Conclusiones del entrevistado sobre la entrevista.

The increasing legislation regarding the resistance of polymeric waste to degradation and its disposability have resulted in an increased interest for the use of biodegradable polymers for microparticle synthesis. A wide range of both natural and synthetic degradable polymers have been used for microparticle synthesis (Table 1.1). As the polymers decompose, they ideally form non-toxic, low molecular weight species which can be easily metabolised or adsorbed by organisms both within the body and in the environment.19, 112, 113 Upon degradation, several degradable polymers are known to form toxic species, hence the chemical nature of the degradation products is a key factor of determining the polymer biocompatibility.114 Polymer biocompatibility is typically characterised by performing cell studies during degradation.

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Table 1.1: Table summarising the different types of polyesters, their preferred degradation route and their use when applied as a microparticle

Polymer Degradable Bond Degradation Pathway

Polymeric Microparticle Application

Polyanhydride Hydrolysis Poly(sebaic anhydride-co- 1,6-bis(p- carboxyphenoxy)hexane115 Delivery of ovalbumin for enhanced antibody response Polyorthoester Hydrolysis Poly(cyclohexane-1,4-diyl acetone dimethylene ketal)116 Delivery of superoxide dismutase for the treatment of inflammator y diseases Polyurethane Hydrolysis, enzymatic Copolymer of toluene-2,4- diisocyanate, bis(4- hydroxybutyl)8,8’-(5,6- dihexylcyclohex-3-ene- 1,2-diyl)dioctanoate and 1,4-butanediol117 Delivery of isosorbide for anticorrosio n/ self- healing coatings Polyester Hydrolysis, enzymatic PLGA 118 Controlled release of insulin Polycarbonate Hydrolysis, enzymatic Polycarbonate 119 Release of aspirin, griseofulvin and p- nitroaniline to the intestine Polyamide Hydrolysis, enzymatic Poly(hexamethylene terephthalimide)120 Controlled release of ascorbic acid for improved skin treatments

The use of biodegradable polymers for the synthesis of matrix type microparticles has been intensively studied as a consequence of the attractive potential to control the encapsulated AI release rate solely by the polymer degradation rate.121 In general, microparticles can undergo homogenous (bulk) degradation or heterogeneous

26 (surface) erosion (Figure 1.11).122 However, it is not uncommon to observe both degradation profiles within the same microparticle degradation system. In more detail, bulk degradation involves the random hydrolytic scission of hydrolysable bonds throughout the particle matrix.111 _{During homogeneous degradation, both the particle} mass and density decrease, whereas the total volume of the particle remains constant throughout. Furthermore, as a consequence of the reduced diffusivity observed within a particle matrix, acidic degradation products can be trapped and accumulate within pockets or pores within the particle.123 Consequently, the observed change in pH within the system can in turn result in autocatalytic degradation of the polymeric matrix.124, 125 This is usually coupled with a loss of structural integrity and mechanical stability which typically results in the break down and collapse of the particle.

On the other hand, heterogeneous degradation necessitates that hydrolysis at the particle surface is faster than water penetration into the particle matrix.110 This in turn results in an observable degradation of the particle from the outside towards the core. Surface erosion is typically characterised by a linear decrease in particle volume with mass, which results in the density remaining constant throughout. Unlike bulk degradation, the generated degradation products can rapidly diffuse away from the system.126 Therefore, no auto-catalytic effects within the particle matrix are observed, hence, degradation is solely based on the polymer degradation rate at the particle surface.

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Figure 1.11: Schematic representation of surface and bulk degradation occurring within a matrix microparticle and the corresponding drug release rate

1.2.2.2.1 Polyesters for Biodegradable Microparticles

In this demanding area, as a consequence of their synthetic versatility, good mechanical and thermal properties and their easy degradability under a variety of conditions, polyesters have become the most intensively studied and investigated degradable particles.64, 127 Indeed, investigations into the synthesis of PLA, PVL, PCL and PLGA microparticles are well known in the literature. Research has shown depending on the polyester used and the degradation conditions, the AI, which can be encased or dispersed within a polyester particle, can be slowly and continuously released over a period of days to years. In particular, Gonzalez et al., investigated the degradation of PLA microparticles incubated at 37 °C in a buffer solution over 8 months (Figure 1.12).128 _{SEM characterisation displayed signs of particle degradation}

28 after 9 days. Further characterisation of the PLA particles revealed the formation of large pores within the particle after 143 days in the buffer solution, thus implying that bulk degradation had occurred. Interestingly, characterisation of the particles by X- ray diffraction, Gonzalez et al., discovered that the PLA particles displayed an increase in crystallinity during degradation, which fit well with previous PLA characterisation by Migliaresi et al., who termed the behaviour as “degradation-induced

crystallisation”.129 _{Further elucidation of the X-ray diffraction spectrum by Gonzalez} et al. revealed the formation of a crystalline oligomeric structure formed during

particle degradation. Crystallisation is a highly interesting phenomenon and has been shown to influence the resultant polymer degradation rate.130 Moreover, as a consequence of the increased interactions enabled by tightly packed crystalline polymer chains, an amorphous polymeric matrix will display increased diffusivity within the particle matrix. Therefore, the increased diffusivity enables an increased influx of water and consequently an increased rate of hydrolysis. Therefore, the observed crystallisation of low molecular weight species within PLA particles could act to decrease the particle degradation and subsequent AI release rate.

Figure 1.12: SEM characterisation of PLA microparticle degradation in Titrisol buffer solution (pH 7, merck reagent) after a) 0 days, b) 9 days and c) 143 days as observed by Gonzalez et al.128

29 The degradability of a particle is primarily determined by the degradation rate associated with the applied polymer.121 Therefore, with the aim to incorporate tuneable degradability within a microparticle system, particle synthesis using a wide selection of polyester copolymers has been investigated.71, 131 _{The use of copolymers for particle} synthesis has also been shown to be an ideal pathway for the incorporation of functionality within the system. A second approach to incorporate tuneable degradation profiles has been to create particles from homopolymer blends, thus enabling the combining of the desired polymeric properties without the complexity and time required for copolymerisation.132, 133