1. Intelligent Drug Delivery
System (IDDS)
By
Dr. Shreeraj Shah
Associate Professor,
Dept. of Pharmaceutical Technology,
L.J. Institute of Pharmacy, Ahmedabad
1

2. Contents
Introduction of IDDS
Classification (Types of IDDS)
Pulsatile system
Responsive system
System utilizing enzymes
System utilizing chelation
Systems utilizing antibody interactions
Recent Advances
References
2

3. Introduction
 The conventional manner of introducing drug to patient is inefficient
and often lead to toxic side effect.
 The dramatic advance in controlled and targeted drug delivery system
over past few decades have lead to enormous expectation for treatment
of no. of complicated aliments with minimum side effect.
 One class of such system is intelligent drug delivery system.
 Intelligent drug delivery systems are capable of adjusting drug release
rates in response to a physiological need.
 This system help to maintain drug in therapeutic range with single
dose, localize delivery of drug (at targeted site) to particular
compartment, preserve the medicament that are rapidly
destroyed ,improve the patient compliance. 3

4. How it works…..
4

5. Schematic Diagram of working of IDDS
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6. Intelligent drug delivery system may be
1.Open- loop system or
2.Closed-loop systems.
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7. 1. Open-loop control systems
In the controlled drug delivery field, open-
loop systems are known as pulsed or
externally regulated system.
The externally controlled devices apply
external triggers for pulsed delivery of drug
such as: magnetism, ultrasound, and electrical
effect etc.
It involves following systems :
◦ Magnetically modulated drug delivery system
◦ Ultrasonically modulated drug delivery system
◦ Electrically modulated drug delivery system
◦ Thermo sensitive drug delivery system etc.
7

8. 2. Closed-loop control systems
 The closed-loop systems are known as self regulated system.
In the self-regulated devices release rate of drug is controlled
by feedback information, without any external intervention.
 In closed-loop control systems the controlled variable is
detected and as a result the system output is adjusted
accordingly.
 The self-regulated systems utilize several approaches as rate-
control mechanisms like pH-sensitive polymers, enzyme-
substrate reactions, pH-sensitive drug Solubility, competitive
binding and metal concentration-dependent hydrolysis. It
involve following system:
◦ pH responsive drug delivery
◦ Glucose-responsive insulin delivery
◦ Urea-responsive drug delivery system
◦ Inflammation-induced pulsatile release
◦ Morphine triggered Naltrexone delivery system etc.
8

9. Classification of Intelligent Drug Delivery
System (IDDS)
 Classification (Types of IDDS)
 Pulsatile system
 Magnetically Modulated Systems
 Electrically Regulated System
 Ultrasonically Modulated Systems
 Photoresponsive Systems
 Responsive system
 pH responsive drug delivery
 Inflammation-induced drug release
 Thermoresponsive drug delivery system
 Glucose and Other Saccharide Sensitive Polymers
 System utilizing enzymes
 Glucose-responsive insulin release devices
 Urea-responsive delivery
 Morphine triggered Naltrexone delivery
 System utilizing chelation
 Systems utilizing antibody interactions
9

10. Schematic representation of classification
10

11. 1. Pulsatile system
PDDS (pulsatile drug delivery systems) are
gaining importance in the field of
pharmaceutical technology as these systems
deliver the right dose at specific time at a
specific site. Some of the disease conditions
wherein PDDS are promising include
duodenal ulcer, cardiovascular diseases,
arthritis, asthma, diabetes, neurological
disorder, cancer, hypertension etc.
In pulsatile drug delivery system drug
release is programmed by external stimuli
like magnetism, ultrasound, electrical effect
and irradiation etc. 11

12. a) Magnetically control drug delivery system :
Magnetic drug delivery by particulate carriers is a
very efficient method of delivering a drug to a
localized disease site.
Very high concentrations of chemotherapeutic and
radiological agents can be achieved near the target
site, such as a tumor without any toxic effects to
normal surrounding tissue or to the whole body.
This approach involves incorporation of magnetic
beads in elastic polymer(generally ethylene vinyl
acetate copolymer) .
Application of oscillating magnetic field leading to
swelling of polymer which modulate drug release
from polymer matrix.
12

13. In magnetic targeting, a drug bound to a magnetic
compound is administered to patient and then
stopped with a powerful magnetic field in the
target area. Depending on the type of drug, it is
then slowly released from the magnetic carriers .
Magnetic carriers receive their magnetic response
to a magnetic field from incorporated materials
such as Magnetite (Fe3O4), Iron, Nickel, Cobalt etc.
For biomedical applications, magnetic carriers
must be water-based, biocompatible, non-toxic and
non-immunogenic.
13

14. b) Electrically modulated drug delivery
system :
This system exhibit drug release under the effect of
an applied electrical field due to action of an
applied electrical field on rate limiting membrane
or directly on solute thereby controlling its
transport across the membrane.
Electrically modulated delivery systems are
prepared from polyelectrolytes (polymers which
contain relatively high concentration of ionisable
groups along the backbone chain) and are thus, pH-
responsive as well as electro-responsive.
In this system drug is disperse in hydrogel which
is implanted subcutaneously.
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15.  When drug release is desired, an electro conducting patch
is applied on skin directly over gel and electrode are
plugged into patch and electrical field is applied.
 Under influence of electrical field, electro responsive
hydrogel swells or bends and release the drug.
 Also hydrogel in the form of beads can be injected
subcutaneously or polymer solution which can be injected
as liquid but which form gel at body temperature.
 Electrical current is also use in form of Iontophoresis or
electroporation in field of transdermal drug delivery.
 Examples of naturally occurring polymers include
hyaluronic acid, chondroitin sulphate, agarose, carbomer,
xanthan gum and calcium alginate.
 The synthetic polymers are generally acrylate and
methacrylate derivatives such as partially hydrolyzed
polyacrylamide, polydimethylaminopropyl acrylamide
15

16. c) Ultrasonically modulated system:
In this system release rate of drug is repeatedly
modulated externally by ultrasound.
Both non erodible as well as bioerodible polymer
are used for preparation of polymer matrices.
Bioerodible polymers include polylactide,
polyglycolide, poly(bis(p-carboxyphenoxy)alkane
anhydrides and their copolymers with sebacic
acid.
16

17. The bioactive used are p-aminohippurate,
insulin and bovin serum albumin etc.
On exposure to ultrasound, polymer erosion
occur and drug is released in controlled manner
from polymer metrices.
While in the non erodible polymer system,
drug release is diffusion controlled.
Studies revealed that release rate of bovine
serum insulin from ethylene vinyl acetate
copolymer matrices were 15 times higher when
exposed to ultrasound.
It has been found that extent of enhancement
can be regulated by the frequency, intensity, or
cycle of applied ultrasound.
17

18. d) Photoresponsive system:
This approach involves use of photo responsive
polymer.
The photo responsive polymer consist of
photoreceptor usually photochromic chromophore
and functional part.
 Photoresponsive system is triggered by light
stimulus leading to macroscopic changes in the
system for controlled release of drug in terms of
quantity, location and time.
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19. The Photoresponsive system is a molecular scale
polymer matrix of photolabile conjugate with drug,
which can be exposed to light stimuli with high
level of control in terms of wavelength, duration,
intensity and location; leading to photo-chemical
reaction yielding deformation of conjugates and
drug liberation from matrix.
 Photoresponsive system has found applications
in the ophthalmology (Intra ocular lenses for
cataract treatment) as well as in administration of
NSAIDS.
19

20. 2. Responsive system
This system involves the use of polymer which
are responsive to change in body enviroment.
In this system drug delivery is controlled by
means of an interaction with the surrounding
environment without the aid of any external
stimuli.
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21. a) pH responsive drug delivery
This approach utilizes the existence of pH
change in different part of body.
There exists obvious change in pH along the
GI tract from acidic in the stomach to basic
in the intestine (pH=5–8).
Also ,there are changes within different
tissue like Certain cancers as well as inflamed
or wound tissue exhibit a pH different from
7.4 . For example, chronic wounds have been
reported to have pH values between 7.4 and
5.4 and cancer tissue is also reported to be
acidic extracellularly .
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22. pH in various tissues and cellular
compartments:
Tissue/cellular compartment pH
◦ Blood 7.35–7.45
◦ Stomach 1.5–3.5
◦ Small intestine 5.5-6.8
◦ Colon 6.4–7.0
◦ Lysosome 4.5–5.0
◦ Golgi 6.4
◦ Tumour, extracellular 6.5-7.2
22

23. This approach involve use of pH sensitive
polymer.
By selecting the pH dependent polymers drug
release at specific location can be obtained.
Examples of pH dependent polymers include
Cellulose Acetate Phthalate, polyacrylates,
HPMCP, etc.
Coating of the drug core with pH sensitive
polymers has been successfully used for
colonic drug delivery.
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24. b) Inflammation-induced drug release :
 This approach is used to treat patients with inflammatory diseases like
rheumatoid arthritis using anti-inflammatory drug.
 This approach involves dispersion of drug loaded lipid microspheres in
to degradable metrices of cross linked hyaluronic acid.
 Hyaluronic Acid gel is injected at inflammatory sites which is
specifically degraded by hydroxyl radicals produced from
inflammation-responsive cells during inflammation.
 The degradation of hyaluronic acid by hydroxyl radicals may be
dominant and rapid as compared to that by hyaluronidase
 Hyaluronic acid has been extensively used in vivo as a therapeutic
agent for ophthalmic surgery and arthritis
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25. c) Thermoresponsive drug delivery system:
 The use of temperature as a signal has been justified by the fact
that the body temperature often deviates from the physiological
temperature (37°C) in the presence of pathogens or pyrogens.
 This deviation is a useful stimulus that activates the release of
therapeutic agents from various temperature-responsive drug
delivery systems for diseases accompanying fever.
 The drug delivery systems that are responsive to temperature
utilize various polymer properties, including the thermally
reversible transition of polymer molecules, swelling change of
networks, glass transition and crystalline melting.
 Examples of thermoresponsive polymers are Poly (N,N-
diethylacrylamide),Poly (methyl vinyl ether),Poly (N-
vinylcaprolactam) , Pluronics, tetronics
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26. d) Glucose and Other Saccharide Sensitive Polymers:
Brownlee and Cerami (1979) firstly presented the
basic principle of competitive binding and its
application in controlled drug delivery.
They proposed the preparation of glycosylated
insulin that is complementary to the major binding
site of carbohydrate binding proteins like
concanavalin A (Con A).
In this system, Con A is immobilized on sepharose
beads and glycosylated insulin is attached to Con A.
When glucose is found in vicinity, glycosylated
insulin is displaced from the Con A by glucose in
proportion to the amount of glucose present.
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27. Sato et al., 1990, showed that the release rate of
insulin is also dictated by the binding affinity of
an insulin derivative to the Con A and can be
influenced by the choice of saccharide group in
glycosylated insulin.
With the encapsulation of glycosylated insulin
bound Con A in a suitable polymer membrane,
permeable to both glucose and insulin, the glucose
influx and insulin efflux can be controlled.
(the responsive system also includes Ionic Cross-
linking In Situ Gelling System and Enzymatic
Cross-linking In Situ Gelling System)
27

28. Self regulating insulin delivery device 28

29. 3. System utilizing enzyme:
a) Glucose-responsive insulin release devices :
In case of Diabetes mellitus there is rhythmic
increase in the levels of glucose in the body,
requiring injection of the insulin at proper time.
Several systems have been developed which are
able to respond to changes in glucose
concentration.
One such system includes pH sensitive hydrogel
containing glucose oxidase, immobilized in the
hydrogel encapsulating saturated insulin solution..
29

30. When glucose concentration in the blood
increases, glucose oxidase converts glucose
into gluconic acid which changes the pH of the
system.
This pH change induces swelling of the
polymer which results in insulin release.
Insulin by virtue of its action reduces blood
glucose level and consequently gluconic acid
level also gets decreased .
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31. b) Urea-responsive delivery
Heller and Trescony firstly reported the alteration
in local pH by immobilization of enzymes that lead
to change in polymer erosion rate.
The proposed system is based on the conversion of
urea to NH4HCO3 and NH4OH by the action of
urease.
As this reaction causes a pH increase, a polymer
that is subjected to increased erosion at high pH is
required.
 A partially esterifled copolymer of methyl vinyl
ether and maleic anhydride was developed that
displays pH dependent drug release.
31

32.  This polymer dissolves by ionization of the carboxylic
acid group.
 This pH sensitive polymer containing dispersed drug is
surrounded by a hydrogel, containing urease,
immobilized by crosslinking of urease and bovine
serum albumin with gluteraldehyde.
 Diffusion of urea into hydrogel and its subsequent
interaction with urease lead to increase in pH which
causes erosion of polymer with concomitant drug
release. 32

33. c) Morphine triggered Naltrexone
delivery
Naltrexone is long acting opiate antagonist that
blocks opiate induced euphoria and thus used for
treatment of heroin addiction. It has been found
that it is necessary to maintain opiate addicted
subject on a dose of Naltrexone.
In this system, Naltrexone is dispersed in
biodegredable polymer metrices.This polymer
metrics is in turn covered by lipid layer that
prevents water entry into the matrix and there by
retards its degradation
33

34. Then system attached to enzyme-morphine
conjugate which is complexed with the morphine
antibody.
As antibodies are large molecules, access of
subtracts to enzyme active site is sterically
prevented, thus rendering the enzyme inactive.
When morphine is present in vicinity of device,
morphine displaces enzyme-morphine conjugate
from the antibody allowing now activated enzyme
to degrade the protective lipid layer that permits the
polymeric core degradation and release of
naltrexone into body.
34

35. Naltrexone dispersed in
biodegradable polymer
Morphine-lipase conjugate complexed
With antibody
Showing Naltrexone delivery device
35

36. 4. System Utilizing Chelation
 This system includes certain antibiotics and drugs for treatment of
arthritis, as well as chelator used for treatment of metal poisoning.
 The concept is based on ability of metals to accelerate the hydrolysis
of carboxylate or phosphate ester and amides.
 Attachment of chelator to a polymer chain by a covalent ester and
amide link serves to prevent its premature loss by excretion and
reduces its toxicity
 In presence of specific metal ion, bound chelating agent form
complex followed by metal accelerated hydrolysis and subsequent
elimination of metal chelate.
 Controlled drug release devices of poly (ethylene glycol-diacrylate)
(PEG-DA)- hydrogels were prepared by free radical UV
polymerization in the presence of chelating agent EDTA.
 Presence of chelating agent leads to a sustained drug release profile
from hydrogel
36

37. 5. Systems utilizing antibody interactions
 This approach has been proposed for antibody mediated
release of contraceptive agent. The β- subunit of human
chorionic gonadotropin (HCG) is grafted to the surface of
the polymer, which is then exposed to antibodies to β-HCG
 After implantation, this delivery system remains quiescent
until triggered by the first biochemical indication of
pregnancy, i.e appearance of HCG in the circulatory system.
 The HCG competes for the polymer bound antibodies to
HCG and initiates release of the contraceptive drug.
 This approach to contraception serves to minimize the
frequency of drug administration and the side effects
associated with contraceptive drugs.
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38. Recent Advances
Insulin Pump
 Two or three injections of Insulin are required a day to maintain the
normal blood glucose level. Because this method is burdensome and
invasive to living organisms, the patient’s situation would not be good
regarding the quality of life. Therefore, an electrical and mechanical
controlled insulin pump that injects insulin automatically into the
bloodstream has been developed.
 Wang developed an insulin reservoir consisting of silicone rubber,
which releases insulin stored inside by generation of a pressure
gradient by compression
 Siegel and Firestone designed an insulin release device using a
polymer material as an actuator, which generates the pressure gradient
for insulin release. The actuator is made from enzyme glucose oxidase
and cationic hydrogel, whose swelling would change in response to
glucose concentration through an enzymatic reaction. Insulin is
released from these devices through the orifice.
38

39.  Polymer materials used for insulin pumps should have superior
biocompatibility. For this purpose, polymer membrane should have
biocompatibility, insulin permeability, mechanical properties, and
processability
 Segmented polyurethane (SPU) can be used as an elastic material for
preparation of the insulin reservoir.
 For enhancement of insulin permeability and biocompatibility, a
novel copolymer composed of 2-methacryloyloxyethyl
phosphorylcholine (MPC) and 2-ethylhexyl methacrylate (EHMA) can
be designed.
 Dis adv: The main problem of intraperitoneal insulin infusion from
implantable pumps is the occurrence of under delivery of insulin. Two
main mechanisms are generally involved in under delivery events:
insulin aggregation in the pump insulin pathway and catheter
occlusions.
39

40. GlucoWatch™
 GlucoWatch™ biographer is non-invasive,
watchlike device that measures glucose.
 Automatic reading every 10 min up to 13 h is taken by it.
 This system is based upon the principle of reverse Iontophoresis
A low electric current pulls glucose through the skin. Glucose is
accumulated in two gel collection discs in the auto sensor.
Another electrode in the auto sensor measures the glucose.
 A signal in proportion to interstitial glucose level can thus be
generated.
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41. MICROFABRICATED DRUG DELIVERY SYSTEMS
 Possible applications include micromachined silicon membranes to
create implantable biocapsules for the immunoisolation of
pancreatic islet cells as a possible treatment for diabetes and
sustained release of injectable drugs needed over long time
periods.
 The development of microneedles for transdermal drug delivery
came about as an approach to enhance the poor permeability of the
skin by creating microscale conduits for transport across the
stratum corneum.
 Microfabrication technology has also created a new class of
controlled release systems for drug delivery based on
programmable devices called microchips.
 Microchips are particularly intriguing due to their small size,
potential for integration with microelectronics and their ability to
store and release chemicals on demand.
 The ultimate goal is to develop a microfabricated device devoid of
moving parts, but with the ability to store and release multiple
chemical substances.
41

42. Microneedles for transdermal drug delivery
42

43. References :
Vyas S.P. And Khar Roop K., “Controlled
Drug Delivery Concepts and Advances”;
Vallabh Prakashan, Delhi. Page no. 36-44
Joseph Kost and Robert Langer, Advanced
Drug Delivery Reviews, 6 (1991),19-50
Patel DM, et al., An Overview On Intelligent
Drug Delivery Systems, International Journal
of Advances in Pharmaceutical Research,
(2011), 57-63
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