Common Forms of Polymer-Based Protein Delivery Systems
Common examples of polymer-based systems that have been utilized in recent years to deliver various drug molecules, including therapeutic proteins, include micro/ nanoparticles, hydrogels and porous scaffolds (Fig. 11.2).
Micro/nanoparticles are injectable drug carriers that are usually prepared from hydro- phobic polymers using straightforward processes such as solvent evaporation, phase separation and spray-drying (Sokolsky-Papkov et al., 2007). In the solvent evaporation method, an organic phase is first formed by dissolving a hydrophobic polymer and the drug molecules to be encapsulated in a water-immiscible, volatile organic solvent. This phase is then dispersed in an aqueous phase containing stabilizers such as polyvinyl alcohol under continuous mechanical agitation to form an oil-in-water (O/W) emulsion. Drug-loaded particles are formed upon evaporation of the organic solvent from the inner phase at reduced or atmospheric pressure. The particles can then be collected by filtration or centrifugation, washed to remove the stabilizing molecules adsorbed to the particle surface and lyophilized to minimize hydrolytic degradation of the particles during long-term storage. However, the single emulsion technique may not be suitable for encapsulating hydrophilic drugs such as proteins as they tend to diffuse into the external aqueous phase during the emulsification step.
FIGURE 11.2 Common polymer-based systems for drug delivery applications.
FIGURE 11.3 Examples of micro/nanoparticle preparation process.
Therefore, in a process commonly referred to as double-emulsion solvent evaporation, protein molecules are first solubilized in an aqueous solvent, and then dispersed in a polymer-containing organic phase to form a primary water-in-oil (W/O) emulsion, followed by dispersion in another aqueous solvent to form the secondary O/W emulsion (Ding and Zhu, 2018; Iqbal et ah, 2015). The preparation of the primary W/O emulsion is also relevant to the phase separation method (Fig. 11.3). Following this step, instead of adding an aqueous solvent, an organic solvent that is non-solvent to the dissolved polymer is gradually introduced to extract the solvent of the polymer and decrease its solubility. The phase separation of the polymer from its solution contributes to the formation of polymer-rich liquid phase (coacervate) that surrounds the inner drug-containing aqueous phase. Upon completion of the phase separation process, the coacervate solidifies to produce drug-loaded particles (Tran et ah, 2012). An obvious drawback of this method is the requirement for a large volume of organic solvent. Recent work proposed the use of water-miscible organic solvents to dissolve the polymer. This replaces the need for organic solvents to induce phase separation as aqueous media can be used to extract the polymer solvent (Kohane, 2007). Finally, in the spray-drying method, the W/O emulsion is sprayed into a heated chamber that leads to a spontaneous production of drug-loaded particles. This method is more rapid and convenient and has fewer processing parameters than the other two but is limited by the adhesion of the formed particles to the inner surfaces of the drying chamber (Sokolsky-Papkov et al., 2007).
Due to their small size, micro/nanoparticles can be administered either directly to the intended site of action or into the systemic circulation to reach a desired location by passive or active targeting mechanisms (Yang and Pierstorff, 2012). Several peptide-loaded polymer-based microparticle formulations have been approved by the FDA for clinical use. The first is Lupron Depot®, which received approval in
1989 to provide sustained release of leuprolide acetate for prostate cancer treatment (Lee et al., 2016). A more recent example is Bydureon® that was approved in 2012, which releases exenatide to improve glycemic control in type 2 diabetes patients (Singh and Lillard, 2009).
In general, drug release from the particles is dependent upon the diffusion rate of the drug molecules and the degradation rate of the polymer-based matrix (Sokolsky- Papkov et al., 2007; Lee et al., 2016). However, as significant proportion of the drug load can be weakly adsorbed onto the large surface area of the micro/nanoparticles rather than incorporated into the polymer-based matrix, the drug release profile of this system is usually characterized by a huge initial burst that is followed by relatively short duration of release of the remaining drug load. Another disadvantage of this system is that the particles can move away from the targeted drug release site. The gradual translocation of the particles can become more prominent as the size of the particle decreases (Yang et al., 2012).
Hydrogels are three-dimensional networks of cross-linked hydrophilic polymers. The cross-linking can be mediated by the physical interactions (e.g. hydrogen bonds, electrostatic interactions) between the polymer chains (Kimura et al., 2004; Ren et al., 2015) or the covalent bonds resulting from the use of chemical cross-linkers (e.g. carbodiimide, glutaraldehyde) (Lu et al., 2008; Rafat et al., 2008; Tian et al., 2016; Mirzaei et al., 2013). Most hydrogels are characterized by highly porous structure. The pore size can range from 10 pm to 500 pm and is dependent upon the degree of cross-linking in the hydrogel matrix (Chai et al., 2017; Li and Mooney, 2016). The porous structure is responsible for the deformability of hydrogels, enabling them to conform to the shape of the site to which they are applied (Hoare et al., 2008). Due to their hydrophilicity, water-soluble drug molecules can be conveniently loaded into the porous structure of a pre-formed hydrogel. However, this is not always true for high molecular weight drug molecules such as proteins, which have diffusive limitations to their partitioning into the pores of the hydrogel (Van Tomme et al., 2005). The high dependency of the drug loading process on the pore size of the hydrogel also means that the loaded drug molecules are usually released rapidly at the site of application as the release process is governed mainly by the diffusion rate of the drug molecules through the pores. In fact, the release of hydrophilic molecules from a hydrogel system typically lasts for only several hours or days, shorter than the release durations achieved with micro/nanoparticles made of hydrophobic polymers (Lee et al., 2016). To counter this, several strategies to enhance drug-hydrogel interactions have been proposed, including the introduction of charged moieties into the hydrogel to boost ionic interactions (Schneider et al., 2016) and the direct conjugation of the drug molecules to the hydrogel via covalent bond formation (Sutter et al., 2007). Another credible strategy to prolong drug release is to load the drug molecules directly into the hydrogel matrix during the hydrogel fabrication process instead of loading into the pores of a pre-formed hydrogel (Chen et al., 2004). Finally, several groups proposed the strategy of pre-encapsulating drug molecules into suitable micro/nanoparticles and co-formulating the particulate system into the hydrogel matrix to achieve sustained drug release (Gao et ah, 2012; Kim et ah, 2012).
As virtually any water-soluble polymer can be manipulated to produce this system, it is possible to obtain hydrogels with physicochemical and biological properties that are useful for a wide range of applications. Despite this, the number of hydrogel- based drug delivery systems approved for clinical use is still limited. An example of these is Regranex®, which consists of a carboxymethylcellulose gel that releases recombinant human platelet-derived growth factor (becaplermin) for the treatment of diabetic foot ulcers (Hoare and Kohane, 2008).
In addition to the rapid drug release issue mentioned above, hydrogels possess several drawbacks that could limit its use for applications. Their poor mechanical strengths make them susceptible to premature dissolution (Van Tomme et ah, 2005), limiting the time window for acting in the microenvironment. In addition, in the absence of cell-adhesive proteins, hydrogels tend to have low capacity for cell adhesion and attachment due to their low stiffness (Sarker et ah, 2014; Shen et ah, 2017; Autissier et ah, 2010).