NDDS Introduction
1
www.DuloMix.com
Just as cars are useless without roads, drugs are useless
without an effective delivery system.
The active ingredient in a medicine is only part of the
arsenal against disease.
The drug must somehow get to the right place at the
right time. That’s where drug delivery comes in.
2
www.DuloMix.com
Drug delivery companies work to devise new dosage forms
for medications to place the drug.
Historically, this has meant product life-cycle management, a
process in which a pharmaceutical company looks for ways
to set apart a product reaching the end of its patent.
For example, a company might tinker with a drug that
patients must take multiple times a day and reduce that to a
single dose.
3
www.DuloMix.com
Nowadays, the competition is so intense in the
pharmaceutical marketplace that companies look to
drug delivery as a way to gain a competitive advantage.
The value that drug delivery adds can be improved
safety, efficacy, convenience, and patient compliance.
4
www.DuloMix.com
ERA OF DRUG DELIVERY
As a result of biotechnology development, many people
believe that proteins are going to comprise an increasing
proportion of the new-drug market.
Many existing peptide and protein drugs are coming off
patent, fueling the interest in developing new dosage
forms.
5
www.DuloMix.com
There is the equivalent of a generic industry that will
likely be developed for peptides and proteins,
analogous to [what evolved with] small molecules.
The race is on to develop alternatives to injection for
macromolecules. The main methods being explored
are pulmonary (inhalation) and oral formulations. In
addition, transdermal and extended-release injectable
formulations are being targeted.
6
www.DuloMix.com
THIS IS Done for
Better control of plasma drug levels and less frequent
dosing.
For Linear one compartment PK drugs:
Dose interval (ּד) < t1/2
TI is therapeutic index = LD50/ED50
7
www.DuloMix.com
The dosing interval may be increased by :
Modifying the drug molecule to decrease
the rate of elimination.
OR
Modifying the release rate of a dosage
form to decrease the rate of absorption.
8
www.DuloMix.com
Drug delivery system
Goal of any drug delivery system is to provide a
therapeutic amount of a drug to a proper site in the
body so that the desired concentration can be
achieved promptly and then maintained.
Drug delivery system should deliver the drug dictated
by the needs of the body over a specified period of
time.
9
www.DuloMix.com
This involves two aspects most important for drug delivery.
Spatial placement – related to targeting drugs to special
tissues, organs or cells.
Temporal delivery refers to controlling the rate of drug
delivery to target site.
Science and technology is responsible for development of
these aspects.
10
www.DuloMix.com
Conventional drug delivery
Oral
Parentral route – IV
11
www.DuloMix.com
Problems inherent in multiple dose therapy –
1. Large peaks and valleys
2. Drug conc. May not be within therapeutic range for
long time.
3. Patient non compliance with multiple therapy.
12
www.DuloMix.com
An Ideal Drug Delivery System
1. Release rate dictated by the needs of the body over
the period of treatment
Constant, 0-order
2. Channel the drug to the active site, cell, tissue, organ
(drug targeting)
3. “No such DDS exists which combines 1 and 2…!!!”
13
www.DuloMix.com
Terminology
Systems which can provide “some” control of drug
release in the body
Temporal
Spatial
Both
Specify release rate and duration in vivo by simple in
vitro tests
14
www.DuloMix.com
Delayed release systems – are either those that use repetitive,
intermittent dosing of a drug from one or more immediate
release units incorporated into a single dosage form, or an
enteric delayed release system.
e.g. repeat action tablet, enteric coated tablet,
Extended release system – systems include any dosage form
that maintains therapeutic blood or tissue level of the drug for a
prolonged period.
Extended release is not equivalent to controlled release.
15
www.DuloMix.com
Site specific or receptor targeting – refer to targeting a
drug directly to a certain biological location. The target is
adjacent to or in the diseases organ or tissue.
Controlled drug delivery – can be defined as delivery of a
drug at a pre determined rate and/or to a location
according to the needs of the body and disease states for
a definite period of time.
16
www.DuloMix.com
Controlled Delivery Attempts to:
1. Extend drug action at a predetermined rate by maintaining a relatively
constant, effective drug level in the body with concomitant minimization
of undesirable side effects associated with a saw – tooth kinetic pattern
of conventional release.
2. Localize drug action by spatial placement of a controlled release system
(usually rate controlled) adjacent to or in the diseased tissue or organ
3. Target drug action by using carriers or chemical derivatization to deliver
drugs to a particular “target” cell type
4. Provide a physiologically/therapeutically based drug release system
means that the amount and rate of drug release are determined by the
physiological/ therapeutic needs of the body.
17
www.DuloMix.com
Controlled Release vs. Sustained Release
Sustained release
Complexation, slowly dissolving coatings, use of derivatives with
reduced solubility
Sensitive to environmental conditions to which they are exposed
Sustains drug level for prolonged time.
Controlled release
Release rate is determined by the device itself
More accurate, predictable administration rate
Controls time as well as site of release.
18
www.DuloMix.com
Advantages of Controlled drug delivery
systems
1. achieve more effective therapies while eliminating the
potential for both under- and overdosing.
2. the maintenance of drug levels within a desired range.
3. the need for fewer administrations, optimal use of the
drug in question.
4. increased patient compliance.
19
www.DuloMix.com
Employ less total drug
A) minimize or eliminate local side effects
B) minimize or eliminate systemic side effects
C) Obtain less potentiation in drug activity with chronic
use.
D) Minimize drug accumulation with chronic dosing
Improve efficiency in treatment
a) Cure or control condition more promptly
b) Reduce fluctuation in drug level
c) Make use of spatial effects.
E) Economic savings
20
www.DuloMix.com
Disadvantages of controlled drug delivery
1. The possible toxicity or nonbiocompatibility of the
materials used.
2. Undesirable by-products of degradation.
3. The chance of patient discomfort from the delivery
device for instance if any surgery required to
implant or remove the system.
4. The higher cost of controlled-release systems
compared with traditional pharmaceutical
formulations.
21
www.DuloMix.com
Controlled drug delivery – history
1950-1970 – Hydrophobic polymers, waxes used to extend drug
action. Lacks anatomic and physiologic basis.
1970-1980- Determined needs in CDDS, understanding the barriers
for various routes of administration, zero order importance, drug
targeting.
1980-1990- Biotechnology research and molecular biology research
Post1990 – modern era of CDDS, optimization of formulations,
novel polymers, temporal aspect. Newer approaches are allowing
spatial placement as well.
22
www.DuloMix.com
Factors influencing the design and performance of
a controlled release systems
The design of modified release system is subject to several
variables including route of drug administration, type of
delivery system, disease being treated, patient and length of
therapy.
Most important constraints are imposed by Physico- chemical
properties of drug.
Biological properties of drug are the function of Physico-
chemical properties of drug.
23
www.DuloMix.com
A) Physico chemical properties
1. Dose size
If an oral product has a dose size greater that 0.5gm it is a
poor candidate for sustained release system
in most cases generates a substantial volume product that
unacceptably large.
24
www.DuloMix.com
Aqueous Solubility :
dc/dt = K A Cs
Dc/dt – rate of dissolution
K – dissolution rate constant
A – surface area of dosage form
Cs – aq. solubility of drug
Drugs aqueous solubility will generally be decreased by conversion to an
unchanged form for drugs with low water solubility will be difficult to
incorporate into sustained release mechanism.
Extremes of solubility of drug are unsuitable for formulation.
The lower limit on solubility for such product has been reported 0.1mg/ml.
25
www.DuloMix.com
Aqueous Solubility :
since the unchanged form of a drug preferentially permeates
across lipid membranes.
Drugs aqueous solubility will generally be decreased by
conversion to an unchanged form for drugs with low
water solubility will be difficult to incorporate into
sustained release mechanism.
The lower limit on solubility for such product has been
reported 0.1mg/ml.
26
www.DuloMix.com
Pka
The relationship between Pka of compound and pH of
absorptive environment.
Presenting drug in an unchanged form is adventitious for
drug permeation but solubility decrease as the drug is in
unchanged form. (pH partition hypothesis)
St = So (1 + 10pH – pKa )
R = (1 + 10pHb – pKa ) / (1 + 10pHg – pKa )
27
www.DuloMix.com
E.g. aspirin
pHb – 7.4
pHg – 2
Pka of aspirin – 3.4
Therefore – R = 3.4 or 4
And pHi – 7
Therefore – R = 1
Hence more absorption is from stomach where it is in
unionized form.
28
www.DuloMix.com
Pka
The relationship between Pka of compound and absorptive
environment.
Presenting drug in an unchanged form is adventitious for
drug permeation but solubility decrease as the drug is in
unchanged form
29
www.DuloMix.com
Partition Coefficient
Defined as the fraction of drug in an oil phase to that of an
adjacent aqueous phase.
high partition coefficient – predominantly lipid soluble
consequently have very law aqueous solubility.
Low partition coefficients – difficulty in penetrating
membranes resulting poor bioavailability.
30
www.DuloMix.com
31
www.DuloMix.com
Drug Stability
Orally administered drugs can be subject to both acid base
hydrolysis and enzymatic degradation.
drugs that are unstable in stomach, systems that prolong
delivery ever the entire course of transit in GI tract are
beneficial.
Compounds that are unstable in the small intestine may
demonstrate decreased bioavailability when administered
from a sustaining dosage from.
32
www.DuloMix.com
Drug unstable In stomach are formulated to deliver
contents in intestine and drugs unstable in intestine
should release contents in stomach.
Delivery systems that are localized in particular area are
proffered . E.g. bio adhesive systems that are localized and
act as reservoir of drug.
33
www.DuloMix.com
Drug Stability
Orally administered drugs can be subject to both acid base
hydrolysis and enzymatic degradation.
drugs that are unstable in stomach, systems that prolong
delivery ever the entire course of transit in GI tract are
beneficial.
Compounds that are unstable in the small intestine may
demonstrate decreased bioavailability when administered
from a sustaining dosage from.
34
www.DuloMix.com
Molecular size and diffusivity:
The ability to diffuse through membranes – called diffusivity
& diffusion coefficient is function of molecular size (or
molecular weight)
logD= -Sv logV + Kv
logD= -Sm logM+ Km
values of diffusion coefficient – 10-8 to 10-9 cm2 / sec.
10-8 being most common for drugs with molecular weight
up to 500
Large molecular weight drugs display very slow release
kinetics in sustained release device
35
www.DuloMix.com
Molecular size and diffusivity:
The ability to diffuse through membranes – called diffusivity
& diffusion coefficient is function of molecular size (or
molecular weight)
values of diffusion coefficient – 10-8 to 10-9 cm2 / sec.
10-8 being most common for drugs with molecular weight
up to 500
Large molecular weight drugs display very slow release
kinetics in sustained release device
36
www.DuloMix.com
Protein binding
Many drugs bind to plasma proteins with a concomitant
influence on the duration of drug action.
Drug Protein binding can serve as a depot for drug
producing a prolonged release profile.
Extensive binding to plasma proteins will be evidenced by a
long half life of elimination for drugs.
Eg. amitryptyline. diazepam, diazoxide, dicumarol
37
www.DuloMix.com
B) Biological factors:
Release rate and dose
The goal of controlled drug delivery is
K0
r = Rate in = Rate out = Ke Cd Vd
W= Di +Dm
Consist of two doses Di that releases drug immediately and a
maintenance dose Dm,
For zero order release
W= Di + K0
r Td
Td time required for extended release from one dose.
W= Di + K0
r Td – K0
r Tp
K0
r Tp is amount of drug provided during the period t =0 to the time
of peak drug level, Tp.
No correction is needed if system does not begin to release drug
until time Tp.
38
www.DuloMix.com
For first order process
W= Di + Ke Cd/ KrVd
Kr first order release rate
If maintenance dose begin to release drug at t= 0 a correction
factor is needed
W= Di + Ke Cd/ KrVd – Dm Ke Tp
Extended release system is designed to alleviate repetitive
dosing, it naturally will contain greater amount of drug than
corresponding conventional dosage form.
For IM, SC, IV route the tolerance may be produced at site of
injection due to large size.
For potent drugs, incorporation of large amount of drugs is
potentially dangerous if system fails to control release.
39
www.DuloMix.com
B) Biological factors:
Elimination and Biological Half Life
The rate of elimination of a drug is described quantitatively
by its biological half life. And given by
T1/2 = 0.693V/Cl = 0.693 V. AUC/dose (since Cl =dose/AUC)
Under steady state
Ri = R0
R0 = Css Cl
Half life helpful to Determine dosing interval.
Therapeutic compounds with short half lives are excellent
candidates for sustained release preparations. Since this
can reduce dosing frequency.
40
www.DuloMix.com
In general drugs with half-lives shorter than 2hrs are poor
candidates of sustained release dosage forms as dose size
and large release rates are required. Eg. Ampicilin,
levodopa, penicilin.
As well as compounds with long half lives, more than 8 hrs
are also not used in sustained release forms because their
effect is already sustained. E.g. diazepam, digoxin,
phenytoin.
41
www.DuloMix.com
Absorption:
As the rate limiting step in drug delivery from a sustained-release
system is its release from a dosage form, rather than absorption.
(Kr <<<< Ka)
Rapid rate of absorption of drug, relative to its release is essential if
the system is to be successful.
It we assume that transit time of drug must in the absorptive areas
of the GI tract is about 9-12 hrs.
The maximum half life for absorption should be approximately 3-4
hrs.
Absorption rate constant should be between 0.17 to 0.23 hr-1 for
80- 95% absorption in transit of 9-12hrs.
Therefore release rate should be less than 0.17 hr-1
Slowly absorbed drugs will be difficult to formulate into extended
release systems where this criteria of Kr <<<< Ka must be met.
42
www.DuloMix.com
Extent of absorption is low that means Bioavailability of
drug is low for variety of reasons like poor water
solubility, low partition coefficient, acid hydrolysis,
metabolism, site specific absorption.
These problems can be overcome by appropriately
designed extended release system.
43
www.DuloMix.com
Absorption:
As the rate limiting step in drug delivery from a sustained-
release system is its release from a dosage form, rather than
absorption. (Kr <<<< Ka)
Rapid rate of absorption of drug, relative to its release is
essential if the system is to be successful.
It we assume that transit time of drug must in the absorptive
areas of the GI tract is about 8-12 hrs.
The maximum half life for absorption should be approximately
3-4 hrs.
Absorption rate constant should be between 0.17 to 0.23 hr-1
Therefore release rate should be less than 0.17 hr-1 which is
practically difficult. It result in unacceptable lower
bioavailability.
44
www.DuloMix.com
Distribution
The distribution is important factor in the overall drug
elimination kinetics.
Since it not only lowers the concentration of circulating drug but
it also can be rate limiting in its equilibrium with blood and
extra vascular tissue.
It restricts magnitude of release rate and dose size.
For design of sustained/ controlled release products, one must
have information of disposition of drug.
Two important factor are – Volume of distribution and T/P ratio
is needed.
45
www.DuloMix.com
V=dose/Co
Greater is V needs for larger dose and frequent
administration
T/P= K12 (K21 – β)
β disposition rate constant.
T/P determines relative distribution of drug between
compartments
Vss determines extent of distribution in body.
Both contributes for estimation of distribution
characteristics.
46
www.DuloMix.com
Metabolism
The location, rate and extent of metabolism should be known
to formulate successful extended release system.
Drugs that are significantly metabolized before absorption, either
in lumen or the tissue of the intestine, can show decreased
bioavailability.
Intestinal metabolism – salicylamide, nitroglycerine, levodopa,
isoproterenol, chlorpromazine.
As drug is released at a slower rate to these regions less total
drug is presented to the enzymatic degradation.
47
www.DuloMix.com
Fluctuation in drug blood level due to first pass effect.
First pass effect – phenacetin, propranolol, lidocaine.
These are suitable candidates for modified release system
Enzyme inhibitors – cimetidine, ciprofloxacin, fluconazole
increases conc. Of drg due to enzyme inhobition.
Enzyme inducers – Carbamazepine, phenobarbital, rifampin
are inducers therefore increased metabolism reduces conc.
Of drug.
48
www.DuloMix.com
A drug can be both metabolized by and inhibit the same enzyme (e.g.,
erythromycin), or it can be metabolized by one enzyme and inhibit
another enzyme (e.g., terbinafine).
Drugs may be intentionally combined to take advantage of CYP450
inhibition. Ritonavir a protease inhibitor and potent CYP3A4 inhibitor, is
added to lopinavir to boost serum levels in patients with human
immunodeficiency virus.
These factors of first pass metabolism, drug degradation in GI tract,
enzyme inhibition and induction are to consider for modified release
systems.
49
www.DuloMix.com
Metabolism
Drugs that are significantly metabolized before absorption,
either in lumen or the tissue of the intestine, can show
decreased bioavailability.
Intestinal metabolism – salicylamide, nitroglycerine,
levodopa
As drug is released at a slower rate to these regions less
total drug is presented to the enzymatic degradation.
50
www.DuloMix.com
Flactuation in drug blood level due to first pass effect.
First pass effect – phenacetin, propranolol, lidocaine.
These are suitable candidates for modified release system
51
www.DuloMix.com
Protein binding
Many drugs bind to plasma proteins with a concomitant
influence on the duration of drug action.
Drug Protein binding can serve as a depot for drug
producing a prolonged release profile.
Extensive binding to plasma proteins will be evidenced by a
long half life of elimination for drugs.
Eg. amitryptyline, diazepam, diazoxide
52
www.DuloMix.com
Elimination and Biological Half Life
The rate of elimination of a drug is described quantitatively
by its biological half life. And given by
T1/2 = 0.693V/Cl = 0.693 V. AUC/dose
(since Cl =dose/AUC)
For achieving control release we need
Ri = R0
R0 = Css Cl
Input rate is determined by steady state conc. And systemic
clearance.
53
www.DuloMix.com
Half life helpful to Determine dosing interval.
Therapeutic compounds with short half lives are excellent
candidates for sustained release preparations. Since this
can reduce dosing frequency.
Drugs with long half life is dosed at greater time intervals,
thus there is less need for extended release systems.
54
www.DuloMix.com
In general drugs with half-lives shorter than 2hrs are poor
candidates of sustained release dosage forms as dose size
and large release rates are required. Eg. Ampicilin,
levodopa, penicilin, furosemide,
As well as compounds with long half lives, more than 8 hrs
are also not used in sustained release forms because their
effect is already sustained. E.g. diazepam, digoxin,
phenytoin, warfarin.
55
www.DuloMix.com
Efficacy and safety
Have a thorough knowledge of relationship between
concentration and effect and its dependence on disease and time
profile of drug input to have a more rational design of extended
release delivery system.
PK/PD model is required to obtain a rational design of extended
release dosage form.
E.g. a constant drug blood level does not necessarily produce a
constant pharmacological effect in some cases
Nitroglycerin – a constant level leads to tolerance and result in
decreased pharmacological effect. Hence an OFF period is
required for adequate nitroglycerin therapy.
56
www.DuloMix.com
Therapeutic index
Above therapeutic conc., result in increasing toxic effects
and a fall off in desired therapeutic response observed
below this range.
TI = TD50/ED50
TD50 median toxic dose
ED50 median effective dose.
For potent drugs therapeutic conc. Range is narrow and
value of TI is small.
Larger the value of TI the safer is drug.
57
www.DuloMix.com
Drugs with very small values of TI are poor candidates
for formulations into extended release products.
TI value should be above 10. Below 10 are barbiturates
and cardiac glycosides.
Controlled release system can minimize side effects for a
particular drug by controlling its plasma conc. And using
less total drug over the time course of therapy.
58
www.DuloMix.com
Other factors
Release rate and dose
Efficacy and safety,
therapeutic index
59
www.DuloMix.com
Compounds Those Are Unsuitable For
Controlled Release
Drugs with elimination half life less than two hrs
Drugs those that are administered in large doses
Administering drugs like warfarin, whose pharmacological effect
is delayed relative to its blood profile, offers no clinical advantage.
Incorporating drugs like fluorouracil, and perhaps some beta
lactum antibiotics and thiamine diuretics that appears to exhibit
an “absorption window” may reduce absorption efficiency.
60
www.DuloMix.com
References
61
www.DuloMix.com