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` The aim of NDDS is to provide a therapeutic
amount of drugg to the appropriate
pp p site in the
body to accomplish promptly and then
maintain the desired drug concentration.
` The drug-delivery system should deliver drug
at a rate control by thenecessarily of the body
over a specified
ifi d term off treatment.
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This idealized objective switch to the two
p
aspects most important
p to drugg delivery
y are:
I. Spatial Drug Delivery:
` Targeting a drug to a particular organ or
tissue.
II. Temporal Drug Delivery:
` The drug delivery rate to the target tissue is
controlled.
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` Maintenance of optimum therapeutic drug
concentration in blood/cell
` Predictable and reproducible release rates for
extended periods of time
` Enhancement of activity duration for short half-
life drugs
` Eli i
Elimination
i off side-effects,
id ff frequent
f dosing,
d i
waste of drug, optimized therapy
` Better patient compliance
1. Convenience and compliance
2. Efficiency
3. Protecting franchises
4. Adding value to generics
5. Market expansion
6. Creating new markets
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` “Added value” to a product with convenient dosage regimes.
` Convenience linked with better compliance.
compliance
` Poor compliance – a problem with asymptomatic conditions such as
essential hypertension, for elderly due to forgetfulness.
` β-blockers (e.g. propranolol) had short t1/2 and 3-4 times dosing
was required.
required
` Products with long acting formulations have commercial advantage.
` Later β-blockers such as atenolol had longer duration of action.
7
` NSAIDS (indomethacin, ibuprofen) used to
give relief in pain and stiffness in arthritis.
` First generation NSAIDS were short-acting
drugs (4-6 hr) – inconvenient and inefficient
` SR formulations – treatment more effective by
matching timing of pharmacological effect to
patient’s clinical need.
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` Transdermal patches – maintain constant
blood-levels without p
peaks and troughs.
g e.g.
g
◦ Glyceryl trinitrate for prophylaxis of angina pectoris
◦ Estradiol for hormone replacement therapy and
prevent postmenopausal osteoporosis
` Possibility of repatenting successful drugs and
prolong commercial viability of original brands
` Proprietary products loses its patent exclusivity
and then it is open to other manufacturers to
manufacture and sell the same drug.
` Generic drugs – always cheaper, and the
company which developed the drug loses its
market
k share.
h
` Drug delivery technology – resource to a
company to preserve its market share
10
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` If original product – short-acting, originator
p y may
company y launch a p
prolonged-action
g
form shortly before expiry of original patent
` Prescribers encouraged to switch their “brand
loyalty” to new form, which usually has the
same brand name with a suffix to indicate
prolonged
l d release
l (V
(Voltarol
l lRRetard)
d)
11
` Generic manufacturers may also use advanced
drug delivery technology to:
◦ give their product added value and
◦ distinguish them from the original brand / rival generics
12
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` Providing means for convenient
administration of drugs which had to be
given
i b
by iinjection.
j i
` E.g. poor candidates for oral use like insulin,
calcitonin
` Possible for patients to self-administer
self administer drug
and more widely available for general use
(esp. in primary care environment)
13
` Useful where the market opportunity has not
yet been matched by proven and practical
technical
h i l solutions
l i
` Main candidate is gene therapy – an
experimental and speculative area: vast
markets exist but technology is still in
development stage
14
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1. Physiological factors
` suc
such as gast
gastroo intestinal
test a e enzyme,
y e, act
activates
ates
pH /gastric and intestinal transit rates, food
and disease which often influence drug
bioavailability from conventional dosage
forms may interfere with the accuracy of
control release and absorption of drug from
the system
system.
15
` 2. The products which remain intact may
become accommodates at some sites results
slow release of drug from the dosage form
may produce a high localized concentration
of drug which produces local irritation.
16
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` 3. Drugs with half- life of 1hr or less are
difficult to be formulated as sustained release
formulation. The high rate of elimination of
such drugs from the body requires an highly
large maintenance dose which provides 8-12
hrs of continuous release.
17
` 4. Since these products contain a large amount of
drug. There is a chance of unsafe over dosage, if
the product
prod ct is improperl
improperly made and the total
drug contained there is released at one time or
over too short time of interval.
` 5. It is difficult to cease the therapy once after
administration may be for reasons of toxicity or
any other.
other
` 6. It may be not suitable to encomposs potent
drugs in such system.
18
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` Temporal control – deliver drug at a rate dictated by the
needs of the body over period of treatment
◦ At a constant rate or
◦ At a variable rate
` Spatial control – channel the active entity solely to the
site of action
◦ To specific receptors as with H1 & H2 antagonists
◦ Localization to tumour cells as in cancer treatments
◦ Specific areas of the body as for arthritis and gout
19
Novel drug delivery system can be divided into
classes:
` 1. Sustained release drug delivery system.
` 2. Controlled release drug delivery system.
20
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` to retard the release of a therapeutic effect
pp
such that its appearance in the systemic
y
circulation is delayed and/or prolonged and
the plasma profile is sustained in duration.
` The onset of its pharmaceutical action is
often slow, and the duration of its therapeutic
effect
ff is
i sustained.
i d (eg:
( coated
d granules)
l )
21
` This system has a meaning that goes beyond
the scope
p of sustained drug g action.
` It manifests a predictability and
reproducibility in the drug release kinetics.
` The release of drug substances from a
controlled release drug delivery system gains
at a rate profile that is not only predictable
ki
kinetically
i ll bbut also
l reproduced
d d ffrom one unit
i
to another.
22
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They are classified as follows
I. Rate-preprogrammed drug delivery system
II. Activation–Modulated drug delivery system
III. Feed–Back Regulated drug delivery system
IV. Site–Targeting drug delivery system
23
` This technology
controls amount,
timing and location
of release in body.
` Formulation with
predictable and
reproducible drug
release profile.
` Controls rate of drug
diffusion throughout
release process,
ensuring 100%
release
24
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(A) soaked in pH 1.2 or resident in the stomach and
(B) soaked in pH 6.8 or in transit in intestinal tract
25
Triple-layered
structure of GLARS Morphological changes in
GLARS upon water contact
26
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Patients demand patches with these attributes:
` Comfortable (non-irritating)
` Adherent (stay put)
` Reproducible blood levels
` Small (discreet)
27
28
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` The microneedle technology can result in more
effective contact of the vaccine with the antigen-
presenting Langerhans cells
` The needles can be fabricated to be long enough to
penetrate the stratum corneum, but short enough to
not come into contact with nerve endings.
29
` Utilize osmotic pressure as the
driving force for the delivery of
drugs.
` Components: an osmotic core,
which is coated with a semi-
permeable membrane, and a
delivery orifice on the
membrane, which is created by
a laser drill.
` After orally taking, as soon as
the tablet comes into contact
with
h water in stomach,h water
will be imbibed through the
membrane because of the
resultant osmotic pressure,
and then the drug will be
released through the orifice at
a controlled rate
30
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31
Ancient civilizations, Scientist & physicians
current smokers & later discovered that
drug abusers know inhaled drugs:
that inhaled drugs:
` Go directly to the lung
` Act quickly ` Minimizes side effects
` Minimal dose ` Avoids hepatic
p first-
requirement
i t pass metabolism
` Are non-invasive ` Are systemically
absorbed
32
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33
Nebulizer pMDIs DPIs
Air‐jet Ultrasonic
Suspension or
Aqueous solution of Dry powder
solutions or drug but in a inhaled
suspensions volatile
aerosolized propellant
34
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Dispersion & aerosilization
g about by:
is brought y
` Air-jet: a high velocity air
stream (Venturi effect)
` Ultrasonic: the high
frequency sound waves
Generates small particles with
produced by a piezo-
higher delivery capacities than electric crystal transducer.
pMDIs and DPIs
35
` Involves the use of a propellant
` Device is composed of:
◦ Container
◦ Metering Valve: releases a fixed
volume of product during each
actuation
◦ Elastomer Seal: controls
propellant
ll t lleakage
k
◦ Actuator: permits easy actuation
of the valve and provides an orifice
through which the spray is
discharged
36
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Advantage over pMDIs: it is breath actuated so:
` no need for propellant
propellant.
` no need for coordination of actuation and
inhalation.
` slow rate of travel of the particles to avoid drug loss
by impaction in the throat.
Disadvantage:
` High inspiratory effort may be required.
37
` It combines precise
particle size control and
breath control to
minimize aerosol
deposition in the mouth
and throat and
maximize the efficient
AERx® system:
AER t iincrease peripheral
i h l
deposition delivery of drug to the
lungs.
38
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39
40
20
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41
42
21
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43
The liposome was adopted
as a promising delivery
system because its
organized structure which
could hold drugs,
depending on their
solubility characteristics,
in both the aqueous and
lipid phases.
44
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9 Liposomes are self-
assembling spherical
closed colloidal structures
composed of lipid bilayers
that surround a central
aqueous space.
9 Liposome based
formulations of several
anticancer agents have
b
been approved
d ffor th
the
treatment of metastatic
breast cancer and
Kaposi’s sarcoma.
45
` A Niosome is a non-ionic
surfactant-based Vesicle.
` Niosomes are formed
Ni f d mostly
l
by non-ionic surfactant and
cholesterol incorporation as an
excipient.
` Other excipients can also be
used.
` They have more penetrating
capability than the previous
preparations
p p of emulsions.
` They are structurally similar to
liposomes in having a bilayer,
however, the materials used to
prepare niosomes make them
more stable.
46
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47
= Polymer Matrix
Drug Core
Polymer Coat } = Entrapped Drug
MICROCAPSULES MICROSPHERES
•Microspheres are essentially spherical in shape, whereas,
microcapsules may be spherical or non-spherical in shape.
•Microparticles, either microcapsules or microspheres.
48
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` Implants are drug eluting-devices designed
g release over long
for local sustained drug g
periods
` They circumvent multiple punctures with
needles and associated complications
` Devices are usually surgically implanted
49
` Implants can be classified as:
◦ Biodegradable implants:
x Not required to be surgically removed
x with polylactic acid, polyglycolic acid, poly lacide-co-glycolide,
polycaprolactone
◦ Nonbiodegradable implants:
x Not to be surgically removed
x with polyvinyl alcohol, ethylene vinyl acetate, polysulfone
50
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` Drawbacks of traditional biodegradable
polymer
p y delivery
ypplatforms include side
effects associated with high initial drug
release on implantation (drug burst), poor
drug stability and complex processing
requirements.
51
` Polymers used in implants
◦ Introduced for a chronic period
x Cardiovascular surgery,
surgery orthopedics,
orthopedics plastic surgery
x Stability of materials used
◦ Sterilization challenges
` Biological properties of Polymers
◦ Chemical composition, ingredients, fabrication methodologies
◦ Blood incompatibility, clotting, thrombosis
x Affect plasma protein, enzyme, clotting factor (platelet,
erythrocytes,
y y , leukocytes)
y )
◦ Carcinogenesis induced by chemical and/or physical
mechanism
◦ Injury or sensitization to blood elements leading to hemolysis
and aggregation of leukocytes
◦ Adverse drug responses
52
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` Deliver drugs for periods of days to a month.
` ALZAMER® technology offers a nonaqueous
polymer solution for the stabilization of
macromolecules and a unique state-of-the-art
delivery profile.
` Decreased exposure of the drug to water until
it is released into the body.
` low initial drug burst.
53
` WHAT IT DOES
◦ sustained delivery of drug for periods of weeks to months.
◦ can deliver therapeutics both locally and systemically
◦ composed of stabilized drug particles in a PLGA polymer
solution.
` Low Drug Burst
` Maintained Protein Stability:
◦ ALZAMER® formulations isolate protein in a non-aqueous
polymer solution to prevent premature exposure to water,
which maintains better drug g stability
y and helps
p minimize
burst while controlling release over long periods off time.
` Low Cost Processing:
◦ Preloaded syringes and standard manufacturing equipment,
solvents and polymers may reduce processing costs.
54
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` Subdermal implantation of silastic capsules or rods
◦ Effectiveness not depend
p on ppatient compliance
p
◦ Longer duration of action
◦ Termination of action by removing the implant
◦ Possibility of implant migrating
◦ Norplant
x Medical-grade silastic capsule 34 mm long containing
levonorgestrel
x 6 capsules subdermally (5 mm incision)
x Used for 5 years
55
FDA approved
◦ Design
x Reservoir consisting of 6 capsules containing crystalline
l
levonorgestrel
t l iin Sil ti ® membrane
Silastic b
◦ Steroid
x Low dose progestin-only
◦ Duration of use
x 5 years
x 70 µg/day first few months,
x 30 µg/day thereafter
x 0.25 ng/mL therapeutic dose (Norplant 20x min dose)
◦ R
Release
l rate
t
x Diffusion controlled
56
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` Intravitreal implant for the treatment of
chronic posterior non-infectious uveitis.
` A sterile
l implant
l that
h releases
l fl
fluocinolone
l
initially at a rate of 0.6 µg/day to the posterior
segment of the eye decreasing over the month
to 0.3-0.4 µg/day over approx 30 months.
57
58
29
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59
` The DUROS® implant is a miniature cylinder made
from a titanium alloy, which protects and stabilizes the
drug inside, using ALZA's proprietary formulation
technology.
` Water enters into one end of the cylinder through a
semipermeable membrane; the drug is delivered from
a port at the other end of the cylinder at a controlled
rate appropriate to the specific therapeutic agent.
60
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` Chronic Condition Delivery: Chronic conditions
often require long-term treatment and multi-day
dosing regimens. DUROS® can provide precise
delivery with a single application of up to one year.
` Improved Patient Compliance: Success in
treatment chronic conditions is highly dependent on
patient compliance. DUROS®, which can be applied
and removed in an outpatient setting, helps promote
compliance.
` Enhanced Drug Stability: A common concern with
long-term drug delivery is how the body's
environment will affect protein stability. The design
and non-aqueous formulation of DUROS®
enhances drug stability until release.
61
◦ External control of the
drug delivery
◦ D
Driving
i i fforce not
concentration difference
but pressure difference by:
x osmosis action or
x by direct mechanical
actuation
◦ “Artificial pancreas“ :
electromechanical
l t h i l
devices for control of
hyperglycemia in insulin-
dependent diabetes
62
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x Deliver prescribed rate for extended periods
x Reliability, chemical, physical and biological stability
x Compatible with drug
x Noninflammatory, nonantigenic, noncarcinogenic,
nonthrombogenic, overdose protection
x Convenient to use by patients and health professionals
x Long reservoir and battery life, easy programmability,
implantable under local anesthesia
x Simple means to monitor the status and performance of pump
63
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