POLYMER SCIENCE By: Prof. Dr. Basavaraj K. Nanjwade KLE University’s College of Pharmacy BELGAUM -590010, Karnataka, India Cell: 00919742431000 Cell No: [email protected] M.
Download ReportTranscript POLYMER SCIENCE By: Prof. Dr. Basavaraj K. Nanjwade KLE University’s College of Pharmacy BELGAUM -590010, Karnataka, India Cell: 00919742431000 Cell No: [email protected] M.
POLYMER SCIENCE By: Prof. Dr. Basavaraj K. Nanjwade KLE University’s College of Pharmacy BELGAUM -590010, Karnataka, India Cell: 00919742431000 Cell No: [email protected] M. Pharm., Ph.D CONTENTS INTRODUCTION TO POLYMERS CLASSIFICATION OF POLYMERS GENERAL MECHANISM OF DRUG RELEASE APPLICATION IN CONVENTIONAL DOSGAE FORMS APPLICATIONS IN CONTROLLED DRUG DELIVERY BIODEGRADABLE POLYMERS NATURAL POLYMERS REFERENCESS 7th Sept. 2010 KLECOP, Nipani 1 INTRODUCTION A polymer is a very large molecule in which one or two small units is repeated over and over again The small repeating units are known as monomers Imagine that a monomer can be represented by the letter A. Then a polymer made of that monomer would have the structure: -A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-AA-A-A-A 7th Sept. 2010 KLECOP, Nipani 2 In another kind of polymer, two different monomers might be involved If the letters A and B represent those monomers, then the polymer could be represented as: -A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-B-A-BA-B-A A polymer with two different monomers is known as a copolymer. 7th Sept. 2010 KLECOP, Nipani 3 Chemistry of the polymers a. b. c. Polymers are organic, chain molecules They can, vary from a few hundreds to thousands of atoms long. There are three classes of polymers that we will consider:Thermo-plastic - Flexible linear chains Thermosetting - Rigid 3-D network Elastomeric - Linear cross-linked chains 7th Sept. 2010 KLECOP, Nipani 4 THERMOPLASTICS In simple thermoplastic polymers, the chains are bound to each other by weaker Van der Waal’s forces and mechanical entanglement. Therefore, the chains are relatively strong, but it is relatively easy to slide and rotate the chains over each other. 7th Sept. 2010 KLECOP, Nipani 5 ELASTOMERS Common elastomers are made from highly coiled, linear polymer chains. In their natural condition, elastomers behave in a similar manner to thermoplastics (viscoelastic) – i.e. applying a force causes the chains to uncoil and stretch, but they also slide past each other causing permanent deformation. This can be prevented by cross-linking the polymer chains 7th Sept. 2010 KLECOP, Nipani 6 Polymers can be represented by – 3-D solid models – 3-D space models – 2-D models 7th Sept. 2010 KLECOP, Nipani 7 MOLECULAR STRUCTURE The mechanical properties are also governed by the structure of the polymer chains. They can be: Linear Network (3D) Branched Cross-linked 7th Sept. 2010 KLECOP, Nipani 8 POLYMER MOLECULES Before we discuss how the polymer chain molecules are formed, we need to cover some definitions: The ethylene monomer looks like The polyethylene molecule looks like: 7th Sept. 2010 KLECOP, Nipani 9 Polyethylene is built up from repeat units or mers. Ethylene has an unsaturated bond. (the double bond can be broken to form two single bonds) The functionality of a repeat unit is the number of sites at which new molecules can be attached. 7th Sept. 2010 KLECOP, Nipani 10 MOLECULAR WEIGHT When polymers are fabricated, there will always be a distribution of chain lengths. The properties of polymers depend heavily on the molecule length. There are two ways to calculate the average molecular weight: 1 Number Average Molecular Weight 2. Weight Average Molecular Weight 7th Sept. 2010 KLECOP, Nipani 11 Number Average Molecular Weight Mn= Σ Xi Mi Where, xi = number of chains in the ith weight range Mi = the middle of the ith weight range Weight Average Molecular Weight M w = Σ Wi M i Where, wi = weight fraction of chains in the ith range Mi = the middle of the ith weight range 7th Sept. 2010 KLECOP, Nipani 12 MOLECULAR SHAPE The mechanical properties of a polymer are dictated in part by the shape of the chain. Although we often represent polymer chains as being straight, They rarely are. 7th Sept. 2010 KLECOP, Nipani 13 Contd… The carbon – carbon bonds in simple polymers form angles of 109º 7th Sept. 2010 KLECOP, Nipani 14 7th Sept. 2010 KLECOP, Nipani 15 POLYMER CRYSTALLINITY Thermoplastic polymers go through a series of changes with changes in temperature. (Similar to ceramic glasses) In their solid form they can be semi-crystalline or amorphous (glassy). 7th Sept. 2010 KLECOP, Nipani 16 7th Sept. 2010 KLECOP, Nipani 17 CRYSTALLINE THERMOPLASTIC 1. 2. 3. 4. 5. The ability of a polymer to crystallize is affected by: Complexity of the chain: Crystallization is easiest for simple polymers (e.g. polyethylene) and harder for complex polymers (e.g. with large side groups, branches, etc.) Cooling rate: Slow cooling allows more time for the chains to align Annealing: Heating to just below the melting temperature can allow chains to align and form crystals Degree of Polymerization: It is harder to crystallize longer chains Deformation: Slow deformation between Tg and Tm can straighten the chains allowing them to get closer together. 7th Sept. 2010 KLECOP, Nipani 18 CLASSIFICATION POLYMERS: ON BASIS OF INTERACTION WITH WATER: Non-biodegradable hydrophobic Polymers E.g. polyvinyl chloride, polyethylene vinyl acetate Soluble Polymers E.g. HPMC, PEG Hydrogels E.g. Polyvinyl pyrrolidine BASED ON POLYMERISATION METHOD: Addition Polymers E.g. Alkane Polymers Condensation polymers E.g. Polysterene and Polyamide Rearrangement polymers BASED ON POLYMERIZATION MECHANISM: Chain Polymerization Step growth Polymerization 7th Sept. 2010 KLECOP, Nipani 19 Contd…. BASED ON CHEMICAL STRUCTURE: Activated C-C Polymer Polyamides, polyurethanes Polyesters, polycarbonates Polyacetals, Polyketals, Polyorthoesters Inorganic polymers Natural polymers BASED ON OCCURRENCE: Natural polymers E.g. 1. Proteins-collagen, keratin, albumin, 2. carbohydrates- starch, cellulose Synthetic polymers E.g. Polyesters, polyamides 7th Sept. 2010 KLECOP, Nipani 20 Contd…. BASED ON BIO-STABILITY: Bio-degradable Non Bio-degradable 7th Sept. 2010 KLECOP, Nipani 21 CHARACTERISTICS OF AN IDEAL POLYMER Should be versatile and possess a wide range of mechanical, physical, chemical properties Should be non-toxic and have good mechanical strength and should be easily administered Should be inexpensive Should be easy to fabricate Should be inert to host tissue and compatible with environment 7th Sept. 2010 KLECOP, Nipani 22 CRITERIA FOLLOWED IN POLYMER SELECTION The polymer should be soluble and easy to synthesis It should have finite molecular weight It should be compatible with biological environment It should be biodegradable It should provide good drug polymer linkage 7th Sept. 2010 KLECOP, Nipani 23 GENERAL MECHANISM OF DRUG RELEASE FROM POLYMER There are three primary mechanisms by which active agents can be released from a delivery system: namely, Diffusion, degradation, and swelling followed by diffusion Any or all of these mechanisms may occur in a given release system Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlledrelease device. The diffusion can occur on a macroscopic scale as through pores in the polymer matrix or on a molecular level, by passing between polymer chains 7th Sept. 2010 KLECOP, Nipani 24 Drug release from typical matrix release system 7th Sept. 2010 KLECOP, Nipani 25 For the reservoir systems the drug delivery rate can remain fairly constant. In this design, a reservoir whether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix is surrounded by a film or membrane of a rate-controlling material. The only structure effectively limiting the release of the drug is the polymer layer surrounding the reservoir. This polymer coating is uniform and of a nonchanging thickness, the diffusion rate of the active agent can be kept fairly stable throughout the lifetime of the delivery system. The system shown in Figure a is representative of an implantable or oral reservoir delivery system, whereas the system shown in b. 7th Sept. 2010 KLECOP, Nipani 26 Drug delivery from typical reservoir devices: (a) implantable or oral systems, and (b) transdermal systems. 7th Sept. 2010 KLECOP, Nipani 27 7th Sept. 2010 KLECOP, Nipani 28 ENVIRONMENTALLY RESPONSIVE SYSTEM It is also possible for a drug delivery system to be designed so that it is incapable of releasing its agent or agents until it is placed in an appropriate biological environment. Controlled release systems are initially dry and, when placed in the body, will absorb water or other body fluids and swell, The swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. 7th Sept. 2010 KLECOP, Nipani 29 Examples of these types of devices are shown in Figures a and b for reservoir and matrix systems. Most of the materials used in swelling-controlled release systems are based on hydrogels, which are polymers that will swell without dissolving when placed in water or other biological fluids. These hydrogels can absorb a great deal of fluid and, at equilibrium, typically comprise 60–90% fluid and only 10–30% polymer. 7th Sept. 2010 KLECOP, Nipani 30 7th Sept. 2010 Drug delivery from (a) reservoir and (b) matrix swellingcontrolled release systems. KLECOP, Nipani 31 Stimulus Hydrogel Mechanism pH Acidic or basic hydrogel Change in pHswelling- release of drug Ionic strength Ionic hydrogel Change in ionic strength change in concentration of ions inside gel change in swelling release of drug Chemical species 7th Sept. 2010 Hydrogel containing electron-accepting groups KLECOP, Nipani Electron-donating compounds formation of charge/transfer complex change in swelling release of 32 drug Enzyme- Hydrogel substrate containing immobilized enzymes Substrate present enzymatic conversion product changes swelling of gel release of drug Magnetic Magnetic particles dispersed in alginate microshperes Applied magnetic field change in pores in gel change in swelling release of drug Thermal Thermoresponsive hrydrogel poly(Nisopropylacrylamide Change in temperature change in polymer-polymer and water-polymer interactions change in swelling release of drug 7th Sept. 2010 KLECOP, Nipani 33 APPLICATIONS The pharmaceutical applications of polymers range from their use as binders in tablets Viscosity and flow controlling agents in liquids, suspensions and emulsions Polymers are also used as film coatings to disguise the unpleasant taste of a drug, to enhance drug stability and to modify drug release characteristics. 07/09/2010 KLECOP, Nipani 34 Applications in Conventional Dosage Forms Tablets : - As binders - To mask unpleasant taste - For enteric coated tablets Liquids : - Viscosity enhancers - For controlling the flow Semisolids : - In the gel preparation - In ointments In transdermal Patches 7th Sept. 2010 KLECOP, Nipani 35 Applications In Controlled Drug Delivery Reservoir Systems - Ocusert System - Progestasert System - Reservoir Designed Transdermal Patches Matrix Systems Swelling Controlled Release Systems Biodegradable Systems Osmotically controlled Drug Delivery 7th Sept. 2010 KLECOP, Nipani 36 BIO DEGARADABLE POLYMERS 7th Sept. 2010 KLECOP, Nipani 37 BIO DEGRADABLE POLYMER Biodegradable polymers can be classified in two: Natural biodegradable polymer Synthetic biodegradable polymer Synthetic biodegradable polymer are preferred more than the natural biodegradable polymer because they are free of immunogenicity & their physicochemical properties are more predictable &reproducible 7th Sept. 2010 KLECOP, Nipani 38 FACTORS AFFECTING BIODEGRADATION OF POLYMERS PHYSICAL FACTORS Shape & size Variation of diffusion coefficient Mechanical stresses CHEMICAL FACTORS Chemical structure & composition Presence of ionic group Distribution of repeat units in multimers configuration structure Molecular weight Morphology Presence of low molecular weight compounds 7th Sept. 2010 KLECOP, Nipani 39 CONTD Processing condition Annealing Site of implantation Sterilization process PHYSICOCHEMICAL FACTORS Ion exchange Ionic strength pH 7th Sept. 2010 KLECOP, Nipani 40 ADVANTAGES OF BIODEGRADABLE POLYMERS IN DRUG DELEVERY Localized delivery of drug Sustained delivery of drug Stabilization of drug Decrease in dosing frequency Reduce side effects Improved patient compliance Controllable degradation rate 7th Sept. 2010 KLECOP, Nipani 41 ROLE OF POLYMER IN DRUG DELIVERY The polymer can protect the drug from the physiological environment & hence improve its stability in vivo. Most biodegradable polymer are designed to degrade within the body as a result of hydrolysis of polymer chain into biologically acceptable & progressively small compounds. TYPES OF POLYMER DRUG DELIVERY SYSTEM: MICRO PARTICLES: These have been used to deliver therapeutic agents like doxycycline. NANO PARTICLES: delivery drugs like doxorubicin, cyclosporine, paclitaxel, 5- fluorouracil etc 7th Sept. 2010 KLECOP, Nipani 42 POLYMERIC MICELLES: used to deliver therapeutic agents. HYDRO GELS: these are currently studies as controlled release carriers of proteins & peptides. POLYMER MORPHOLOGY: The polymer matrix can be formulated as either micro/nano-spheres, gel, film or an extruded shape. The shape of polymer can be important in drug release kinetics. 7th Sept. 2010 KLECOP, Nipani 43 Application For specific site drug delivery- anti tumour agent Polymer system for gene therapy Bio degradable polymer for ocular, non- viral DNA, tissue engineering, vascular, orthopaedic, skin adhesive & surgical glues. Bio degradable drug system for therapeutic agents such as anti tumor, antipsychotic agent, anti-inflammatory agent and biomacro molecules such as proteins, peptides and nucleic acids 7th Sept. 2010 KLECOP, Nipani 44 BIO DEGRADABLE POLYMERS FOR ADVANCE DRUG DELIVERY Polymers play an vital role in both conventional as well as novel drug delivery. Among them , the use of bio degradable polymer has been success fully carried out. Early studies on the use of biodegradable suture demonstrated that these polymers were non- toxic & biodegradable. By incorporating drug into biodegradable polymer whether natural or synthetic, dosage forms that release the drug in predesigned manner over prolong time 7th Sept. 2010 KLECOP, Nipani 45 DRUG RELEASE MECHANISM The release of drugs from the erodible polymers occurs basically by three mechanisms, I. The drug is attached to the polymeric backbone by a labile bond, this bond has a higher reactivity toward hydrolysis than the polymer reactivity to break down. The drug is in the core surrounded by a biodegradable rate controlling membrane. This is a reservoir type device that provides erodibility to eliminate surgical removal of the drug-depleted device. a homogeneously dispersed drug in the biodegradable polymer. The drug is released by erosion, diffusion, or a combination of both. II. III. 7th Sept. 2010 KLECOP, Nipani 46 Schematic representation of drug release mechanisms In mechanism 1, drug is released by hydrolysis of polymeric bond. In mechanism 2, drug release is controlled by biodegradable membrane. In mechanism 3, drug is released by erosion, diffusion, or a combination of both 7th Sept. 2010 KLECOP, Nipani 47 POLYMER EROSION MECHANISM The term 'biodegradation' is limited to the description of chemical processes (chemical changes that alter either the molecular weight or solubility of the polymer) ‘Bioerosion' may be restricted to refer to physical processes that result in weight loss of a polymer device. The erosion of polymers basically takes place by two methods:- 1. 2. Chemical erosion Physical erosion 7th Sept. 2010 KLECOP, Nipani 48 CHEMICAL EROSION There are three general chemical mechanisms that cause bioerosion 1. The degradation of water-soluble macromolecules that are crosslinked to form three-dimensional network. As long as crosslinks remain intact, the network is intact and is insoluble. Degradation in these systems can occur either at crosslinks to form soluble backbone polymeric chains (type IA) or at the main chain to form water-soluble fragments (type IB). Generally, degradation of type IA polymers provide high molecular weight, water-soluble fragments, while degradation of type IB polymers provide low molecular weight, water soluble oligomers and monomers 7th Sept. 2010 KLECOP, Nipani 49 7th Sept. 2010 KLECOP, Nipani 50 2. The dissolution of water-insoluble macromolecules with side groups that are converted to water-soluble polymers as a result of ionization, protonation or hydrolysis of the groups. With this mechanism the polymer does not degrade and its molecular weight remains essentially unchanged. E.g. cellulose acetate 3. The degradation of insoluble polymers with labile bonds. Hydrolysis of labile bonds causes scission of the polymer backbone, thereby forming low molecular weight, water-soluble molecules. E.g. poly (lactic acid), poly (glycolic acid) The three mechanisms described are not mutually exclusive; combinations of them can occur. 7th Sept. 2010 KLECOP, Nipani 51 PHYSICAL EROSION The physical erosion mechanisms can be characterized as heterogeneous or homogeneous. In heterogeneous erosion, also called as surface erosion, the polymer erodes only at the surface, and maintains its physical integrity as it degrades. As a result drug kinetics are predictable, and zero order release kinetics can be obtained by applying the appropriate geometry. Crystalline regions exclude water. Therefore highly crystalline polymers tend to undergo heterogeneous erosion. E.g polyanhydrides 7th Sept. 2010 KLECOP, Nipani 52 Homogeneous erosion, means the hydrolysis occurs at even rate throughout the polymeric matrix. Generally these polymers tend to be more hydrophilic than those exhibiting surface erosion. As a result, water penetrates the polymeric matrix and increases the rate of diffusion. In homogeneous erosion, there is loss of integrity of the polymer matrix. E.g poly lactic acid 7th Sept. 2010 KLECOP, Nipani 53 Natural polymers Polymers are very common in nature some of the most widespread naturally occurring substances are polymers Starch and cellulose are examples Green plants have the ability to take the simple sugar known as glucose and make very long chains containing many glucose units These long chains are molecules of starch or cellulose If we assign the symbol G to stand for a glucose molecule, then starch or cellulose can be represented as: -G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G- 7th Sept. 2010 KLECOP, Nipani 54 NATURAL POLYMERS Natural polymers remains the primary choice of formulator because - They are natural products of living organism - Readily available - Relatively inexpensive - Capable of chemical modification Moreover, it satisfies most of the ideal requirements of polymers. But the only and major difficulty is the batch- to-batch reproducibility and purity of the sample. 7th Sept. 2010 KLECOP, Nipani 55 Examples : 1) Proteins : - Collagen : Found from animal tissue. Used in absorbable sutures, sponge wound dressing, as drug delivery vehicles - Albumin : Obtained by fabrication of blood from healthy donor. Used as carriers in nanocapsules & microspheres - Gelatin : A natural water soluble polymer Used in capsule shells and also as coating material in microencapsulation. 7th Sept. 2010 KLECOP, Nipani 56 2) Polysaccharides : - Starch : Usually derivatised by introducing acrylic groups before manufactured int microspheres. Also used as binders. - Cellulose : Naturally occuring linear polysaccharide. It is insoluble in water but solubility can be obtained by substituting -OH group. Na-CMC is used as thickner, suspending agent, and film formers. 3) DNA & RNA : They are the structural unit of our body. DNA is the blueprint that determines everything of our body. 7th Sept. 2010 KLECOP, Nipani 57 CURRENTLY AVAILABLE POLYMERS FOR CONTROLLED RELEASE Diffusion controlled systems Solvent activated systems Chemically controlled systems Magnetically controlled systems 7th Sept. 2010 KLECOP, Nipani 58 DIFFUSION CONTROLLED SYSTEM Reservoir type Shape : spherical, cylindrical, disk-like Core : powdered or liquid forms Properties of the drug and the polymer : diffusion rate and release rate into the bloodstream Problems : removal of the system, accidental rupture Matrix type Uniform distribution and uniform release rate No danger of drug dumping 7th Sept. 2010 KLECOP, Nipani 59 SOLVENT ACTIVATED SYSTEM Osmotically controlled system Semipermeable membrane Osmotic pressure decrease concentration gradient Inward movement of fluid : out of the device through a small orifice Swelling controlled system Hydrophilic macromolecules cross-linked to form a three-dimensional network Permeability for solute at a controlled rate as the polymer swells 7th Sept. 2010 KLECOP, Nipani 60 CHEMICALLY CONTROLLED SYSTEMS Pendant-chain system Drug : chemically linked to the backbone Chemical hydrolysis or enzymatic cleavage Linked directly or via a spacer group Bioerodable or biodegradable system Drug : uniformly dispersed Slow released as the polymer disintegrates No removal from the body Irrespective of solubility of drug in water 7th Sept. 2010 KLECOP, Nipani 61 MAGNETICALLY CONTROLLED SYSTEMS Cancer chemotherapy Selective targeting of antitumor agents Minimizing toxicity Magnetically responsive drug carrier systems Albumin and magnetic microspheres High efficiency for in vivo targeting Controllable release of drug at the microvascular level 7th Sept. 2010 KLECOP, Nipani 62 RECENTLY DEVELOPED MARKETED FORMULATIONS • • • • Medisorb Microencapsulation by PLA, PGA, PLGA Drug release : week to one year Alzamer Bioerodible polymer : release at a controlled rate Chronic disease, contraception, topical therapy 7th Sept. 2010 KLECOP, Nipani 63 USE OF FEW POLYMERS IN DRUG DELIVERY Poly(L-lactic acid) for release of progesterone, estradiol, dexamethasone Copolymer of gluconic acid and –ethyl-L-glutamte as bioerodible monolithic device PLA, PGA, PLGA for parenteral administration of polypeptide Sustained release (weeks or months) Orahesive® : sodium carboxymethyl cellulose, Pectin, gelatin Orabase ® : blend in a polymethylene/mineral oil base 7th Sept. 2010 KLECOP, Nipani 64 REFERENCES Novel drug delivery systems – Y.W.Chien – Dekker 50 Bio–adhesive drug delivery system – Dekker 98 Encyclopedia of controlled drug delivery systems. www.google.com 7th Sept. 2010 KLECOP, Nipani 65 ANY QUERIES? 7th Sept. 2010 KLECOP, Nipani 66 T H A N K Y O U Cell No: 00919742431000 E-mail:[email protected] 7th Sept. 2010 KLECOP, Nipani 67