A Text Book of: NOVEL DRUG DELIVERY SYSTEMS Strictly As Per Syllabus Prescribed for B.Pharmacy, ‘Semester-Vil by Pharmacy Council of India, New Delhi ? a Y Dr. Aljaz A. Sheikh i ‘5 Dr. Md: Rageeb Dr. Kallash® A Text Book of NOVEL DRUG DELIVERY SYSTEMS Strictly As Per Syllabus Prescribed for B.. Pharmacy, Semester-Vil by Pharmacy Council of India, New Delhi Dr. Aijaz A. Sheikh Dr. Subhash V. Deshmane M. Pharm., Ph.D M. Pharm., Ph.D Associate Professor Associate Professor Department of Pharmaceutics Department of Pharmaceutics Anuradha College of Pharmacy, Anuradha College of Pharmacy, Chikhli, Dist. Buldana (MH) Chikhli, Dist. Buldana (MH) Dr. Md. Rageeb Md. Usman M. Pharm., Ph.D., FAPP, FICPHS, FSRHCP, FRSH, FSPER Associate Professor Department of Pharmacognosy Smt. S. S. Patil College of Pharmacy, Chopda, Maharashtra & Dr. Kailash R. Biyani M. Pharm., Ph.D., DPPM. Professor & Principal Anuradha College of Pharmacy, Chikhli, Dist. Buldana & Joint Secretaries So joint Secre SGB Amravati University, Amravati SPER Central Branch ere President IPA/APP/RSH/SRHCP Mabarashtra State Branch ‘Scanned with CamScannerChapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 CONTENTS Controlled Drug Delivery System 1-23 1.1 Introduction 1, 1.2 Terminology 2, 1.3 Rationale of controlled drug delivery 4, 1.4 Selection of drug candidate 5, 1.5 Approaches to design controlied release formulations 7, 1.6 Factors influencing the formulation of controlled drug delivery system 14, 1.6.1 Physicochemical factors 14, 1.6.2 Biological factors 16 Polymers 24-44 2.1 Introduction 24, 2.2. Classification of polymers 26, 2.3 Characteristics of an ideal polymer 26, 2.4 Criteria followed in polymer selection 27, 2.5 Polymer properties 27, 2.6 Advantages of biodegradable polymers 29, 2.7 Biodegradable polymers 30, 2.8 Applications of polymers 30 Microencapsulation 45-59 3,1. Introduction 45, 3.2. Microspheres 46, 3.2.1. Ideal characteristics of microspheres 46, 3.2.2 Types of microspheres 47, 3.2.3. Advantages of microspheres 49, 3.3. fundamental considerations 49, 3.4 Methods of microencapsulation 51, 3.5. Application of microencapsulation 57 Mucosal Drug Delivery System 60-74 4.1, Introduction 60, 4.2. Mucosal membrane 60, 4.2.1. Functions of mucus layer 61, 4.2.2. Advantages of mucosal dug delivery system 62, 4.2.3. Disadvantages of mucosal dug delivery system 62, 4.3. Mechanism of bioadhesion 63, 4.4. Principles / theory of bicadhesion or mucoadhesion 65, 4.5. Transmucosal permeability 69, 4.6. Formulation consideration of buccal drug delivery system 70 Implantable Drug Delivery Systems 75-87 5.1. Introduction 75, 5.1.1. Ideal requirements of implantable drug delivery systems 75, 5.1.2 Advantages of implantable drug delivery systems 76, 5.1.3 Disadvantages of implantable drug delivery systems 76, 5.2. Classification of implantable drug delivery systems 77, 5.3 Applications of implantable drug, delivery system 82 Transdermal Drug Delivery System 88-108 6.1, Introduction 88, 6,2. Anatomy and physiology of skin 90, 6.3. Factors affecting transdermal drug delivery 94, 6.3.1. Physicochemical properties st Permeate 94, 63:2. Physiological and pathological conditions of skin , 6.33. Environmental factors 96, 6.4.1. Permeation enhancers 96, 6.4.2. Ideal properties of penetration enhancers 98, 6.5. Basic components of transdermal drug delivery system 98, 6.6. Formulation approach for transdermal drug delivery systems 101, 6.7. Evaluation parameters 105 Gastroretentive Drug Delivery Systems 109-122 7.1. Introduction 109, 7.2. Approaches for GRDDS 110, 7.2.1. High-density Reems 111, 7.2.2. Swelling and expandable system 112, 7.2.3. tucoadhesive systems 113, 7.2.4. Floating drug delivery systems 115, 7.2.5, ‘Scanned with CamScanneescent (gas generating) systems ntages of GRDDS 119, 7.4. Non-effervescent systems 116, 7.2.6 Efferve gastroretentive drug +27, Raft systems 118, 7.3. Advani 117. vantages of GRDDS 119, 7.5 Applications of delivery systems 120 aid i System 1 Chapter8 Nasopulmonary Drug Delivery Sy ‘ apt 8.1. Nasal drug delivery system 123, 8.1.1. LT sg 48.1.3. Limitations 124, 8.1.4. Anatomy and physiology o ee absorption 126, 8.1.6. Factors nasal cavity 125, 8.1.5. Mechanism of nasal influencing nasal drug absorption 126, 8.1.7. Nasal spray 127, 8.1.8. Characterization of nasal spray 129, 8.2. Pulmonary drug delivery system 129, 8.2.1. Introduction 129, 8.2.2. Advantages of pulmonary drug delivery 131, 8.2.3. Disadvantages of pulmonary drug delivery 151, 8.2.4, Anatomy and physiology of lungs 131, 8.2.5. Principal mechanisms of respiratory deposition 133, 8.2.6. Formulation of inhalers 134, 8.2.7. Recent trend in applications of pulmonary drug delivery 141 Chapter 9 Targeted Drug Delivery 145-165 9.1. Introduction 145, 9.2. Concepts 146, 9.3. Properties of targeted drug delivery 147, 9.4. Components of targeted drug delivery 147, 9.5. Drug delivery vehicles 147, 9.6. Advantages of targeted drug delivery 148, 9.6.1. Disadvantages of targeted drug delivery 148, 9.7. Type of drug carrier 149, 9.7.1. Targeting moieties 149, 9.8. Strategies of drug targeting 149, 9.9. Properties influencing drug targeting 151, 9.10. Liposomes 151, 9.11. Niosomes 153, 9.12. Nanoparticles 156, 9.13 Monoclonal antibodies 161, 9.13.1 Applications 162 f Chapter 10 Ocular Drug Delivery 166-187 10.1. Introduction 166, 10.1.2 The anatomy of the eye 166, 10.1.3. Ideal characteristics of ophthalmic drug delivery system 170, 10.2. Intra ocular barriers to drug delivery systems 170, 10.3 Methods to overcome intra- ocular barriers 172, 10.4 Approaches to improve ocular bioavailability 175, 10.5. Ophthalmic formulations 178, 10.5.1 Eye drops 178, 10.5.2 Ophthalmic solutions 178, 10.5.3 Microemulsions 178, 10.5.4. In situ gels 179,.10.55. Eye ointments 179, 10.5.6 Contact lenses coated with drugs 179, 10.5.7 Liposomes 179, 10.5.8. Niosomes and discosomes 180, 10.5.9. Ocuserts 181), Chapter 11 Intra Uterine Drug Delivery System 188-197, 11.1. Introduction 188, 11.2. Historical baground 188, 11.3 Anatomy of the uterus 189, 11.4. Types of IUD 190, 11.4.1. First-generation IUDS: plastic devices 190, 11.4.2 Second generation IUDS: copper-bearing devices... 191, 11.4.3. Third generation IUDS: steroid medicated devices 193, 11.5: as of action 193, 11.6. Advantages of intra-uterine devices 194 .7. Disadvantages of intra-uterine devi icati ey los 8 levices 195, 11.8. Applications Bibliography 198-199 INDEX ‘Scanned with CamScannerSYLLABUS Unit-I Controlled Drug Delivery Systems: Introduction, terminology /definitions and ratio- nale, advantages, disadvantages, selection of drug candidates. Approaches to design con- trolled release formulations based on diffusion, dissolution and ion exchange principles. Physicochemical and biological properties of drugs relevant to controlled release for- mulations. Polymers: Introduction, classification, properties, advantages and application of poly- mers in formulation of controlled release drug delivery systems. Unit-II Microencapsulation: Definition, advantages and disadvantages, microspheres / microcapsules, microparticles, methods of microencapsulation, applications. Mucosal Drug Delivery system: Introduction, Principles of bioadhesion /mucoadhesion, concepts, advantages and disadvantages, transmucosal permeability and formulation con- siderations of buccal delivery systems. Implantable Drug Delivery Systems: Introduction, advantages and disadvantages, con- cept of implantsand osmotic pump. Unit-III Transdermal Drug Delivery Systems: Introduction, Permeation through skin, factors affecting permeation, permeation enhancers, basic components of TDDS, formulation ap- proaches. Gastroretentive Drug Delivery Systems: Introduction, advantages, disadvantages, ap- proaches for GRDDS - Floating, high density systems, inflatable and gastroadhesive sys- tems and their applications. Nasopulmonary Drug Delivery System: Introduction to Nasal and Pulmonary routes of drug delivery, Formulation of Inhalers (dry powder and metered dose), nasal sprays, nebulizers. Unit-IV Targeted Drug Delivery: Concepts and approaches advantages and disadvantages, in- : ; F ep! PP) gs 8 troduction to liposomes, niosomes, nanoparticles, monoclonal antibodies and their applica- tions. Unit-V Ocular Drug Delivery Systems: Introduction, intra ocular barriers and methods to over- come Preliminary study, ocular formulations and ocuserts. Intrauterine Drug Delivery Systems: Introduction, advantages and disadvantages, de- velopment of intra uterine devices (IUDs) and applications. ‘Scanned with CamScanneeCHAPTER-1 — Over the past 40 years, as the expense and complications involved in marketing new drug entities have increased, with concomitant recognition of the therapeutic advantages of novel drug delivery, greater attention has been focused on development of controlled release drug delivery system. The role of drug delivery today is to take a therapeutically effective molecule with sub-optimal physiochemical and/or physiological properties and develop an optimized product that will still be therapeutically effective with added benefits. New drug delivery systems have been developed or are being developed to overcome the limitation of the conventional drug delivery systems to meet the need of the health care system. These systems can be characterized as controlled drug release systems and targeted drug delivery systems. The term “controlled release” has a meaning that goes beyond the scope of sustained drug action. It also implies predictability and reproducibility in the release rate kinetics, which mean that the release of drug ingredients from a controlled release drug delivery system proceeds at a rate profile that is not only predictable kinetically but also reproducible from one unit to another. Controlled release drug delivery system provide uniform concentration of drug to the absorption site and thus allows the maintenance of plasma concentration within the therapeutic range which minimizes not only the side effects but also the frequency of administration. Controlled-release systems are designed to lead to predictably constant plasma concentrations, independently of the biological environment of the application site. This means that they are actually controlling the drug concentration in the body, not just the release of the drug from the dosage form, as is the case in a sustained-release system. Another difference between sustained- and controlled-release dosage forms is that the former are basically restricted to oral dosage forms whilst controlled-release systems are used in a variety of administration routes, including transdermal, oral and vaginal administration. Controlled release of drugs from a dosage form maybe achieved by the use Of so-called therapeutic systems. These are drug delivery systems in which the drug is released in a predetermined pattern over a fixed period of time. The release kinetics is usually zero-order. In contrast to sustained-release systems, the dose in the therapeutic systems is of less importance than the release rate from the therapeutic system. Ideally the @ ‘Scanned with CamScannerES PY ATEXT BOOK OF NOVEL DRUG DELIVERY SYSTEMS rm should be the rate-determining step for the absorption g ; tion in the plasma and target site. Howeye, target-specific, which means that they do nop release rate from the dosage for the drug and in fact for the drug ae controll ae i organ. This may be achieved by so-called targetg Raney sytems which aim to exploit the characteristics of the drug carrier and the drug target to control the biodistribution of the drug. More precisely, controlled delivery can be defined as: 7 / «Sustained drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects. «Localized drug action by spatial placement of a controlled release system adjacent to or in the diseased tissue. * Targeted drug action by using carriers or chemical derivatives to deliver drug toa particular target cell type. * Provide a physiologically / therapeutically based drug release system. In other words, the amount and the rate of drug release are determined by the physiological or therapeutic needs of the body. A controlled drug delivery system is usually designed to deliver the drug at particular rate. Safe and effective blood levels are maintained for a period as long as the system continues to deliver the drug. This predetermined rate of drug release is based on the desired therapeutic concentration and the drug's pharmacokinetics. RMINOLOGY The controlled release system is to deliver a constant supply of the active ingredient usually at a zero-order rate by continuously releasing for a certain period of time, an amount of the drug equivalent to the eliminated by the body. An ideal controlled drug delivery system is the one which delivers the drugs at a predetermined rate, locally or systematically, for 4 Specific period of time. In general, controlled delivery attempts to: 1, Sustain drug action at a predetermin i ed rate by maintaining a relatively constant effective drug level in the bod : 'y with concomitant minimization of undesirable sid? effects associated with a saw tooth kinetic pattern. I 2. Localize di i i ji eee by spatial placement of a controlled release system (usually 1 F adjacent to or in the diseased tissue or organ. ‘Scanned with CamScanneeCONTROLLED DRUG DELIVERY SYSTEM a Various designations such as smart, targeted, intelligent, novel, and therapeutic, have been given to controlled release systems. Therapeutic systems have also been used interchangeably with rate-controlled release systems. These usually operate on an advanced engineering system control approach, consisting of a logic element with or without a sensor. Three types of therapeutic systems are available, namely, passive preprogrammed, active preprogrammed, and active self-programmed. Most rate controlled release systems fall in the category of passive preprogrammed, in which the release rate is predetermined and is irresponsive to the external biological environment. Examples of active preprogrammed are few and include most metered insulin pumps, whose release rate can be altered by a source external to the body. The active, self-programmed therapeutic systems modulate release rate of the drug in response to information, registered by a sensor, on the changing biological environment such as blood sugar level in diabetes. ZERO-ORDER CONTROLLED RELEASE SUSTAINED RELEASE CONVENTIONAL TABLET OR CAPSULE PLASMA CONCENTRATION TIME Fig. 1.1: Plasma drug concentration-profiles for conventional tablet or capsule formulation, a sustained release formulation and a zero order controlled release formulation Figurel shows comparative blood drug level profiles obtained from administration of conventional, controlled as well as prolonged release dosage forms. Thus, the conventional tablet or capsule provides only a single and transient burst of drug. As long as the amount of drug is above the minimum effective concentration, a pharmacological response is observed. Problems occur when the therapeutic range is very narrow or when the peak is greater than the upper limit of this range. Indeed, one of the main purposes of controlled release is to improve safety and minimize side effects of the drug by reducing fluctuations in drug level. Prolonged release dosage forms also reduce fluctuations in. plasma drug levels by slowing down the absorption rate due to slower drug release rate. In many cases, this is achieved by _ ‘Scanned with CamScannee| 3U ATEXT BOOK OF NOVEL DRUG DELIVERY SYSTENs termi a small burst of drug over longed period of time as tently releasing a iS a prolonged pe! in the inte of repeat-action dosage forms. 1.3 RATIONALE OF CONTROLLED D. iG DELIVERY 7 The basic rationale of a controlled release drug delivery system is to optimize the biopharmaceutics, pharmacokinetics and pharmacodynamics Propertis fad a Such a way that its utility is maximized through reduction in side effects an OF control of disease condition in the shortest possible time by using smallest \ aed Of drug, administered by most suitable route. The immediate release drug delivery system lacks some features like dose maintenance, controlled release rate and site targeting. The decrease in the frequency of daily doses is more convenient to the patient and can lead to improved patient compliance. Reduction of dosing from three or four times daily to once or twice daily has been shown to increase patient compliance. Reduction in fluctuation of drug blood levels | about the mean. A controlled release dosage form may decrease the drug concentration’s | fluctuation by reducing the peak blood levels, thus potentially reducing dose related adverse effects and increasing the minimum plasma concentrations, thereby increasing efficacy if a threshold concentration is required. An ideal drug delivery system should deliver the drug | ata rate dictated by the need of body over a specified period of treatment. It is desirable that the duration of drug action become more to design properly. Rate controlled dosage form and less or not at all, a property of the drug molecules inherent kinetic properties. ADVANTAGES OF CONTROLLED DRUG THERAPY > Patient compliance due to reduction in the frequency of designing, Employ minimum drug. Minimize or eliminates local and systemic side effects, Obtain less protentiation or deduction in drug activity with chronic use. Minimize drug accumulation with chronic dosing. Improves efficacy in treatment. Cure or control confirm more promptly. vvvvvvvVv Improve control of condition i.e. reduce Improve bioavailability of same drugs, Make use of special effects, e. Sustained rele; ming relief a ined i i a I fe lease aspect for morning 7 fluctuation in drug level. i DISADVANTAGES OF CONTROLLED DRUG THERAPY > The physician has less flexibility in ei... dosage torm design, NY in adjusting the dosage regimen. This is fixed ‘Scanned with CamScannerCONTROLLED DRUG DELIVERY SYSTEM Ew > Administration of this type of dosage form does not permit the prompt termination of therapy. Economic factors include more costly processes and equipments that are involved in manufacturing many controlled release dosage forms. » All drugs are not suitable candidates for controlled release medication, Drugs with long biological half life (e.g. digoxin-34 hours) are inherently long acting and thus are viewed as questionable candidates for sustained release formulations. > Drugs with narrow requirements for absorption (e.g. drugs which depend on position of G1T for optimum absorption is also poor candidates). > Drugs like riboflavin and ferrous salt, which are not effectively absorbed in lower intestine, are poor candidates. > Drugs which are having very short half life (<1 hour) e.g.: penicillin, furosemide are poor candidates for sustained release formulations. > Patients may need substantial additional information as to the proper use of sustained release products e.g. Do not crush or chew the dosage unit. > In controlled release dosage form, the rate of drug release is deliberately reduced to achieve drug release possibly over a large region of gastrointestinal tract. Here the so called ‘Absorption window’ becomes important and may give rise to unsatisfactory drug absorption in vivo despite excellent in-vitro release characteristics. 4 SELECTION OF DRUG CANDIDATE A detailed knowledge of absorption, distribution, metabolism and excretion (ADME) characteristics of drug is essential in the design of controlled/sustained release products. An optimum range of given pharmacokinetic parameter of a drug is necessary beyond which controlled/ sustained delivery is difficult. Criteria to be met by drug proposed to be formulated in controlled release dosage forms are as follows. 1. Desirable Half Life The half life of a drug is an index of its residence time in the body. If the drug has a short half life less than 2 hours, the dosage form may contain a prohibitively large quantity of the drug. On the other hand, drug with elimination half life of eight hours or more are sufficiently sustained in the body, when administered in conventional dosage from and controlled release drug delivery system is generally not necessary in such cases. Ideally, the drug should have half-life of three to four hours. ‘Scanned with CamScannerK OF NOVEL DRUG DELIVERY SYSTEys 2. High Therapeutic Index are unsuitable for incorporation in controlled reeage ith low therapeutic index ing may occur, leading to fatalig Drugs with dose dumping may es formulations. If the system fails in the body, eg. digitoxin. oe is hij i itability as a candi ae ce drug in the conventional dosage form is high, its ares esac wae for controlled release is seriously undetermined. This is chiefly ee piokia ose controlled release formulation would become too big to adminis 4. Desirable Absorption and Solubility Characteristics z . | imite Absorption of poorly water soluble drug is often dissolution rate limi aera compounds into controlled release formulations is therefore unrealistic a reduce d. Incorporating such overall absorption efficiency. 5. Desirable Absorption Window a Certain drugs when administered orally are absorbed only from a specific part of gastrointestinal tract. This part is referred to as the ‘absorption window’. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as controlled release dosage form are unsuitable. 6. First Pass Clearance Delivery of the drug to the body in desired concentrations is seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism when administered in controlled release forms. : Table 1.1: Physicochemical parameter for drug selection ‘Parameters Criteria Molecular weight Less than 600 Daltons Aqueous solubility O.1mj mg/ml for pH 1 Partition coefficient Ko/w 1-2 mers Dissociation constant pka Acidic drug, pka> 25 Basic dru; : Absorption mechanism Passive Sle < 10 Stability in GI miliew Tonization at physiological pH Release rate ‘Scanned with CamScannerCONTROLLED DRUG DELIVERY SYSTEM En Table 1.2: Pharmacokinetic parameters for drug selection Parameters ‘Comments Elimination half life Between 2-6 hrs “Absolute bioavailability > 75% or more Absorption rate constant High Metabolism rate Not too high Total clearance Should not depend on dose Therapeutic concentration Lower therapeutic concentration(Css) and smaller apparent volume of distribution (Vd) 1.5 APPROACHES TO DESIGN CONTROLLED RELEASE FORMULATIONS The oral route of administration is the most preferred route due to flexibility in dosage form, design and patient compliance. But here one has to take into consideration the various pH that the dosage form would encounter during its transit, the gastrointestinal motility, the enzyme system and its influence on the drug and the dosage form. The majority of oral sustained release systems rely on dissolution, diffusion or a combination of both mechanisms, to generate slow release of drug to the gastrointestinal milieu. Theoretically and desirably a sustained release delivery device should release the drug by a zero-order process which would result in a blood level time profile similar to that after intravenous constant rate infusion. The controlled drug release has been attempted to be achieved with various classes are discuss below. 1. Diffusion systems a) Reservoir devices b) Matrix devices 2. Dissolution systems a) Reservoir devices b) Matrix devices 3. Methods using ion exchange 4, Methods using osmotic pressure 5. pH independent formulations 6, Altered density formulations 1. Diffusion Systems It is a major process for absorption in which no energy required. Basically diffusion process shows the movement of drug molecules from a region of a higher concentration to one of lower concentration until equilibrium is attained and it is directly proportional to the concentration gradient across the membrane. In this system release rate is determined by its _/ ‘Scanned with CamScannerLIVERY SYSTEMs py ATEXT BOOK OF NOVEL DRUG DE amount / area time) tux of the drug J Gn by Fick’s law. soluble polymer. The fl rug centration is given lecreasing con’ diffusion through a water-i across a membrane in the direction of Je-D de/dx Where, D = diffusion coefficient in a1 de/dx = change of concentration '' in common form, when a wal diffuse through the membrane. a, Reservoir Devices lled as laminated matrix device. It is a hollow system containing an inner core ane and polymer can be applied by coating or micro partition into membrane and that drug will ‘on. Commonly used polymers are products are Nico-400, Nitro-Bid, kness of coating and hardness of rea/ time n ‘c' with distance ; ter insoluble membrane encloses a core of drug, it must It is also ci surrounded by water insoluble membr. encapsulation. The rate controlling mechanism is exchange with the fluid surrounding the drug b HPC, ethyl cellulose and polyvinyl acetate. Examples of Rate controlling steps is polymeric content in coating, thic y diffusi microcapsule. Polymer ° eC) ° Drug e 2 Time-0 ° Time-t Fig, 1.2: Schematic representation of reservoir diffusion controlled drug delivery device The rate of drug released (dm/dt) can be calculated using the following equation dmv/dt= ADKx AC/¢ 4 Where, A= Area D = Diffusion coefficient K = Partition coefficient of the di irug between the dru; ae ig core and the membrane pee difference across the membrane jffusion reservoir devices have been s cess ome of the widel systems. eke a ze s. Common methods used to develop reservoi ee a, el a de encapsulation of drug particles and film coating of ane ae lets. In most cases, if ‘Scanned with CamScannerCONTROLLED DRUG DELIVERY SYSTEM Ee coated by microencapsulation form a system in which the drug is contained in the coating film as well as in the core of the microcapsule. Drug release usually involves a combination of dissolution and diffusion, with dissolution being the process that controls the release rate. If the encapsulating material is selected properly diffusion will be the controlling process. Some materials used as the membrane barrier coat, alone or in combination, are hardened gelatin, methyl or ethyl celluloses, polyhydroxymethacrylate, hydroxypropylcellulose, polyvinylacetate, and various waxes. Drug release from these products probably is based primarily on diffusion, but dissolution may occur as well. Diffusion controlled reservoir devices are also used in other routes such as parental, ocular, transdermal and vaginal. By this system zero order delivery is possible release rates variable with polymer type. Disadvantage is that system has to be physically removed from implant sites. Difficult to deliver high molecular weight compound generally increased cost per dosage unit, potential toxicity if system fails. b. Matrix Devices In the matrix devices the drug or active is dispersed in polymer matrix to form a homogeneous system known as a matrix system. Diffusion occurs when the drug passes from the polymer matrix into the external environment. As the release continues, its rate normally decreases with this type of system, since the active agent has a progressively longer distance to travel and therefore requires a longer diffusion time to release. The three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices that have been investigated include methyl acrylate methyl methacrylate, polyvinyl chloride and polyethylene. The Gradumet tablet (Abbott) was an example of a dosage form using a plastic matrix. Hydrophilic polymers include methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, and carbopol 934. Fatty compounds include various waxes such as carnauba wax and glyceryl tristearate. The most common method of preparation is to mix the drug with the matrix material and then compress the mixture into tablets. In the case of wax matrices the drug generally is dispersed in molten wax which is then congealed, granulated and compressed into cores. In any extended release system, it is necessary for a portion of the drug to be available immediately as a priming dose and the remainder to be released in a sustained fashion. This is accomplished in a matrix tablet by placing the priming dose in a coat of the tablet. The coat can be applied by press coating or by conventional pan or air suspension coating. Some marketed matrix diffusion products for oral dosing are Gradumet tablets, Procan SR, Tral. Similar to reservoir devices, matrix ‘Scanned with CamScanneepy ATEXT BOOK OF NOVEL DRUG VELIVERT SYSTEMS drags in other routes: parental and transdermal Higuchi pa, © i Iso used to deliver 3 mm tc ee ingrnae _ Q-=De/TI2 A-eCs] Cst% Where, : Q= Weight in gms of drug released per unit area of surfa D = Diffusion coefficient of drug in the release medium e = Porosity of the matrix ; Cs = Solubility of drug in release medium T= Tortuosity of the matrix ‘oncentration of drug in the tablet, as gm/ ml ce at time t Polymer Drug ee Time-t Fig. 1.3: Schematic representation of monolithic matrix diffusion controlled drug delivery device Time-0 Although active agent release from monolithic system does not proceed by zero order Kinetics, it is the simplest and most convenient ways to achieve prolong release of an active agent. Such devices can be conveniently prepared by using simple polymer fabrication technique involving a physical blending of the active agent with a polymer matrix followed by compression molding, injection molding, extrusion, calendaring or solvent casting: Examples of diffusion controlled devices are discussed bel low, i, Diffusion Controlled Implants "e : Implants are most commonly used for parental administration over a_ significantly Prolonged period of time (days to years). Norplant (Wyeth-Ayerst) is a commercial a levonorgestrel implant system, indicated for the prevention of pregnancy for i os years. Although implants possess such evident advantages as convenience concerns over body responses ” toa fore i = f and safety issues. Application of bioc ‘ ign material often rales biocompy achieving better control over the durati, construction of implant ‘Scanned with CamScannerCONTROLLED DRUG DELIVERY SYSTEM ii. Transdermal Patches . Membrane modulated system is a one type of transdermal patches. In this system the drug, reservoir is totally encapsulated in a shallow compartment molded from a drug impermeable backing and a rate controlling polymeric membrane. The drug molecules are released only through the rate controlling polymeric membrane. The rate limiting membrane can be microporous or nonporous. On the external surface of the membrane, a thin layer of drug-compatible, hypoallergenic, adhesive polymer (e.g. silicone or polyacrylate adhesive) may be applied to achieve intimate contact of the transdermal system with the skin. The rate of drug release from this type of drug delivery system can be tailored by varying the polymer composition, permeability coefficient, or thickness of the rate limiting membrane and adhesive. 2. Dissolution Systems The dissolution process can be considered diffusion layer controlled, where the rate of diffusion from the solid surface to the bulk solution through an unstirred liquid film is the rate determining step. In this case the dissolution process at steady state is described by the Noyes-Whitney equation. dC/dt = kD A(Cs-C) =(DIh)A(Cs - ©) Where, dC/dt = Dissolution rate KD = Dissolution rate constant ‘A= Total surface area Cs = Saturation solubility of the solid C = Concentration of solute in the bulk solution D= Diffusion coefficient h = Thickness of the diffusion layer The above equation predicts a constant dissolution rate if the surface area, diffusion coefficient, diffusion layer thickness, and concentration difference are kept constant. However, as dissolution proceeds, all of these parameters may change especially surface area. Dissolution controlled products can be sub divided into following two types: a, Encapsulated/Reservoir Devices Encapsulated dissolution systems can be prepared either by coating particles or granules of drug with slowly soluble polymers whose thicknesses vary or by microencapsulation. The coating materials may be selected from a wide variety of natural and synthetic polymers, depending on the drug to be coated and the release characteristics desired. The most commonly used coating materials include gelatin, carnauba wax, shellac, cellulose acetate phthalate, and cellulose acetate butyrate. Drug release from microcapsules is a mass ‘Scanned with CamScanner1 DRUG DELIVERY SYSTEQATT K OF NOVE! py ATEXT BOO! 7 ize of microcapsiijes djusting the *! : , led by ae materials. The thickness can 4, ammount of coating material from 3%, 5, arses are used, usually UATE’ oF fou, transport phenomenon and can be controll thickness of coating materials, and the diffusi varied from less than 1p m to 200 pm by changing the 30% of the total weight. If only a few different thicks nea delayed release effect 5 drugs will be released at different, predetermined times to 1” £ rr repeat action). Ifa spectrum of different thicknesses is employed, ee aiyeet the drug can be obtained from the dosage form as a whole. Microcapsut les hn a Med into capsules and rarely tableted as their coatings tend to disrupt during ‘ Presson Spansule capsules and Dexedrine and Hispril are some of the marketed products relying primarily on encapsulated dissolution system. Dissolving coat ‘ © ae ivity of core Dissolving Coat Fig. 1.4: Encapsulation dissolution controlled systems | b. Matrix devices A matrix dissolution device is prepared by compressing the drug with a slowly soluble polymer carrier into a tablet form. There are two general methods of preparing drug-wax Particles: congealing and aqueous dispersion. In the congealing met i 5 : hod, drug is mixed with a wax material and either spraycongealed or congealed and screened. In the aqueous Y sprayed or placed in water, and the also made by direct compression of # dispersion method, the drug-wax mixture is simpl | resulting particles are collected. Matrix tablets are mixture of drug, polymer, and excipients. ‘Scanned with CamScannee; CONTROLLED DRUG DELIVERY SYSTEM tablet, Bayer]) Matrix dissolution devices are also widely used in parenteral therapy (eg, Zoladex subcutaneous implant for delivery of goserelin. 3, Methods using Ion Exchange This system is designed to provide the controlled release of an ionic or ionizable drug. It is prepared by first absorbing an ionized drug onto the ion exchange resin granules such as codeine base with Amberlite, and then after filtration from the alcoholic medium, coating the drug resin complex granules with a water permeable polymer, e.g. a modified copolymer of polyacrylic and methacrylic ester, and then spray drying the coated granules to produce the polymer coated drug resin preparation. The drug is released by exchanging with appropriately charged ions in the GIT. The drug is then diffuse out of the resin. Resint - drug: + X- resin‘ - X- + drug” Where, X- Are ions in the GI tract The rate of diffusion control by the area of diffusion, diffusion path length and rigidity of resin. Thus, drug release depends on the ionic environment (pH, electrolyte conc.) and the properties of resin. This method is helpful for those drugs which are highly susceptible to degradation by enzymatic processes since it offers a protective mechanism by temporarily altering the substrate. The release rate is proportional to the concentration of the ions present in the vicinity of administration site. So variable diet, water intake and intestinal contents affects the release rate of drug. There are mainly two types of resins i.e. cation exchange and anion exchange resin. a. Cationic Drugs A cationic drug forms a complex with an anionic ion exchange resin e.g. a resin with a SOs group. In the Gl tract Hydronium ion (H*) in the gastrointestinal fluid penetrates the system and activity the release of cationic drug from the drug resin complex. H* + Resin - SOsdrug + + Resin - SOx H* + Drug b. Anionic Drugs ‘An anionic drug forms a complex with a cationic ion exchange resin, e.g. a resin with a [N (CHs)s4] group. In the GI tract the Chloride ion (Cl) in the gastrointestinal fluid penetrates the system and activates the release of anionic drug from the drug resin complex. Cl: + Resin — [N (CHa) “I drug’ = Resin - [N (CHs)s *] Cl'+ Drug: ‘Scanned with CamScannerEXT BOOK OF NOVEL DRUG DELIVERY SYSTEMS PATI NIOISO NINO MEDIO FORMULATIO et 1.6 FACTORS INFLUENCING TH 1.6.1 PHYSICOCHEMICAL FACTORS 1. Aqueous Solubility Most of the drugs are weak acids or weak bases. difficult to incorporate into sustained release mechanism. and rapid dissolution rate, it is often quite difficult to ret higher water solubility can dissolve in water or gastrointestinal release its dosage form in a burst and thus is absorbed quickly. Leadi P in the blood drug concentration compared to less soluble drug. It is often difficult to incorporate a highly water soluble drug in the dosage form and retard the drug release especially when the dose is high. The pH dependent solubility particularly in the physiological pH range would be another problem for the controlled release formulations because of the variations in the pH throughout the gastrointestinal tract and variation in the dissolution rate. The biopharmaceutical classification system (BCS) allows estimation of likely contribution of three major factors solubility, dissolution and intestinal permeability which affect the oral absorption. Class III (high solubility- low permeability) and class IV (low solubility-low permeability) drugs are poor candidates for controlled release dosage form. Compound with solubility <0.1mg/ml face significant solubilisation obstacles and often compounds with solubility 10mg/ml presents difficulties to solubilisation dosing formulation. In general, high soluble drugs are undesirable for formulation in to a controlled release product. 2. Partition Coefficient Drugs with low water solubility will be For a drug with high solubility rd its dissolution rate. A drug of I fluid readily and tends to ling to a sharp increase Partition coefficient is defined as the fraction of drug in an oil phase to that of an aqueous phase. It governs the permeation of drug particles through biological membrane. Drugs with high partition coefficient value easily permeate through biological membrane, The diffusion of drug molecules across rate controlling membrane or through the matrix relies on partition coefficient. Drugs that have lower partition coeffic oral controlled release drug delivery system and drugs that have hi are also not suitable for oral controlled drug delivery system becau out of the lipid membrane once it gets in the membrane, 3. Drug pKa and ionization at physiological pH system essentially ient are not suitable for igher partition coefficient se they will not partition Drugs existing largely in ionized form are poor candidate for delivery system because absorption rate of ionized drug ig unionized form. The pKa range for acidic drug whose ioniza oral controlled release drug 3-4 times less than that of tion is PH sensitive is around + } if ‘Scanned with CamScannerCONTROLLED DRUG DELIVERY system 7.5 and for basic drug whose ionization is timum positive absorption. 4, Drug Stability ‘The stability of a drug in the environment to which it is exposed is another physicochemical factor to be considered in the design of the sustained/ controlled release system. Drugs undergo both acid/base hydrolysis and enzymatic degradation when administered oral route. A drug in a solid state undergoes degradation at a much slower rate than a drug in suspension or solution. Drugs that are unstable in gastric pH can be developed as slow release dosage form and the drugs can be delayed till the dosage form reaches the intestine. Drugs that undergo gut wall metabolism and show instability in small intestine are not suitable for oral controlled drug delivery systems. 5, Protein Binding PH sensitive is around 7.0-11.0 are ideal for The drug can bind to components like blood cells and plasma proteins and also to tissue proteins and macromolecules. It is well known that many drugs bind to plasma proteins with a concomitant influence on the duration of drug action. Drug protein binding is a reversible process. As the free drug concentration in the blood decreases, the drug-protein complex dissociates to liberate the free drug and maintain equilibrium. A protein bound drug due to its high molecular size is unable to enter into hepatocytes, resulting in reduced metabolism. The bound drug is not available as a substrate for liver enzymes there by further reducing the rate of metabolism. The glomerular capillaries do not permit the passage of plasma-protein and drug protein complexes. Hence only unbound drug is eliminated. The elimination half life of drugs generally increases when the percent of bound drug to plasma increases. Such drugs need not be formulated into sustained/controlled release formulations, 6. Molecular Size and Diffusivity Diffusivity defined as the ability of a drug to diffuse through membrane is inversely related to molecular size. Diffusivity depends on size and shape of the cavities of the membrane. More than 95% of drugs are absorbed by passive diffusion. The upper limit of drug molecular size for passive diffusion is 600dalton. The examples of the drugs which are difficult to control release rate of medicament from dosage form are proteins and peptides. 7. Mechanism and Site of Absorption Drugs that are absorbed by carrier mediated transport process or through a window are Poor candidates for controlled release system, e.g. vitamin B. 8. Route of Administration For controlled release oral and parenteral routes are the most preferred which is the followed by transdermal route, In case of oral route drug must get absorbed through the ‘Scanned with CamScannerDELIVERY STSTEMg ed for drugs which show with low dose. Important skin condition, skin is select act. Transdermal route 15 3° ral administration oF drug: entire length of gastrointestinal t ay coefficient of drugs, comtact are extensive first pass metabolism upon factors to be considered are partition permeability of drug and skin perfusion rate. 1.6.2 BIOLOGICAL FACTORS ict is to place a control on delivery system, 1. Absorption 7 A . ju The aim of formulating controlled release pr‘ or ahould release comple orbed. The fraction of drug absorbed The desirable quality of oral controlled delivery sy drug should be completely abs g absor Sextet cnn bo ver dd due to degradation of drug, protein binding, lubility and small partition from the system can be lower than the expecte t process (carrier mediated) site specific, dose dependent absorption, coefficient. Drugs which are absorbed by specialized transpor! : (absorption window) are and drug absorption at special sites of the gastrointestinal trac poor candidates for sustained release products. With respect to oral route it is well known that that absorptive character of the different segments of the GI tract varies, which in turn can influence the amount and the rate of absorption for certain drugs. The oral anticoagulant dicumarol, the quaternary ammonium compounds hexamethonium and decamethonium are examples of such drugs. Iron is not uniformly well absorbed along the length of the GI tract. The greatest uptake of drug occurs at the upper part of the duodenum with significantly reduced absorptive capacity in the lower segment of the intestine. poor water sol 2. Distribution The distribution of drugs into tissue can be an important factor in the overall drug elimination kinetics since it not only lowers the concentration of circulating drug but it also can be rate limiting in its equilibration with blood and extracellular fluid. One aspect ofthis distribution is binding of drug to tissues and proteins in the blood. In general, the bound portion of a drug can be considered inactive and unable to cross membranes, At high bindings one sees prolonged drug action. The apparent volume of distribution is one of the important parameter of drugs that describes the magnitude of distribution as well as proteit binding within the body. Drugs with high apparent volume of distribution, which intlt the rate of elimination of drug, are poor candidate for oral drug delivery system: The apparent volume of distribution influences the concentration and amount of drug either circulating in the blood or in target tissues. It can also influence the elimination kinetics of a drug. The distribution of drug can be determined by the volume of distribution at steady state and T/P ratio. * T/P=K12/ (K21-b) ‘Scanned with CamScannerCONTROLLED DRUG DELIVERY system Where, J-Amount of drug in peripheral compartment, p-Amount of drug in central compartment, K12-Constant for distribution of drug from central to peripheral compartment, K21=Constant for distribution of drug from peripheral to central compartment p-Slow disposition constant. 3, Metabolism Drug metabolism can result in either inactivation of an active drug or conversion of an inactive drug to an active metabolite. The process of metabolism can take place in variety of tissues but the organ mainly responsible for metabolism is liver as it contains variety of enzyme systems and thus greatest metabolic alteration of a drug takes place after its absorption into the systemic circulation. Thus the metabolic pattern of a drug may influence the choice of the route of administration. There are two factors associated with metabolism that significantly limit controlled release product design. First, if a drug is capable of either inducing or inhibiting enzyme synthesis it will be difficult to maintain uniform blood levels, of drug upon chronic administration. Second, if the drug undergoes intestinal (or other tissue) metabolism or hepatic first pass metabolism this also will result in fluctuating drug blood levels. Examples of drugs that undergo intestinal metabolism upon oral administration are hydralazine, salicylamide, nitroglycerin, isoproterenol, chlorpromazine, and levodopa. Examples of drugs that undergo hepatic first pass metabolism are; Propoxyphene, nortriptyline, phenacetin, propranolol and lidocaine. Successful controlled release products for drugs that are extensively metabolized can be generated as long as the location, rate and extent and metabolism are known and the rate constant(s) are not too large. It can be assumed that a controlled release product can be developed as long as the metabolism remains predictable. 4. Therapeutic Index Margin of safety can be described by considering therapeutics index, which is the ratio of median toxic dose and median effective dose. Therapeutic index = TD50/ED50 Where, ne ss median toxic dose ae median effective dose / ’ — ith low therapeutics index are unsuitable for drug incorporation in controlled release formulation, The side effects can be minimized by controlling the concentration within therapeutic range. A drug is considered to be safe if its therapeutic index value is greater than 10, ‘ ( a ‘Scanned with CamScanneeG DELIVERY SYSTEM PY ATEXT BOOK OF NOVEL DRU! 5, Therapeutic Range nave a therapeu A candidate drug for controlled release drug delivery system an we a the ea range wide enough such that variations in the release rate do not ré beyond this level. Therapeutic index= Median toxic dose/ Median = TD so! ED 0 , a However, the ratio provides no information on the nature of the distribution of toxicity and effectiveness, the size of doses producing therapeutics and toxic effects and plasma or serum drug concentrations corresponding to toxic and therapeutic levels. Consequently it can only be used as crude estimate of the relative safety of a drug. In designing controlled or sustained release systems for drugs with narrow therapeutic indices, it is imperative that the drug release pattern be precise so that the plasma concentration achieved is within the therapeutic safe and effective range. However, a precise release pattern by itself is not sufficient to ensure attainment of such plasma levels. There are other factors, such as patient variability and the very important drug accumulation upon multiple dosing factors that can potentially alter plasma drug level. 6. Biological Half Life The half life of a drug is an index of its residence time in the body. The biological half life and hence duration of action of a drug obviously play a major role in the process of considering a drug for controlled release. Factors influencing the biological half life of a drug include its elimination, metabolism and distribution patterns. Therapeutic compounds with half-life less than 8 hrs are excellent candidates for sustained release preparations. Drugs with very short half life (less than 2 hrs) will require excessively large amounts of drug in each dosage unit to maintain controlled effects. Thus forcing the dosage form itself to become too large to be administered. Compounds with relatively long half lives, generally greater than 8 hrs are not used in the sustained release dosage forms, since their effect is already sustained and also GI transit time is 8-12 hrs. So the drugs which have long half life and short half life, are poor candidates for sustained release dosage forms. Some examples of drug with half-lives of less than 2 hours are ampicillin, cephalexin, cloxacillin, furosemide, levodopa, penicillin G and propylthiouracil. Examples of those with half-lives, of greater than 8 hours are dicumarol, diazepam, digitoxin, digoxin, guanethidine, phenytoin and warfarin. 7. Plasma Concentration Response Relationship Drugs such as reserpine whose pharmacological activity is independent of its concentration are poor candidates for controlled release system. effective dose ‘Scanned with CamScannerCONTROLLED DRUG DELIVERY SYSTEM eae 8. Size of Dose If the dose of a drug in the conventional dosage form is high then it is less suitable candidates for controlled release drug delivery system. This is because the size of a unit dose controlled release oral formulation would become too big to administer without difficulty. 9, Absorption Window Certain drugs when administered orally are absorbed only from a specific part of GI tract. This part is known as ‘absorption window’. These kinds of drugs are not suitable for controlled release drug delivery system. 10. Disease State Disease state is an important factor in considering a drug for controlled release system. In some instances better management of the disease can be achieved by formulating the drug as controlled release system. For example, in case of rheumatoid arthritis, sustained release form of aspirin would provide desired drug blood levels, particularly throughout the night, thus relieving morning stiffness. Other examples include nitroglycerin in the management of angina pectoris and belladonna alkaloids and synthetic anti-cholinergics in the treatment of peptic ulcers. 11. Circadian Rhythm Many biological parameters like liver enzyme activity, blood pressure, intraocular pressure and some disease states like asthma, acute myocardial insufficiency, and epileptic seizures have been shown to be influenced by circadian rhythm. Hence the response to certain drugs like digitalis glycosides, diuretics, amphetamines, barbiturates, carbamazepine, ethyl alcohol, and chlordiazepoxide display time dependent nature. 12. Side Effects The side effects of some drugs are mainly developed due to fluctuation in the plasma concentration. It is believed that for some drugs, the incidence of side effects is a function of plasma concentration. The incidences of side effects can be minimized by controlling the concentration within the therapeutic range at any given time. The sustained release drug delivery is the most widely used to the incidences of the GI (local) side effects rather than a systemic side effect of the drug. The drug properties which include local or systemic side effects can be circumvented or modified by their incorporation in the suitable oral Sustained release deliver system that employs a specific controlled release mechanism. One of the common complaints of oral potassium therapy is gastric irritation assdciated with its use, ‘Scanned with CamScanneeELIVERT 3) T BOOK OF NOVEL DRUG DI YS) 9 Py ATEX release system such oS wax Mati lled To be a satisfactory solution. Morey,” r Placement of potassium chloride in a control s their non-sustained counterparts, Programmed to release its content over 4-6 hr oe it has been shown that such tablets are as bioavailable Reveew questions ee el THEORETICAL QUESTIONS Define and explain controlled drug delivery system? Write advantages and disadvantages of controlled drug d ° Explain terminology and rationale of controlled drug delivery system? Enlist different factors which affect formulation of controlled drug delivery? Discuss various physicochemical factors which influence formulation of oral controlled drug delivery system? yen delivery? Dae biological factors which affect the formulation of oral controlled drug delivery system? What are the different criteria met by drug to be formulated in controlled release dosage form? 8. Explain in detail diffusion controlled release system with various examples? 9. Write a note on dissolution controlled release system? 10. Enlist various approaches to design controlled release formulations? 11. Write a note on ion exchange resin? 2 MULTIPLE CHOICE QUESTIONS 1. Controlled drug delivery system provides the concentration of drug, to the absorption site. a. Uniform b. Consistent c. Reliable 4 d. Same : 2 a aa drug delivery system frequency of drug administration, b b. Decrease « Nil d. None of the above 3. Controlled release systems are des a. Constant ” Hane tolead to Predictably plasma concentrations. b. Variable cc. Uneven 4. Changeable ‘Scanned with CamScannercoNTROLLED DRUG DELIVERY SYSTEM 1 rie) sae on controlled drug delivery is usually follow order. pb, Zero order ¢. pH dependent 4. None of the above ‘Various designations given to controlled release systems, a. Smart & novel pb. Targeted, c._ Intelligent 4. Allofthe above 6 A controlled release dosage form may have this effect on the drug concentration’s fluctuation. a, Increase b. Decrease c. Constant 4. Nil 7° Immediate release drug delivery system lacks this feature. a. Dose maintenance b. Controlled release rate c. Site targeting 4. Allof the above 8. Advantage of controlled release dosage form. a. Patient compliance b. Reduction in the frequency of designing, ¢. Improved efficacy in treatment 4. Allofthe above 9. Drugs having very short half life (<1 hour) are candidates for controlled release formulations. a. Excellent b. Best © Great 4. Poor 10. Ideally, the drug should have half-life to be formulated in controlled release dosage form. a 34thrs ’. 12hrs © 67hrs | i ae hrs ‘8S with therapeutic index are unsuitable for in mulations, High > Low ‘ 4 corporation in controlled release Moderate * None of the above ‘Scanned with CamScanner12. 13. S 14. e 15. mB 16. 17. 18. B Drugs having molecular weight! More than 1000 daltons Less than 600 daltons Over and above 1500 daltons a b. © qd. ‘ Implants are most commonly admini None of the above of time. a b. c d. Drugs with water solubility will b a. b. © d. It is the fracti a b. © dad. Drugs that undergo gut wall metabolism and show instability in small intestine are the Parental Dermal Sublingual Rectal High Low Rapid None of the above pKa Dissolution Permeation Partition coefficient tare good candid stered by this Fo" .¢ difficult to incorporate ‘on of drug in an oil phase to that of an aqueous P candidate for oral controlled drug delivery systems. a b. © d. Not suitable Suitable Excellent None of the above More than 95% of drugs are absorbed by this mechanism. a. b. c d. Dissolution Diffusion Passive diffusion Direct absorption The ratio of median toxic dose and median effective dose. a b. © d. Therapeutic range Therapeutic index pKa Partition coefficient fate for contro ied release dosage form, te over @ significantly prolonged Petig into sustained release mechanism, hase. ‘Scanned with CamScannerCONTROLLED DRUG DELIVERY SYSTEM 49, Itis an index of drug residence time in the body. a. Halflife b. Therapeutic index c. Partition coefficient d. None of the above 20. One of the common complaints associated with oral potassium therapy is: a, Headache b. Insomnia c. Gastric irritation d. Sedation KEYS La 2d 3a 4b 5.d 6.b 7.4 8.d 9d 10.a 11.b 12.b 13,a 14.b 15.4 16.a 17.¢ 18.b 19.4 20.¢ ‘Scanned with CamScannereee i ield of drug delivery, Polymers are becoming increasingly imporian! © we use as binders in ae pharmaceutical applications of polymers range 70M TS" cons Polymers can be viscosity and flow controlling agents in liquids, ae a to enhance drug stability ang + " ‘ t taste of a a used as film coatings to disguise the unpleasan' emicals or drugs are i in which ch : teristics. The ways in whic to modify drug release character a neades. The oe administered have gained increasing attention in 7 half life required frequent dosing. This is not only costly but also produces side effects because of every time administration particularly in case of parenterals. As a consequence, increasing attention has been focused on methods of giving drugs continually for a prolonged time periods and in a controlled fashion. The primary method of accomplishing this controlled release has been through incorporating the drug chemicals within polymers. This technology now spans many fields and includes pharmaceutical, food and agricultural applications, pesticides, cosmetics, and household products. . In recent years, there has been a rapid growth in the area of drug discovery, facilitated novel technologies such as combinatorial chemistry and high-throughput screening. These novel approaches have led to drugs which are generally more potent and have poorer solubility than drugs developed from traditional approaches of medicinal chemistry. The development of these complex drugs has resulted in a more urgent focus on developing novel techniques, to deliver these drugs more effectively and efficiently. The application of the polymeric materials for medical purposes is growing fast. Polymes have found applications in diverse biomedical fields such as drug delivering sys! developing scaffolds in tissue engineering, implantation of medical devices and arti organs, prosthesis, ophthalmology, dentistry, bone repair, and many other medical wis Polymers have been used as a main tool to control the dru; r te formulations. Extensive applications of polymers in drug a release al because polymers offer unique properties which. have not ivery have if materials. Advances in polymer science have led to the deve delivery systems. A proper consideration of surface and been attained by lopment of several 2 bulk properties can # ‘Scanned with CamScannerPOLYMERS os designing of polymers for various drug delivery applications. These newer technological development include drug modification by chemical means carrier based drug delivery and drug entrapment in polymeric matrices or within pumps that are placed in desired compartments. These technical development in drug delivery/targeting approaches improve the efficacy of drug therapy thereby improve human health. Polymer chemists and chemical engineers, pharmaceutical scientists are engaged in bringing out design predictable, controlled delivery of bio active agents. Extensive biodegradable polymers have been widely used in biomedical applications because of their known biocompatibility and biodegradability. In the biomedical area polymers are generally used as implants and are service. These improvements contribute to make medical expected to perform long term treatment more efficient and to minimize side effects and other types of inconveniences for patients. Some nano particulate polymeric systems possess ability to cross blood brain barrier. They offer protection against chemical degradation, Smart polymers are responsive to atmospheric stimulus like change in temperature; pressure pH, etc. thus are extremely beneficial for targeted drug delivery. Some polymeric systems conjugated with antibodies/specific biomarkers help in detecting molecular targets specifically in cancers. Surface coating with thiolated PEG, Silica-PEG improves water solubility and photo stability. Surface modification of drug carriers e.g. attachment with PEG or dextran to the lipid bilayer increases their blood circulation time. Diffusion based drug delivery systems and solvent activated drug delivery systems are the other areas being explored for utilizing the polymers. In diffusion based drug delivery systems drug is dissolved in a non-swell able system or a fully swollen matrix which does not decompose during their activation time. Solvent activated systems like hydrogels swell and release the drug when exposed to aqueous environment. They are hydrophilic in nature. Biocompatible polymers offer a safe passage for drug delivery due to their well engineered molecular architecture according to the transitions in the underlying mechanisms of the biological process. Biodegradable polymers break due to cleavage of covalent bonds between them and bio erodible polymers bring about erosion of the polymer due to dissolution of linking chains without bringing about any change in chemical structure of the molecule. An appropriate selection of the polymer matrix is necessary in order to develop a successful drug delivery system. The polymer could be non-degradable or degradable. A major disadvantage with non-degradable polymers is that a surgery is required to harvest these Polymers out of the body once they are depleted of the drug. Hence, non-degradable polymers can be used only if removal of the implant is easy (such as an ocular implant), Degradable polymers on the other hand, do not require surgical removal and hence are ‘Scanned with CamScannerthey degrade to smaller abso, e re non-toxic in nature. Theme, slylactide (PLA) and! poly Cactiders jon are Pp piomedi cal applications for More thay din non-toxic. sinc’ preferred for drug delivery application sehen sure applicati have been uses molecules, it is important to make commonly used polymers for this Glycolide) (PLGA). These polymers 20 years and are known to be biodegradable, tible and biocompa! I chloride v Based on interaction with water 5 a. Non-biodegradable hydrophobic Polymers: €-8: bath b. Soluble Polymers: e.g. HPMC, PEG c. Hydro gels: e.g. polyvinyl pyrrolidine > Based on polymerisation method a. Addition polymers: e.g, alkane polymers | b. Condensation polymers: e.g. polysterene and polyamide > Based on polymerization mechanism a. Chain polymerization b. Step growth polymerization > Based on chemical structure a. Activated C-C Polymer b. Inorganic polymers c. Natural polymers > Based on occurrence 34 a. Natural polymers: e.g. Proteins-collagen, keratin, albumin, cellulose b. Synthetic polymers: e.g, Polyesters, polyamides > Based on bio stability a. Biodegradable b. Non biodegradable 2.3 CHARA ¢ It should be versatil properties. «It should be non-toxic and have administered. + Itshould be inexpensive and easy to fabricate, ¢ It should be inert to host tissue and compatible with envi ‘ironment, and poss Possess a wide range of mechanical, physical, Seed mechanical strength and should be & ‘Scanned with CamScanner"POLYMERS 2.4 CRITERIA FOLLOWED IN POLYMER SE «The polymer should be soluble and easy to synthesis. « Itshould have finite molecular weight. « Itshould be compatible with biological environment. « Itshould be biodegradable. « Itshould provide good drug polymer linkage. 2.5 POLYMER PROPERTIES 4. Molecular Weight and Molecular Weight Distribution As polymerization is a random process, molecules within a given polymer mass will have different molecular weights, and for this reason molecular weights of polymers are describe in terms of average molecular weights. The broadness of molecular weight distribution or polydispersity depends on the preparative method used to synthesis the polymer. Anionic living polymer techniques can produce polymer with a polydispersity index close to one, whereas other chain polymerizations can have a polydispersity index as high as 20. Step growth polymerizations have a polydispersity index of about two, known as the most probable molecular weight distribution. The Knowledge of molecular weight and molecular weight distribution of polymer is important because there is a definite relationship between polymer molecular weight and polymer properties. Thus, at very low molecular weights the polymer has essential no useful mechanical properties but as molecular weight rises the magnitude of mechanical property of interest also rises. 2. Polymer Hydrophobicity When a polymer is placed in an aqueous environment, it will gradually absorb water, and the amount absorbed water is determined by the polymer structure. Because use of polymeric controlled release device exposes the polymer to an aqueous environment, its interaction with water is of considerable importance. According to the nature of polymer water interactions, polymers can be broadly classified into hydrophobic polymers, hydrophilic polymer, water soluble polymers and hydrogels. a. Hydrophobic Polymers These polymers are essentially water impermeable and when placed in an aqueous environment will absorb very little water. Clearly there is no fixed value for the amount of absorbed water below which a polymer is hydrophobic and above which it is hydrophilic but for the purpose of this classification the amount of absorbed water should be less than 5%. Structural parameters that contribute to polymer ‘Scanned with CamScanner— pu ATEXT BOOK OE ind presence Of high stallinity 4) yy . high degree of cry’ d by C-F bonds. hydrophobicity are chain pee dig have Bee” replace’ on hydrophobic groups where CH b. Hydrophilic Polymers These are polymers that absorb more ae variation between polymers in their abil that contribute to polymer hydrophilicity and presence of certain group such as amino early there can be considerab, ity to absorb water and structural paran a stalling e chain fle ibility, absence of crysti are . corboxy] and RYAEOXYT n 5% water cl .n though they are of very high molecula, c. Water Soluble Polymer ve Pon ol), poly (acrylic acid), poly. Some polymers are freely soluble in wa eH weight. Examples of such polymer include poly (viny! acrylamide and poly (ethylene oxide). a. i oe hydrophilic or water soluble polymers that have been cree inet means of covalent bonds. Because the polymer cannot dissolve Cr to covalent crosslink water uptakes far in excess of those achievable with hydrophilic linear polymers can be obtained. 3. Glass Transition Temperature At low enough temperature all amorphous polymers exist in a glassy state where no larger scale molecular motion can take place and while in the glassy state polymers are characterized by their hardness, stiffness and brittleness. As the temperature is raised polymers undergo a transition known as the glass transition temperature, Tg where they change from a glass to a rubbery elastomer or flexible plastic. This transition takes place over a narrow temperature range and correspond to the onset of segmental motion of long segments of the polymer chain, which is brought about by the availability of sufficient thermal energy to overcome intermolecular interactions, ‘As the consequence of this transition, thi ' properties. Among these are coefficient of open undergoes an abrupt change is index and hardness. Thus, in designing a rea eee heat content, refrarall whether at use the polymer will be above or below its — - levice it must be known transition temperature also known as second order tra ansition temperature. The gla ’ nsition is a characteristic of # particular polymer structure and its value is clo : sel} A chain stiffness Thus, because above the Tg sogorensat a. the intermolecular forces enti i it follows that very flexible polymers, where free et motions of polymer chain takes place nei P ans, ‘Otati 3 chains is possible, will in general have low Tg values ‘ation about bonds along the polymé é ‘Scanned with CamScanner| mers ea 4, Crystallinity Polymers that have a regular structure are able to achieve a regular packing of polymer chains and crystallize. The driving force for crystallization is a closer packing of polymer chains with consequent enhancement of intermolecular attractions. However, unlike small molecules, where crystallization results in the regular packing of molecules or ions into a three dimensional lattice, polymers only exhibit crystallinity in domains that occur within the amorphous polymer. However, a few polymers among these polyethylenes can be prepared as a single crystal. The presence of crystallinity has a significant effect on polymer properties because crystalline regions act as crosslinks for the regions. Because crystalline regions are impermeable to diffusing molecules, an enhancement of crystallinity results in a decrease in polymer permeability. Crystalline regions are also essentially impermeable to water so the rate of polymer hydrolysis in crystalline regions is significantly reduced. 216 ADVANTAGES OF BIODEGRADABLE POLYMERS > The product can be implanted directly at the site where drug action is needed and hence systemic exposure of the drug can be reduced. The drug encapsulated is released over extended periods and hence eliminates the need jections. This feature can improve patient compliance especially for drugs v for multiple i for chronic indications, requiring frequent injections Favourably alter bio distribution, if formulated into dense nanoparticles. Enable hydrophobic drug administration if formulated as micelles. vv v Make drugs available in response to stimuli. The polymer can protect the drug from the physiological environment and hence improve its stability in vivo. This particular feature makes this technology attractive for the delivery of labile drugs such as proteins. » The degradable polymers are ruptured into biologically suitable molecules that are assimilated and discarded from the body through normal route. Reservoir based polymers is advantageous in various ways like it increase the solubility of incompetently soluble drugs and it lowers the antagonistic side effects of drugs. Dextran is the common polymer used for coating of iron oxide (plasma expander and affinity for iron) in treatment of iron anemia. . The biodegradable polymer system is biocompatible and it will not show dose leaving behind at any time and the polymer will keep its properties till exhaustion of the drug, _ Gold nanoparticles possess good capability of co existence and their capacity to attach with other biomolecules without changing their properties. Vv ‘Scanned with CamScanneeK OF A TEXT BOO) Table 2.1: Bi Polymers Sr. No. [ree lycolide (PLGA) Poly-D,L-lactide-co Polyglycolide (PGA) Poly-L-lactide (PLLA) Poly ~-caprolactone (PCL) zylates PAC) PTMO) Poly-alkyPeyano-ac Poly-trimethylene-carbonate 0 Polylactic acid (PLA) Poly-P-hydroxy-butyrate Poly(orthoester) Poly(a-amino acids) Pseudo-poly(amino acids) Polyphosphazene Polyanhydrides Chitosan Gelatin 1. Dendrimers PLICATIONS OF POLYMERS First discovered in the early 1980's by Dx molecules were calle eres mcs lane on nr mg the core, leaving spaces which pla Bhiy Packed in the per say and lobe There are attempts to use end fe fa role in the dra apps abing aa agents. Drug molecules can ie ae dalvery fee loaded both in the re of drugs and other ther@P of the dendrimers as ‘Scanned with CamScannerattached to the surface groups. Dendri eee Se be be used as coating agents to protect or ee ime-release vehicles for biologically active agents ; 8 ¥ Macromolecules of nanometer size and possess a distinct molecular architecture that consists ‘of three different domains: (i) a central core that comprises either a single atom or a 8roup of atoms having at least two chemical functionalities that provide linkage for the branches; (ii) branches that emerge from the core, comprising repeating units with at least one junction of branching, whose repetition is organized in a geometric progression that results in a series of radially concentric layers termed generations and (iii) terminal functional groups, present at the outer surface of the macromolecule, that dictate the efficacy of nucleic acid complexation or drug entrapment. Usually, the presence of highly interactive functionalities on the surface of dendrimers confers on them high reactivity, solubility, and binding properties. Dendrimers of defined size and structure and with a low polydispersity index (PDI) can be engineered by a step- wise chemical synthesis approach. Generally, dendrimers are synthesized by two conceptually different approaches, the divergent and the convergent. Poly(amidoamine), or PAMAM, is perhaps the most well-known molecule for synthesis of dendrimers. Fig. 2.1: Structure of dendrimers 2. Polymeric Nanoparticles / Nanoparticles are morphologically similar to microspheres, but the sizes of particles are in the submicron range. Polymeric NPs are composed of a core polymer matrix in which drugs can be embedded, with sizes usually between 60 and 200 nm. These particles can be prepared by different methods and using a variety of starting materials that include biopolymers (eg., gelatin, albumin, casein, and polysaccharides) and synthetic pole (cg. polyesters, polyanhydrides, polycaprolactone, and alkyt--eyanoaeryiates) = ci of polymer depends on the therapeutic application of the system, pores a 7: drug release profile, etc. Drug release ranging from few hours to several mont ‘Scanned with CamScannera; WA jals have been employeg fog of materi Seen . icle formulations: rane" ers have been Gesieneé Primay ebiained from er jin recent Ye one Pe niolled release of bioactive agen, i In particular, delivery of drugs. In pai tered the renal” say, Most popular ones ar, for medical applications and have @ re wit Beira ra Many of these materials are designed '° oa poly(actide-co a devel icy polylactides (PLA), polyglycolides rolactone. In spite 0! lopment of polyanhydrides, polycyanoacrylates, and Eee atural polymers such as chitosan cay 5 js also ni ee ; thetic and semi-synthetic polyme’ ilable describing an enhance ee ae case EA polymeric NPs, reports are av drug delivery to the brain mediated by these device® 3. Hydrogel System nd are three dimensio, Hydrogels are cross-linked networks of water-soluble polymers en Tey at a Hydrogels can be made both from natural and synthetic P mntrolled drug deli , absorbent. Biodegradable hydrogels are being used as carriers fOr CO ae Hs) because oftheir ineriness for many drugs and their biocompatibility. Hydroge’s have vey depends upon the diffusion high porosity due to which the release rate of drug crucially i coefficient of the drug molecules. The tailoring of porosity of hydrogel can be done by controlling the level of cross-linking, which in turn affect the rate of delivery of the entrapped drug particles. The ability of hydrogels to rapidly swell in aqueous medium, promote the rate of release of the entrapped drug and degradation of the polymer. M 4, Solid Lipid Nanoparticles all ® 3 Fig, 22: Solid lipid nanoparticl Solid lipid nanoparticles SLN) are 7 biocompatible biodegradable lipid matrix that is g Collois loidal particles comy Olid at body temperature and ‘Scanned with CamScannery range ‘of 100 to 400 nm. SLN are a st hobic lipid core, in which the drug ca ation above the sub- ‘able lipid based nanocarrier with a solid micron sized lipid cilaoas oie Ne aa a eo ha os se Tens is where the liquic id (oil is been bstituted by a solid lipid and are mainly composed of a Sameer a dispersed in water or in aqueous surfactant solution. Replacement of liquid oil with solid lipid represents amilestone in achieving controlled drug release, because the mobility of a drug in solid lipid js usually lower compared to liquid oil, which made them attractive for their potential use in improving the performance of pharmaceuticals, nutraceuticals and other such materials. The most formidable obstacles that often impede drug delivery to the brain are characterized by the presence of relatively impermeable endothelial cells with tight junctions, enzymatic activity and the presence of active efflux transporter mechanisms like P-glycoprotein efflux. However, the bioacceptable and biocompatible nature of SLNs makes them less toxic compared to polymeric nanoparticles and they are taken up by the brain because of their lipidic nature. The advantages of SLN are their biocompatibility, drug entrapment efficiency comparatively higher than other NPs, and the ability to provide a continuous release of the drug for several weeks. Moreover, the composition of SLN can be controlled modifying their surface properties to target molecules to the brain and to limit RES uptake. Solid lipid nanoparticles are well tolerated in a biological system because they are composed of physiological lipids. 5. Magnetic Nanoparticles (MNPS) The magnetic nanoparticles are composed of an iron oxide core most often magnetite (e804) or maghemite (y-Fe203). This iron oxide core is a main feature, enabling movement in a magnetic field. Magnetic nanoparticles are currently being used for a variety of in vivo and in vitro purposes, for example, as contrast agents for MRI, treatment in hyperthermia, cell labeling and separation, magnetofection and drug delivery by magnetic targeting. For Such purposes the magnetic nanoparticles can be polymer coated, but they can also be encapsulated inside liposomes, hence forming magnetoliposomes. ‘Scanned with CamScanneray ATEXT BOOK OF NO Fig. 2.3: Magnetic nanoparticle tile diagnostic tool in biology ang ints of superparamagnetic iron oxide g magnetic resonance imaging re used to label specific gnetic nanoparticles can be divided into two Magnetic nanoparticles are a powerful and versa medicine. It is possible to incorporate sufficient amow nanoparticles into cells, enabling their detection in vivo usin; (MRD. Bound to a suitable antibody, magnetic nanoparticles a molecules, structures, or microorganisms. Maj subdivisions, in other words, paramagnetic nanoparticles (PMNPs) and super paramagnetic iron oxide nanoparticles (SPIONs). The PMNPs are larger than 100 nm but still within the nanometer scale and the SPIONSs are less than 100 nm. SPIONs with a size of less than 50nm are also referred to as ultrasuper paramagnetic iron oxide nanoparticles (USPIONs). The physical properties of SPIONs are of high importance, because they allow the particles to become magnetic with a high magnetic susceptibility in the presence of an external magnet as opposed to the much weaker magnetic susceptibility of PMNPs that have a larget diameter. This feature makes SPIONs highly attractive for drug delivery purposes, because they are more easily attracted toward a magnet over large distances in comparison with the PMPs. SPIONs lea rend ier both targeting purposes and conjugation with | iotherapeutics, as Tetain wit is 21 a a one 7 i ae long and still undergo biocompal a ; in liposomes. When circulation, magnetic nanoparticles are at risk of bein; administered into | 8 taken up by phagocytic cells modifications are therefore made i cleared by the reticulo-endothelial system. Surface increase their biocompatibility and systemic half-life. 6. Polymeric Micelles (PMs) PMs are self-assembled core-shell nanostructures formed of amphiphilic block copolymers. Formation of ey i in an aqueous solution concentration of the block copolymer increases above » aueous solution Sertain concentr ‘ation ; ‘Scanned with CamScanneetical eas oe) (CAC) or critical micelle concentration (CMC). At the CAC or CMC, | ydropho! ‘ segments of block copolymers start to associate to minimize the contact with water molecules, leading to the formation of a vesicular or core-shell micellar structure. Fig. 2.4: Polymeric micelle ‘Theoretically, the formation of micelles is driven by decrease of free energy. The removal of hydrophobic fragments from the aqueous environment and the reestablishing of hydrogen bond network in water decrease free energy of the system and finally form the micelles. The typical methods used for encapsulation of poorly water soluble drugs are dialysis method, oil-in-water emulsion solvent evaporation method, and solid dispersion method. Other methods used are direct dissolution, complexation, chemical conjugation, and various solvent evaporation procedures. Most of the drugs being poorly water soluble can be easily incorporated into the core of polymeric micelles to overcome solubility problems. Solubility enhancement usually results in better oral bioavailability of the hydrophobic drugs. Surfactant micelles tend to disintegrate upon dilution triggering lysis of cell membranes. Polymeric micelles are considerably more stable towards dilution than surfactant micelles and hence exhibit minimal cytotoxicity. The hydrophilic shell and the nanoscopic size prevent mechanical clearance of micelles by filtration or in the spleen. This is beneficial for Prolonging the blood circulation of drug. Also, the shell stabilizes the micelle, interacts with the plasma proteins and cell membranes and its nature controls biodistribution of the carrier. Nanoscopic size minimizes the risk of embolism in capillaries, contrary to larger drug carriers. It also favors the particular absorption in gastrointestinal system. Along with these features, low toxicity and faster rate of clearance of polymeric micelles from the body make them suitable for intravenously administered drug delivery systems. Additionally, there is No need of modification of chemical structure of the drugs. Polymeric micelles provide al to targeting because of the high drug-loading capacity of the inner core as well as the unique disposition characteristics in the body due to their size. Polymeric micelles have ‘Scanned with CamScanneepy ATEXT BOOK OF NOVEL DRUG DELIVERy SY snp hy, tt pharmaceutical carriers because of their attractive P . come i i wide variety of poorly soluble dry, Polymeric micelles can be easily loaded with a gs, th ate in enhanced bioavailability of these drugs. Importantly, these can be etn oa on certain pathological areas in the body with compromised vasculature suk tumors, infarcts because of their size and EPR effect. Targeting can also be achieved attaching specific ligands or specific antibodies onto their surface. Thus polymeric ica, as drug carriers, have a promising future. Tumor-specific targeting of polymer micelles b molecular markers expressed at the surface of the cancer cells has also been explore to eradicate tumor cells. The studies on the application of polymer micelles in drug delivery have mostly focused on the following areas that are considered below. a. Delivery of anticancer agents to treat tumors. b. Drug delivery to the brain to treat neurodegenerative diseases. c. Delivery of antifungal agents. d. Delivery of imaging agents for diagnostic applications. e. Delivery of polynucleotide therapeutics. emerged as imp 7. Liposomes ‘ Liposomes are spherical, self-closed structures formed by one or several concentric lipid bilayers with an aqueous phase inside, which were first proposed and tested as a-drug delivery system in the early 1970s. Since then, they have been adopted as the vehicle of choice for drug delivery and targeting, due to their very unique and attractive biological and physical chemical properties. Liposomes are biocompatible and can both entrap and protect water-soluble (hydrophilic) molecules in their internal water compartment and water-insoluble (hydrophobic) into the membrane. Moreover, they provide a unique opportunity to deliver pharmaceuticals into cells or even inside individual cellular compartments. Indeed, in order to facilitate the association and interaction with the target site size, charge and surface properties of liposomes can be easily changed by simply adding new ingredients to the lipid mixture before liposome preparation and/or by variation of preparation methods. . To’ deliver liposomes to the brain, they can be firstly modified into long circulation vesicles by decreasing particle size (<100 nm) or by linking polyethylene glycol (PEG) chains to bier’ surface. Then, they have to be specifically designed to release the encapsulated drug in target site. ‘Scanned with CamScanneeFig. 2.5: Liposomes The most advantageous features of liposomes, than other carriers, are the ability to incorporate and deliver relatively large amounts of drug, and the possibility to decorate their surface with different ligands. Moreover, liposomes have been used clinically as delivery systems because of their ability to increase both the safety and the efficacy of many drugs. For CNS drug delivery, pharmacokinetics and biodistribution, including binding to plasma proteins or degradation of the drug in blood, play an important role in the overalll efficacy of the system. Indeed, early problems with liposomes for brain delivery involved their rapid uptake by the reticuloentdothelial system (RES) and consequent removal from circulation. However, once the liposomes had been sterically stabilized through the incorporation of PEGylated phospholipids into their bilayer, loss via the RES was largely reduced. Limitations of liposomes include not only fast systemic elimination, but also metabolic degradation of the phospholipids, vesicle stability issue after large scale production and storage, and inability to provide sustained release of drugs. Indeed, some of these problems have been partially overcome and marketed liposomes of the newest generation are more Stable with shelf-lives up to several months. However, it seems still difficult to ensure long term administration into brain in the treatment of neurodegenerative diseases. 8. Implants |n most ofthe implants a permeable polymeric membrane surrounds the core of solid drugs. The implants can be modified into different shapes, such as films, pellets, plugs, rods and discs. The implants can be classified as non-biodegradable and biodegradable implants, depending on the polymer used. The polymers mostly used in the non-biodegradable implants include polyvinyl alcohol (PVA, silicone and ethylene vinyl acetate (EVA), Silicone can be customized to be both a permeable or impermeable layer depending on the grade and ‘Scanned with CamScanner