Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier

Polymers 2011, 3, 1377-1397; doi:10.3390/polym3031377 OPEN ACCESS polymers ISSN 2073-4360 www.mdpi.com/journal/polymers Review Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier Hirenkumar K. Makadia 1 and Steven J. Siegel 2,? 1 Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA; E-Mail: hiren.makadia@gmail.com 2 Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA ? Author to whom correspondence should be addressed; E-Mail: siegels@mail.med.upenn.edu; Tel.: +1-215-573-0278; Fax: +1-215-573-2041. Received: 20 June 2011; in revised form: 8 August 2011 / Accepted: 22 August 2011 / Published: 26 August 2011 Abstract: In past two decades poly lactic-co-glycolic acid (PLGA) has been among the most attractive polymeric candidates used to fabricate devices for drug delivery and tissue engineering applications. PLGA is biocompatible and biodegradable, exhibits a wide range of erosion times, has tunable mechanical properties and most importantly, is a FDA approved polymer. In particular, PLGA has been extensively studied for the development of devices for controlled delivery of small molecule drugs, proteins and other macromolecules in commercial use and in research. This manuscript describes the various fabrication techniques for these devices and the factors affecting their degradation and drug release. Keywords: poly lactic-co-glycolic acid; drug delivery; PLGA degradation; sustained release; PLGA fabrication techniques 1. Introduction A considerable amount of research has been conducted on drug delivery by biodegradable polymers since their introduction as bioresorbable surgical devices about three decades ago. Amongst all the biomaterials, application of the biodegradable polymer poly lactic-co-glycolic acid (PLGA) has shown immense potential as a drug delivery carrier and as scaffolds for tissue engineering. PLGA are a family Polymers 2011, 3 1378 of FDA-approved biodegradable polymers that are physically strong and highly biocompatible and have been extensively studied as delivery vehicles for drugs, proteins and various other macromolecules such as DNA, RNA and peptides [1–3]. PLGA is most popular among the various available biodegradable polymers because of its long clinical experience, favorable degradation characteristics and possibilities for sustained drug delivery. Recent literature has shown that degradation of PLGA can be employed for sustained drug release at desirable doses by implantation without surgical procedures. Additionally, it is possible to tune the overall physical properties of the polymer-drug matrix by controlling the relevant parameters such as polymer molecular weight, ratio of lactide to glycolide and drug concentration to achieve a desired dosage and release interval depending upon the drug type [4–6]. However the potential toxicity from dose dumping, inconsistent release and drug-polymer interactions require detailed evaluation. Here we present a review on the PLGA primarily as a delivery vehicle for various drugs, proteins and other macromolecules in commercial use and in research. We also present possible directions for future uses of PLGA in drug delivery applications. 2. Biodegradable Polymers Biodegradable materials are natural or synthetic in origin and are degraded in vivo, either enzymatically or non-enzymatically or both, to produce biocompatible, toxicologically safe by-products which are further eliminated by the normal metabolic pathways. The number of such materials that are used in or as adjuncts in controlled drug delivery has increased dramatically over the past decade. The basic category of biomaterials used in drug delivery can be broadly classified as (1) synthetic biodegradable polymers, which includes relatively hydrophobic materials such as the α-hydroxy acids (a family that includes poly lactic-co-glycolic acid, PLGA), polyanhydrides, and others, and (2) naturally occurring polymers, such as complex sugars (hyaluronan, chitosan) and inorganics (hydroxyapatite) [7–9]. The breath of materials used in drug delivery arises from the multiplicity of diseases, dosage range and special requirements that may apply. Biocompatibility is clearly important, although it is important to note that biocompatibility is not an intrinsic property of a material, but depends on the biological environment and the tolerability that exists with respect to specific drug-polymer-tissue interactions [9]. 2.1. Poly Lactic-co-Glycolic Acid (PLGA) Polyester PLGA is a copolymer of poly lactic acid (PLA) and poly glycolic acid (PGA). It is the best defined biomaterial available for drug delivery with respect to design and performance. Poly lactic acid contains an asymmetric α-carbon which is typically described as the D or L form in classical stereochemical terms and sometimes as R and S form, respectively. The enantiomeric forms of the polymer PLA are poly D-lactic acid (PDLA) and poly L-lactic acid (PLLA). PLGA is generally an acronym for poly D,L-lactic-co-glycolic acid where D- and L- lactic acid forms are in equal ratio. 2.1.1. Physico-Chemical Properties In order to design a better controlled drug delivery device, it is essential to understand the physical, chemical and biological properties of PLGA. The physicochemical properties of optically active PDLA and PLLA are nearly the same. In general, the polymer PLA can be made in highly crystalline form Polymers 2011, 3 1379 (PLLA) or completely amorphous (PDLA) due to disordered polymer chains. PGA is void of any methyl side groups and shows highly crystalline structure in contrast to PLA as shown in Figure 1. PLGA can be processed into almost any shape and size, and can encapsulate molecules of virtually any size. It is soluble in wide range of common solvents including chlorinated solvents, tetrahydofuran, acetone or ethyl acetate [7,10]. In water, PLGA biodegrades by hydrolysis of its ester linkages (Figure 2). Presence of methyl side groups in PLA makes it more hydrophobic than PGA and hence lactide rich PLGA copolymers are less hydrophilic, absorb less water and subsequently degrade more slowly. Due to the hydrolysis of PLGA, parameters that are typically considered invariant descriptions of a solid formulation can change with time, such as the glass transition temperature (Tg), moisture content and molecular weight. The effect of these polymer properties on the rate of drug release from biodegradable polymeric matrices has been widely studied. The change in PLGA properties during polymer biodegradation influences the release and degradation rates of incorporated drug molecules. PLGA physical properties themselves have been shown to depend upon multiple factors, including the initial molecular weight, the ratio of lactide to glycolide, the size of the device, exposure to water (surface shape) and storage temperature [11]. Mechanical strength of the PLGA is affected by physical properties such as molecular weight and polydispersity index. These properties also affect the ability to be formulated as a drug delivery device and may control the device degradation rate and hydrolysis. Recent studies have found, however, that the type of drug also plays a role in setting the release rate [12]. Mechanical strength, swelling behavior, capacity to undergo hydrolysis and subsequently biodegradation rate of the polymer are directly influenced by the degree of crystallinity of the PLGA, which is further dependent on the type and molar ratio of the individual monomer components in the copolymer chain. Crystalline PGA, when co-polymerized with PLA, reduces the degree of crystallinity of PLGA and as a result increase the rate of hydration and hydrolysis. As a rule, higher content of PGA leads to quicker rates of degradation with an exception of 50:50 ratio of PLA/PGA, which exhibits the fastest degradation, with higher PGA content leading to increased degradation interval below 50%. Degree of crystallinity and melting point of the polymers are directly related to the molecular weight of the polymer. The Tg (glass transition temperature) of the PLGA copolymers are reported to be above the physiological temperature of 37 ◦C and hence are glassy in nature, thus exhibiting fairly rigid chain structure. It has been further reported that Tg of PLGAs decrease with a decrease of lactide content in the copolymer composition and with a decrease in molecular weight [13]. Commercially available PLGA polymers are usually characterized in terms of intrinsic viscosity, which is directly related to their molecular weights. Figure 1. Structure of poly lactic-co-glycolic acid (x is the number of lactic acid units and y is number of glycolic acid units). Polymers 2011, 3 1380 Figure 2. Hydrolysis of poly lactic-co-glycolic acid. 2.1.2. Pharmacokinectic and Biodistribution Profile The drug delivery specific vehicle, i.e., PLGA, must be able to deliver its payload with appropriate duration, biodistribution and concentration for the intended therapeutic effect. Therefore, design essentials, including material, geometry and location must incorporate mechanisms of degradation and clearance of the vehicle as well as active pharmaceutical ingredients (API). Biodistribution and pharmacokinetics of PLGA follows a non-linear and dose-dependent profile [14]. Furthermore, previous studies suggest that both blood clearance and uptake by the mononuclear phagocyte system (MPS) may depend on dose and composition of PLGA carrier systems [15]. Additionally whole-body autoradiography and quantitative distribution experiments indicate that some formulations of PLGA, such as nanoparticles, accumulate rapidly in liver, bone marrow, lymph nodes, spleen and peritoneal macrophages. The degradation of the PLGA carriers is quick on the initial stage (around 30%) and slows eventually to be cleared by respiration in the lung [16]. To address these limitations, studies have investigated the role of surface modification, suggesting that incorporation of surface modifying agents can significantly increase blood circulation half-life [17]. 2.2. Copolymers of PLGA The need for better delivery formulations that incorporate a variety in drugs and methods of administration has resulted in the development of various types of block copolymers of polyesters with poly ethylene glycol (PEG). PLGA/PEG block copolymers have been processed as diblock (PLGA-PEG) [18,19] or triblock molecules with both ABA (PLGA-PEG-PLGA) [20] and BAB (PEG-PLGA-PEG) [21] types. In diblock types, PEG chains orient themselves towards the external aqueous phase in micelles, thus surrounding the encapsulated species. This layer of PEG acts as a barrier and reduces the interactions with foreign molecules by steric and hydrated repulsion, giving enhanced shelf stability [22]. However, the addition of PEG to the system also results in reduction of encapsulation efficiency for drugs and proteins, even with the most appropriate fabrication techniques. The reduced drug incorporation may be due to steric interference of drug/protein-polymer interaction by the PEG chains. The precise mechanism for this effect is unclear. Better release kinetics from formulations of diblock copolymers have been demonstrated in comparison to PLGA alone. Various mechanisms of targeted delivery of drugs from diblock nanoparticles have also been reported [18,23,24]. Triblock copolymers of both ABA and BAB type can act as a thermogel with an A-block covalently coupled with a B-block via ester link. The copolymer is usually a free flowing solution at low temperature and can form a high viscosity gel at body temperature. These temperature-responsive copolymers, Administrator Highlight Polymers 2011, 3 1381 PLGA-PEG-PLGA or PEG-PLGA-PEG, are a kind of block copolymers composed of hydrophobic PLGA segments and hydrophilic PEG segments. The hydrophobic PLGA segments form associative crosslinks and the hydrophilic PEG segments allow the copolymer molecules to stay in solution. At lower temperatures, hydrogen bonding between hydrophilic PEG segments and water molecules dominates the aqueous solution, resulting in their dissolution in water. As the temperature increases, the hydrogen bonding becomes weaker, while hydrophobic forces among the PLGA segments are strengthened, leading to solution-gel transition. The ease of handling during fabrication, formulation, filtration and filling makes such thermoresponsive polymers attractive candidates. Drug and/or protein release from both ABA and BAB copolymers occurs by two principal mechanisms: (i) drug diffusion from the hydrogel during the initial release phase; and (ii) release of drug by the erosion of the hydrogel matrix during the later phase. During the degradation of a PEG-PLGA-PEG gel, there is a preferential mass loss of PEG-rich components. Therefore, the remaining gel becomes more hydrophobic in an aqueous environment, resulting in less water content [20,25–28]. This motif can also be applied to other co-polymer combinations, including but not limited to various copolymers of PLGA and polycaprolactone [29,30]. 3. Fabrication Techniques for PLGA Carriers Drugs and proteins are the most rapidly growing class of pharmaceuticals for which controlled or targeted release is used to increase specificity, lower toxicity and decrease the risk associated with treatment. However, the stability and delivery challenges associated with these agents have limited the number of marketed products. Maintaining adequate shelf-life of peptide and protein drugs often requires solid-state formulation to limit hydrolytic degradation reactions [31]. Drug delivery of peptides and proteins may also require parenteral formulations to avoid degradation in the digestive tract and first pass metabolism, while the short circulating half-lives of peptides and proteins contribute to the need for parenteral formulations that will reduce dosing frequency. In order to avoid the inconvenient surgical insertion of large implants, injectable biodegradable and biocompatible PLGA particles (microspheres, microcapsules, nanocapsules, nanospheres) could be employed for controlled-release dosage forms. Drugs formulated in such polymeric devices are released either by diffusion through the polymer barrier, or by erosion of the polymer material, or by a combination of both diffusion and erosion mechanisms. In addition to its biocompatibility, drug compatibility, suitable biodegradation kinetics and mechanical properties, PLGA can be easily processed and fabricated in various forms and sizes. This section describes various fabrication techniques of PLGA controlled drug delivery devices [9]. 3.1. Microparticle Preparation Techniques 3.1.1. Solvent Evaporation Method (1) Single emulsion process Oil-in-water emulsification processes are examples of single emulsion processes. Polymer in the appropriate amount is first dissolved in a water immiscible, volatile organic solvent (e.g., dichloromethane (DCM)) in order to prepare a single phase solution. The drug of particle size around 20–30 µm is added to the solution to produce a dispersion in the solution. This Administrator Highlight Polymers 2011, 3 1382 polymer dissolved drug dispersed solution is then emulsified in large volume of water in presence of emulsifier (polyvinyl alcohol (PVA) etc.) in appropriate temperature with stirring. The organic solvent is then allowed to evaporate or extracted to harden the oil droplets under applicable conditions. In former case, the emulsion is maintained at reduced or atmospheric pressure with controlling the stir rate as solvent evaporates. In the latter case, the emulsion is transferred to a large quantity of water (with or without surfactant) or other quench medium to diffuse out the solvent associated with the oil droplets. The resultant solid microspheres are then washed and dried under appropriate conditions to give a final injectable microsphere formulation [32–35]. (2) Double (Multiple) emulsion process Water-in-oil-in-water emulsion methods are best suited to encapsulate water-soluble drugs like peptides, proteins, and vaccines, unlike single emulsion methods which is ideal for water-insoluble drugs like steroids. First, an appropriate amount of drug is dissolved in aqueous phase (deionised water) and then this drug solution is added to organic phase consisting of PLGA and/or PLA solution in DCM or chloroform with vigorous stirring to yield a water-in-oil emulsion. Next, the water-in-oil primary emulsion is added to PVA aqueous solution and further emulsified for around a minute at appropriate stress mixing conditions. The organic solvent is then allowed to evaporate or is extracted in the same manner as oil-in-water emulsion techniques. In double emulsion processes, choice of solvents and stirring rate predominantly affects the encapsulation efficiency and final particle size [32,36,37]. 3.1.2. Phase Separation (Coacervation) Coacervation is a process focused on preparation of micrometer sized biodegradable polymer encapsulation formulations via liquid-liquid phase separation techniques. The process yields two liquid phases (phase separation) including the polymer containing coacervate phase and the supernatant phase depleted in polymer. The drug which is dispersed/dissolved in the polymer solution is coated by the coacervate. Thus, the coacervation process includes the following three steps as reported in literature [38–40] (1) Phase separation of the coating polymer solution, (2) Adsorption of the coacervate around the drug particles, and (3) Quenching of the microspheres. Solutions are prepared by mixing polymer and solvent in appropriate ratios. Hydrophilic drugs like peptides and proteins are dissolved in water and dispersed in polymer solution (water-in-oil emulsion). Hydrophobic drugs like steroids are either solubilized or dispersed in the polymer solution (oil-in-water emulsion). Gradual addition of organic medium to the polymer-drug-solvent phase while stirring, extracts the polymer solvent resulting in phase separation of polymer by forming a soft coacervate of drug containing droplets. The size of these droplets can be controlled by varying stirring rate and temperature of the system. The system is then quickly dipped into a medium in which it is not soluble (both organic or aqueous) to quench these microdroplets. The soaking time in the quenching bath controls the coarsening Polymers 2011, 3 1383 and hardness of the droplets. The final form of the microspheres is collected by washing, sieving, filtration, centrifugation or freeze drying. The processing parameters including polymer concentration, quenching temperature, quenching time and solvent composition affect the morphology and size of the microspheres [41–43]. 3.1.3. Spray Drying Emulsion techniques require precise control of processing parameters for higher encapsulation efficiency, and phase separation techniques tend to produce agglomerated particles and also require removal of large quantities of the organic phase from the microspheres. This makes the process difficult for mass production. Alternatively, spray drying is very rapid, convenient and has very few processing parameters, making it suitable for industrial scalable processing. In this process, drug/protein/peptide loaded microspheres are prepared by spraying a solid-in-oil dispersion or water-in-oil emulsion in a stream of heated air. The type of drug (hydrophobic or hydrophilic) decides the choice of solvent to be used in the process. The nature of solvent used, temperature of the solvent evaporation and feed rate affects the morphology of the microspheres. The main disadvantage of this process is the adhesion of the microparticles to the inner walls of the spray-dryer. Various spray drying techniques have been reported [44–49]. This method