biodegradable polymers: emerging excipients for the

Biodegradable polymers: emerging excipients for thepharmaceutical and medical device industries.

Bhavesh Patel*, Subhashis Chakraborty

Technical Service-Pharma Polymer & Services, Evonik India Pvt Ltd, Research Centre India (RCI), Krislon house-first floor, Opp.Marwah Centre, Sakivihar road, Sakinaka, Andheri (E), Mumbai 400 072, Maharashtra, India

Received: September 13, 2013; Accepted: October 12, 2013Review Article

ABSTRACT

Worldwide many researchers are exploring the potential use of biodegradable polymerics as carriers for a widerange of therapeutic applications. In the past two decades, considerable progress has been made in thedevelopment of biodegradable polymeric materials, mainly in the biomedical and pharmaceutical industriesdue to their versatility, biocompatibility and biodegradability properties. The present review focuses on theuse of biodegradable polymers in various therapeutic areas like orthopedic and contraceptive device, surgicalsutures, implants, depot parenteral injections, etc. Biodegradable polymers have also contributed significantlyto the development of drug-eluting stents (DES) used for the treatment of obstructive coronary artery disease,such as angioplasty. Biodegradable synthetic polymers have potential applications in orthopedic devicefixation due to properties that impact bone healing, formation, regeneration or substitution in the humanbody. The present review also emphasizes areas such as the chemistry of polymer synthesis, factors affectingthe biodegradation, methods for the production of biodegradable polymer based formulations, the applicationof biodegradable polymers in dental implants, nasal drug deliveries, contraceptive devices, immunology, gene,transdermal, ophthalmic and veterinary applications, as well as, the sterilization of biodegradable basedformulations and regulatory considerations for product filing.

KEY WORDS: Biodegradable polymers, degradation, orthopedic implants, sterilization, drug eluting stents, tissueengineering

INTRODUCTION

The term “Biodegradable polymers” is quitefascinating in the pharmaceutical and medicaldevice community. In fact, this class ofpolymers has been known for more than a 100years in the chemical industry but unfortunately

has not received much attention because oftheir tendency to degrade under normalenvironmental conditions. Interestingly, it waslater realized that this was an advantage fordesigning a biodegradable implant which wouldavoid the necessity of a second surgicalprocedure required to remove the remnants ofa previous implant, as was the case for metallicimplants. The first FDA approvedbiodegradable product, Dexon® was a sutureintroduced in 1970 by Davis and Geck (1).

*Corresponding author: Technical Service-Pharma Polymer & Services,Evonik India Pvt Ltd, Research Centre India (RCI), Krislon house-firstfloor, Opp. Marwah Centre, Sakivihar road, Sakinaka, Andheri (E),Mumbai 400 072, Maharashtra, India, Tel: +91 98337 46909; Fax: +91 226691 6996, E-Mail: [email protected]

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 126

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Since then, there has been a revolution in themedical device industry which has introducedseveral orthopaedic implants such as pins,screws, cranio-maxilla-facial plates and so on.After about two decades, in the 1990s, thepharmaceutical industry entered in to this newera of biodegradable polymers introducingdepot injections. One of the most popular andcommercially successful depot injection isLupron®, manufactured by Takeda primarilyused for the treatment of prostate cancer (2,3).Although there has been significant scientific,as well as, commercial progress in this area, theunderstanding of this technology remainslimited to a few global companies. This isprimarily because of the complexities involvedin the polymer chemistry, depot injectionformulation technology and high precisionmolding. There is tremendous scope for theadoption of these technologies by a greaternumber of pharmaceutical and medical devicecompanies. This will help in extending thebenefits of these novel technologies to largerpatient populations world-wide, offering betterpatient compliance, especially in the case ofchronic disease management.

Through understanding polymer degradation inthe presence of hydrolyzing agents available inthe biological systems, various novel drugdelivery systems for sustained and targetedrelease have been formulated as depotinjections for weekly or monthly administrationas implants, microspheres, microcapsules,nanoparticles, in situ gels etc., (4). Propertiessuch as f lex ibi l i ty , durabi l i ty andbiocompatibility have made these polymers the preferred vehicles to administer safely in vivo forhuman use in the form of medical devices suchdental and orthopedic implants, inserts, sutures,drug eluting stents, and contraceptive devices(4). Considering the sincere approach ofenvironment protection, future outlook in thearea of biodegradable polymers seems to bequite promising.

The objective of this review is to present aconsolidated view on the basic aspects

pertaining to polymer chemistry, polymersynthesis and optimal polymer selection forpharmaceutical and medical applications. Thisreview also attempts to discuss factorsinfluencing the biodegradation process,together with recent developments in the areaof novel drug delivery systems such gene andcancer therapy, the application in dental andorthopedic devices during surgery, drug elutingstents, orthopedic devices, sutures for tissueand scaffold engineering, veterinary and nasaldrug delivery using biodegradable polymers.

CLASSIFICATION

Broadly, biodegradable polymers can beclassified into natural or synthetic. Naturalbiodegradable polymers are proteins orpolysaccharides e.g., alginate, chitosan, agaroseand collagen or starch based derivatives whichundergo enzymatic degradation in the body.Synthetic polymers contain hydrolysablelinkages such as esters, amide, peptide, urea,urethane or anhydride in the polymericbackbone that easily hydrolyzes in the humanbody. Examples of such synthetic polymersinclude (i) polyesters such as poly lactic acid(PLA), poly glycolic acid (PGA), poly l-lactideco-glycolide (PLGA) co-polymer, poly ε-caprolactone (PCL) (ii) poly anhydrides (iii)poly ethylene glycol and their derivatives (iv)poly vinyl alcohol (v) poly peptide and polyamide (vi) polyhydroxy alkonates (PHA)derivatives, etc., (5, 6). A broad classification ofbiodegradable polymers is shown in Table 1.

Polyester PLGA is a copolymer of poly lacticacid (PLA) and poly glycolic acid (PGA). It iscurrently considered the best biomaterialavailable for drug delivery with respect todesign and performance. Poly lactic acidcontains an asymmetric carbon which istypically described as the D or L form andsometimes as R and S form, in classical stereochemical terms. The enantiomeric forms of thepolymer PLA are poly D-lactic acid (PDLA)and poly L-lactic acid (PLLA).


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Figure 1 Synthesis and biodegradation cycle of PLGAbased biodegradable polymer

Table 1 Classification of biodegradable polymers (5-7)

Sr.No

SYNTHETIC BIODEGRADABLEPOLYMER

NATURALBIODEGRADABLE

POLYMER

1

Polyesters (Polyhydroxy alkanoates,polycaprolactone, poly L-lactide, polylactic acid, poly p-dioxanones, polyurethane, poly vinyl alcohol, nylon, Polyphosphor esters, Poly glycolic acid,Poly lactic-co-glycolic acid)

Proteins based (collagen,gelatin and albumin)

2Polyethers (Poly ethylene, polytetramethylene and poly propylene glycols)

Polysaccharides (starch,dextran, hyaluronic acid, andchitosan)

3 Polyethylene (PE)

4 Polycarbonates (PC)

5 Polyphosphazenes

6 Polyamide and Polyimide

7 Polyacrylamide

8 Polytetra fluoro ethylene (PTFE)

9 Poly ortho esters (POE)

10Poly anhydrides poly [bis(p-carboxyphenoxy) propane-co-sebacicacid]

PLGA is generally an acronym for poly D, L-lactic-co-glycolic acid where D- and L- lacticacid forms are in equal ratio (7). Trade nameand major global manufacturers ofbiodegradable polymer are shown in Table 2.

Table 2 Trade name and some of global manufacturersof biodegradable polymers (8, 9)

Sr. No COMPANY NAME TRADE NAME

1 Galactic Galacid®

2 Chronopol Heplon®

3 Treofan Treofan®

4 Mitsubishi Corporation Ecoloju®

5 Biomer Biomer® L

6 Evonik Industries Resomer® and Lakeshore®

7 Dow Cargill NatureWorks®

8 Toyota Eco Plastic®

9 Mitsui Chemicals Lacea®

10 Purac Biochem L-PLA®

11 Shimadzu Corporation Lacty®

12 Durect Corporation Lactel®

13 BASF Ecoflex®, Ecovio®

14 DuPont Biomax®

15 Eastman Chemical company Eastar Bio Ultra copolyester

16 Cereplast Bioplastic resin

17 Procter and Gamble Nodax®

18 PolyScience Inc PLA-PGA and PCL co-polymer

19 Metabolix Inc Poly hydroxyl alkanoates (PHA)

20 Wako speciality chemical PLA and PLGA

Chemistry and synthesis

PLGA polymers are polyester basedbiodegradable polymers, manufacturedsynthetically from monomers like lactic acid,glycolic acid, dioxanone, tri-methyl carbonate

and ε-caprolactone (see Figure 1).

When polymers are made of only one type ofmonomer, they are termed “homo-polymers”e.g., poly glycolic acid (PGA), poly lactic acid(PLA) and poly-dioxanone. If polymers aregenerated using a combination of monomers,they are termed as “co-polymers” e.g., poly (D,L-lactide co-glycolide) (PLGA), poly-(l-lactide-co-trimethylene carbonate), poly-(glycolide-co-trimethylene carbonate), poly-(glycolide-co-trimethylene carbonate-co-caprolactone) and soon.

The basic monomer unit of PLA is lactic acidand is primarily produced in large quantitiesthrough bacterial fermentation of carbohydratessuch as corn, sugar cane, whey, and so on, i.e.,rich carbon sources. The majority of thefermentation processes are carried out usingLactobacilli species which offer high yields oflactic acid. After obtaining a monomer such aslactic acid, PLA can be further synthesizedthrough a polycondensation reaction, or viaring-opening polymerization of cyclic diesters.The monomer’s concentration, ratio andsequence in the polymer and end groupchemistry dictate their mechanical properties,degradation kinetics, solubility, thermal andrheological properties, and water uptake.Furthermore, the polymers can be tailored forcontrolled degradation through the addition ofnumerous functional groups including


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Figure 2 Degradation mechanism of biodegradablepolymer

carboxylic acids, esters, amides, anhydrides, andothers. Synthetically, the polymers are preparedthrough ring-opening polymerization of themonomers in the presence of a catalyst. Postsynthesis, the polymers are purified usingsupercritical carbon dioxide (for crystallinepolymers) or aqueous precipitation fromacetone (for amorphous polymers) in order toreduce the residual monomer content. Theoverall low residual monomer content andminimal impurities imparts high quality andstability to the final product (8).

MECHANISM OF DEGRADATION

The term degradation designates the process ofpolymer chain cleavage which leads to a loss inmolecular weight. Degradation induces thesubsequent erosion of the material which isdefined as mass loss of material. Forbiodegradable polymer, mainly two differentprocesses of polymeric degradation can beproposed (1) Bulk erosion and (2) Surfaceerosion. The difference between the twodegradation mechanisms is shown in Figure 2.

Biodegradable polymers contain a hydrolysablebackbone which is susceptible to hydrolysis orenzymatic degradation in the cell environmentby bulk erosion and surface erosion. Theformer involves degradation all over the crosssection because of water penetration followedby slow scissions of long polymer chains, whilethe latter is a surface phenomenon. The rate of

surface erosion depends on the area exposed tothe hydrolytic environment and the rate of bulkerosion depends on the crystalline nature andporosity of the polymer matrix. The drugrelease pattern from the polymer matrix ofmicrospheres and implants follow the followingthree step process, that is an initial burst releasedue to dissolution of surface drug, followed byslow release due to degradation-dependentnetwork relaxation that creates sufficient freevolume for drug dissolution, and finally anaccelerated drug release. The accelerated drugrelease is triggered by the acidic micro-environment within the particle generated bythe autocatalytic degradation of the polymersinto lactic and glycolic acids. Overall, therelease profile is dependent on the nature of thedrug, polymer degradation rate, waterpermeability and drug-polymer matrixinteraction. Once degraded, the solubilizedmomomers/oligomers such as lactic acid andglycolic acid are excreted by the kidney andfinally metabolized into carbon dioxide andwater through the tricarboxylic acid (Kreb’s)cycle (10-12).

Various advanced analytical techniques aregenerally useful to understand and illustrate thepolymer degradation mechanisms. A simple butrelatively effective technique to characterize thedegradation of a polymeric matrix is byrecording the loss of mass during thedegradation process. In most cases the mainparameter used for monitoring degradation arechanges in molecular weight, crystallinity, pHand thermal changes inside the core. Qualitativeevaluation of polymer degradation can beperformed using scanning electron microscopy(SEM) and atomic force microscopy (AFM)which offer insight into the external andinternal morphology of degradable polymersystems. Other methods determine themolecular weight reduction of the polymer bymeans of gel permeation chromatography(GPC) or by intrinsic viscosity. For the changesthat degradable polymers undergo duringdegradation, thermal analysis such as


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differential scanning calorimetry (DSC) andthermo gravimetric analysis (TGA) aresomewhat beneficial. Some of the moreadvanced techniques that are useful for thestudying of polymer degradation are thedetermination of the molar fraction of themonomer using nuclear magnetic resonance(1H NMR), changes in crystallinity using wideangle x-ray diffraction (XRD), determination ofmonomer release using HPLC, end-groupanalysis using FT-IR and the study of polymerstructure and degradation using ramanscattering (12).

MARKET ANALYSIS FOR PLGA BASEDFORMULATION

The worldwide manufacturing capacity ofbiodegradable polymers (natural and synthetic)has grown dramatically since the mid-1990s. In1995, they were primarily produced on pilotplant scale with total worldwide capacityaccounting for not more that 25,000 to 30,000tonnes. In 2005, the global capacity forbiodegradable polymer had increased to around360,000 tones and continues to show anupward trend (9).

In March 2012 Global Industry Analyst, Increleased a comprehensive global report on themarket for biodegradable polymers forecastingthat it is bound to reach 2.44 billion pounds byyear 2017. The ever increasing demand inpackaging, the largest end-use market, growingenvironmental concerns, soaring petroleumcosts, launch of new types of biodegradablepolymers, concerns over depleting landfills, anda shift towards renewable sources fromtraditional sources of fossil fuel are the keyfactors driving the demand for biodegradablepolymers. Markets could further grow throughtechnological innovat ions , emergingapplications, increased regulations to prohibitpackaging waste and disposal at landfills andimprovements in infrastructure (13).

The major global players using biodegradablepolymers in the pharmaceutical industry aremainly multinational companies such asAbbott, Astra-Zeneca, Takeda, Novartis,Astellas and Sanofi Aventis. A review of thesales data of biodegradable formulations (suchas depot injections or medical devices)manufactured by the above key pharmaceuticalcompanies indicates revenues of approximately4.2 billion Euros generated to the year 2010.Out of the total revenue of 4.2 billion Euros, Janssen-Cilag has 72% of the market and therest is split between other customers. There isan increasing trend in the growth of dosageforms and the the total volume of dosage formswas 316 kilograms in 2007 increasing to 374kilograms in 2009, i.e., at a rate of 9% increaseper annum. Fragmenting the volume of eachindividual dosage forms shows that Risperidonehas the highest market share at 73% followedby Leuprolide acetate with a 14% market share.The remaining dosage forms were formulationsof Goserelin, Buserelin and Octreotide (14).

EMERGING TRENDS IN FORMULATIONDEVELOPMENT USING BIODEGRADABLEPOLYMERS

There is a continuing increase in the number ofdrugs, drug therapies and diseases whichrequire different kinds of formulations usingnovel manufacturing technologies and modifiedrelease kinetics. There is no single polymer thatcan satisfy all these requirements. Therefore thelast 30 years has seen tremendous advances inarea of biodegradable polymer. The use ofbiodegradable polymers in a formulation canaid in extending the release of the drug for aconsiderable period of time (weeks to months)and removes the need to remove device fromthe patient at the end of the treatment period.In addition, they also offer advantages in termsof targeted delivery of the drug and stabilizationof the drug molecules in polymeric matrix (15-18). A list of some commercial formulationsmanufactured using PLA/PLGA polymers areshown in Table 3.


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Table 3 PLA/PLGA based commercial formulation (19-21)

PRODUCTNAME

DOSAGEFORM

MANUFACTURER ACTIVEDURATIONMONTHS

Decapeptyl® Microparticle FerringTriptorelinacetate

1

Decapeptyl® SR Microparticle Ipsen-Beaufour Triptorelinacetate

1, 3, 6 (PLGA)

Zoladex® Implant AstraZeneca Goserelin acetate 1, 3 (PLGA)

Lupron Depot® Microparticle Takeda –AbbottLeuprolideacetate

1, 3, 4 (PLGA)

SandostatinLAR® Microparticle Novartis

Octreotideacetate

1 (PLGA)

Nutropin®

DepotMicroparticle Genentech

Somatropin(hrGH)

1,2 (PLGA)

Profact® Depot Implant Sanofi-Aventis Buserelin acetate 2, 3 (PLGA)

Suprecur® MP Microparticle Sanofi-Aventis Buserelin acetate 1

Eligard® Implant Sanofi-AventisLeuprolideacetate

1, 3 (PLGA)

Luprogel® Liquid MediGene AGLeuprolideacetate

1

Trelstar® Depot Microparticle WatsonTriptorelinpamoate

1 (PLGA)

Trelstar® LA Microparticle Watson-DebioTriptorelinpamoate

1, 3 (PLGA)

Arestin® Microparticle OraPharma Minocycline HCl 0.5

Atridox® Implants CollaGenex Doxycycline 0.25 (PLA)

Risperdal®

ConstaMicroparticle Johnson & Johnson Risperidone 0.5 (PLGA)

SMARTShotB12

Microparticle Stockguard Vitamin B12 4, 8

Vivitrol® Microparticle Alkermes Naltrexone 1 (PLGA)

Revalor®-XS Implant Intervet Trenbolone/estradiol

6

Ozurdex® Implant Allergan Dexamethasone 1

Gliadel® Implants MGI Pharma Carmustine 20

VARIOUS APPROACHES TO DEVELOP BIODEGRADABLE POLYMER BASED FORMULATIONS

Single emulsion (w/o or o/w) technique

Lakshmana et al., proposed a simpleemulsification process followed by solventevaporation for the preparation of sustainedrelease microspheres containing Aceclofenac.Using this method, microspheres were preparedby dissolving the polymer and the drug into acommon solvent such as dichloromethanefollowed by adding this oil phase into thehigher volume of aqueous phase containingemulsifying agent, PVA (0.1 to 1% w/v) undercontinuous stirring for a specified period oftime and revolutions per minute in a propellerstirrer. This mixture was then immediatelytransferred to a magnetic stirrer for completesolvent evaporation. The microspheres werecollected through filtration, washed with de-ionized water and dried in vacuum desiccatorsand then further characterized and the

microsphere morphology analysed (22).Although this is a simple procedure it may notbe suitable for proteins and peptides which maybe denatured in the presence of organicsolvents. It is also important to note that theencapsulation efficiency achieved by thisprocess is quite low and therefore may not be apractical approach for manufacturing (23-24).

Multiple (double) emulsification (w/o/w oro/o/w) technique

The microencapsulation process in whichemulsification (single or multiple) is followedby the removal of the solvent has been widelyused for the preparation of PLGA basedmicrospheres and microcapsules.

w/o/w multiple emulsification

In general, this method is used for thehydrophilic drug moieties which are easilysoluble in aqueous media. First, an aqueousphase containing dissolved drug (~ 0.5 to 1 ml)is emulsified into an oil phase (containing aPLGA polymer) (~ 5 to 10 ml) using a highspeed homogenizer. Suitable emulsifiers orsurfactants such as Poloxamer 407 or 188(~2% w/v) or Span 20 (1% to 20% v/v) can beincorporated during the initial emulsificationprocess. Then the initial emulsion is added to agreater volume of different concentrations ofpoly vinyl alcohol (0.1 to 1% w/w) (~ 200 to300 ml) continuously stirring using amechanical stirrer to form a w/o/w multipleemulsions. Homogenization is continued for afew hours at room temperature until thesolvent has completely evaporated. Themicroparticles that are generated are collectedthrough suitable size filtration and are furtherwashed with purified water and dried overnightat room temperature (25-27). Giovagnoli et al.,used a similar method to prepare microspheresof Capreomycin molecules using PLGA (50:50ratio, Mw: 10 kDa) for pulmonary delivery (28),as did Herman and Bodmeier who preparedmicrospheres of Somatostatin using PLA (Mw= 6,000 Da) using this method.


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Figure 3 Schematic illustration of multiple emulsificationsfollowed by solvent evaporation method

The above studies showed that using varioussalts such as NaCl or CaCl2 in the internal orexternal aqueous phases affected directly thedrug release pattern because of the formationof micro pore like structures in the microsphere(29). Crotts and Park prepared microspheres ofbovine serum albumin (BSA) using PLGA(75:25 ratio, Mw: 82,000 D) and studied theeffect of the inner aqueous phase volume onthe morphology and porosity of microspheres,under the assumption that the volume of theinner phase is directly related to the rate ofsolvent removal. It was found that at 5.6%inner aqueous volume fraction, dense andnonporous microspheres were formed while at22.7% more porous microspheres weregenerated (30). Pandey et. al., preparednanoparticles encapsulating the anti-tuberculosis drugs Isoniazid and Rifampicinincorporating PLGA (50:50 ratio). Theyobserved effective encpsulation of both drugs(~ 60%) and a prolonged blood circulation andanti-tubercular (TB) effect up to 9-11 dayssuggests that drug therapy based on PLGAnanoparticles can be capable of reducing dosingfrequency (31).

o/o/w multiple emulsification

In general, the method of o/o/w multipleemulsification is suitable and, has been widelyused, for lipophilic drugs. PLA or PLGA isdissolved in an oil phase (O2) such asdichloromethane (~ 5 ml) together with anemulsifier e.g,. Labrafil as a lipid vehicle. Theprimary o/o emulsion is prepared by addingolive oil (O1) (~ 0.2 to 1 ml) into a second oilphase such as dichloromethane and then themixture is sonicated using a probe typesonicator for ~30 seconds. Finally, the primaryemulsion is re-emulsified into distilleddeionized water containing PVA (0.1 to 1%w/v; ~ 100 ml) using a vigoroushomogenization process for 3 minutes. Aftercomplete solvent evaporation the microspheresare collected by centrifugation and washed withdistilled de-ionized water (32). A schematicdiagram of multiple emulsification process isshown in Figure 3. A list of drugs manufactured

using emulsification based solvent evaporationare shown in Table 4.

Phase separation (co-acervation) method

Phase separation, also known as a co-acervationtechnique, is a process focused on thepreparation of microspheres through non-ionicliquid-liquid phase separation techniques. Phaseseparation methods consist of decreasing thesolubility of the encapsulating polymer byadding a third immiscible component to thepolymer solution. Similar to a solventevaporation technique, this method is also usedfor both hydrophilic and hydrophobic drugs.Water-soluble drugs such as peptides andproteins are dissolved in water and dispersed inthe polymer solution to make a w/o emulsion.Hydrophobic drugs, such as steroids, are eithersolubilized or dispersed in the polymersolution.


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Table 4 List of drugs encapsulated using emulsification based solvent evaporation techniques

No NAME OF DRUG POLYMER USEDPREPARATIONMETHOD

REF

1 Capreomycin Sulfate PLGA 50:50 (Mw =10 kd) w/o/w multiple emulsion (28)

2 Bovine serum albumin PLGA 75:25 (Mw = 82,000D) w/o/w multiple emulsion (30)

3 Isoniazid + Rifampicin PLGA 50:50 (Mw = 25,000D) w/o/w multiple emulsion (31)

4 Labragfil® M 1944 PLA Mw = 2kDa o/o/w multiple emulsion (32)

5 Triptoreline PLGA 50:50 w/o/w multiple emulsion (33)

6 Bovine Superoxide Dismutase PEG 6000 s/o/w multiple emulsion (34)

7 Ganciclovir PLGA 65:35 Mw = 70,000D o/w emulsion (36)

8 Somatostatin PLA Mw = 6,000 D w/o/w emulsion (37)

9 Insulin PLGA 50:50 o/o emulsion (38)

10 Bovine serum albumin PLGA 50:50 Mw = 13,600D w/o/w multiple emulsion (39)

11 Diclofenac Sodium PLGA 50:50 Mw = 34,000D o/w emulsion (40)

12 5- Fluoro uracil PLA Mw = 3,400 D o/o emulsion (41)

13 ABT 627 (NCE) PLGA 50:50 Mw = 34,000D o/w emulsion (42)

14 Risperidone PLGA 75:25 o/w emulsion (43)

15 Dexamethasone PLGA 50:50 Mw = 60,000D o/w emulsion (44)

16 Leuprolide Acetate PLA and PLGA o/o/w multiple emulsion (45)

17 Doxorubicin PLGA 50:50 Mw = 13,000D o/w emulsion (46)

18 Campothecin PLGA 50:50 iv: 0.32-0.44 dl/g o/w emulsion (47)

19 Octreotide Acetate PLGA 50:50 Mw = 53,600D w/o/w multiple emulsion (48)

20 Insulin PLA Mw = 17,000D and PLGA 50:50 Mw = 14,100D w/o/w multiple emulsion (49)

21 Isoniazid+ Rifampicin PLGA 50:50 Mw = 2,500D Double emulsification (50)

Organic non-solvents such as liquid paraffin,silicone, coconut or sunflower oil is then addedto the solvent system (containing both the drugand polymer) under continuous stirring toextract the polymer solvent from the mixture.As a result, the polymer is subjected to phaseseparation forming very soft coacervatedroplets (size controlled by stirring) whichentrap the drug. This system is then added to alarge quantity of another organic non-solventsuch as formaldehyde or glutaraldehyde toharden the micro-droplets and form the finalmicrospheres which are collected by washing,sieving, filtrating/ centrifuging, and finallydrying (51-56). Thus, the co-acervation processincludes the following three steps: (1) phaseseparation of the coating polymer solution byadding a third component (2) removal of thepolymer solvents and adsorption of thecoacervate around the drug particles and (3)solidification of microparticles and collection ofthe microspheres by washing, filtrating/centrifuging and freeze drying. In a phaseseparation method, the rate of adding the firstnon-solvent must be controlled to ensure thatthe polymer solvent is extracted slowly so that

the polymer has sufficient time to precipiateand coat evenly onto the drug particle surfaceduring the co-acervation (57).

Jayan et. al., developed gelatin microspherescontaining salbutamol sulphate using a co-acervation phase separation method utilizingtemperature change. Gelatin was selected as awater-soluble naturally occurring biodegradablepolypeptide which is easily hydrolyzed byproteolytic enzymes present in the body. Themicrospheres obtained were uniform andspherical in shape with mean particle sizearound 12.58 µm providing sustained drugrelease over a period of 8 1/2 hours (58).Surendiran et. al., developed microspheres froma gelatin-carbopol polymeric mixture usingibuprofen as the model drug using a similarmethod where microspheres with a highamount of carbopol showed more sustaineddrug release when compared to microspheresthat contained a high amount of gelatin (59).These studies provide a basis for selectingsuitable excipients for the design of sustainedrelease biodegradable microspheres.


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Supercritical CO2 anti-solvent precipitationmethod

Submicrometer-sized and nano-sized particlescan be designed using various supercritical fluid(SCF) methods. A supercritical fluid can eitherbe a liquid or gas and is used above itsthermodynamic critical point of temperatureand pressure. Most commonly used SCFs arecarbon dioxide (CO2) and water (60). In thisprocess, the hydrophilic drug is dissolved in acommon solvent and injected in supercriticalCO2 with an ultrasonic field for enhancedmolecular mixing. Supercritical CO2 rapidlyextracts methanol leading to the instantaneousprecipitation of drug nanoparticles which areencapsulated in PLGA polymeric microspheresusing a non-aqueous anhydrous solid-oil-oil-oil(s/o/o/o) technique. In this technique, PLGAis dissolved in dichloromethane (DCM) solventinto which drug nanoparticles are addedcontinuously whilst stirring. In the next step, asmall amount of silicone oil is added to themixture resulting in the precipitation of PLGAin the form of the drug encapsulated inmicrospheres. Finally, the suspension is addedto a large quantity of precooled hexane toextract the DCM and silicone oil.

Thote et. al., developed PLGA (50:50 ratio,inherent viscosity: 0.39 dl/g) nanoparticles (150- 200 nm) containing dexamethasone as themodel drug using a supercritical CO2 method.Interestingly, in vitro dissolution of themicroencapsulated nanoparticles showedsustained release over a period of 700 hourswithout an initial burst release (61-64). Jordanet. al., developed PLGA (50:50 ratio, inherentviscosity: 0.16-0.24 dl/g) based sustainedrelease microspheres of human growthhormone using the SCF method forsubcutaneous injections. The sustained releaseeffect was observed for 14 days with minimalburst release. The formulation was welltolerated by both rats and monkeys without anyevidence of subcutaneous inflammation orchronic inflammatory response (65). Salmaso et.al., prepared PLA (Mw: 102 kDa) nanoparticles(200-400 nm) of Nisin as the model drug using

semi- continuous compressed CO2 anti-solventprecipitation wherein the drug was released inthe active form and the antibacterial activitywas maintained up to 45 days (66).

Kluge et. al., prepared PLGA micro- andnanocomposites (50:50 ratio) using supercriticalfluid extraction of emulsions (SFEE) for thedelivery of lysozyme. Particle sizes of around100 nm and encapsulation efficiency of 48.5%was observed (67). Similarly, Lee et. al.,prepared PLA based microparticles usingsupercritical anti-solvent using an enhancedmass transfer (SAS-EM) process wherein drugencapsulation efficiency achieved was 83.5%and the drug release was controlled for morethan 30 days. As compared to conventionalSAS processes, SAS-EM process has majoradvantage of effective residual organic solventsremoval (68).

Spray/freeze drying

When freeze drying a solution of PLA orPLGA it is first dissolved in organic solventswhich are further emulsified into an aqueousPVA solution using a homogenization process.This emulsion is then immediately added dropby drop to liquid nitrogen. The water andorganic solvent is removed from the frozensample under vacuum at 0EC, leaving behindthe dry hollow PLA or PLGA particles.Similarly, when spray drying an organic solutionthat contains the polymer and a suitablesurfactant such as dimethyl carbonate it isatomized using a coaxial spray nozzle underpressure. Then the sprayed particles arecollected in liquid nitrogen and dried undervacuum at room temperature. In order toencapsulate the drug, these hollow PLAparticles are dispersed into an aqueous solutionof the drug by placing the solution in anultrasonic bath for several seconds. Microcapsules are finally formed after stirring withthe plasticizing solution (DCM/CO2 in excess).Later the solution is washed throughcentrifugation/dispersion with water and thendried under vacuum (69). Christopher et. al.,


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prepared spray dried nanoparticles ofovalbumin using a PLGA (50:50 ratio)containing an antigen carrier device for vaccinedelivery. Electron microscopy confirmed thatthe cross-penetration of the microencapsulatedantigen occurred quite easily wherein lysosomeswere retained within the endosome for up to 3days (70).

The laser ablation method

The laser ablation method involves theproduction of microparticles by cutting astream of drug-polymer-solvent solution usinga pulsating laser, powerful enough to vaporizeat intervals, thus producing continuous beadsof micron-size particles. In this process, thePLGA polymer is dissolved in an organicsolvent such as DCM and the solution iscontinuously pumped through a glass capillarywith an opening of 10-100 µm. A modulatedlaser constantly fires at the ejected stream to cutit into discrete droplets which are then collectedin a large quantity of a PVA solution. This isthen left overnight to harden the microparticlesby extraction of DCM. The extracted particlesare then collected by ultracentrifuge and driedor lyophilized to obtain the final product (71).There are only a few studies demonstrating thisapproach, probably because of the lack ofaccess to the necessary equipment.

Micro and nano fibrous scaffolds

In tissue engineering, an ideal scaffold shouldstimulate the growth of a natural extracellularmatrix (ECM) in order to support cellattachment and guide three-dimensional (3D)tissue formation. PLGAs work as superiorbiodegradable candidates satisfying the needs ofvarious tissue repairs. Pores should also be largeenough to facilitate the growth of tissue cells(72).

Jifu et al., prepared PLGA based macroporousand nanofibrous scaffolds together with saltparticles using a phase separation technique.

The scaffold was prepared using a PLGApolymer (50/50) casted into a screw-cap.Sodium chloride particles with diameters of200–450 µm as porogens were inserted into thenanofibrous matrixes (72). After 7 days the cellswere observed to show good morphologyindicating their viability for tissue repair.

IMPLANT PREPARATION TECHNIQUES

Solvent casting and compression molding

Biodegradable implants, particularly PLGA- orPLA- based implants can be prepared usingsolvents. A PLA or PLGA based polymer anddrug mixture is dissolved in an appropriates o l v e n t ( e . g . , d i c h l o r o m e t h a n e ,trichloromethane or acetone) in the desiredproportion, and the solvent is cast over a teflonmold at room temperature or slightly highertemperature and finally vacuum dried toremove the residual solvent. The resultantstructure is a composite material of the drugtogether with the polymer. The solvent castmaterial is then compressed into the desiredform at around 80EC and 25,000 psi obtaininga final density of 1 g/cc. Such an implant canbe subcutaneously delivered into the body. Adrawback of the above method is the presenceof an organic solvent in the formula. Thereforestability of the incorporated drug becomes anissue, particularly for therapeutic proteins. It isnecessary to test the stability of a drug in thepresence of an organic solvent (73-75).

Extrusion

Solvent casting techniques are not ideal forindustrial scale-up for several reasons. First, theprocess requires large amounts of organicsolvents increaseing the risk of denaturation ofthe drug and/or protein during theencapsulation. Such inactive entities can causeunpredictable side effects, e.g., immunogenicityor other toxicity. Second, this process requires avery long time for complete solvent removalfrom the final product. It is a batch processwhich may result in increased occurrences ofbatch-to-batch variation in the composition of


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the implants. Unlike solvent casting, extrusionis a continuous process of pressing thepolymer-drug mixture through a die to createimplants of fixed cross-sectional profile withoutany use of solvent (73).

Felt-Baeyens et. al., prepared triamcinoloneacetonide loaded biodegradable scleral implantsusing a modified compression molding methodfor ocular drug delivery. In vivo studies indicatedthat stearic acid acted as an excellent plasticizertogether with the polymer resulting in stableimplants that had good ocular biocompatibilityin rabbit eyes showing no inflammatoryreaction and provided drug release for up to 5weeks (74). Witt et. al., developed biodegradableimplants for parenteral and controlled drugdelivery systems using ABA triblockcopolymers, consisting of poly (lactide-co-glycolide) A-blocks and poly (oxyethylene) B-blocks, and PLG, poly (lactide-co-glycolide)polymer by compressing them using a ramextruder. An electron paramagnetic resonancestudy showed that the implants remains intactand swells during erosion due to presence ofPEO blocks as well as the pH inside the ABAtriblock copolymers remains in the neutralrange which indicates that ABA triblockcopolymers are promising biomaterials for theparenteral delivery of pH-sensitive drugs (75).

The extrusion process is the most convenientroute for manufacturing implants. Screwextruders are basically inside a stationarycylindrical barrel with either a single or twinhelical rotating screws. The extruder is mainlydivided into three subdivisions: feeding zone,transition zone, and mixing zone. The processconstitutes an extruder and polymer-drugmixture with required micron size feed material.During the process, the polymer-drug mixtureis heated to a semi-liquid state achieved by thecombination of heating elements and shearstress from the extrusion screw. The screwpushes the mixture through the die. Theresulting extrudate is then cooled and solidifiedbefore cutting into desired lengths for implantsor other applications. Exposure of drug to hightemperature can be disadvantageous as

denaturation can take place. Therefore, theextrusion process poses a limitation for drugsthat cannot be used because of their meltingpoint, polymorph stability and chemicalinteractions with PLGA (76-79).

Atrix Laboratories, USA developed aninjectable in situ implant where a PLGApolymer together with the drug was dissolvedinto a biocompatible solvent (N-methylpyrollidone (NMP) and Dimethyl sulfoxide(DMSO). This manufacturing technology isalso known as the “Atrigel Delivery System”.Once injected, the polymer precipitates out orcoagulates immediately in the body fluid due toits water insolubility. The key factor in theabove system is the precipitation threshold (i.e.,the limit above which the polymer mayprecipitate out from the aqueous media) andthe polymer solubility in different solventswhich can be calculated using the FloryHuggins solubility equation. When theformulation was subcutaneously administeredinto rats, the formulation with a polymercontent below the precipitation threshold hadtwice the initial release compared to theformulation where the polymer content wasabove the precipitation threshold (80).

Rothen-Weinhold et. al., studied the influenceof extrusion and injection molding on in vitrodegradation and release profile. PLA (Mw: 6000D) implants were prepared using aSomatostatin analogue such as Vapreotide as amodel drug. In the extrusion method, implantswere prepared by extruding a mixture of PLAand Vapreotide using a laboratory scale ramextruder. In this method, a powder mixture ofthe drug and the polymer was put into a barrelwhich had a 10 mm inside diameter at 80°C asthe extrusion temperature. The die diameterwas 4.6 mm die and the rods were cut into 2.75cm long implants (81). Although both methodsproved to be feasible for manufacturing theimplants, the most important differenceobserved between these two methods was thein vitro release rate of Vapreotide which washigher in the extruded implants. The possiblereason may be the significant porosity observed


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in extrusion molded implants (81).

Kunou et al., developed controlled releaseimplants of Ganciclovir using PLGA (75:25Mw: 20,000 D) based on lyophilisationcompression molding. The drug, together witha PLGA polymer was first dissolved in aceticacid and lyophilized to obtain a homogeneouscake. The cake was then further compressed ona hot plate in the temperature range of 80 to100°C. In vivo drug release studies in rabbitsshowed that the fragments of implantsdisappeared from the subconjunctival spaceafter 5 months (82).

Orloff et. al., prepared biodegradable implantsfor repairing vascular thrombosis whichshowed good results in a broad variety ofvascular disorders (83). Baro et. al., developedPLA (Mw:30 kDa) based bone implantscontaining gentamicin sulfate as a model drugusing a compression molding technique using ahydraulic press and further coated with PLA(Mw: 200 kDa). Mixtures of hydroxyapatite andtricalcium phosphate powder were used in themanufacturing of PLA based ceramic implants,because it has similar chemical composition tobone minerals acting as a good carriers fortreating bone infection. In vitro gentamicinrelease was delayed due to an additional PLAcoating but when tested in the femur of rabbits,it showed faster release which was probably dueto a greater degree of PLA degradation,changes in the concentration of phosphateblend along with PLA polymer and in vivoinvading of the implant by the bone tissue (84).

FACTORS INFLUENCING THE DEGRADATIONOF PLGA BASED FORMULATIONS

In general, the polymer degradation/ hydrolysisrate is accelerated by greater hydrophilicity inthe backbone or end groups, amorphousnature, lower molecular weight, and smaller sizeof the finished device. In order to understandthe release rate of a drug entrapped in thebiodegradable polymeric matrix the erosion rateof the polymer must be understood. In general,

drug release rate from PLGA microspheresfollows a triphasic profile: (1) an initial burstrelease of surface and pore associated drug, (2)a lag phase until sufficient polymer erosion hastaken place and (3) a secondary burst withapproximately zero order release kinetics (85,86). In addition, the PLGA polymer is insolublein water, but it is unstable in hydrolytic mediaand is degraded through hydrolytic attacks onits ester bonds. Due to this hydrolytic attack,random chain degradation occurs, resulting inthe generation of smaller monomers such aslactic acids and glycolic acids.

Various factors can inf luence thebiodegradation of a PLGA based formulationand simultaneously affect the release profile ofmicrospheres, e.g., (1) polymeric propertiessuch as molecular weight, the lactide:glycolideratio and the end group and viscosity of thepolymer, (2) the solubility of the drug, (3) thetype of solvent, (4) the rate of agitation, (5)solvent evaporation, (6) the temperature (7) thedrug loading (8) sterilization (9) residualsolvents (10) porosity and (11) the pH of thebiodegradation media (86).

The effect of polymer composition

Higher glycolic acid content in the polymericcomposition can increase the intensity of theloss of molecular weight and simultaneousdegradation of the polymer. For example, thePLGA 50:50 (PLA/PGA) has a fasterdegradation rate than the PLGA 65:35 due tothe higher hydrophilicity of the glycolic acid inthe PLGA 50:50. Subsequently PLGA 65:35has a faster degradation rate than the PLGA75:25 and PLGA 75:25 than PLGA 90:10. Thereason for the lower degradation rate of lacticacid compared to glycolic acid is the presenceof an additional methyl group in the structureof lactic acid, which acts as hydrophobicmoieties and minimizes the attack by the watermolecules. The amount of glycolic acid is acritical parameter in controlling thehydrophilicity of the polymer and, thus thedegradation and drug-release rate (87). Janoriaet. al., studied the effect of different lactic acid


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and glycolic acid on drug release. They usedPLGA 50:50 and PLGA 65:35 to preparemicrospheres of Ganciclovir (GCV) as a modeldrug using an o/o emulsification followed bysolvent evaporation. The Tg of the PLGA65:35 was higher than the PLGA 50:50 due tothe higher lactide content. Although the lactidecontent in the polymer composition did notaffect the Ganciclovir release, the higher lactidecontent of the polymer provided betterentrapment properties due to its lipophilicnature (88).

The effect of crystallinity (or Tg) of polymer

The degree of crystallinity and melting point ofa polymer is directly related to its molecularweight. The glass transition temperature (Tg) ofPLGA copolymers are reported to be above thephysiological temperature of 37°C, hence areglassy in nature and thus exhibiting a fairly rigidchain structure. The Tg of the PLGA decreaseswith decreasing lactide in the copolymercomposition and molecular weight (88).Copolymer compositions also affect importantproperties such as the Tg and the crystallinitywhich have an indirect effect on thedegradation rate. At the moment, there areconflicting opinions on the effect ofcrystallinity on the degradation rate. In addition,crystallinity of lactic acid (PLA) increases thedegradation rate as a result of an increase in thehydrophilicity of polymer (89).

The effect of molecular weight

PLGA polymers are usually characterized interms of intrinsic viscosity which is directlyrelated to their molecular weight (Mw) anddegradation rate. In general, a polymer with ahigher molecular weight contains longpolymeric chains resulting in lower degradationrates. As the Mw of the polymer decreases, thedegradation rate increases due to reduced Tg.Polymers with higher molecular weight polymerexhibiting high Tg value are glassy in natureand have slow degradation kinetics (87, 90).Graves et. al., studied the effect of Mw on aPLGA polymer on Pendamidine microspheres

prepared by a double emulsification solventevaporation method. They used two differentPLGA 50:50 polymer grades (Mw = 1,00,000daltons and i.v. = 0.8 dl/g and Mw = 14,000,i.v. = 0.2 dl/g). The formulation with thehigher mol/wt polymer took 0.6 days to release50% of the drug together with a burst releasecompared to the other which took about 6.3days to release 50% of the drug without anyburst release. This experiment demonstrates theinfluence of Mw and i.v. on the rate of drugrelease (91).

Physicochemical properties of incorporateddrugs

In general, polymer-drug matrix degradationand the drug release rate vary as a function of adrug’s physicochemical properties. Thesolubility of encapsulated drug(s) maysignificantly influence the degradation rate ofthe polymeric matrix. For example, thepresence of a high amount of hydrophilic watersoluble groups (-OH or -COOH group)increases the uptake of water molecules fromthe surrounding environment into thepolymeric matrix. This process may result inthe leaching of a water soluble drug from thepolymer matrix and create a highly porousmembrane-like structure very quickly. Incontrast, a hydrophobic drug can retard thewater diffusion into the polymeric matrix andsimultaneously slow down the polymericdegradation. In addition, highly acidic or basicdrug(s) may also influence the polymericdegradation kinetics. Studies indicate that suchdrug moieties auto catalyze the ester backbonehydrolysis resulting in an enhanced polymericdegradation rate (91, 92). The presence ofspecific functional groups such as amines in thedrug molecule can induce polymeric chaindegradation through nucleophilic reactionwherein nitrogen atom works similar to oxygenatom in water (93).

The effect of size and shape of the matrix

The ratio of surface area to volume has beenfound to be a significant factor for degradation


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of large devices in general. Greater surface areato volume ratio leads to a greater degradationof the matrix (94). Witt et. al., studied theerosion of parenteral delivery systems such asrods, tablets, films and microspheres generatedusing PLGA (50:50 lactide to glycolide ratio)polymers. Upon evaluation of the onset timefor bulk erosion (tonset) and the apparent rate ofmass loss (kapp) parameters for each device, itwas found that in the case of PLGA, the tonset

was 16.2 days for microspheres, 19.2 days forfilms and 30.1 days for cylindrical implants andtablets. The kapp was 0.04 days-1 formicrospheres, 0.09 days-1 for films, 0.11 days-1

for implants and 0.10 days-1 for tablets. Theresults indicate that the rate of erosiondecreased in the following order: rods andtablets > film > microspheres and wasdependent on the size of device (95).

The effect of pH and salts concentration

The in vitro biodegradation/hydrolysis of PLGAshowed that both alkaline and strongly acidicmedia accelerates the polymer degradationprocess. The degradation was also found to beaffected by the salt concentration in bufferedsolutions, suggesting that the cleavage reactionof the polymer ester bonds is acceleratedthrough the conversion of the acidicdegradation product into neutral salts. Studiesby Li et. al., showed that at alkaline pH (10.08)microparticles exhibit rapid weight loss butslower molecular weight decrease and thedegradation pattern was close to surfacedegradation. However, in acidic pH (1.2) itshowed faster reduction in molecular weightwhile slower weight loss and homogeneousdegradation (96). Recently, Zolnik and Burgesshave studied the effect of acidic (pH 2.4) andneutral (pH 7.4) condition on the degradationof a PLGA polymer and drug release kinetics.In vitro dissolution studies indicated that theinitial burst and lag phases were similar for bothpH values, but the secondary drug releasekinetics was substantially higher in acidic pH as

compared to neutral pH. Thermal andmorphological analysis showed that in an acidicenvironment the oligomeric units of thepolymer accumulate within the microspheresdue to their low solubility in acidic pHcompared to the neutral pH (pKa of lactic acid:3.8). These are crystallized inside the matrix andimpart a brittleness to polymer due to whichthey become more susceptible to fracturing andrapid release (97).

The effect of monomer content and purity ondegradation

Synthesis of PLGA based biodegradablepolymer involves a continuous chain co-polymerization process between the lactic acidand the glycolic acid molecules. There may be achance of free traces of monomer remaining inthe final product even after purification withdifferent solvents. This free monomer contentin the final product may get convertedreversibly into the polymer during the storageof the product which may affect the drugrelease. During the manufacturing of anyPLGA based formulation the monomercontent of the PLGA product must beconsidered. PLGA polymers with monomercontent as low as 0.5% are considered highlypurified (98). Several purification steps arecarried out in the final stage of the polymermanufac tu r ing e . g . , u l t r a f i l t r a t i on ,crystallization, distillation or passing ofsupercritical CO2, etc., to remove free residualmonomers from the amorphous polymer blendand to provide a better purity of the finalproduct. Unbound monomers contain higherfree acid contents and acts as an impurity andsource for faster degradation of the product.

PHARMACEUTICAL APPLICATION OF PLGABASED MEDICAL DEVICES

Biodegradable polymers have become animportant group of materials with an increasingdiversity in biomedical devices. Major


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applications of PLGA polymers in some novelareas are shown in Table 5.

Table 5 Novel areas of PLGA application

BIOMEDICAL APPLICATION AREA OF APPLICATION

Biodegradable surgical suture Wound closure

Biodegradable medical deviceScrews, plates & pins for hard tissuefixation and tissue regeneration,contraceptive device, dental implants

Long active parenteral drugdelivery system

Solid rods, injectable microparticles (assuspensions), in situ forming systems,depot controlled release injection,oncological application, gene therapy andproteomics, xenobiotics, immunology andveterinary application

Nasal and ocular delivery Nasal and ocular drug application

Third generation fullybiodegradable stents

Very innovative therapeutic approach forrecovery after heart attack or stroke

Drug eluting stents

In order to minimize the formation of fibrosis,thrombosis or clots, a metallic stent can beinserted within the peripheral or coronary arteryby a cardiologist or radiologist performingangioplasty surgery. These bare metallic stents(BMS) made of cobalt or stainless steel are the1st generation stents. They comprise of anelaborate mesh-like design to allow expansion,flexibility and, in some cases, the ability toenlarge constricted blood vessels. Cobaltchrome alloy is stronger and more radio-opaque than the usual 316L stainless steel(L605 CoCr alloy has less nickel than 316Lstainless steel and so may be less allergenic). Ino r d e r t o a v o i d g r a f t r e j e c t i o n ,immunosuppressants are administered orallyusually minimizing adverse effects (99).

2nd generation stents are drug-eluting stents(DES) which were approved by the FDA afterbeing clinically proven to be better than BMS.DES contain a coating, typically of abiodegradable polymer such as PLGA on themetallic stents which holds and releases (elutes)the drug into the arterial wall by contacttransfer. The stents are typically spray or dipcoated. One to three, or more, layers can becoated e.g. a base layer for adhesion, a mainlayer for holding the drug, and sometimes a topcoat to slow down the release of the drug andto extend its effect. DES contains a drug which

is mainly useful to inhibit neointimal growth(due to the proliferation of smooth musclecells), arterial restenosis and neointimalhyperplasia. Generally combinations ofimmuno-suppressive and anti-proliferativedrugs (Sirolimus, Paclitaxel and Everolimus) areused for medical applications in coronarystents. Because metal is a foreign substance, itcan induce inflammation, scarring, andthrombosis (clotting). DES coated withpolymers of biocompatible nature largelyprevent some of these effects. However,neointimal hyperplasia occurring within thestent leading to in-stent restenosis is a mainobstacle in the long-term success ofpercutaneous coronary intervention (PCI).Many large randomized clinical trials using DEShave shown a remarkable reduction inangiographic restenosis and target vesselrevascularization when compared with baremetal stents. DES has revolutionized the fieldof interventional cardiology by proving itssafety and efficacy to prevent restenosis ofcoronary arteries using local drug delivery inmany clinical trials (100-116).

Recently, 3rd generation stents have beendeveloped and clinically approved. Here themetallic components have been completelyreplaced with a biodegradable polymerframework. The benefit of 3rd generation stentsis that they prevent problems such asthrombosis and at the same reduces thenecessity of taking lifelong medication of anti-platelets. The development of these types ofstents has been a breakthrough innovation inthe treatment of obstructive coronary arterydisease since the introduction of balloonangioplasty. Ma et. al., prepared Paclitaxel/Sirolimus loaded DES using a PLGA (65:35lactide:glycolide ratio) polymer for thetreatment of coronary artery disease. The stentprovided controlled release of Paclitaxel andSirolimus for 21 days both in vitro and in vivowith minimal burst release. This study showedthat the combination of two drugs in a DESwill not affect the individual drug release kineticand, therefore, can be developed for thetreatment of coronary arterial diseases (117).


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Similarly, Raval et. al., successfully developed aDexamethasone loaded DES using poly L-lactide-co-caprolactone as the biodegradablepolymer for intravascular drug administrationfor the treatment of tissue hyperplasia. The invitro dissolution profile showed that the releaseof Dexamethasone can be modulated up to 3weeks by optimizing the concentration of thepolymeric blend. SEM data also showed asmooth surface of DES without anyirregularities which suggests that the coatingprocess parameters were optimum and efficientfor a multiple layer coating (118).

Contraceptive devices

Biodegradable polymers have recently beenapplied for the controlled release delivery ofhormones and fertility regulating agents.Biodegradable or erodible delivery systems arerepresented by contraceptive devices where thematrix dissolves to release the drug and othercomponents into the systemic circulation. Animplantable contraceptive is likely to be apromising new option for fertility control, aswell as, for the long term treatment of sexuallytransmitted diseases such as AIDS. Thesebiodegradable systems have primarily twoadvantages: (1) no need for surgical removal ofthe system after the completion of the drugdelivery period and, (2) the device reservoirsshow zero order release kinetics which isnecessary for efficient therapeutic treatment.Contraceptive systems that provide sustainedrelease of low doses of synthetic hormones areof special interest because they have importantclinical advantages over conventional oralcontraceptive pills (119-127).

Alaee et. al., developed PLA (Mw = 680,000,i.v. = 3.3 to 4.3 dl/g) based reservoir type ofimplantable contraceptive device for thecontrolled delivery of levonorgestrol (300 days)using a simple dip casting method. Dissolutionstudies showed that the drug was released fromthe reservoir for at least 9 months. Moreover, itwas found that various formulation andmanufacturing processes affected the release ofthe drug from implants such as implant weight,

presence or absence of polyethylene glycol(PEG) in the formulation, molecular weightand amount of PEG, presence of osmoticallyactive agents, etc., (128). Similarly, Nonomuraet. al., developed a LH-RH antagonist loadedintrauterine device (IUD) to release the drugfor a prolonged period of time using a PLGAblock co-polymer (75:25 lacide: glycolide ratio).Once inserted into the uterus, the druggradually released from the IUD during aperiod of several months (129).

Dental implants

Though useful, the potential of biodegradablepolymers have unfortunately not been exploredin the field of medicated dental implants.Dental or orthodontic braces are devices usedin orthodontics that align and straighten teeth,help to position them with regard to a person'sbite and also improves dental health. Braces canbe either cosmetic or structural. Abiodegradable polymer could be goodreplacement for metallic dental braces becausesubsequent operative procedures are notrequired and it aligns the teeth in a particularperiod of time. In the past, dental implantsmade of tinidazole were formulated using poly(e-caprolactone) which showed good clinicalefficacy to control acute periodontitis (130-138).

Nasal delivery

Intranasal (IN) administration has attractedconsiderable interest because it provides a non-invasive method for bypassing the blood brainbarrier (BBB) delivering drugs directly to thebrain. The nasal cavity is a promising site forthe delivery of vaccines because (1) its reducedenzymatic activity compared to other possibleadministration routes (e.g. oral route), (2) itsmoderately permeable epithelium, and (3) thehigh availability of immune-reactive sites (139-141).

Vila et. al., developed PLA-PEG basednanoparticles to enhance the absorption ofprotein molecules across the nasal mucosa


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using, for example, tetanus toxoid (TT) as amodel drug. They showed that the efficacy in invivo studies of the vaccine developed using nanoparticles showed approximately 70-80%bioavailability compared to intravenousadministration (142). Yildiz et. al., developedheparin loaded microspheres using poly lacticacid. A SEM study showed a uniform particlesize of heparin loaded microparticles withsmooth surface at around 1-5 micron. In vitroand in vivo analysis showed a sustained releaseprofile for heparin of up to 8 hours and goodabsorption confirmed by a 143.63 % AUC level(143). Recently, Seju et. al. developed a PLGA(50:50 as lactide to glycolide content) loadedOlanzepine nanoparticulate system for directnose-to-brain delivery. In vivo studies indicatedan increased drug uptake at ~10 times whichwas more efficient for the treatment of centralnervous system disorders (144). Li et. al.,developed microspheres using α-Cobrotoxin asa model drug and a mixture of biodegradablepolymers comprised of PLGA (50:50, i.v. = 0.8dl/g) and poly [1,3-bis(p-carboxy-phenoxy)propane-co–p-(carboxyethylformamido)benzoic anhydride CPP:CEFB] using a w/o/oemulsion solvent evaporation method forintranasal delivery. The microspheres showedhigh entrapment efficiency (80%) with a 25 µmmean particle size and effective sustainedrelease profile (145). Tail flick assay indicatedthat compared to free α-cobrotoxin and PLGAmic rosphe r e s , PLGA/P(CPP :CEFB)microspheres showed an apparent increase inthe strength and duration of antinociceptiveeffect at the same dose of α-cobrotoxin (80Ag/kg body weight) (145).

Tissue engineering

Tissue engineering uses a combination ofengineering and biologic materials to improvebiological functions, as well as, for successfultissue and bone replacement. The requirementsof a scaffold material for tissue engineering areimportant to support cell growth andproliferation as follows: (a) the material mustnot induce any unresolved inflammatoryreaction or any foreign body reaction, (b) the

polymer should be absorbed completely intothe body after fulfilling its function, (c) themechanical properties of the scaffold materialsmust not collapse during handling, nor during apatient’s routine activities and (d) the materialmust be easily sterilizable to prevent unwantedinfections (146-158).

Suture materials are classified into two broadcategories , biodegradable and non-biodegradable. Biodegradable sutures lose theirentire tensile strength within 2-3 months, whilenon-biodegradable materials retain theirstrength longer than 2-3 months. Biodegradableor bioresorbable sutures are made from eithercollagen derived from sheep intestinal submucosa or synthetic polymers such as PGA.Surgical suture is a term used for medicaldevices which are used to close body tissueafter an injury or surgery. Suture threads comesin very specific sizes and can be classified asmainly absorbable (made from biodegradablepolymers such as PGA, PLA or polydioxonones) or non-absorbable (made frompolypropylene, polyesters or nylon) dependingon weather or not, the body will naturallydegrade and absorb the suture material overperiod of time. Absorbable surgical sutures aresometimes also coated with an antimicrobialsubstance to reduce the chance of infection ofthe wound.

Park et. al., developed biodegradable polymericmicro needles using PLA and PLGA basedsynthetic polymers for transdermal drugdelivery. They concluded that the newarthroscopic fixation device utilized knotlesssuture-based anchors eliminating the need forknot tying during arthroscopic surgery (159).Casalini et. al., successfully developed a transient1-dimensional model to show the release ratefrom a bioresorbable drug eluting suturetogether with its pharmacologic behavior andbiodegradation rate (160). The model primarilyhighlights the degradation kinetics of a drugloaded resorbable suture in the tissue, as well


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as, the behavior of a drug in the tissue. A modelcan provide predictive data without expensiveand time consuming experimental activity basedon the principal laws of conservation, masstransfer and hydrolysis (160). Morizumi et. al.,developed a novel drug eluting suture coatedwith Tacrolimus for the treatment ofneointimal hyperplasia. In vivo results from aporcine model confirmed that the DE-suturescan successfully inhibit neointimal hyperplasiaat the anastomotic suture site without anyinflammatory response indicating usefulness ofthis novel suture in both coronary artery bypassgraft surgery and peripheral vascular bypasssurgery (161).

Orthopedic devices

During orthopedic surgery, bone fragments orfilaments are usually fixed with metallic platesand screws. When the fracture has healed thesemetallic plates are usually removed from thebody through a second surgery requiringgeneral anesthesia to minimize pain. In order toavoid the second surgery, resorbable polymerscan be used as alternative materials in a range ofdevices in trauma and fracture surgery satisfyingvarious operational and technical requirements(162, 163). This is because they can overcomevarious issues such as stress protection,potential for corrosion, wear and debrisformation, as well as, the necessity of implantremoval (164).

These devices also maintain adequatemechanical properties in vivo for the timerequired for a bone fracture to heal anddecompose gradually wherein the stresses aretransferred gradually to the healing bone ortissues so that no stress shielding occurs (165,166). Rangdal et al., performed clinical studiesto see how PLGA based biodegradable platesand screws affect the tissues of patientssuffering of bimalleolar fractures. They foundthat only one patient had tissue reaction at 14weeks post-surgery which settled down bydebridement without the need of implantremoval while the rest of the patients did not

show any signs of tissue reaction at the end of18 months (167). Enislidis et. al., investigatedzygomatic fracture fixation using abiodegradable osteosynthesis system(BioSorbFX®) to evaluate its stability, as well as,complications observed during the firstpostoperative year. They found that fixation offractures of the zygoma using the BioSorbFX®

system was simple and safe without showingany post-operative complication (168). Tasca et.al., successfully performed thyroid cartilagefracture surgery on a 29-year old man (injuredwhile playing rugby) using Inion biodegradableplates that had been made with lactic andglycolic acid based polymers and specificallydesigned with the consideration of the thyroidcartilage structure and recommended in thetreatment of laryngeal fractures (169). Kyriakouet. al., performed clinical studies on 20 patientsbetween the ages of 18 to 40 years (both maleand female) with facial skeleton maxillafractures treated with resorbable plates. Theyfound that none of the patient reported anyinfection or secondary mobility indicatingexcellent biocompatibility for resorbable plates(170).

Ocular drug delivery

Currently, the most common way ofadministering therapeutic agents to the eye isusing topical applications placed into theconjunctival cul-de-sac. Eye drops or ointmentsare, however, not very effective as they arerapidly cleared from the eye by continuouseyelid movements and drainage throughlachrymal fluids. In order to increase thecontact time between ophthalmic formulationsand the eye corneal, more invasive proceduresmust be used such subconjunctival injections,retro-ocular injections containing biodegradablepolymers to minimize clinical complication andside effects (171). Choonara et. al., developed anovel doughnut-shaped mini tablet (DSMT)containing different PLGA (50:50, i.v. = 0.16 -8.2 dl/g) grades loaded with two anti-retroviraldrugs such as foscarnet and ganciclovir forintraocular drug delivery. They used a specialset of punches fitted with a central-rod in a


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tableting press to manufacture the DSMTdevice providing a first-order release of bothanti-retrovirals. The novel geometric design andveracity of the DSMT device was retained evenafter 24 weeks of use (172).

Transdermal drug delivery

Biodegradable polymer based transdermalpatches usually do not require removal post-implantation and as a result these systems havebecome quite common (173). Colloidalnanoparticles developed from poly (alkylcyanoacrylate) (PACA) based biodegradablepolymers have opened up new and excitingavenues in the field of transdermal drugdelivery due to their biocompatibility and smallsize which permits increased transport acrossthe epithelium and intracellular penetration.Miyazaki et. al., developed poly n-butylcyanoacrylate (PNBCA) polymer basedbiodegradable nanocapsules loaded withindomethacin to evaluate the possibility ofdelivering the drug systemically after its topicalapplication. Nanocapsules prepared by aninterfacial polymerization process showed 188nm as average particle size with 76.6% drugloading. Conventional gel formulationscontaining indomethacin made from PluronicF-127 was used as a reference formulation forin vivo comparison which showed a higher drugplasma concentration for the nanocapsuleformulation than the conventional gelformulation containing Pluronic F-127. Due tothe ultra-fine particle size and their oilyves icu lar nature , a lky lcyanoacry la tenanocapsules can easily cross the stratumcorneum layer of the skin and act as a micro-reservoir to provide sustained drug release(174).

Cancer treatment

Various biodegradable polymer-based novelformulations such as depot injectionscontaining microparticles or nanoparticles canbe useful in chemotherapy treatment. Recently,Kun et al., prepared nanoparticles using poly(ethylene glycol)/ poly (L-lactic acid) alternating

multi-block copolymers and investigated themfor use as anti-cancer drug carriers. Thethermo-sensitive nanoparticles responded wellto local hypothermic temperatures and therelease of doxorubicin was also dependent onthe temperature at the tumor site (175). Bhuskeet al., developed PLGA based nanoparticlescontaining Curcumin which is a poorly solubleanti-cancer drug. They demonstrated animprovement in the aqueous solubility andanticancer activity of the drug (176). PLGApolymers have also been used for tumorimaging, for example Diou et al., reported theuse of PEGylated PLGA nanocapsulescontaining per-fluorooctyle bromide by 19FMRI (177). There are numerous other reportsof using PLGA based applications for targetingincreased drug delivery at target site and cancertreatment (178-181).

Recently, Jin et. al., developed doxorubicin–poly(d,l lactic- co-glycolic acid)–poly(ethyleneglycol) (DOX–PLGA–PEG) micelles decoratedwith the bivalent fragment HAb18 F(ab’)2 fortreatment of hepatocellular carcinoma (HCC).They found that the developed micelles had anacceptable morphology and high drug loadingefficiency. Cellular uptake and accumulation inthe tumor was observed to be dependent on thedual effects of passive and active targeting. Thedrug-loaded micelles showed cytotoxicity ontumor cells in vitro and in vivo consideredresponsible for the improvement in thetherapeutic response (178). Similarly, Li et. al.,p r epa red po l ymer - coa ted magne t i cnanoparticles as carriers for doxorubicin using adouble emulsification method (179). Currentresearch also shows the usefulness ofmultiblocks such as dicarboxylated poly(ethylene glycol) (PEG; Mw 2000) with poly (l-lactic acid) (PLLA)/PEG/PLLA triblockcopolymers for targeting cancer cells.

Gene therapy and proteomic applications

Luten et. al., demonstrated the use of PLGAand other biodegradable polymers in plasmidgene delivery by developing DNA loaded microand nanoparticles (182). Recently, Ahn et. al.,


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developed a PLA and PEG based non-viralgene carrier by synthesizing a multi-block co-polymer (183). Benfer and Kissel preparedPLGA based nanoparticles using poly [vinyl-3-(dialkylamino) alkylcarbamate-co-vinylacetate-co-vinylalcohol]-graft-poly (D,L-lactide-co-glycolide) or DEAPA-PVA-g-PLGA loadedwith siRNA to improve the cellular uptake andthus increase therapeutic activity (184). Lewis et.al., demonstrated that oligonucleotides can beentrapped into a PLGA matrix to improvenuclease stability in serum, and thus achieve anacceptable release profile of antisenseoligopeptides such as very potent anti-HIVphosphorothioates (185).

Much attention has been focused on proteins(186-188), oligopeptide (189) and RNA (190)delivery using PLGA devices. It has beenshown that specific genes such as syntheticshort interfering RNA (siRNA) is a promisingroute for specific and efficient therapy ofdisease-related genes. However, in vivoapplication of siRNA requires an effectivedelivery system. Commonly used siRNAcarriers are based on polycations which formelectrostatic complexes with siRNA and suchpoly- or lipoplexes are of restricted use in vivodue to severe problems associated with toxicity,serum instability and non-specific immune-responses. In order to minimize somecomplications associated with non-biodegradable polymers, Cun et. al., developednanoparticles (NPs) loaded with siRNA usingbiodegradable PLGA polymers withoutincluding polycations. The NPs were found tobe spherical in shape with an average particlesize of 300 nm, poly dispersibility index < 0.2,encapsulation efficiency of 57% and zetapotential value of ~ 40mV. The integrity ofsiRNA was preserved during the preparationindicating that siRNA-NPs based on PLGApolymers without any cationic excipient canwork as a potential and promising carrier forthe delivery of siRNA (190). Recently, Tang et.al., developed calcium phosphate embeddedPLGA nanoparticles for plasmid DNA

(pDNA) delivery. It is known that DNA hasnegatively charged macromolecules whichhinders its entry into the tumor cells throughthe negatively charged lipid bilayer. Therefore,the calcium phosphate was used to neutralizethe DNA before entry and to achieve increasedefficiency with improved release kinetics. Basedon promising in vitro transfection efficiencyformulations, calcium phosphate embeddedPLGA nanoparticles can be considered asuitable vector for pDNA based gene delivery(191). Much work has been carried out inrecent years to improve the delivery of DNA(192-196), gene (197), growth hormone (198),peptide (199) and bovine serum albumin (200)using PLGA devices or formulations.

Immunological applications

A considerable amount of research has beencarried out in the field of immunology usingPLGA devices. Slutter et. al., worked on particleengineering for nasal vaccine delivery anddemonstrated good absorption of N-trimethylated chitosan along with PLGA vianasal mucosa (201). Sivakumar et. al., developedan alternative adjuvant for Hepatitis B vaccine(HBsAg) that provides a long-lasting immuneresponse after a single administration. Thesuitability of poly (D, L)-lactide-co-glycolic acid(PLGA), poly lactic acid (PLA) and chitosanpolymers as adjuvants for HBsAg (202) werestudied. Salvador et. al., studied combinations ofdifferent immune stimulating adjuvants usingPLGA microspheres to improve the immuneresponse of a model vaccine. In this study,PLGA microspheres containing BSA was co-encapsulated with different adjuvants such asmonophosphoryl lipid A (MPLA), polyinosinic-polycytidylic acid, α-galactosyl ceramide andalginate. It was observed that a mixture ofMPLA and α-galactosyl ceramide within themicrospheres provided a higher cellularresponse to increase vaccines immunogenicityas compared to other adjuvants (203). Otherstudies in this area include imaging (204), autobooster vaccines (205) and immunogenic


Review Article

properties of antigens delivered through PLGAmicroparticles (206).

Veterinary applications

In the recent years there has been an increasinginterest in biodegradable polymers forveterinary use because they could providesignificant benefits such as a reduction in stressresulting from reduced animal handling, noneed to physically remove the delivery systemand reduced cost in terms of the time spent byanimal owner or caretaker. Presently, only a fewbiodegradable formulations are commerciallyavailable for veterinary use. The possible reasonbehind it is the cost of the biodegradabledevice, followed by regulatory considerationsand challenges in formulation stability (207).Walduck et. al., developed biodegradableimplants using a cholesterol and lecithinpolymeric mixture for recombinant antigendelivery to sheep. They also investigaged therelease profiles of antigen in vitro as well as invivo and found that sheep produced significantlevels of antibodies when immunized withimplants showing promis ing t issuecompatibility (208). Khan et. al., developedbiodegradable implantable matrix systems(pellets) from a cholesterol and lecithin mixturecontaining bovine serum albumin (BSA) as amodel antigen for parenteral delivery in mice.For in vivo studies, pellets were subcutaneouslyinjected into the mice which provided sustaineddrug release until 40 days with significantantibodies generation (209).

Packaging and sterilization

As discussed previously, these polymers arevery sensitive to moisture which causedegradation during manufacturing, as well as,during product storage. Therefore to minimizethe effects of moisture uptake, biodegradablepolymers are typically stored under refrigeratedconditions. The solution for hydrolysisinstability is simple in theory, eliminatemoisture and prevent degradation. Therefore,precautions should be taken during the final

packaging of a product by placing the device orformulation in an airtight moisture-proofcontainer containing a desiccant.

For example, sutures are wrapped around aspecially dried paper holder that acts as adesiccant. The final devices should not besterilized by autoclaving or dry heat becausethis may degrade the device since even dry heatcan contain a lot of moisture (210). Gammaradiation, particularly at doses above 2 Mrad,can result in significant degradation of thepolymer chain, resulting in a reduced molecularweight and altered mechanical properties anddegradation times. Poly (glycolide), poly(lactide) and poly (dioxanone) are especiallysensitive to gamma radiation and are usuallysterilized by exposure to EtO (210). However,residual EtO is very toxic and takes a long timefor degassing which adds to the final cost.Typically, a device is sterilized using gammaradiation (211-213), ethylene oxide (EtO) gas(214, 215), or other less-known techniques suchas synchroton or electron beam irradiation(216).

The effect of gamma radiation in either vacuumor in air at a dose of 25 kGy on the stability ofPLGA 50:50 (Mw = 34000 D and i.v. = 0.39dl/g) based microsphere was studied.Microspheres irradiated under vacuum werefound to be stable over a period of 6 monthsand microsphere irradiated in presence of airshows showed that release rate were increasedby 10% but did not change further during thestorage time. Electronic paramagneticresonance analysis confirmed the free radicalsgenerated from both the polymeric matrix andthe active ingredient during gamma radiation.In addition, they also confirmed the radio-stabilizing effect of the drug (clonazepam) bypolymer/clonazepam spin transfer reactions.Furthermore, due to the same radio stabilizingeffect, microspheres showed a 54% decrease inoverall radiation yield as compared to placebomicrospheres because the radiation wasabsorbed by the clonazepam during thesterilization process. It can be concluded thatthe type of API , as well as, the sterilization


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conditions must be considered carefully on caseto case basis (217). Mohr et. al., studied theeffect of gamma radiation on the stability ofPLGA micropsheres. Interestingly, on exposingmicrospheres to 5.1 to 26.6 kGy gammaradiations it was found that the drug loadedmicrospheres were converted to conjugationproducts with PLGA. The average molecularweight decreased with an increasing irradiationdose (218). Another study showed that gammairradiation exposure has no apparent effect onthe integrity and formulation properties such usmorphology, size and peptide loading. Uponsubcutaneous administration of irradiated andnon-irradiated PLGA microspheres into miceinduced a similar immune response (219).

Regulatory consideration

For example, the maximum daily intake or IIGlimit of lactic acid is known (220). If thequantity of the polymer is higher than the IIGlimit, toxicity data from the manufacturers ofthe polymer can be submitted as a supportivedocuments to the regulatory agencies forproduct approval. To obtain FDA approval forformulations based on microspheres it isnecessary to submit various clinical data, e.g., preclinical and toxicity data of biodegradablepolymers, monomer content in the finalformulation, the molecular structure of thepolymer, residual solvent levels in the finalformulation, composite formulations includingnumber of laminates, etc. In addition, it is alsomandatory to state possible clinical adverseinformation in detail on the product label (221,222). Tegnander et. al., reported swelling at thesite of administration and sinus formulationwhen a patient with a fracture was treated withPGA or PLA based pins (223). In vivo and invitro testing of polymeric materials should bedesigned to investigate polymer-skin interfacereactions, effects on the subsurface tissue andsystemic effects. In vivo procedures usuallyinvolve a subcutaneous and/or intramuscularimplant test and a surface patch test for acuteand chronic toxicity study. Preclinical andtoxicological studies must be performed inaccordance with guidelines set by FDA toeliminate formulations that are too toxic forhuman use. Similarly, for dossier submission,

roughness, porosity, surface area of device,coating layer or thickness as well as the effect ofsterilization on properties of formulation andshelf life of product with specificrecommendation storage guidelines should beclearly mentioned (224, 225).

CONCLUSION

Biodegradable polymers are used extensively inpharmaceutical formulations, from drugdelivery to implants and stents. To this effect,PLGA devices can be said to have becomewidely utilized in the pharmaceutical industrybecause of their many useful properties andcompatibility with in vivo conditions. As evident,these polymers have found usage within variouscategories of drugs such as anti-cancer,antibiotics, contraceptive devices, orthopedicdevices and biotechnology products such asantibodies and vaccines. Their flexibility is alsodefined through their various routes ofadministration such as parental, subcutaneous,nasal or ocular and, therefore, has the potentialto be used widely in pharmaceuticalformulations.

An in-depth knowledge and thoroughunderstanding of the factors influencingpolymeric degradation and release rate are veryimportant to achieve a successful product. Atany stage, drug delivery using PLGA based co-polymers is an attractive area with countlessopportunities for further research anddevelopmental work. However, theachievement in these areas depends on the deepefforts and extensive research of scientists fromdiverse disciplines such as microbiology,pharmacy and polymer science to ensure muchbetter health service to mankind as well asnature.

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