below LCST
below LCST.
.
Ex:
Ex: N-alkyl acrylamide homopolymers &
N-alkyl acrylamide homopolymers & Co-Polymer.
Co-Polymer.
Drugs can be immobilized in such temperature – sensitive
Drugs can be immobilized in such temperature – sensitive
polymers for effecting controlled - release .
polymers for effecting controlled - release .

81
7. Photo – Activated DDS
7. Photo – Activated DDS
Photo-responsive systems (Gels) change
Photo-responsive systems (Gels) change their
their physical
physical
and
and chemical properties
chemical properties reversibly upon photo-radiation
reversibly upon photo-radiation.
.
A
A photo-responsive polymer consists
photo-responsive polymer consists of a
of a photoreceptor,
photoreceptor,
usually a
usually a photo-chromic cromophore
photo-chromic cromophore and a
and a functional
functional
part
part.
.
The
The photochrome molecules capture
photochrome molecules capture the
the optical signal
optical signal
and then the
and then the isomerization
isomerization of the chromophores
of the chromophores in the
in the
photoreceptor converts it to a chemical signal
photoreceptor converts it to a chemical signal.
.

82
8. Photomechanical Waves (Laser) Activated DDS:
8. Photomechanical Waves (Laser) Activated DDS:
Photomechanical waves (also known as
Photomechanical waves (also known as Laser generated
Laser generated
stress waves
stress waves) are the
) are the pressure pulses produced by
pressure pulses produced by
ablation
ablation of a
of a material target by lasers
material target by lasers.
.
The mechanism(s) by which photomechanical waves
The mechanism(s) by which photomechanical waves
increase the permeability of drug thorough stratum
increase the permeability of drug thorough stratum
corneum for transdermal delivery is not entirely clear.
corneum for transdermal delivery is not entirely clear.

83
9. Phonophoresis/Sonophoresis –
9. Phonophoresis/Sonophoresis –
Activated/Ultrasound Activated DDS:
Activated/Ultrasound Activated DDS:
This type of activation-controlled drug delivery system
This type of activation-controlled drug delivery system
utilizes
utilizes ultrasonic energy (low frequency)
ultrasonic energy (low frequency) to activate or
to activate or
trigger the delivery of drugs from a
trigger the delivery of drugs from a polymeric drug
polymeric drug
delivery device through skin into systemic circulation
delivery device through skin into systemic circulation.
.
The system can be
The system can be fabricated from either a non-
fabricated from either a non-
degradable polymer
degradable polymer, such as
, such as ethylene-vinyl acetate
ethylene-vinyl acetate
(EVAc) co-polymer
(EVAc) co-polymer or a
or a bioerodible poiymer such as
bioerodible poiymer such as
poly(lactide-glycolide) co-polymer
poly(lactide-glycolide) co-polymer.
.

84
10. Electrically – Activated DDS: Iontophoresis &
10. Electrically – Activated DDS: Iontophoresis &
Electroporation.
Electroporation.
This type of CRDDS
This type of CRDDS uses electrical current to activate
uses electrical current to activate
and modulate the diffusion of a charged drug molecule
and modulate the diffusion of a charged drug molecule
across a biological membrane
across a biological membrane, such as skin, in a manner
, such as skin, in a manner
similar to passive diffusion under a concentration
similar to passive diffusion under a concentration
gradient but at a much faster rate.
gradient but at a much faster rate.
https://www.youtube.com/watch?v=reG-
rsjd9Ng

85
It is a painless procedure
It is a painless procedure. Since
. Since like charges repel each
like charges repel each
other, application of a positive current drives positively
other, application of a positive current drives positively
charged drug molecules away from the electrode and
charged drug molecules away from the electrode and
into the tissues, and vice-versa
into the tissues, and vice-versa.
.
In
In Iontophoresis
Iontophoresis, the flux is related to the total charge
, the flux is related to the total charge
transported through the system and is a result of low
transported through the system and is a result of low
voltage constant current density.
voltage constant current density.
Ex:
Ex: Anti-inflammatory drugs such as Dexamethasone
Anti-inflammatory drugs such as Dexamethasone.
.

86
In
In electroporation
electroporation,
, relatively high voltage
relatively high voltage but
but transient
transient
pulses produce transient increases in permeability of the
pulses produce transient increases in permeability of the
stratum corneum to effect drug transport through the
stratum corneum to effect drug transport through the
skin
skin.
.

87
B. Chemical Process-Activated DDS
B. Chemical Process-Activated DDS
1. pH-Activated DDS
1. pH-Activated DDS
 Stimuli – responsive DDS based on pH sensitive
Stimuli – responsive DDS based on pH sensitive
polymers have been developed on three different
polymers have been developed on three different
approaches:
approaches:
i. pH DEPENDENT SOLUBILITY SYSTEM
ii pH DEPENDENT EROSOIN DEGRADATION
ii pH DEPENDENT EROSOIN DEGRADATION
SYSTEM
SYSTEM
iii pH DEPENDENT SWELLING SYSTEM
iii pH DEPENDENT SWELLING SYSTEM

88
 These systems are
These systems are designed for acid-labile drugs
designed for acid-labile drugs
or
or drugs irritating to gastric mucosa
drugs irritating to gastric mucosa and
and target
target
their delivery to the intestinal tract.
their delivery to the intestinal tract.
It is
It is fabricated by coating a core tablet
fabricated by coating a core tablet of such a
of such a
drug with a
drug with a combination of intestinal fluid-
combination of intestinal fluid-
insoluble polymer,
insoluble polymer, like ethyl cellulose
like ethyl cellulose, and
, and
intestinal fluid-soluble polymer,
intestinal fluid-soluble polymer, like HPMCP
like HPMCP
 In the stomach
In the stomach, the
, the coating membrane resists
coating membrane resists
dissolution
dissolution in
in pH 1-3
pH 1-3.
.

89
After gastric emptying, the system travels to the
After gastric emptying, the system travels to the
small intestine, and the intestinal fluid-soluble
small intestine, and the intestinal fluid-soluble
component in the coating membrane is dissolved in at
component in the coating membrane is dissolved in at
pH above 5 thereby producing a microporous
pH above 5 thereby producing a microporous
membrane that controls the release of drug from the
membrane that controls the release of drug from the
core tablet.
core tablet.
Ex:
Ex: Oral controlled delivery of
Oral controlled delivery of potassium
potassium
chloride
chloride, which is highly irritating to gastric
, which is highly irritating to gastric
• Note:
Note: By adjusting the ratio of intestinal fluid soluble polymer to the intestinal fluid
By adjusting the ratio of intestinal fluid soluble polymer to the intestinal fluid
insoluble polymer, the membrane permeability is modified.
insoluble polymer, the membrane permeability is modified.
pH – dependent formation of micro-porous membrane

Ion-Activated DDS:
Ion-Activated DDS:
90

91
• H
H+
+
+ Resin- SO
+ Resin- SO3
3
‾
‾
*
* Drug
Drug+
+
Resin-SO
Resin-SO3
3
‾
‾
*H
*H+
+
+ Drug
+ Drug‾
‾
• Cl‾ + Resin-[N{CH
Cl‾ + Resin-[N{CH3
3}
}3
3]
]+
+
* Drug‾ [N{CH
* Drug‾ [N{CH3
3}
}3
3]
]+
+
*Cl‾ + Drug
*Cl‾ + Drug+
+
Diagram of Ion-activated drug release
Diagram of Ion-activated drug release

Hydrolysis-Activated DDS
Hydrolysis-Activated DDS:
:
•This type of system depends on the hydrolysis process
This type of system depends on the hydrolysis process
to activate the release of drug.
to activate the release of drug.
•Drug reservoir
Drug reservoir is
is either encapsulated
either encapsulated in
in
microcapsules
microcapsules or
or homogenously dispersed in
homogenously dispersed in
microspheres
microspheres.
.
• Can also be fabricated as an implantable device.
Can also be fabricated as an implantable device.
•Systems prepared from biodegradable polymers.
Systems prepared from biodegradable polymers.
•It is activated by
It is activated by hydrolysis-induced degradation
hydrolysis-induced degradation of
of
polymer chain & is controlled by rate of polymer
polymer chain & is controlled by rate of polymer
degradation.
degradation.
•Ex: Releasing biodegradable subdermal implants
Ex: Releasing biodegradable subdermal implants,
,
designed to deliver
designed to deliver Luprolide
Luprolide upto
upto 4 months
4 months
treatment of prostate carcinoma
treatment of prostate carcinoma.
. 92

Chelation - Activated DDS
Chelation - Activated DDS:
:
•These are based on the ability of
These are based on the ability of metals to accelerate
metals to accelerate
the hydrolysis
the hydrolysis of
of carboxylate
carboxylate or
or phosphate esters
phosphate esters
and amides
and amides.
.
•When chelating agent such as
When chelating agent such as Quinaldic Acid
Quinaldic Acid is
is
attached to a
attached to a polymer chain such as PVA
polymer chain such as PVA by an
by an ester
ester
or amide linkage
or amide linkage,
, the renal excretion rate is reduced
the renal excretion rate is reduced
and toxicity is increased
and toxicity is increased.
.
• In the
In the presence of metal ion
presence of metal ion such as
such as Co(II)
Co(II),
, Zn(II)
Zn(II),
,
Cu(II)
Cu(II),
, a
a complex with the polymer bound chelating
complex with the polymer bound chelating
agent is formed wherein the
agent is formed wherein the metal ion facilitates the
metal ion facilitates the
hydrolysis resulting in release of metal-chelate
hydrolysis resulting in release of metal-chelate
complex and subsequent elimination of chelated
complex and subsequent elimination of chelated
metal
metal.
. 93

I. Enzyme-Activated
I. Enzyme-Activated
DDS:
DDS:
94
C. Biochemical Process-Activated DDS
C. Biochemical Process-Activated DDS
 This type of biochemical system depends on the
This type of biochemical system depends on the
enzymatic process to activate the release of drug.
enzymatic process to activate the release of drug.
 Drug Reservoir-
Drug Reservoir-
 Physically Entrapped in Microsphere
Physically Entrapped in Microsphere or
or
 Chemically bound to polymer chains from
Chemically bound to polymer chains from
biopolymers(albumins or polypeptides)
biopolymers(albumins or polypeptides)
 The release of drug is activated by enzymatic
The release of drug is activated by enzymatic
hydrolysis of biopolymers by specific enzyme in target
hydrolysis of biopolymers by specific enzyme in target
tissue.
tissue.
Ex: Albumin microspheres release
Ex: Albumin microspheres release 5- fluorouracil
5- fluorouracil in a
in a
controlled manner
controlled manner by protease- activated
by protease- activated biodegradation.
biodegradation.

II. Feedback-Controlled DDS :
II. Feedback-Controlled DDS :
 In this group of CRDDSs:
In this group of CRDDSs:
 The release of drug molecules is activated by a
The release of drug molecules is activated by a
triggering agent such as a:
triggering agent such as a:
 Biochemical substance in the body via some
Biochemical substance in the body via some
feedback mechanisms.
feedback mechanisms.
 The rate of drug release is regulated by the
The rate of drug release is regulated by the
concentration of a triggering agent detected by a
concentration of a triggering agent detected by a
sensor built into the CRDDS.
sensor built into the CRDDS.
A. Bioerosion-Regulated Drug Delivery System
 Developed by
Developed by Heller and Trescony
Heller and Trescony.
.

 The system consisted of
The system consisted of drug-dispersed bioerodible
drug-dispersed bioerodible
matrix
matrix fabricated from
fabricated from polyvinyl methyl ether) half-
polyvinyl methyl ether) half-
ester
ester,
, which was coated with a layer of
which was coated with a layer of immobilized
immobilized
urease
urease
 In a solution with
In a solution with near neutral pH
near neutral pH, the
, the polymer only
polymer only
erodes very slowly
erodes very slowly. In the
. In the presence of urea
presence of urea,
, urease at
urease at
the surface of drug delivery system metabolizes urea
the surface of drug delivery system metabolizes urea
to form ammonia.
to form ammonia.
 This
This causes the pH to increase
causes the pH to increase and
and a rapid
a rapid
degradation of polymer matrix as well as the release of
degradation of polymer matrix as well as the release of
drug molecules.
drug molecules.

B. Bioresponsive Drug Delivery System
 Developed by
Developed by Horbett
Horbett et al
et al.
.
 In this system the
In this system the drug reservoir
drug reservoir is
is contained in a
contained in a
device enclosed by a bioresponsive polymeric
device enclosed by a bioresponsive polymeric
membrane
membrane whose drug permeability
whose drug permeability is
is controlled
controlled
by the concentration of a biochemical agent
by the concentration of a biochemical agent in the
in the
tissue where the system is located
tissue where the system is located.
.
 A typical example:
A typical example:
Development of a
Development of a glucose-triggered insulin delivery
glucose-triggered insulin delivery
system
system in which the
in which the insulin reservoir
insulin reservoir is
is encapsulated
encapsulated
within a hydrogel membrane having pendant
within a hydrogel membrane having pendant NR2
NR2
groups
groups.
.

 In alkaline solution,
In alkaline solution, —
— NR
NR2
2 groups are neutral
groups are neutral
and the
and the membrane is unswollen
membrane is unswollen and
and impermeable to
impermeable to
insulin
insulin.
.
 As glucose
As glucose,
, a triggering agent
a triggering agent,
, penetrates into
penetrates into
the membrane
the membrane, it is oxidized enzymatically by the
, it is oxidized enzymatically by the
glucose oxidase entrapped in the membrane to form
glucose oxidase entrapped in the membrane to form
gluconic acid.
gluconic acid.
 The
The — NR
— NR2
2 groups are protonated
groups are protonated to form
to form -
-
NR
NR2
2H+
H+ and the
and the hydrogel membrane
hydrogel membrane then
then becomes
becomes
swollen
swollen &
& permeable to insulin molecules
permeable to insulin molecules.
.

The
The amount of insulin
amount of insulin delivered is thus
delivered is thus
bioresponsive to the concentration of glucose
bioresponsive to the concentration of glucose
penetrating
penetrating the
the insulin delivery system
insulin delivery system.
.

101
III. Self-Regulating DDS :
III. Self-Regulating DDS :
 In this feedback-controlled DDS:
In this feedback-controlled DDS:
 A
A reversible & competitive
reversible & competitive binding mechanism
binding mechanism to
to
activate and to regulate the release of drug
activate and to regulate the release of drug.
.
 Drug reservoir
Drug reservoir is a
is a drug complex
drug complex
encapsulated
encapsulated within a semipermeable polymeric
within a semipermeable polymeric
membrane
membrane.
.

 The release of drug is activated by the membrane
The release of drug is activated by the membrane
permeation of a biochemical agent from the tissue
permeation of a biochemical agent from the tissue
where the CRDDS is located.
where the CRDDS is located.
 An example:
An example: Development of
Development of self regulating
self regulating
insulin delivery system
insulin delivery system that
that utilizes complex of
utilizes complex of
glycosylated insulin-concanavalin A
glycosylated insulin-concanavalin A,
, which is
which is
encapsulated inside a polymer membrane
encapsulated inside a polymer membrane.
.
As
As glucose penetrates into the system
glucose penetrates into the system,
, it
it
activates the release of glycosylated insulin from
activates the release of glycosylated insulin from
the complex
the complex for a controlled release from the
for a controlled release from the
system.
system.
 The
The amount of insulin released
amount of insulin released is thus
is thus self-
self-
regulated by the concentration of glucose
regulated by the concentration of glucose that has
that has
penetrated into the insulin delivery system
penetrated into the insulin delivery system.
.

103
Inflammatory Activated DDS:
Inflammatory Activated DDS:
 In this systems
In this systems drug – loaded lipid microspheres
drug – loaded lipid microspheres
are
are dispersed in biodegradable hydrogels
dispersed in biodegradable hydrogels of
of cross –
cross –
linked Hyaluronic acid
linked Hyaluronic acid.
.
 Hyaluronic acid
Hyaluronic acid is
is specifically degraded
specifically degraded by
by
hydroxyl radicals
hydroxyl radicals which are
which are produced by
produced by
phagocytic cells
phagocytic cells such as
such as leukocytes
leukocytes &
&
macrophages
macrophages locally at inflammatory sites.
locally at inflammatory sites.

104
Antigen Activated DDS:
Antigen Activated DDS:
 These systems are based on the principle that in the
These systems are based on the principle that in the
absence of free antigen
absence of free antigen the
the hydrogel remains Shrink
hydrogel remains Shrink
due to the intra-chain antigen –antibody binding in the
due to the intra-chain antigen –antibody binding in the
polymer network
polymer network.
.
 While in the
While in the presence of the free antigen
presence of the free antigen it
it swells
swells
because of dissociation of the intra-chain binding
because of dissociation of the intra-chain binding by
by
exchange of the grafted antigen for free antigen.
exchange of the grafted antigen for free antigen.
 This
This swelling/shrinking process
swelling/shrinking process was shown to be
was shown to be
reversible
reversible.
.
 Former
Former three categories
three categories of
of Biologically activated
Biologically activated
DDS
DDS that
that respond to
respond to the
the presence of certain Biological
presence of certain Biological
compounds
compounds in the body
in the body are
are called as
called as Analyte –Sensitive
Analyte –Sensitive
DDS
DDS.
.

105
Antibody Interaction Activated DDS:
Antibody Interaction Activated DDS:
 These systems are based on the principle that in the
These systems are based on the principle that in the
Hapten Antibody Interaction
Hapten Antibody Interaction suppresses the enzymatic
suppresses the enzymatic
degradation of polymer
degradation of polymer matrix/Permeability of
matrix/Permeability of
polymeric reservoir of the drug
polymeric reservoir of the drug Naltrexone
Naltrexone.
.
 The device is
The device is coated by covalently grafting with
coated by covalently grafting with
Morphine
Morphine to the surface
to the surface.
.
 When surface is
When surface is exposed to morphine antibodies
exposed to morphine antibodies
blocks the
blocks the release of Naltrexone.
release of Naltrexone.
 However
However exposure to exogeneous morphine
exposure to exogeneous morphine,
, the
the
process is reversed
process is reversed i.e
i.e the antibodies are uncoated
the antibodies are uncoated and
and
Naltrexone is released
Naltrexone is released.
.

3.
3. Site-Targeted
Site-Targeted DDS
DDS
 Most conventional dosage forms deliver drug into
Most conventional dosage forms deliver drug into
the body that eventually reaches the site of action by
the body that eventually reaches the site of action by
multiple steps of diffusion and partitioning.
multiple steps of diffusion and partitioning.
 In addition to the target site, the drug also
In addition to the target site, the drug also
distributes to non-target tissues that may result in
distributes to non-target tissues that may result in
toxicity or adverse reactions.
toxicity or adverse reactions.
 Selective and targeted drug therapy
Selective and targeted drug therapy could result
could result
in not just
in not just Optimum
Optimum &
& More Effective
More Effective therapy but
therapy but
also a
also a significant reduction
significant reduction in
in drug dose
drug dose & cost
& cost.
.
Targeted- or site-specific DDS
Targeted- or site-specific DDS refer to systems that
refer to systems that
place the drug at or near the receptor site
place the drug at or near the receptor site or
or site of
site of

 Site-targeted DDS
Site-targeted DDS can be classified into three
can be classified into three
broad categories:
broad categories:
1. First-order Targeting – refers to DDS that
delivers the drug to the capillary bed or the active
site
2. Second-order Targeting
2. Second-order Targeting –
– refers to DDS that
refers to DDS that
delivers the drug to a special cell type such as the
delivers the drug to a special cell type such as the
tumour cells
tumour cells and
and not to the normal cells
not to the normal cells.
.
3. Third-order targeting
3. Third-order targeting –
– refers to DDS that
refers to DDS that
delivers the drug intracellularly
delivers the drug intracellularly.
.

Site-targeted DDSs
Site-targeted DDSs have also been characterized
have also been characterized
as:
as:
 Passive Targeting
Passive Targeting –
– refers to
refers to natural or passive
natural or passive
disposition
disposition of a
of a drug carrier
drug carrier based on the
based on the
physicochemical characteristics
physicochemical characteristics of the
of the system in
system in
relation to the body
relation to the body.
.
2. Active Targeting
2. Active Targeting –
– refers to
refers to alterations of the
alterations of the
natural disposition of the drug carrier
natural disposition of the drug carrier,
, directing it
directing it
to specific cells
to specific cells,
, tissues or organs
tissues or organs; for e.g:
; for e.g: use of
use of
ligands
ligands or
or monoclonal antibodies
monoclonal antibodies which can target
which can target
specific sites
specific sites.
.
 Drug targeting
Drug targeting often
often requires carriers
requires carriers for
for
selective delivery
selective delivery and
and can serve following purposes
can serve following purposes:
:

1. Protect the drug from degradation after
1. Protect the drug from degradation after
administration;
administration;
2. Improve transport or delivery of drug to cells
2. Improve transport or delivery of drug to cells
3. Decrease clearance of drug; or
3. Decrease clearance of drug; or
4. Combination of the above.
4. Combination of the above.
 Carriers for drug targeting are of two types:
Carriers for drug targeting are of two types:
 Carriers covalently bonded to drug – where the
drug release is required for pharmacological
activity.
 Carriers not covalently bonded to drug – where
simple un-coating of the drug is required for
pharmacological activity.

110
An ideal site-targeting
controlled-release drug delivery

1. Polymeric carriers
1. Polymeric carriers
2. Albumin
2. Albumin
3. Lipoproteins
3. Lipoproteins
4. Liposomes.
4. Liposomes.
The various carriers used for drug targeting are :
The various carriers used for drug targeting are :
1. Polymeric Carrier Systems for Drug Targeting
1. Polymeric Carrier Systems for Drug Targeting
The basic components of a polymeric targeted DDS
The basic components of a polymeric targeted DDS
are –
are –
i. A polymeric backbone which is
which is non-immunogenic
non-immunogenic
&
& biodegradable
biodegradable that contains following three
that contains following three
attachments.
attachments.
Polymeric carrier system for drug
targeting

112
 Polymers used for drug targeting include:
Polymers used for drug targeting include:
Polyethylenediamine
Polyethylenediamine
Polylysine
Polylysine
Chitosan
Chitosan
Dextran
Dextran
PEG
PEG
Mcromolecular drugs
Mcromolecular drugs
Gene therapy
Gene therapy
ii. A homing device also called as
also called as site-specific
site-specific
targeting moiety
targeting moiety, which is
, which is capable of leading the
capable of leading the
drug delivery system to the vicinity of a target
drug delivery system to the vicinity of a target
tissue (or cell)
tissue (or cell)
The homing
The homing
device is a :
device is a :
Monoclonal Antibody
Monoclonal Antibody
Recognized Sugar Moiety
Recognized Sugar Moiety
 A small Cell-Specific Ligand.
A small Cell-Specific Ligand.

iii. A solubiliser which enables the
which enables the drug delivery
drug delivery
system to be transported to and preferentially
system to be transported to and preferentially
taken up by the target tissue
taken up by the target tissue; and
; and
iv. A drug which is
which is covalently bonded to the
covalently bonded to the
polymeric backbone
polymeric backbone,
, through a spacer
through a spacer,
, and
and
contains a linkage that is cleavable only by a
contains a linkage that is cleavable only by a
specific enzyme(s) at the target tissue
specific enzyme(s) at the target tissue
At present
At present,
, most site-specific DDS
most site-specific DDS are limited to
are limited to
parenteral administration
parenteral administration and
and primarily utilize
primarily utilize
soluble polymers.
soluble polymers.

Besides their use as regular carriers
Besides their use as regular carriers,
, polymers may also be
polymers may also be
formulated as
formulated as microparticles
microparticles or
or nanoparticles,
nanoparticles, wherein the
wherein the
drug is encapsulated
drug is encapsulated in a
in a biodegradable colloidal polymer
biodegradable colloidal polymer.
.
The
The small size of nanospheres
small size of nanospheres allows
allows good tissue
good tissue
penetration
penetration while
while providing protection or sustained
providing protection or sustained
release
release.
.
The disposition of micro- or nano-sphere depends
The disposition of micro- or nano-sphere depends
upon their size –
upon their size –
i. Particles > 12 are lodged in the capillary bed at the site
i. Particles > 12 are lodged in the capillary bed at the site
of injection
of injection
ii. Particles from 2 – 12 are retained in
ii. Particles from 2 – 12 are retained in lung
lung,
, liver
liver
or
or spleen
spleen
iii. Particles < 0.5 (500 nm) deposit in
iii. Particles < 0.5 (500 nm) deposit in spleen
spleen &
&
bone marrow
bone marrow

2. Albumin as Carrier for Drug Targeting
 Distribution of
Distribution of albumin is not site-specific
albumin is not site-specific
 It has been
It has been conjugated with drugs such as
conjugated with drugs such as
methotrexate
methotrexate to
to increase duration of drug action
increase duration of drug action &
&
deliver drug to liver
deliver drug to liver.
.
3. Lipoproteins as Carrier for Drug Targeting
 Low Density Lipoproteins are used.
Low Density Lipoproteins are used.
 Because they enter the cell by
Because they enter the cell by Endocytosis
Endocytosis, thus
, thus
they have potential for transporting drugs into cell.
they have potential for transporting drugs into cell.
In cell, this
In cell, this lipoprotein-Drug complex
lipoprotein-Drug complex can be
can be
hydrolyzed by
hydrolyzed by Lysomal Enzymes
Lysomal Enzymes.
.

4. Liposomes as Carrier for Drug Targeting
 Size ranges between 0.5 – 100 µ.
Size ranges between 0.5 – 100 µ.
 Reduces side effects.
Reduces side effects.
 Increases Efficacy of drugs such as:
Increases Efficacy of drugs such as:
 Site specificity of liposomes
Site specificity of liposomes can be
can be conferred
conferred
either by means of using
either by means of using
 Specific Type of Lipid
Specific Type of Lipid
 Doxirubicin
Doxirubicin
Amphotericin - B
Amphotericin - B
 By inclusion of Targeting Agent on its
By inclusion of Targeting Agent on its
Liposomal Bilayer.
Liposomal Bilayer. Ex:
Ex: Monocolonal Antibody
Monocolonal Antibody

TRANSDERMAL DRUG
DELIVERY SYSTEM
PREPARED BY:
Dr. B. Sree Giri Prasad
M.Pharm. Ph.D
Dept. of Pharmaceutics
NNRG.

Biological Properties:
Biological Properties:
• Transdermal drug delivery (TDD)
Transdermal drug delivery (TDD) is defined as
is defined as self
self
contained
contained,
, discrete dosage form
discrete dosage form which, when applied
which, when applied
to
to intact skin delivers the therapeutic agents
intact skin delivers the therapeutic agents at a
at a
Controlled Rate
Controlled Rate through the skin
through the skin for
for Systemic
Systemic
Effect
Effect.
.
• Only a small number of drug products are
Only a small number of drug products are
available for TDD.
available for TDD.
Problems :
Problems : Physical Properties:
Physical Properties:
Drugs
Drugs
Polarity
Polarity
 Molecular Size
Molecular Size
 Dermal Irritation
Dermal Irritation
 Insufficient Bioavailability
Insufficient Bioavailability

History
History
 The
The first Transdermal patch
first Transdermal patch was approved in
was approved in 1981
1981
to prevent the
to prevent the nausea
nausea and
and vomiting
vomiting associated with
associated with
motion sickness
motion sickness.
.
 The US Transdermal market approached $1.2 billion
The US Transdermal market approached $1.2 billion
in 2001. It was based on 11 drug molecules:
in 2001. It was based on 11 drug molecules: Fentanyl
Fentanyl,
,
Nitroglycerin
Nitroglycerin,
, Estradiol
Estradiol,
, Ethinylestradiol
Ethinylestradiol,
, Nor-
Nor-
Ethindroneacetate
Ethindroneacetate,
, Testosterone
Testosterone,
, Clonidine
Clonidine,
,
Nicotine
Nicotine,
, Lidocaine,
Lidocaine, Prilocaine
Prilocaine &
& Scopolamine
Scopolamine.
.
 Two new
Two new,
, recently approved
recently approved Transdermal patch
Transdermal patch
products
products (a contraceptive patch containing
(a contraceptive patch containing Ethinyl
Ethinyl
Estradiol
Estradiol and
and Nor-Elgestromin
Nor-Elgestromin)
) and a patch to treat
and a patch to treat
overactive bladder containing
overactive bladder containing oxybutynin
oxybutynin.
.

Advantages:
Advantages:
 Avoids first pass hepatic metabolism.
Avoids first pass hepatic metabolism.
 Maintains constant blood levels for longer period of time.
Maintains constant blood levels for longer period of time.
 Decrease the dose of administration.
Decrease the dose of administration.
 Decrease unwanted/ side effects.
Decrease unwanted/ side effects.
 Decreases gastro-intestinal side effects.
Decreases gastro-intestinal side effects.
 Easy to discontinue in case of toxic effects.
Easy to discontinue in case of toxic effects.
 Increased patient compliance.
Increased patient compliance.
 Great advantage for patients who are unconscious.
Great advantage for patients who are unconscious.
 Provides an ability to modify the properties of biological
Provides an ability to modify the properties of biological
barriers to improve absorption.
barriers to improve absorption.
 Relatively large area of application in comparison to buccal /
Relatively large area of application in comparison to buccal /
nasal cavity.
nasal cavity.

Disadvantages:
Drug must have some desirable physico-chemical properties to
Drug must have some desirable physico-chemical properties to
penetrate through stratum corneum.
penetrate through stratum corneum.
Drugs for daily dose less than 5 mg/day are preferred, If drug
Drugs for daily dose less than 5 mg/day are preferred, If drug
dose is more than 10-25 mg/day the TDD will be difficult.
dose is more than 10-25 mg/day the TDD will be difficult.
Local irritation at the site of administration may be caused by
Local irritation at the site of administration may be caused by
drug, adhesive/ other excipients in patch.
drug, adhesive/ other excipients in patch.
Clinical need must be clearly established.
Clinical need must be clearly established.
The barrier function of skin changes form one site to another,
The barrier function of skin changes form one site to another,
from person to person and with age.
from person to person and with age.
Poor skin permeability limits the number of drug that can be
Poor skin permeability limits the number of drug that can be
delivered in this route.
delivered in this route.
TDD can not deliver ionic drug.
TDD can not deliver ionic drug.
TDD can not achieve high drug levels in Blood/ plasma.
TDD can not achieve high drug levels in Blood/ plasma.
Drugs of large molecular size can not be formulated as TDD.
Drugs of large molecular size can not be formulated as TDD.
TDD can not deliver the drugs in pulsatile fashion.
TDD can not deliver the drugs in pulsatile fashion.

The skin is very effective as a selective penetration barrier. The
epidermis provides the major control element for drug penetration.

SKIN STRUCTURE:
1.Non-viable epidermis (stratum corneum):
Outer most layer of skin and physical barrier to most of the
substances. It is 10-20 cell layer thick with lipids (5-15%), proteins
(75-85%) mainly keratin.
2. Viable epidermis:
This layer is in between stratum corneum and dermis (Stratum
Granulosam, Spinosum & Basale) with 50-100 µm thickness & 90%
water content.
3. Viable dermis (cornium):
Thickness is 2000-3000 µm, consists of matrix of loose connective
tissue composed of fibrous protein (collagen, elastin, reticulum)
4. Subcutaneous connective tissue (hypodermis):
It has loose textured white, fibrous connective tissue with fat and
elastic fibers. It contains blood, lymph vessels, base of hair follicles,
secretory portion of sweat glands and cutaneous nerves.

Routes of drug penetration across skin
Three potential entry MACRO ROUTES to the viable tissue:
1.Via the sweat ducts
2.Across the continuous stratum corneum (diffusion)
3.Through the hair follicles with their associated
sebaceous glands.

1. Transcellular permeation through the stratum corneum.
2. Intercellular permeation through the stratum corneum.
3. Transappendageal permeation via hair follicle,
sebaceous & sweat gland.

• Transcellular and inter cellular permeation requires
diffusion through epidermis and dermis.
• Transappendageal permeation allows diffusional
leakage of polar molecules in to epidermis and
direct permeation in to dermis.
• The relative importance of these routes depends on
factors like time of permeation, physico-chemical
properties (Pka, molecular size, stability, partition
coefficient), integrity and thickness of stratum
corneum, density of sweat glands and follicles, skin
hydration, metabolism and vehicle effects.

pH Activated DDS:
pH Activated DDS:
•This system permits targeting the delivery of a drug
This system permits targeting the delivery of a drug
only in the region with a selected pH range.
only in the region with a selected pH range.
•Fabricated by coating the drug core with a pH
Fabricated by coating the drug core with a pH
sensitive polymer
sensitive polymer
•Example:-
Example:-
139
139

Drug selection for Controlled Drug Delivery.ppt

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