Intelligent drug delivery system
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The document discusses intelligent drug delivery systems (IDDS). It defines IDDS as systems capable of adjusting drug release rates in response to physiological needs to maintain therapeutic drug levels. The document then classifies and describes different types of IDDS, including pulsatile, responsive, enzyme-utilizing, and chelation systems. It provides examples of each system type and explains how they work to intelligently control drug release.
Intelligent drug delivery system
- 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 5
- 6. Intelligent drug delivery system may be 1.Open- loop system or 2.Closed-loop systems. 6
- 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. 14
- 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. 18
- 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. 20
- 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 . 21
- 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. 23
- 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 24
- 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 25
- 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. 26
- 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 . 30
- 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. 37
- 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. 40
- 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 43