Controlled drug delivery occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or

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1 Available through Online ISSN: X CODEN: IJPTFI Review Article CONTROLLED DRUG DELIVERY SYSTEM AND POLYMERS Patel Gaurang *, Sahu Deepak, Dashora Ashok, Garg Rahul, Patel Ankit, Patel Pratik, Patel Parth * Department of Pharmaceutics, Geetanjali Institute of Pharmacy, Dabok, Udaipur (Raj.) gappharma13@gmail.com Received on Accepted on Abstract Controlled drug delivery occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released from the material in a predesigned manner. The release of the active agent may be constant over a long period, it may be cyclic over a long period, or it may be triggered by the environment or other external events. In any case, the purpose behind controlling the drug delivery is to achieve more effective therapies while eliminating the potential for both under- and overdosing. Other advantages of using controlled-delivery systems can include the maintenance of drug levels within a desired range, the need for fewer administrations, optimal use of the drug in question, and increased patient compliance. Biodegradable materials are used in packaging, agriculture, medicine and other areas. In recent years there has been an increase in interest in biodegradable polymers. Two classes of biodegradable polymers can be distinguished: synthetic or natural polymers. There are polymers produced from feedstocks derived either from petroleum resources (non renewable resources) or from biological resources (renewable resources). In general natural polymers offer fewer advantages than synthetic polymers. The following review presents an overview of the different biodegradable polymers that are currently being used and their properties, as well as new developments in their applications. Keywords: Controlled drug delivery system, Biodegradable polymers; Synthetic Polymers; Natural Polymers. Introduction Oral controlled release drug delivery is a drug delivery system that provides the continuous oral delivery of drugs at predictable and reproducible kinetics for a predetermined period throughout the course of GI transit and also the system IJPT July-2013 Vol. 5 Issue No Page 2632

2 that target the delivery of a drug to a specific region within the GI tract for either a local or systemic action. All the pharmaceutical products formulated for systemic delivery via the oral route of administration, irrespective of the mode of delivery (immediate, sustained or controlled release) and the design of dosage form (either solid, dispersion or liquid), must be developed within the intrinsic characteristics of GI physiology. In recent years scientific and technological advancements have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Several approaches are currently utilized in the prolongation of the GRT, including floating drug delivery systems (FDDS), also known as hydrodynamically balanced systems (HBS), swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density systems, and other delayed gastric emptying devices. To design the oral controlled release tablet to increase the residence time of the drug in to the stomach and release for extended period of time in order to; Increase bioavailability of the drug, reduce the dosing frequency, Improve patient compliance. Interest in controlled and sustained release drug delivery has increased considerably during the past decade and, in selected areas, it s now possible to employ fairly sophisticated system which is capable of excellent drug release control. The self-regulating insulin delivery system by using lectin and oral osmotic tablet are illustrative examples. However, for oral administration, all of these systems are limited to some extent because of gastrointestinal (GI) transit. Thus, the duration of most oral sustained release products is approximately 8-12 hours due to the relatively short GI transit time, and the possibilities to localize drug delivery system in selected regions of the gastrointestinal tract (GIT) for the purpose of localized drug delivery are under investigation. The controlled drug delivery system is one, which delivers the drug at a predetermined rate, locally or systemically for a predetermined period of time. The targeted drug delivery system is one, which delivers the drug only to its site of action and not to the nontarget organs or tissues. The two main advantages of controlled drug delivery systems are maintenance of therapeutically optimum drug concentrations in the plasma through zero-order release without significant fluctuations; and elimination of the need for frequent single dose administrations. The oral and other therapeutic systems in human use have validated the concept that controlled continuous drug release can minimize the daily dose of a drug required to maintain the required therapeutic effect, while minimizing unwanted IJPT July-2013 Vol. 5 Issue No Page 2634

3 pharmacological effects. By minimizing patient intervention, a design feature of therapeutic systems, compliance is automatically enhanced. Oral drug delivery systems, in particular, have required innovation in materials science to provide materials biocompatible during prolonged contact with body tissues, bioengineering to develop drug delivery modules, and clinical pharmacology for elucidation of drug action under conditions of continuous controlled drug administration. Recent work in advanced oral delivery has been primarily focused on liposome technology and the concept that substances that are normally destroyed by the stomach can be protected long enough before they could be absorbed downstream. For cost and patient convenience, oral delivery certainly would be an attractive method. The nature of biologic substances, however, with their unique technical problems, will probably limit greatly those that can be delivered orally. Besides, where delivery rate control is critical, oral delivery, even when possible, would probably be insufficiently precise. Oral delivery would also limit the substance to bloodstream delivery to the disease site. Even so, oral controlled drug delivery systems will likely find primary usefulness in specific carefully controlled therapies and prophylactic situations with due regard for drug interactions. This system represents a potentially very significant therapeutic modality. These delivery systems will find usefulness primarily in certain well defined and well-controllable areas with due regard for individual patient variations. The purpose of the present article is to review oral controlled release drug delivery systems, with particular emphasis on the practical aspects of testing and fabricating these systems and the underlying mechanisms by which control over drug release rate is accomplished Conventional oral controlled dosage forms suffer from mainly two adversities. The short gastric retention time (GRT) and unpredictable gastric emptying time (GET). A relatively brief GI transit time of most drug products impedes the formulation of single daily dosage forms. These problems can be overwhelmed by altering the gastric emptying. Therefore it is desirable, to formulate a controlled release dosage form that gives an extended GI residence time. Extended release dosage form with prolonged residence time in stomach are highly desirable for drugs. that are locally active in stomach, that have an absorption window in the stomach or in the upper small intestine, that are unstable in the intestinal or colonic environment, Have low solubility at high ph values. IJPT July-2013 Vol. 5 Issue No Page 2635

4 Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form. Oral route is considered most natural, uncomplicated, convenient and safe due to its ease of administration, patient acceptance, and cost-effective manufacturing process. Pharmaceutical products designed for oral delivery are mainly immediate release type or conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption. These immediate release dosage forms have some limitations such as: Drugs with short half-life requires frequent administration, which increases chances of missing dose of drug leading to poor patient compliance. A typical peak-valley plasma concentration-time profile is obtained which makes attainment of steady state condition difficult. The unavoidable fluctuations in the drug concentration may lead to under medication or overmedication as the CSS values fall or rise beyond the therapeutic range. The fluctuating drug levels may lead to precipitation of adverse effects especially of a drug with small therapeutic index, whenever overmedication occurs. In order to overcome the drawbacks of conventional drug delivery systems, several technical advancements have led to the development of controlled drug delivery system that could revolutionize method of medication and provide a number of therapeutic benefits. IJPT July-2013 Vol. 5 Issue No Page 2636

5 Figure 1: Characteristic representation of plasma concentrations of a conventional immediate release dosage form (IR), a sustained release dosage forms (SR) and an idealized zero-order controlled release (ZOCR) dosage form (in combination with a start-up dose). Controlled Drug Delivery Systems classification: Controlled drug delivery systems have been developed which are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery of drug to a tissue. Controlled drug delivery or modified drug delivery systems are conveniently divided into four categories. 1) Delayed release 2) Sustained release 3) Site-specific targeting 4) Receptor targeting More precisely, controlled delivery can be defined as:- 1) 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. 2) Localized drug action by spatial placement of a controlled release system adjacent to or in the diseased tissue. 3) Targeted drug action by using carriers or chemical derivatives to deliver drug to a particular target cell type. 4) Provide a physiologically therapeutically based drug release system. In other words, the amount and the rate of drug release are determined by the physiological therapeutic needs of the body. 5) 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. Controlled drug delivery usually results in substantially constant blood levels of the active ingredient as compared to the uncontrolled fluctuations observed when multiple doses of quick releasing conventional dosage forms are administered to a patient. Advantages of Controlled Drug Delivery System 1) Decreased incidence and or intensity of adverse effects and toxicity. 2) Better drug utilization. 3) Controlled rate and site of release. IJPT July-2013 Vol. 5 Issue No Page 2637

6 4) More uniform blood concentration. Patel Gaurang*et al. /International Journal Of Pharmacy&Technology 5) Improved patient compliance. 6) Reduced dosing frequency. 7) More consistent and prolonged therapeutic effect. 8) A greater selectivity of pharmacological activity. Disadvantages of Controlled Drug Delivery System 1) Administration of controlled release medication does not permit the prompt termination of therapy. 2) Flexibility in adjustment of dosage regimen is limited. 3) Controlled release forms are designed for normal population i.e. on the basis of average drug biologic half lives. 4) Economic factors must also be assessed, since more costly process and equipment are involved in manufacturing of many controlled release dosage forms. Polymers are becoming increasingly important in pharmaceutical applications especially in the field of drug delivery. Polymers range from their use as binders in tablets to viscosity and flow controlling agents in liquids, suspensions and emulsions; can also be used as film coatings, 1. to disguise the unpleasant taste of a drug, 2. to enhance drug stability and 3. to modify the release characteristics. Around sixty million patients benefit from advanced drug delivery systems today, receiving safer and more effective doses of medicines that are needed to fight a variety of human ailments, including life threatening diseases. What is a Drug Delivery System? A system that formulates or device that delivers therapeutic agent(s) to desired body location(s) and/or provides timely release of therapeutic agent(s), such a system by which a drug is delivered can have a significant effect on its efficacy. Some drugs have an optimum concentration range within which maximum benefit is derived, and concentrations above or below this range can be toxic or produce no therapeutic benefit at all. On the other hand, the very slow progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a multidisciplinary approach to the IJPT July-2013 Vol. 5 Issue No Page 2638

7 delivery of therapeutics to targets in tissues. From this, new ideas on controlling the pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, biorecognition, and efficacy of drugs were generated. These new strategies, often called Drug Delivery Systems (DDS), are based on interdisciplinary approaches that combine pharmaceutics, polymer science, analytical chemistry, bioconjugate chemistry, and molecular biology. Typical schematic examples of drug delivery systems based on polymers and Nano-particulates were given in figure 2. Figure-2: Polymer based drug delivery system. In recent years, controlled drug delivery formulations and the polymers used in these systems have become much more sophisticated, with the ability to do more than simply extend the effective release period for a particular drug. For example, current controlled-release systems can respond to changes in the biological environment and deliver or cease to deliver drugs based on these changes. In addition, materials have been developed that should lead to targeted delivery systems, in which a particular formulation can be directed to the specific cell, tissue, or site where the drug it contains is to be delivered. While much of this work is still in its early stages, emerging technologies offer possibilities that scientists have only begun to explore. IJPT July-2013 Vol. 5 Issue No Page 2639

8 Biomaterials for Delivery Systems Patel Gaurang*et al. /International Journal Of Pharmacy&Technology A range of materials have been employed to control the release of drugs and other active agents. The earliest of these polymers were originally intended for other, nonbiological uses, and were selected because of their desirable physical properties, for example: Poly(urethanes) for elasticity. Poly(siloxanes) or silicones for insulating ability. Poly(methyl methacrylate) for physical strength and transparency. Poly(vinyl alcohol) for hydrophilicity and strength. Poly(ethylene) for toughness and lack of swelling. Poly(vinyl pyrrolidone) for suspension capabilities. To be successfully used in controlled drug delivery formulations, a material must be chemically inert and free of leachable impurities. It must also have an appropriate physical structure, with minimal undesired aging, and be readily processable. Some of the materials that are currently being used or studied for controlled drug delivery include Poly (2-hydroxy ethyl methacrylate), Poly (N-vinyl pyrrolidone), Poly (methyl methacrylate), Poly (vinyl alcohol), Poly (acrylic acid), Polyacrylamide, Poly (ethylene-co-vinyl acetate), Poly (ethylene glycol), Poly (methacrylic acid). However, in recent years additional polymers designed primarily for medical applications have entered the arena of controlled release. Many of these materials are designed to degrade within the body, among them Polylactides (PLA), Polyglycolides (PGA), Poly (lactide-co-glycolides) (PLGA), Polyanhydrides, Polyorthoesters. IJPT July-2013 Vol. 5 Issue No Page 2640

9 Originally, polylactides and polyglycolides were used as absorbable suture material, and it was a natural step to work with these polymers in controlled drug delivery systems. The greatest advantage of these degradable polymers is that they are broken down into biologically acceptable molecules that are metabolized and removed from the body via normal metabolic pathways. However, biodegradable materials do produce degradation by-products that must be tolerated with little or no adverse reactions within the biological environment. Polymer Degradation Polymer degradation is a change in the properties tensile strength, colour, shape, etc of a polymer or polymer based product under the influence of one or more environmental factors such as heat, light or chemicals. Deteriorative reactions occur during processing, when polymers are subjected to heat, oxygen and mechanical stress, and during the useful life of the materials when oxygen and sunlight are the most important degradative agencies. In more specialized applications, degradation may be induced by high energy radiation, ozone, atmospheric pollutants, mechanical stress, biological action, hydrolysis and many other influences. The mechanisms of these reactions and stabilization processes must be understood if the technology and application of polymers are to continue to advance. The study of all these processes has made extensive use of modern instrumental analytical methods and the various spectrometric, chromatographic and thermal analysis techniques have been particularly prominent. Various routes for degradation of polymers are given in figure 3 and factors affecting polymer degradability (biodegradation) is shown in figure 4. Figure-3: Various routes for degradation of polymers. IJPT July-2013 Vol. 5 Issue No Page 2641

10 Figure-4: Factors affecting biodegradation of polymers. Factors Affecting Biodegradation of Polymers: Chemical structure, Chemical composition, Distribution of repeat units in multimers, Presents of ionic groups, Presence of unexpected units or chain defects, Configuration structure, Molecular weight, Molecular-weight distribution, Morphology (amorphous/semi crystalline, microstructures, residual stresses), Presence of low-molecular-weight compounds, Processing conditions, Annealing, Sterilization process, Storage history, Shape, Site of implantation, IJPT July-2013 Vol. 5 Issue No Page 2642

11 Adsorbed and absorbed compounds (water, lipids, ions, etc.), Physicochemical factors (ion exchange, ionic strength, ph), Conclusion Polymers possessing a unique strength in their application towards drug delivery application which enables the new advancement in the formulating new drug delivery systems which improves the therapy and treatment. Although drug delivery technologies, if appropriately applied, should be able to improve therapeutic outcomes, these technologies are required in some instances to simply enable therapy, as is the case with gene therapy and drug targeting. Drug delivery is also intuitively the logical and sensible thing to do. Depositing billions of drug molecules in the blood or gut and allowing the hapless molecules to locate their target, by uncontrolled diffusion, is surely a therapeutic strategy of yesterday and not of tomorrow. Guiding sufficient numbers of molecules in sufficient time directly to their targets is the future. Polymers have helped this endeavor and will continue to enable this effort in the foreseeable future. References 1. Hui HW, Robinson JR, Lee VHL. Design and fabrication of oral controlled release drug delivery systems. In: Robinson JR, Lee V, editors. Controlled drug delivery fundamentals and applications. 2 nd Ed.; Marcel Dekker: New York: Inc; p Chasin M, and Langer R, Biodegradable Polymers as Drug Delivery Systems, New York, Marcel Dekker, Mikos AG, Murphy RM, Bernstein H, et al. Biomaterials for Drug and Cell Delivery, Pittsburgh, Materials Research Society, Park K, Shalaby WSW, and Park H, Biodegradable Hydrogels for Drug Delivery, Lancaster, PA, Technomic, Davis SS, Illum L (1998),Drug delivery systems for challenging molecules, Int J Pharm 176: Heller J, Barr J, Ng SY, Shen HR, Schwach-Abdellaoui K, Emmahl S, Rothen-Weinhold A, Gurny R. Poly(ortho esters) - their development and some recent applications. Eur J Pharm Biopharm Jul;50(1): Bibby DC, Davies NM, Tucker IG. Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems. Int J Pharm Mar 20;197(1-2):1-11. IJPT July-2013 Vol. 5 Issue No Page 2643

12 8. Jain R, Shah NH, Malick AW, Rhodes CT. Controlled drug delivery by biodegradable poly(ester) devices: different preparative approaches. Drug Dev Ind Pharm Aug;24(8): Ulbrich K, Pechar M, Strohalm J, Subr V, Rihova B. Synthesis of biodegradable polymers for controlled drug release. Ann N Y Acad Sci Dec 31;831: Shive MS, Anderson JM. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug Del. Rev. 28, 5-24,1997. Corresponding Author: Patel Gaurang *, gappharma13@gmail.com IJPT July-2013 Vol. 5 Issue No Page 2644