A SEMINAR ON BIODEGRADABLE POLYMERS

Keyur Vasava

INTRODUCTION Definition: - Polymer comprised of monomers linked to one another through functional group
and have unstable linkage in the backbone.Biodegradable polymer degrading in biological fluid with release of dissolved or dispersed drug.

Disadvantage of non biodegradable polymer

(1) Surgical removal of drug depleted polymer is difficult. (2) Toxic (3) Not achieved constant rate of drug release.

Advantage of biodegradable polymers

(1) (2) (3) (4) (5) (6) (7) Not require surgical removal of the drug. Breakdown products are natural and biocompatible. So, there is no toxicity. It give constant drug release. Localized delivery of drug Sustain delivery of drug Stabilization of drug Increase drug permeability

CHARACTERISTICS OF BIODEGRADABLE POLYMERS

It should be biocompatible It should be biosorbable It should be bifunctionl. It should be stable Predictability of biodegradation kinetics Ease of fabrication Absence of toxic endogenous impurities or residual chemicals used in there preparation. Eg. Cross linking agents Achieve controlled heterogenous erosion without any additives Acceptable shelf life Ability to withstand the sterilization process Degradation products that are excreted readily Regulatory approval

Specific physical properties

Water permeability and water solubility: It determines the patterns of hydrolytic degradation(bulk or surface) and rate of hydrolysis. Polymer crystallinity: The crystallinity of the polymer is of importance since only the amorphous phase is susceptible to enzymatic attack. Glass transition temperature: It has bearing on molecular chain mobility and permeability characteristics of the polymer. The molecular chain mobility determines the vulnerability of the polymer to enzymatic attack. Physical dimensions: The physical components like size and surface to volume ratio are of significance in the biodegradation profile.

FACTORS AFFECTING BIODEGRADATION OF THE POLYMERS

(1) Chemical structure (2) Chemical composition (3) Distribution of repeat units in multimers (4) Presence of ionic groups (5) Presence of chain defects or unexpected units (6) Configuration structure (7) Molecular weight (8) Molecular weight distribution (9) Morphology (amorphous/semi crystalline, microstructure, residual stresses) (10) Presence of low molecular weight compound (11) Processing condition (12) Annealing (13) Sterilization process (14) Storage history (15) Shape (16) Implantation site (17) Presence of absorbed or adsorbed compounds (water, lipid, ions, etc.) (18) Physicochemical factors (pH, ion exchange, ionic strength) (19) Physical factors (change in shape and size, variations of diffusion coefficients, mechanical stresses, stress and solvent induced cracking) (20) Hydrolytic mechanism

POLYMER DEGRADATION AND EROSION

The outstanding property of a biodegradable polymer is its degradation and erosion behavior. The degradation is primarily process of chain cleavage leading to reduction in molecular weight. On the other hand, erosion is the sum of all processes leading to the loss of mass from a polymer matrix.

Degradation through hydrolysis:

Generally polymer degradation occurs in two phases. In first phase, water penetrates the bulk of the device and preferentially attacks the chemical bonds in the amorphous phase leading to conversion of long polymer chain into shorter water soluble fragments. In the second phase, there is a rapid loss of polymer mass due to enzymatic attack and fragment metabolization. Typical Hydrolysis Rates for Some Different Types of Polymers Class Polyanhydride Polyketal Polyorthoester Polyacetal Polyester Polyurea Polycarbonate Polyurethane Polyamide Hydrolysis rate 0.1 hours 3 hours 4 hours 0.8 years 3.3 years 33 years 42,000 years 42,000 years 83,000 years

Enzymatic degradation:
Examples of enzymatic degradation of the polymers POLYMER ENZYME

Surface erosion:
In surface erosion, the rate of water penetration into the device is slower than the rate at which polymer is converted into water soluble materials. (eg. Polylactic acid, Polyglycolic acid, polycaprolactone)

Bulk erosion:
In bulk erosion, the rate of water penetration into the device exceeds the rate at which polymer is converted into water soluble materials. (eg. Poly(orthoester), polyanhydride)

The bioerosion mechanism can be classified into three major types: (1) Type I erosion: This type of erosion is evident with water soluble polymers crossed linked to form a three dimensional network. This network remains insoluble till the cross links are intact and when it is placed in an aqueous environment, it swells only to the extent permitted by its cross link density. The erosion in this instance can occur either by cleavage of cross link or by cleavage of the water soluble backbone. Following this bond cleavage the matrix begins to swell and eventually dissolves. (2) Type II erosion: This type of erosion occurs with polymers that were earlier water insoluble but converted to water soluble forms by hydrolysis, ionization or protonation of a pendent group. Here solubilization does not lead to significant changes in molecular weight.

(3) Type III erosion: This type of erosion occurs in polymers that were of high molecular
weight but transformed to small, water soluble molecules via hydrolytic cleavage of labile bonds in the polymer.

GENERAL FABRICATION TECHNIQUES

Molding (formation of drug matrix) compression molding melt molding solvent casting Molding ( compression molding ) Polymer and drug particles are milled to a particle size range of 90 to 150 m Drug / Polymer mix is compressed at ~30,000 psi Formation of some types of tablet / matrix Molding ( melt molding / casting ) Polymer is heated to ~10C above it melting point ( Tm ) to form a viscous liquid Mix drug into the polymer melt Shaped by injection molding Advantages More uniform distribution of drug in polymer Wide range of shapes possible Disadvantages Thermal instability of drugs (heat inactivation) Drug / polymer interaction at high temperature Cost Molding ( Solvent casting ) Co-dissolve drug and polymer in an organic solvent Pour the drug / polymer solution into a mold chilled under dry ice Allow solvent to evaporate Formation of a drug-polymer matrix Advantages Simplicity Suitable for heat sensitive drugs Disadvantages Possible non-uniform drug distribution Proper solvents for drugs and polymers Fragility of the system Unwanted matrix porosity Use of organic solvents / Solvent residues

MEDICAL APPLICATIONS OF BIODEGRADABLE POLYMERS

Wound management Sutures Staples Clips Adhesives Surgical meshes Orthopedic devices Pins Rods Screws Tacks Ligaments Dental applications Guided tissue regeneration Membrane Void filler following tooth extraction Cardiovascular applications Stents Intestinal applications Anastomosis rings Drug delivery system Tissue engineering

CLASSIFICATION OF BIODEGRADABLE POLYMERS

(A) Natural polymers and modified natural polymers Collagen, Albumin, Casein, Gelatin, Fibrinogen, Chitin and Chitosan, Dextran, Alginate, Calcium Pectinate (B) Synthetic polymers Aliphatic Poly(ester)s, Polyphosphoesters, Polyanhydrides, Poly(amino)Acids, Pseudopoly(amino)Acids, Poly(ortho esters) Polyphosphazenes,

(C) Environmentally responsive polymers Thermosensitive polymers, Electrically and Chemically controlled polymers, pH sensitive polymers, Azopolymers

(D) Miscellaneous polymers employed in drug delivery devices Polymeric Phospholipids, Polyethyleneimine, Polyamidoamine, Polyethylene Glycol

(A) Natural polymers and modified natural polymers

Advantages: Derived from natural sources Easily available Relatively cheap Qualified for a number of chemical modification (a) Collagen : It is primary structural protein occurs in the animal tissues. Easy to isolate and purify in large quantities. Biocompatible and non toxic profile Well established physicochemical, structural and immunological properties. Amenable to easy processing to various form In vivo swelling and resultant poor dimensional stability Variability in drug release kinetics Low mechanical strength and elasticity in vivo Residual aldehyde cross linking agents cause tissue irritation Chances of triggering an antigenic response

(b) Albumin : It is major plasma protein components. (more than 55% of the total protein) Albumin microsphere have been employed to deliver many drugs including insulin, 1-norgestrel, haematoporphyrin, sulphadiazine, prednisolone, triamcinolone, 5-fluorouracil, doxorubicin and mitomycin C. Albumin microspheres have been exploited for chemotherapy as with them high local drug concentration can be achieved for a relatively longer period. (c) Gelatin : Easy availability Low antigen profile Poor binding to drug molecules and low temperature preparation technique that reduces the chances of drug degradation.

(d) Chitin and Chitosan : Chitin is highly insoluble in common solvents and has close resemblance to cellulose by having similar solubility profile and low chemical reactivity. Chitosan is a principal derivative of chitin and chitosan are distinguished by their solubility profile in dilute aqueous acid solutions. The characteristics properties of chitosan that render them suitable for pharmaceutical and biomedical applications are: Pharmacological properties like antacid and antiulcer activity, hypocholesterolemic action and wound healing properties. Haemostatic and spermicidal properties owing to their ability to bind strongly to mammalian cells by virtue of their polycationic character. Presence of reactive functional group and cationic character opens up possibilities for their application in controlled drug delivery. Favorable biological properties like biodegradability, biocompatibility and non toxicity. Has gel forming ability at low pH The chitosan matrix formulation floats and gradually swells in acidic medium.

(e) Alginic acid It is hydrophilic carbohydrates obtained from various species of brown seaweeds (Phaephyceae) by the use of dilute alkali. They are particularly beneficial as carriers of peptides and other sensitive drug moieties. Alginate vaccine delivery system offers several benefits. Since use of organic solvents and high temperature is not required, even viable bacteria and viruses can be employed. They protect antigens/vaccines against degradation in gastrointestinal tract allowing simulation of immune response with smaller amount of antigen/vaccine. They act as an adjuvant. They bypass the stomach and thereby deliver the antigen to GALT (gut associated lymphoid tissue).

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(B) Synthetic polymers : (a) Aliphatic Poly(ester)s:Among the degradable polymers identified till date, the ester bond containing aliphatic polyesters are the most attractive and promising owning to their remarkable biocompatibility and versatility in terms of physical, chemical and biological properties. The aliphatic polyesters can be synthesized by two methods, viz. polycondensation of bifunctional hydroxyl acids and ring opening of polymerization of cyclic ester monomers.

Polymers of Aliphatic polyesters family

Polymer Poly (glycolic acid) Poly (lactic acid) Poly (caprolactone) Poly (para-dioxanone) Poly (hydroxybutyrate) Poly (-malic acid) Structure -(O-CO-CH2-)n-(O-CO-CH(CH3)-)n-(O-CO-CH2)5-)n-(O-CO-CH2)2-O-CH2)n-(O-CO-CH(CH3)-CH2-)n-(O-CO-CH(COOH)-CH2)n-

(i) Lactide/Glycolide Polymers Poly(glycolic acid) was the first degradable polymer to appear in 1954. But it has poor thermal and hydrolytic stability. Homo and copolymers based on lactic and glycolic acid have been centre of attention since 1960s in suture, prostheses and surgical implant application. Their nontoxic nature, biodegradable profile, biocompatible nature, ease of fabrication attracted attention to its potential as excipients for drug delivery. The copolymer composition and the mechanical and degradation properties of the material do not have a linear relationship. Eg. The copolymer poly(glycolide-DL-lactide) 50:50 degrades faster than the either homopolymers.

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Synthesis: Lactic acid/Glycolic acid is first polycondensed to yield low molar mass oligomers. The synthesis of homo and copolymer of lactic and glycolic acid is carried out by the ring opening melt condensation of these cyclic dimers, lactide and glycolide. Mechanism: The lactide/glycolide polymer chains are cleaved by hydrolysis to the monomeric acid. They are eliminated in vivo through the krebs cycle, basically as carbon dioxide and urine. The degradation rate at various body sites is more or less identical as the hydrolysis of these polymers is dependant only on significant changes in temperature and pH and presence of catalyst. The biodegradation of lactide/glycolide polymers primarily occurs in two steps. First , random hydrolytic cleavage of the ester linkage leading to the reduction in molecular weight and second, the onset of weight loss and a change in the rate of chain scission. Application: The lactide/glycolide polymers are basically low melting thermoplastics. These offers considerable flexibility and ease in fabrication of lactide/glycolide polymer based drug delivery system, like microparticles, implants and fibres. Lactide/glycolide based microspheres can also be prepared. (by solvent evaporation, phase separation and fluidized bed coating) The lactide/glycolide polymers can be fabricated into mono- or multifilaments. (ii) Poly -caprolactone (PCL) The advantages of PCL as biodegradable controlled drug delivery system includes: Its slow degradation rate renders it suitable for use in long term(1 year) delivery system. Biodegradability can be increased by copolymerization. Non toxic profile Its unique ability to form compatible blend with many other polymers. The PCL and its copolymers have good permeability to low molecular weight drugs(<400D) Synthesis Caprolactones can be synthesized by oxidation of cyclohexanone with peracetic acid in an efficient continuous process. Caprolactone can be polymerized by anionic, cationic, coordination and radical polymerization. Each method offers peculiar benefits per se varying degree of control over

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polymer charecteristics viz., molecular weight, molecular weight distribution, end group composition and sequence(block vs random) distribution of copolymer. Mechanism The degradation mechanism is similar to that of polylactide/glycolide polymers. The degradation of PCL proceeds through two phases within the biosystem. It start with random nonenzymatic hydrolytic chain scission of the ester linkage leading to a reduction in molecular weight and the viscosity. In second phase, the rate of chain scission of the polymer is reduced and weight loss starts. The apparent loss in weight is due to two reasons. Firstly, the increased chances of break up into small fragments (following chain scission of low molecular weight polymer) that can diffuse out of the polymer bulk. Secondly, the generation of smaller fragments which have better permeability of phagocytosis. Application Film of PCL/its copolymer and drug prepared by casting method. PCL tubing prepared by melt extrusion method. Microcapsules of PCL and its copolymers are prepared by solution, air coating and mechanical method. (b) Poly(phosphoester)s (PPE) :-

These polymers are generally referred to as polyphosphates (P-O-C), polyphosphonates (P-C) or polyphosphites depending upon the nature of the side chain attached to the phosphorus. Some of the major limitations presented by this class of polymers are the prohibitive cost of synthesis in comparison to the conventional carbon analogues and their apparent hydrolytic instability. Synthesis PPE based Poly(Ethylene Terephthalate) and cyclohexane-1,4-dimethyl phosphate backbone prepared by polycondensation reaction. Mechanism The PPE are hydrolyzed into non toxic phosphates, alcohol and diols.

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(c) Polyanhydrides :-

It was first synthesize in1909 as raw materials for the manufacture of fibres. But their potential in drug delivery was realized in 1980. Synthesis The various approaches for polyanhydride synthesis are melt polycondensation, dehydrochlorination and dehydrative coupling. There are various monomers are employed for synthesis of the polyanhydrides such as bis(p-carboxyphenoxy)methane (CPM), 1,3-bis(pcarboxyphenoxy)propane (CPP), 1,3-bis(p-carboxyphenoxy)hexane (CPH), p-carboxyphenoxy acetic acid (CPA), p-carboxyphenoxy valeric acid (CPV), p-carboxyphenoxy octanoic acid (CPO) etc. Mechanism The carboxylic anhydride bond in the polymer chain is responsible for the fast erosion of polyanhydrides. Polyanhydrides are insoluble in aqueous media and therefore degrade to water soluble oligomers before erosion occurs. The degradation characteristics of the polyanhydride polymers is affected by the relative ratios of the two monomers. The degradation rates could be increased by copolymerization with sebacic acid. Thus the degradation rates can be altered within a range of 1 day to 3 years by modifying the ratio of CPP-SA. Applications The polyanhydrides are fast eroding polymers and hence suitable for short term delivery. They are also suitable for designing pulsatile drug delivery systems owing to their surfacial erosion pattern. The polyanhydride matrix disc comprised of several layers of polymers carrying different drug doses can facilitate release of drug one after another which is used for vaccination and localized tumor therapy. (d) Polyphosphazenes

Hydrophobic polyphosphazenes R= fluoroalkyl side group

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Hydrophilic polyphosphazenes R= alkylamino side group Polyphosphazenes contain a long chain backbone of alternating phosphorus and nitrogen atoms and to each phosphorus atom two side groups are attached. Generally there are 15,000 or more repeating units in a chain with a corresponding molecular weight 2,00,000 to 50,00,000. Synthesis Variations in the molecular structure of polyphosphazene are accomplished by macromolecular substitution reactions. Mechanism Polyphosphazene undergo hydrolysis to phosphate and ammonia, which are easily metabolized and excreted respectively. Application Hydrogel is prepared from this polymer. The biomedical and pharmaceutical applications of hydrogels are In construction of soft tissue prostheses Tissue like coatings As a material for blood vessel prostheses Lining of heart valves As a matrix for controlled drug delivery For immobilization of antigen and enzymes For construction of soft contact lenses and intraocular lenses

(e) Poly(ortho Esters) (POE):-

POEs have acid labile linkages in their backbones and thereby allow easy manipulation of hydrolysis rate by physical incorporation of acidic or basic excipients into the matrix. Use of acidic excipients :- When a hydrophobic polymer with physically dispersed acidic excipients is placed in an aqueous environment, water diffuses into the polymer leading to
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dissolution of acidic excipients. This leads to lowering of pH and acceleration of hydrolysis of the ortho ester bond. Use of copolymerized acidic monomers :- Polymer erosion can be accelerated by using diols bearing pendent carboxylic group (eg. 9,10-dihydroxystearic acid) as comonomers in the synthesis of polymers. Use of basic excipients :- To achieve long term erosion, the interior of the device must be stabilized to circumvent matrix hydrolysis following water penetration. Basic excipients are employed to achieve such stabilization since ortho ester linkages are stable in base. Synthesis POEs are prepared by transesterification process. Mechanism These polymer undergo hydrolysis regenerates the diols and produced -butyrolactone, which hydrolyses to co-hydroxy butyric acid. Application It is mainly used to fabricate contraceptive steroid bearing bioerodible implants.

(C) Environmentally responsive polymers

The environmentally responsive polymers alter their structure and physical properties in response to external signals like temperature, current, chemical and photomodulation. These polymers are used in preparation of self regulating or auto feedback drug delivery systems.

(a) Thermosensitive polymer Temperature modulation of polymeric devices is an interesting and highly feasible stimuli option. The temperature modulation of drug delivery can be judiciously employed in these conditions: Hyperpyretic drug delivery: The normal body temperature of 37C is elevated by the physiologic presence of pathogens and pyrogens. Thus, self regulating or auto feedback drug delivery devices can be designed that release antipyretic drugs in response to increased body temperature in diseased state. Transdermal delivery system: Thermosensitive polymeric membrane can be used as an on-off switches in transdermal devices to achieve pulsatile drug delivery from the skin.

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Externally modulated devices: Drug delivery devices relying on external modulation for drug release can be designed to respond to external temperature, and monitor or mediate drug release according to therapeutic need. Eg. Poly(N,N-dimethyl acrylamide), Poly(N-ethyl acrylamide), Poly(acryloyl pyrrolidone), Poly(ethylene oxide) (b) Electrically and Chemically controlled polymers Electrical field and chemical composition of the electrolyte phase can be employed for real time control of the swelling and transport profile of hydrogel. Following are the electrochemical and electromechanical mechanisms for transport of the drug molecules: Electrically and chemically induced membrane swelling to modify the effective pore size and permeability. Electrophoretic augmentation of solute flux within the membrane. Electroosmotic increase in solute flux within the membrane. Electrostatic partitioning of charged solutes into charged membrane. These electrically controlled membranes offer some unique advantage in fabricating on demand drug release device as: The gel membrane itself serves as all or a major part of the reservoir. Easy coupling to sensor and microelectronics in feedback controlled systems. Applicable even to high molecular weight drugs. Can be easily adapted to the existing transdermal delivery system to control drug transport. (c) pH sensitive polymers The drug delivery devices based on pH sensitive polymers employ enzymes or antibodies that can interact with specific molecules to produce a pH change. This pH change lead to erosion of the pH sensitive polymer and consequently facilitates the release of incorporated drug. The erosion rate is proportional to the pH change. Eg. A partially esterified copolymer of methyl vinyl ether and maleic anhydride has been employed for designing a urea-urease modulated system for hydrocortisone delivery.

Polyortho ester contain a pH sensitive linkage in the polymer backbone, which erodes as
pH is decreased. Insulin release from this polymer system can be modulated by glucose oxidase-glucose reaction which produced gluconic acid and reduced pH.

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(D) Miscellaneous polymers employed in drug delivery devices

(a) Polymeric phospholipids Polymeric phospholipids are a new class of biomaterials having close similarities to naturally occurring lipids. These polymeric phospholipids have various applications. On incorporation into bilayers of liposomes, they increase their resistance to precipitation and leakage. Since they mimic the surface of biomembranes they can be coated over artificial surfaces to make them more biocompatible.

METHODS OF STUDYING POLYMER DEGRADATION

Morphological changes (swelling, deformation, bubbling, disappearance) Weight lose Thermal behavior changes Differential Scanning Calorimetry (DSC) Molecular weight changes Dilute solution viscosity Size exclusion chromatograpgy(SEC) Gel permeation chromatography(GPC) MALDI mass spectroscopy Change in chemistry Infared spectroscopy (IR) Nuclear Magnetic Resonance Spectroscopy (NMR) TOF-SIMS

COMMERCIALLY AVAILABLE BIODEGRADABLE DRUG DELIVERY SYSTEMS

Name of product Lupron Depot Sandostatin Neutropin Depot Trelstar Depot Gliadel Zoladex Atridox Dosage form Microspheres Microspheres Microspheres Microspheres Waffer Rod Gel Active ingredient Leuprolide octreotide Somatropin Triptorelin Cumustin Goserelin Doxycycline Biodegradable polymer PLGA PLGA PLGA PLGA Polyanhydride PLGA PLGA

PLGA : Poly(lactic-co-glycolic acid) Polyanhydride : Poly[bis(p-carboxyphenoxy)propane:sebacic acid] in a 20:80 molar ratio

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REFERENCES: Vyas S.P. And Khar Roop K., Controlled Drug Delivery Concepts and Advances; Vallabh Prakashan, Delhi. Page no. 97-154 Jain N.K., Controlled and novel drug delivery; CBS publishers and distributors; 27-51 Mark Chasin, Robert Langer, Biodegradable polymers as a drug delivery system, Marcel Dekker Inc., Vol. 45, Pg no. 12-231 Ranade V.V., Drug delivery system, J. Clin. Pharmacol., 30, 10, 1990.

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