A Seminar on

Intelligent drug delivery system

Keyur Vasava

Introduction:
The convetional 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, localize delivery of drug to particular compartment, preserve the medicament that are rapidly destroyed ,improved patient compliance. Intelligent drug delivery system may be open- loop system or closed-loop systems.

1. Open-loop control systems

Open-loop control systems are those in which information about the controlled variable is not automatically used to adjust the system inputs to compensate for the change in the process variables. In the controlled drug delivery field, open-loop systems are known as pulsed or externally regulated The externally controlled devices apply external triggers for pulsed delivery such as: magnetic, ultrasonic, thermal, and electric. It involves following systems : 1. Magnetically modulated drug delivery system 2. Ultrasonically modulated drug delivery system 3. Electrically modulated drug delivery system 4. Thermo sensitive drug delivery system 5. Other stimuli that control drug release

2. closed-loop control systems

In closed-loop control systems the controlled variable is detected and as a result the system output is adjusted accordingly. The closed-loop systems are known as as self regulated. In the self-regulated devices release rate is controlled by feedback information, without any external intervention. The self-regulated systems utilize several approaches as rate-control mechanisms: pH-sensitive polymers, enzyme-substrate reactions, pH-sensitive drug Solubility, competitive binding and metal concentration-dependent hydrolysis. It involve follwing system: 1. pH responsive drug delivery 2. Glucose-responsive insulin delivery
2

3. 4. 5. 6. 7.

Urea-responsive drug delivery system Inflammation-induced pulsatile release Morphine triggred naltrexone delivery system System utilizing antibobody interaction System utilizing chelation

Classification of intelligent drug delivery system :

Schematic Showing Classification of intelligent Delivery Systems.

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 and hypercholesterolemia. In pulsatile drug delivery system drug release is programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation etc.

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. 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, Iron, Nickel, Cobalt etc. For biomedical applications, magnetic carriers must be water-based, biocompatible, nontoxic and non-immunogenic mechanistic approach based on magnetic attraction is the slowing down of oral drugs in the gastrointestinal system. This is possible by filling an additional magnetic component into capsules or tablets.

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
4

 Electrically responsive 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-responsiv. In this system drug is disperse in hydrogel which is implanted subcutaneously. When drug release is desired, an electroconducting patch is applied on skin directly over gel.and electrode are pluuged into patch and electrical field is applied on skin. Under influence of electrical field, electroresponsive hydrogel Deswell or bend and releassse the drug. Also hydrogel in the form of beads can be injected subcuteneously or polymer solution which can be injected as liquid but which form gel at body temparature. 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

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 polyactide, polyglycolide, carboxyphenoxy)alkane anhydridesand their copolymers with sebacic acid.

poly(bis(p-

The bioactive used are p- aminohippurate, , insulin and bovin serum albumin etc. On exposure to ultrasound, polymer erosion occur and drug is release in controlled
manner from polymer metrices.

While in the non erodible polymer system, drug release is diffusion controlled. Studies revealed that that release rate of bovine serum insulin from ethylene vinyl acetate
copolymer matrices were 15 time higher when exposed to ultrasound.

It has been found that extent of enhancement can be regulated by the frequency, intensity,
or or cycle of applied ultrasound.

Photoresponsive system:
This approach involves use of photoresponsive polymer. The photoresponsive 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 photolabile conjugates 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. Light-sensitive conjugates are synthesized by Dicyclohexylcarbodiimide mediated method or Direct acid chloride esterification method. Incorporation of the conjugates into limitedporosity hydrogels like hydrated copolymer of 2-(hydroxyethyl) methacrylate and methyl methacrylate which are crosslinked with ethylene glycol dimethacrylate, leading to formulation of molecular level dosing devices. 3, 5 - dimethoxybenzoin is one of such photolabile conjugate which can be precisely and kinetically controlled to liberate free drug following exposure of 365 nm light for definite time period. Photoresponsive system has found applications in the ophthalmology (Intra ocular lenses for cataract treatment) as well as in administration of NSAIDS. Low energy radiation and accurate control on applied light by sophisticated equipment are the unique features of the system. The synthesis of novel photolabile conjugates and incorporation of more drugs in the Photoresponsive system may enhance patient compliance by reduction in side effect and promote the scientific research towards precisely controlled drug delivery

2. Responsive system :
Polymers responsive to change in their environment are of research interest. Many research groups are engaged in developing delivery system based on these responsive polymer. In this system drug delivery is controlled by means of an interaction with the surrounding environment without the aid of any external agency.

pH responsive drug delivery:

This approach utilizes the existence of pH change in different part of body. The obvious change in pH along the GI tract from acidic in the stomach (pH=2) to basic in the intestine (pH=58) has to be considered for oral delivery of many kind of drug. Also ,there are changes within different tissue like Certain cancers as well as inflamed or wound tissue exhibit a pH different from 7.4 as it is in circulation. 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 . pH in various tissues and cellular compartments:

Tissue/cellular compartment Blood Stomach Small intestine Colon Lysosome Golgi Tumour, extracellular

pH 7.357.45 1.53.5 5.5-6.8 6.47.0 4.55.0 6.4 6.5-7.2

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, s, HPMCP, etc. Coating of the drug core with pH sensitive polymers has been successfully used for colonic drug delivery.

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 .

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 (37C) in the presence of pathogens or pyrogens. This deviation sometimes can be 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. Example of thermoresponsive polymer with phase transition temparature

Polymer

Poly (N,N-diethylacrylamide) Poly (methyl vinyl ether) Poly (N-vinylcaprolactam) PEO-b-PPO (b) Poly (GVGVP) Pluronics, tetronics, Poloxamer The temparature modulation of drug delivery can be employed in following condition: 1. Hyperpyrectic drugdelivery : The normal body temperature of 37 C is elevated by the physiological presence of pathogens and pyrogens. Thus self regulating or auto feedback drug delivery device can be designed that release antipyretic drug in response to inceased body temperature. 2. Transdermal delivery system Thermosensitive polymeric membrane can be used as an on off switches in transdermal devices to achieve pulsatile drug delivery from skin 3. Externally modulated devices: Drug delivery devices relying on external modulationfor drug releasecan be desiged to respond to external temperature, and monitor or mediate drug release according to therapeutic need

Phase transition temperature in aqueous Solution 3234 C 37 C 3050 C 2085 C 2830 C

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 concavalin A(Con A). Con A is immobilized on sepharose beads and glycosylated insulin, which is biologically active is displaced from the Con A by glucose in proportion to the amount of glucose present, which competes for the same bindint sites. 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. Encapsulation of glycosylated insulin bound Con A in a suitable polymer membrane that is permeable to both glucose and insulin, the glucose influx and insulin efflux can be controlled.

 Kitano,1992, developed a glucose sensitive insulin delivery system based on a sol-gel transition. A phenyl boronic acid(PBA) moiety was incorporated in poly(N-vinyl-2pyrrolidone) using radical copolymerization of N-vinyl-pyrrolidone with m-acrylamido phenyl boronic acid[poly(NVP-Co-PBA)]. Insulin was entrapped into the polymer gel formed by a complex of poly(vinyl alcohol) withpoly(NVP-co-PBa). PBA forms reversible Covalent complexes with molecules having diolunits, like PVA or glucose. When glucose is added, PVA from the PVA-bromate complex is replaced by glucose. This leads to the transformation of the system from gel to sol state facilitates the releas of insulin from the polymeric complex

3. System utilizing enzyme:

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. 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.

Urea-responsive delivery
Heller and Trescony were the first to attempt using immobilized enzymes to alter local pH and thus cause changes in polymer erosion rates. The proposed system is based on the conversion of urea to NHaHCO3 and NHaOH by the actionof urease. As this reaction causes a pH increase, a polymer that is subjected to increased erosion at high pH is required. The authors suggested a partially esterifled copolymer of methylvinylether and maleic anhydride. This polymer displays release rates that are pH dependent. The polymer dissolves by ionization of the carboxylic acid group. Release of hydrocortisone from a disk composed of N-hexyl half ester of methylvinylether and maleic anhydride surrounded by a hydrogel containing urease immobilized by glutaraldehyde crosslinking. Although the device has no therapeutic relevance, it established the feasibility of creating self-responsive delivery system.
9

 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 possible to maintain opiate addicted subject on a dose of naltrexone. In this system, naltrexone is dispersed in polymer metrices.this polymer metrices is in turn covered by lipid layer that prevents water entry into the matrix And thereby retards its degradation Then system attached to enzyme-morphine(hepten) conjugate which is complexed with the morphine antibody. As antibodies are large molecules, access of subtracte 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.

naltrexone dispersed in biodegradable polymer

Morphine-lipase conjugate complexed with antibody

System Utilizing Chelation:

This system include 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 esterand amides by several orders of metals to magnitude. Attachment of chelator to a polymer chain by a covalent ester and amide link serves to prevent its premature loss by excretion by excretion and reduces its toxicity

10

 In presence of specific metal iona complexing with bound chelating agent will takeplace, followed by metal accelerated hydrolysis and subsequent elimination of metal chelate.

Delivery system for metal chelators, based on metal promoted hydrolysis of carboxylic esters.

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) page no. 1950

11