Polyanhydride Synthesis Essay

Introduction

For the past few decades, biodegradable polymers have been applied as carriers for controlled delivery of low molecular weight drugs as well as bioactive proteins [1,2,3,4,5]. Biodegradable polymers, either synthetic or natural, are capable of being cleaved into biocompatible byproducts through chemical or enzyme-catalyzed hydrolysis. This biodegradable property makes it possible to implant them into the body without the need of subsequent removal by the surgical operation. Drugs formulated with these polymers can be released in a controlled manner, by which the drug concentration in the target site is maintained within the therapeutic window. The release rates of the drugs from biodegradable polymers can be controlled by a number of factors, such as biodegradation kinetics of the polymers [6,7,8], physicochemical properties of the polymers and drugs [9,10], thermodynamic compatibility between the polymers and drugs [11], and the shape of the devices [12,13,14].

Biodegradable polymer particles (e.g., microspheres, microcapsules, and nanoparticles) are highly useful because they can be administered to a variety of locations in vivo through a syringe needle [15,16]. A variety of drugs, regardless of their molecular weights and water solubility, can be loaded into the biodegradable microparticles using different manufacturing techniques [17,18,19,20,21]. A few examples of biodegradable polymers used in microparticle preparation include polyesters [15,22], polyanhydrides [23,24], poly(ortho esters) [25,26,27], polyphosphazenes [28,29] and polysaccharides [19,30,31]. Figure 1 shows the chemical structures of several biodegradable polymers.

Figure 1. Chemical structures of several biodegradable polymers.

Figure 1. Chemical structures of several biodegradable polymers.

Techniques of Microparticle Preparation

For preparation of microparticles using biodegradable polymers, it is important to choose an appropriate encapsulation process which meets the following requirements. First, the chemical stability and biological activity of the incorporated drugs should be maintained during the encapsulation process. For example, since most proteins are readily denatured upon contact with hydrophobic organic solvents or acidic/basic aqueous solutions, the process should avoid such harsh environments. Second, the encapsulation efficiency and the yield of the microparticles should be high enough for mass production. Third, the microparticles produced should have the reasonable size range (< 250 μm) that can be administrated using the syringe needle via the parenteral pathway. Fourth, the release profile of the drug should be reproducible without the significant initial burst. Fifth, the process employed should produce free-flowing microparticles, thus making it easy to prepare uniform suspension of the microparticles.

There are a number of techniques available for microencapsulation of drugs such as the emulsion-solvent evaporation/extraction method, spray drying, phase separation-coacervation, interfacial deposition, and in situ polymerization. Each method has its own advantages and disadvantages. The choice of a particular technique depends on the attributes of the polymer and the drug, the site of the drug action, and the duration of the therapy [15,32,33]. This review deals with representative techniques, currently being recognized as effective in microencapsulation of drugs.

Single emulsion method

This method has been primarily used to encapsulate hydrophobic drugs through oil-in-water (o/w) emulsification process. The polymer is dissolved in a water-immiscible, volatile organic solvent such as dichloromethane, and the drug is dissolved or suspended into the polymer solution. The resulting mixture is emulsified in a large volume of water in the presence of an emulsifier [15,34,35]. The solvent in the emulsion is removed by either evaporation at elevated temperatures or extraction in a large amount of water, resulting in formation of compact microparticles. The rate of solvent removal is reported to affect the final morphology of microparticles. The solvent removal rate is determined by the temperature of the medium, the solubility characteristics of the polymer, and the solvent used [34,35,36]. This method, however, is only available for the hydrophobic drugs because the hydrophilic drugs may diffuse out or partition from the dispersed oil phase into the aqueous phase, leading to poor encapsulation efficiencies [34,36].

In an attempt to encapsulate hydrophilic drugs (e.g., peptides and proteins), an oil-in-oil (o/o) emulsification method has recently received considerable attention [37,38,39]. In this method, the water-miscible organic solvents are employed to dissolve the drug and polymer, whereas hydrophobic oils are used as a continuous phase of the o/o emulsion. The microparticles are obtained by removing the organic solvents through evaporation or extraction process.

Double emulsion method

Most water-soluble drugs have been encapsulated by water-in-oil-in-water (w/o/w) methods [19,40,41]. The aqueous solution of the water-soluble drug is emulsified with polymer-dissolved organic solution to form the water-in-oil (w/o) emulsion. The emulsification is carried out using either high speed homogenizers or sonicators. This primary emulsion is then transferred into an excess amount of water containing an emulsifier under vigorous stirring, thus forming a w/o/w emulsion. In the subsequent procedure, the solvent is removed by either evaporation or extraction process.

One advantage of this method is encapsulation of hydrophilic drugs in an aqueous phase with the high encapsulation efficiency. For this reason, the w/o/w emulsion system has been used widely for the development of protein delivery systems [19,40,41]. The characteristics of the microspheres prepared by the double emulsion method are dependent on the properties of the polymer (such as composition and molecular weight), the ratio of polymer to drug, the concentration and nature of the emulsifier, temperature, and the stirring/agitation speed during the emulsification process.

Phase separation

This method involves phase separation of a polymer solution by adding an organic nonsolvent [37,42,43]. Drugs are first dispersed or dissolved in a polymer solution. To this mixture solution is added an organic nonsolvent (e.g., silicon oil) under continuous stirring, by which the polymer solvent is gradually extracted and soft coacervate droplets containing the drug are generated. The rate of adding nonsolvent affects the extraction rate of the solvent, the size of microparticles and encapsulation efficiency of the drug. The commonly used nonsolvents include silicone oil, vegetable oil, light liquid paraffin, and low-molecular-weight polybutadiene. The coacervate phase is then hardened by exposing it into an excess amount of another nonsolvent such as hexane, heptane, and diethyl ether. The characteristics of the final microspheres are determined by the molecular weight of the polymer, viscosity of the nonsolvent, and polymer concentration [44,45]. The main disadvantage of this method is a high possibility of forming large aggregates. Extremely sticky coacervate droplets frequently adhere to each other before complete phase separation.

Figure 2. Formation of mononuclear reservoir-type microcapsules by interfacial phase separation. Two different liquid droplets produced from ink-jet nozzles collide each other in the air. The solvent exchange occurs at the interface between two liquids to form a polymer layer on the aqueous core. The formed micro-capsules are collected in the water bath.

Figure 2. Formation of mononuclear reservoir-type microcapsules by interfacial phase separation. Two different liquid droplets produced from ink-jet nozzles collide each other in the air. The solvent exchange occurs at the interface between two liquids to form a polymer layer on the aqueous core. The formed micro-capsules are collected in the water bath.

Recently, a novel method of preparing reservoir-type microcapsules, based on interfacial phase separation, was developed [46,47]. Two different types of liquid droplets (i.e., a polymer solution and a drug solution) were separately produced using a dual microdispenser system consisting of two ink-jet nozzles, and the produced droplets were allowed to collide each other in the air (Figure 2). Upon collision, the drug-containing aqueous core remains spherical due to its high surface tension while the polymer-containing droplet spreads over the aqueous core. As a result, a reservoir-type microcapsule is generated due to the interfacial phase separation by the mutual mass transfer of two solvents (i.e., solvent exchange). Successful formation of microcapsules depends on the polymer concentration and the properties of the solvents, such as surface tension, interfacial tension, and the solvent exchange rate.

This technique is promising for preparation of protein-loaded microcapsules. For example, conventional methods of preparing microparticles involve extensive exposure of proteins to the interface between aqueous and organic phases, to hydrophobic polymer matrix, and to acidic/basic microenviroments resulting from degradation of the polymer. These unfavorable interactions are reported to induce conformational changes of proteins [48,49]. On the contrary, the interfacial phase separation technique is shown to minimize these sources of protein inactivation [46,47].

Spray drying

Compared to other conventional methods, spray drying offers several advantages [19,50,51,52]. It shows good reproducibility, involves relatively mild conditions, allows controlling the particle size, and is less dependent on the solubility of the drug and the polymer. The drug is dissolved or dispersed in the polymer solution, in which volatile solvents (e.g., dichloromethane and acetone) are preferred. The resulting solution or suspension is sprayed in a stream of heated air to produce microparticles. The size of the microparticles is determined depending on the atomizing conditions. The main disadvantage of this technique is a loss of a significant amount of product, primarily due to adhesion of the microparticles to the inner wall of the spray-drier. In addition, large aggregates are frequently obtained because the microparticles are very sticky before the complete removal of the solvent.

In an attempt to minimize aggregation of the microparticles, a double-nozzle spray-drying technique was developed [53]. While the polymer/drug solution is sprayed from one nozzle, aqueous mannitol solution is simultaneously sprayed, which enables the surface of the microparticles to be coated with mannitol. The results indicated that the coating of the microsphere with mannitol reduces the extent of aggregation and augments the yield of the product. A cryogenic, non-aqueous process was used to prepare protein-loaded microparticles [54,55]. In this technique, the liquid droplets of the polymer/drug solution are produced through the spraying nozzle, collected in liquid nitrogen containing frozen ethanol, and hardened by placing them at -80 oC where the solvent extraction occurs. This method is known to encapsulate proteins into microparticles without significant loss of their biological activity [55].

Biodegradable Polymers for Microparticles

Polyesters

Aliphatic polyesters have attracted significant interest as drug carriers due to their biocompatibility and biodegradability [7,9,15,22,56,57]. This class of polymers degrade via the hydrolytic cleavage of the ester bonds in their backbone, whereas the role of enzymatic involvement in biodegradation is unclear. Chemical structures of the representative polyesters are shown in Figure 3. Poly(lactic-co-glycolic acid) (PLGA) copolymers have been most widely used because their degradation rate and mechanical properties can be precisely controlled by varying the lactic acid/glycolic acid ratio and by altering the molecular weight of the polymers.

Figure 3. Chemical structures of polyesters.

Figure 3. Chemical structures of polyesters.

PLGA polymers are cleaved into monomeric acids (i.e., lactic and glycolic acids) which are consequently eliminated from the body as carbon dioxide and water. The degradation rate of PLGA is critical for determining the release rate of the encapsulated drug and depends on the crystallinity, hydrophobicity, and molecular weight of the polymer [58,59]. In general, glycolic acid-rich PLGA copolymers (up to 70%) are amorphous in nature and degrade more rapidly. As the molecular weight of the polymer decreases, the degradation becomes faster because of the higher content of carboxylic groups at the end of polymer chain which accelerate the acid-catalyzed degradation. The PLGA-based microparticles undergo bulk degradation. The PLGA matrix undergoes random chain scission while preserving the original shape and mass until significant degradation (~ 90%) has occurred. In spite of these promising characteristics of biodegradation, recent studies have demonstrated that PLGA copolymers significantly affect the stability and biological activity of the drugs (e.g., peptide and proteins), primarily due to the hydrophobicity of the polymers and the presence of acidic degradation products

Poly(ε-caprolactone) (PCL) is a biodegradable, semicrystalline polymer having a low glass transition temperature (~60 oC). A number of drugs have been encapsulated using PCL. Due to its crystallinity and hydrophobicity, degradation of PCL is very slow, rendering it suitable for long-term delivery over a period of more than one year [62,63]. It has the ability to form compatible blends with other polymers, which provides opportunities to manipulate the drug release rate from microparticles [63]. The PCL-based devices maintain their shape and weight during the initial phase of biodegradation, where the molecular weight decreases by up to 5000 through bulk hydrolysis of the ester bonds. The second phase of PCL degradation is characterized by the onset of weight loss because the continuous chain cleavage produces a fragment small enough to diffuse out of the polymer matrix. On the other hand, the hydrolysis rate is known to decrease at the second phase, due to the increased crystallinity.

Poly(phosphoesters) (PPEs) have been used recently for delivery of low molecular weight drugs as well as high molecular weight proteins and DNA [5,64,65]. This type of polymer degrades under the physiological conditions via hydrolysis or enzymatic cleavage of the phosphate bonds in the backbone. Since their chemical structure can be tailored by varying R and R’ in Figure 3 during synthesis, it is possible to obtain PPEs with a wide range of physicochemical properties. In particular, by choosing biocompatible building blocks of the polymer, degradation products of PPEs can have minimal toxic effects and good biocompatibility. The degradation rate of PPEs is controllable by the percentage of the phosphate content in the backbone: The degradation rate increases with increasing the phosphate content of the polymer. In contrast to other polyesters, PPEs are known to degrade by a combined mechanism of surface erosion and bulk degradation [66]. Recent studies have demonstrated that PPE-based microparticles are promising for protein delivery because they don’t generate acidic environments [5,65,67].

Poly(ortho esters)

Since the 1970s, poly(ortho esters) (POEs) have evolved through four families as biodegradable polymers [68,69,70]: POE I, POE II, POE III, and POE IV. The general chemical structure of each family is shown in Figure 4

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