Presented byMr. MAYUR R. KHINVASARA

(M. Pharm. Sem. III)Roll No. A-11

Department of PharmaceuticsS. S. D. J. COLLEGE OF

PHARMACY,CHANDWAD

INTELLIGENTDRUG DELIVERY

SYSTEMS

IDDS

Guided byDr. SANJAY B. PATIL( M. Pharm., Ph.D.)

CONTENTS

♪ INTRODUCTION♪ MECHANISM OF IDDS♪ INTELLIGENT DRUG

DELIVERY SYSTEM ♪ CLASSIFICATION OF IDDS♪ RECENT ADVANCE♪ REFERENCES

INTRODUCTION† The conventional manner of introducing drug to patient is

inefficient and often lead to toxic side effects.† The dramatic advance in controlled and targeted drug

delivery system over the past few decades have lead to enormous expectation for treatment of number of complicated aliments with minimum side effects.

† Intelligent drug delivery systems (IDDS) 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 to particular compartment. Preserve the medicament that are rapidly destroyed. Improve the patient compliance.

† This new class of “intelligent therapeutics” refers to intelligent and responsive delivery systems that are designed to perform various functions like- Detection, Isolation and/or Release of therapeutic agent for the treatment of diseased

conditions.† Intelligent drug delivery systems are mostly based on stimuli-

responsive polymers which sense a change in a specific variable and activate the delivery; this phenomenon being reversible.

† Development of IDDS open-loop and closed-loop control systems based on stimuli-responsive polymers and their applications in the drug delivery field as pulsatile and self-regulated devices.

HOW IT WORKS

It senses the signal caused by disease(SENSOR FUNCTION)

Judges the magnitude of signal(PROCESSOR FUNCTION)

Then act to release the drug in direct response(EFFECTOR FUNCTION)

Mechanism of Intelligent Drug Delivery System

Schematic diagram of working of IDDS

INTELLIGENT DRUG DELIVERY SYSTEMS

• IDDS may be, 1.Open-loop systems also

known as pulsed or externally regulated systems.

2.Closed-loop systems also known as self regulated systems

The externally controlled devices apply external triggers for pulsed delivery of drug such as: 1. Magnetism. 2. Ultrasound. 3. Electrical effect.It involves following systems :A. Magnetically modulated drug delivery systemB. Ultrasonically modulated drug delivery systemC. Electrically modulated drug delivery systemD. Thermo sensitive drug delivery system

1.Open-loop systems are known as pulsed or

externally regulated systems

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:

1. pH responsive drug delivery2. Glucose-responsive insulin delivery 3. Urea-responsive drug delivery system4. Inflammation-induced pulsatile release5. Morphine triggered Naltrexone delivery system.

2.Closed-loop systems also known as self regulated systems

CLASSIFICATION OF INTELLIGENT DRUG DELIVERY SYSTEM (IDDS)

1. Pulsatile system• Magnetically Modulated Systems• Electrically Regulated System• Ultrasonically Modulated Systems• Photo responsive Systems

2. Responsive system• pH responsive drug delivery• Inflammation-induced drug release• Thermo responsive drug delivery system• Glucose and Other Saccharide Sensitive

Polymers 3. System utilizing enzymes

• Glucose-responsive insulin release devices

• Urea-responsive delivery • Morphine triggered Naltrexone delivery

4. System utilizing chelation5. Systems utilizing antibody interactions

1.PULSATILE SYSTEMSᴥ Pulsatile drug delivery systems (PDDS) are gaining importance

in the field of pharmaceutical technology as these systems deliver the right dose at specific time at a specific site resulting in improved therapeutic efficacy as well as compliance.

ᴥ Chrono pharmacotherapy designed according to the circadian rhythm of the body

ᴥ Ecofriendlyᴥ Intelligent drug delivery system capable of adjusting drug

release rates in response to a physiological need.ᴥ The conditions that demand such release include:

• Follow circadian rhythm, • Protection from gastric environment, • To achieve localized action, • First-pass metabolism can be overcome.

A. MAGNETICALLY MODULATED DRUG DELIVERY SYSTEM

† Magnetically drug delivery by particulate carriers is a very efficient method of delivering a drug to a localized disease site.

† This approach involves incorporation of magnetic beads in elastic polymers. It has been shown that when oscillating magnetic field is applied, more drug will be released.

† Insulin and other macromolecular bioactive can be continuously released by embedding them in a carrier like ethylene vinyl acetate copolymer (EVAc).

† Another system utilizing EVAc-protein matrices containing magnetic beads exhibit enhanced releases rates when placed in oscillating magnetic field.

† Very high concentration of chemotherapeutics and radiological agents can be achieved near the target site, such as tumor without any toxic effects to normal surrounding tissue or to the whole body.

† 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 carrier.

† Magnetic carrier receive their magnetic response to a magnetic field from incorporated materials such as a such as Magnetite (Fe3O4), Iron, Nickel, Cobalt etc.

† For biomedical applications, magnetic carriers must be-• Water-based, • Biocompatible, • Non-toxic and non-immunogenic.

B. ULTRASONICALLY MODULATED DRUG DELIVERY SYSTEM

† In this system release rate of drug is repeatedly modulated externally by ultrasound.

† Both non erodible as well as bio-erodible polymer are used for preparation of polymer matrices.

† Bio-erodible polymers include polylactide, polyglycolide, poly(bis(p-carboxyphenoxy)alkane anhydrides and their copolymers with sebacic acid.

† The bioactive used are p-aminohippurate, insulin and bovine serum albumin etc.

† On exposure to ultrasound enhanced polymer erosion and drug is released in controlled manner from polymer metrics.

† The response of system to the ultrasonic triggering is rapid (within 2 min) and reversible in nature.

C. 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 thus, pH- responsive as well as electro-responsive.

† In this system drug is disperse in hydrogel which is implanted subcutaneously.

† 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 hydrolysed polyacrylamide, poly dimethylaminopropyl acrylamide

D.PHOTO RESPONSIVE

SYSTEMS† 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.

† The Photoresponsive system is a molecular scale polymer matrix of photo labile 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.

2. RESPONSIVE SYSTEM

• This system involves the use of polymer which are responsive to change in body environment.

• In this system drug delivery is controlled by means of an interaction with the surrounding environment without the aid of any external stimuli.

• Drug release is controlled by change in temperature, pH or inflammation.

• Different methods have been employed to cause phase transitions like change in temperature, pH and electrolyte composition.

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).

† 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 .

† 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.

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 matrices of cross linked hyaluronic acid.

† Hyaluronic Acid gel is injected at inflammatory sites which are specifically degraded by hydroxyl radicals produced from inflammation-responsive cells during inflammation.

† Hyaluronic acid is a linear mucopolysaccharide composed of repeating disaccharide subunits of N-acetyl-D-glucosamine and D-gluconic acid.

† Hyaluronic acid has been extensively used in vivo as a therapeutic agent for ophthalmic surgery and arthritis.

† In the living body, hyaluronic acid is known to be degraded by two mechanisms:• Via hyaluronidase as a specific enzyme.• Via hydroxyl radicals as a source of active oxygen.

C. THERMO RESPONSIVE 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 thermo responsive polymers are Poly (N,N- diethyl acrylamide), Poly (methyl vinyl ether), Poly (N- vinyl caprolactam), Pluronics, tetronics.

3. SYSTEM UTILIZING ENZYMES

† 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.

† 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.

A. GLUCOSE-RESPONSIVE INSULIN RELEASE DEVICES

B. UREA-RESPONSIVE DELIVERY SYSTEM

• 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 esterified copolymer of methyl vinyl ether and maleic anhydride was developed that displays pH dependent drug release.

• 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.

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 biodegradable polymer matrices.

† This polymer matrix is in turn covered by lipid layer that prevents water entry into the matrix and there by retards its degradation.

† Then the system is 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.

Showing naltrexone delivery device

† 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.

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.

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.

INSULIN PUMP† The ultimate goal of insulin treatment in diabetes

mellitus is to control the blood glucose level and prevent or stabilize long - term diabetic complications.

† Administration of insulin through subcutaneous injection is currently the major therapy of diabetes.

† Two or three injections 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 insulin pump constructed with polymer materials has been studied.

† Wang developed an insulin reservoir consisting of silicone rubber, which releases insulin stored inside by generation of a pressure gradient by compression.

† Segmented polyurethane (SPU) can be used as an elastic material for preparation of the insulin reservoir.

† The enhancement of insulin permeability and biocompatibility, a novel copolymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and 2-EthylHexyl Methacrylate (EHMA) can be designed.

† Addition of the MPC polymer to other polymers enhances the biocompatibility to the original polymer.

† Two main mechanisms are generally involved in under delivery events: 1. Insulin aggregation in the pump insulin pathway.2. Catheter occlusions.

† Moreover, these aggregates, which are likely to be generated by hydrophobic interactions with the pump circuits, seem to promote an increased production of anti -insulin antibodies in many patients treated by implantable pumps.

† Concomitant improvements of catheter design also contributed to the reduction of under delivery.

† Despite these problems, implantable pumps currently provide the most effective and physiological insulin delivery.

Insulin pump

Insulin pump

Insulin pump

GLUCO WATCH™† Gluco Watch™ biographer is non-invasive, watch like device that

measures glucose. † A plastic part of Gluco watch that snaps into the biographer and

sticks to the skin. † Automatic reading every 10 min up to 13 hrs is taken by it.† Gluco watch presently takes the lead among user-friendly

techniques aimed at glucose monitoring. 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.

Gluco watch

MICROFABRICATED DRUG DELIVERY SYSTEMS† Possible applications include micromachined silicon

membranes to create implantable bio capsules for the immune isolation 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.

REFERENCES

1. Shah Nihar, Patel Nishith, (2013), A Sequential Review on Intelligent Drug Delivery System. Journal of Pharmaceutical Science and Bioscintific Research. 3 (5), pp.158-162.

2. Patel DM*, Patel DK, Patel BK,, (2011). An overview on Intelligent Drug Delivery System. International Journal of Advance in Pharmaceutical Research. 2 (2), pp.57-63