These are man made materials i.e. synthesized in laboratory through chemical reaction. As these polymers are synthesized in laboratory with controlled environment, so they can be tailored to achieve required functionalities which can improve the efficacy of the drug used (Uhrich et al., 1999). But the problem with synthetic polymers is the present of unwanted monomers which can be toxic for in vivo applications (Pillai and Panchagnula, 2001). From a polymer chemistry perspective, it is important to appreciate that different mechanisms of controlled release require polymers with a variety of physicochemical properties. Some of the unique characteristics of synthetic polymers that make them versatile in drug delivery systems include (Kost and Langer, 1991; Angelova and Hunkeler, 1999; Langer, 2000):
x Wide molecular weight distribution x Variety of visco-elastic properties
x Special characteristics associated with phase transitions x Variety of dissolution time
x Specialized chemical reactivity x A variety of manufacturing methods
Figure 1.7: Basic chemical structure of commonly used synthetic polymers in DDS. (A) Polyester, (B) Polyanhydride and (C) Polyamide.
n
1.9.1 Poly(esters)
Poly(esters) are the best characterized, most widely studied synthetic, biodegradable polymer system and extensively employed in drug delivery applications. Poly(esters) based on poly(lactic acid) (PLA), poly-(glycolic acid) (PGA) and their copolymers, poly(lactic acid-co-glycolic acid) (PLGA), are some of the best defined biomaterials with regard to design and performance and are approved by FDA for human use (Lemoine et al., 1996).
They are synthesized through ring opening polymerization of cyclic lactones and degradation of these polymers yields the corresponding hydroxy acid, which are natural metabolites of the body, making them safe for in vivo use. In aqueous media, these polymers degrade by bulk degradation with random hydrolysis of ester bonds of the polymer backbone to form lactic and glycolic acids (Jain et al., 2000). The factors that affect the rate of hydrolytic degradation include type and composition of the polymer backbone, nature of pendent groups, molecular weight, pH, enzymes, and geometry of the particles. The preparation of PLA and PLGA nanoparticles included various techniques such as nanoprecipitation, simple and multiple emulsions, salting out, spray drying and supercritical fluid technology (Jain et al., 2000; Bala et al., 2004; Niwa et al., 1993). The experimental variables for each protocol can be altered to influence the physicochemical properties, such as particle size, particle size distribution, morphology, and zeta potential. The release of encapsulated drug from PLA and PLGA nanoparticles may occur by a combination of diffusion and polymer degradation at a rate that is influenced by properties of the polymer and nanoparticles and the environment (Astete and Sabliov, 2006). Another FDA approved poly(ester) which is widely used is poly(İ-caprolactone) or PCL. It is a semicrystalline polymer synthesized by anionic, cationic, free radical or ring opening polymerization and available in a range of molecular weights (Lemoine et al., 1996). It degrades by bulk
hydrolysis of ester bonds autocatalyzed by the carboxylic acid end groups and the presence of enzymes such as protease, amylase, and pancreatic lipase accelerates polymer degradation (Seppala et al., 2004). The various methods of preparation of poly(İ-caprolactone) NPs include emulsion polymerization, interfacial deposition, emulsion–solvent evaporation, desolvation, and dialysis (Sinha et al., 2004).
Figure 1.8: Chemical structures of commonly used polyesters in drug delivery applications.
(A) Poly (lactic acid), (B) Poly (glycolic acid), (C) Poly (lactic-co-glycolic acid) and (D) Poly (İ-caprolactone).
1.9.2 Polyanhydrides
Polyanhydrides are an important class of synthetic biomaterials used for more than two decades as carriers of drugs to various organs of the human body such as brain, bone, blood vessels, and eyes (Kumar and Langer et al., 2002). Polyanhydrides are biocompatible and degrade in vivo into non-toxic counterparts that are eliminated from the body as metabolites.
Some polyanhydride-based formulations are also clinically available for treating glioblastoma multiforme, a universally fatal form of brain cancer (Dang et al., 1996). These polymers have a hydrophobic backbone with a hydrolytically labile anhydride linkage. High
A B
.
C D
hydrolytic reactivity of the anhydride linkage provides an intrinsic advantage in versatility and control of degradation rates. These polymers vary in chemical composition widely and include aliphatic, aromatic and fatty acid based polyanhydrides. The majority of polyanhydrides studied are based on sebacic acid (SA), p- (carboxyphenoxy) propane (CPP) and p-(carboxyphenoxy) hexane (CPH). The rate of degradation depends on the chemical composition of the polymer. In general, aliphatic polyanhydrides degrade more rapidly than the aromatic polymer. Hence, copolymer blends with varying ratios of aliphatic-to-aromatic polyanhydrides can be synthesized to suit specific applications. Polyanhydride nanospheres are commonly prepared by the emulsion–solvent evaporation method using PVA as a stabilizer (Lee and Chu, 2007). However, as polyanhydrides are hydrolabile, they need to be flash frozen in liquid nitrogen and lyophilized immediately. An example of their use to deliver drugs is entrapment of bovine zinc insulin by phase inversion nanoencapsulation (Cheng et al., 2004).
1.9.3 Polyamides
Polyamides form another important class of polymers particularly as drug delivery matrices.
Polyamides with a structural resemblance to polypeptides are used as matrices for the transport of drugs. Examples include different types of poly (amino acids) such as poly (L- glutamic acid), poly (aspartic acid) are derived from the corresponding natural amino acids (General and Thunemann, 2002). Nakanishi and co-workers have developed a polymeric micelle carrier system consisting of PEG-conjugated doxorubicin: poly (aspartic acid) for the transport of doxorubicin. This carrier system has a highly hydrophobic inner core, and therefore, it can also entrap a useful amount of doxorubicin in addition to the conjugated doxorubicin. The entrapped doxorubicin was released from the inner core by diffusion and
expressed stronger activity than free doxorubicin against all the tumour lines tested (Nakanishi et al., 2001). Li and co-workers have synthesised a novel biodegradable poly (ester amide) derived from 3-morpholine and İ-caprolactone. Increase in morpholine content enhanced water absorption of the polymers. In vitro degradation data and release profiles of 5-fluorouracil showed that both the degradation rate and drug release rate increased with an enhanced morpholine content in the polymers (Li et al., 2002).